41
SBRT in Oligometastasis Joaquin G Mira M.D. START center Clinical professor, Univer. Texas Health Science Center San Antonio, Texas
SBRT in Oligometastasis
Joaquin G Mira MD START center
Clinical professor Univer Texas Health Science Center San Antonio Texas
2007 stage 1 Rt breast cancer mastectomy and adjuvant chemo ( triple negative) March 2011 Rt axillary recurrence with + nodes Chemo-XRT to chest wall and axilla
July 2013 1st Metastasis 1200x5= 6000 Feb 2015 2nd metastasis 1900x3= 5700
June 2015 Last follow up NED (8 year survivor) No chemo since 2012 Metastasis treated with radiosurgery
Editorial oligometastasis
There are tumors states intermediate between purely localized lesions and those widely metastatic We propose the existence of a clinical state of oligometastasis to a single or a limited number of organs
Journal of Clinical Oncology 1995
positron emission tomography scanning has resulted in occult metastases being determined in ~20 of patients with non-small-cell lung cancer
bull Local control is or may be an important element of a curative treatment strategy to treat oligometastases ie metastases limited in number and location
Nature Clinical Practice Oncology Importance of Local Control in an Era of Systemic Therapy
S Hellman RR Weichselbaum
Nat Clin Pract Oncol 20052(2)60-61
bull revolution in tumor imaging that has resulted in better delineation of the primary lesion and earlier detection of metastases
PET is going to allow us to see many oligometastasis
bull Successful colonization of a distant site or metastasis is a complex interaction between the tumor cells tumor microenvironment and host For a tumor cell to acquire the ability to colonize a distant organ genetic and epigenetic changes in expression are required to enable the tumor cell to overcome physical boundaries survive in circulation evade the immune system and colonize the distant organ The tumor microenvironment
bull Wuttig et al60published an evaluation of pulmonary metastases isolated from patients with clear-cell renal cell cancer and demonstrated differential genetic signatures between samples isolated from patients with few or many metastases
bull Improved imaging techniques might exclude patients with apparent limited metastases through the detection of additional disease or confirm the oligometastatic state
bull role for molecular classifiers of oligometastasis to be used with clinical and imaging data
Biology and phenotype of metastasis Kimberly S Corwin
At this time we cannot predict tumors that will produce oligometastasis Possibly in the future
Surgery for oligometastasis
Ann Thorac Surg 1984 Oct38(4)323-30 Surgery for pulmonary metastasis a 20-year experience Mountain CF McMurtrey MJ Hermes KE bull 772 resections at MD Anderson bull selection criteria it is important that only patients in whom all known disease can be
completely removed with the planned resection and who have full control of the primary site are treated
bull The overall survival for the group was 35 For patients with carcinoma survival ranged from 24 for those with primary uterine cervix tumors to approximately 54 for urinary tract male genital tract and corpus of uterus primary tumors In the group with sarcoma patients with skeletal tumors had a 464 survival rate (507) for those with osteogenic sarcoma) and 33 of the patients with soft tissue tumors had long-term survival
bull The outcome for patients with melanoma was poor only 121 survived 5 years bull If the original criteria apply multiple and bilateral lesions can be successfully managed
Different prognosis with different histologies Location might be important (lung skeleton)
Help with surgery in oligomatastasis already known in 1984 Unexpected good survival
2014 by American Society of Clinical Oncology Are We Expanding Oligometastatic NonndashSmall-Cell Lung Cancer Using Advanced Radiotherapeutic Modalities Salma K JabbouruArr bull it has been demonstrated that the reduction of disease burden through local treatment in
some disease settings does improve overall survival and can lead to long-term disease control examples include the use of radical nephrectomy in patients with diffuse renal cell carcinoma1ndash3 surgical extirpation of hepatic metastases from colorectal cancer45 and resection of lung metastases from a variety of primary tumor sites6
Before radiosurgery surgery was the main way to reduce tumor burden
Kathy Boltz PhD September 23 2015 Colorectal cancer with liver metastases Synchronous vs sequential resection bull Analyzing data from patients within specific risk categories the study also found that major
complications after synchronous liver and colorectal resections vary and are related to the extent of liver resection performed and the type of colorectal surgery performed
bull Synchronous resection of primary colorectal tumors and metastatic liver tumors is safe and effective in patients who require only minor liver resections
Synchronous surgery better than metachronous Less morbidity one versus several operations Radiosurgery no need to operate We can treat several either in a synchronous or metachronous way
Ann Surg 1999 Sep230(3)309-18 discussion 318-21 Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer analysis of 1001 consecutive cases Fong Y1 Fortner J Sun RL Brennan MF Blumgart LH bull Seven factors were found to be significant and independent predictors of poor long-term
outcome by multivariate analysis bull positive margin (p = 0004) extrahepatic disease (p = 0003) node-positive primary (p =
002) disease-free interval from primary to metastases lt12 months (p = 003) number of hepatic tumors gt1 (p = 00004) largest hepatic tumor gt5 cm (p = 001) and carcinoembryonic antigen level gt200 ngml (p = 001) When the last five of these criteria were used in a preoperative scoring system assigning one point for each criterion
bull the total score was highly predictive of outcome (p lt 00001) No patient with a score of 5 was a long-term survivor
Number or lesions less better than more Size of tumors smaller better than larger
bull Although lung and liver resections are the largest and most frequently reported surgical interventions for oligometastasis more-limited series for metastases removal in other organs have also revealed long-term survivors with select examples listed in Table 1
copy 2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
bull The most frequently reported tumor histologies in surgical series for oligometastasis are colorectal cancer and sarcoma however a clinically limited metastastic state is supported for other histologies bull The largest database of surgical resection for pulmonary metastases includes 43 epithelial 7 germ cell and 6 melanoma histologies28
bull Additionally natural history studies have suggested that a proportion of esophageal38lung3940 breast41 and other histologies4243 will present with limited sites of failure bull early metastases may be of limited nature and therapy before acquisition of required genetic changes could prevent future spread of malignancy bull The therapeutic outcomes of the surgical treatment of oligometastases suggest that
oligometastases exist they but do not estimate the frequency of occurrence
Surgery for oligometastasis
Review of multiple sites and multiple histologies Attach oligometastasis before genetic changes make them more aggressive
2013 by American Society of Clinical Oncology
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
Surgery thousands of patients from 1995 Mostly colorectal AlsoNSCLC and Melanona
5 year survival 20rsquos to 40rsquos
Big body of evidence about surgery for metastasis
Can we do better than surgery with SBRT
History of radiosurgery Can we replace surgery
Use of orthovoltage tube Leksell Sweden neurosurgeon ( 1967)
History of Gamma Knife Radiosurgery Milestones 1951 Leksell professor in Neurosurgery in Sweden introduces the concept Radiosurgery ( it took 15 years to treat the first patient) 1967 the first Gamma Knife prototype is made and the first patient treated at Studsvik nuclear plant 1968 the first patient treated at the Karolinska Sophiahemmet Hospital in Stockholm Sweden 1974 introduction of the first computer assisted dose planning program for the Gamma Knife 1987 the first Gamma Knife model for serial production installed in Pittsburgh USA 1988 Gamma Knife series B installed at the Karolinska Hospital Sweden 1989 the first publication on gamma knife surgery for cerebral metastases 1990 introduction of the Leksell Gamma Plan dose planning program 1995 International Stereotactic Radiosurgery Society (ISRS) Fabrikant Award to Drs Larsson and Backlund for work with the Gamma Knife 1997 ISRS Fabrikant Award to Dr Lunsford 1996 Image fusion between CT and MRI available in the Leksell Gamma Plan 1998 Semiautomatic outlining of target volumes available in the Leksell Gamma Plan 1999 ISRS Fabrikant Award to Dr Lindquist of the Cromwell Hospital
More than 20 years experience in intracranial radiosurgery
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
2007 stage 1 Rt breast cancer mastectomy and adjuvant chemo ( triple negative) March 2011 Rt axillary recurrence with + nodes Chemo-XRT to chest wall and axilla
July 2013 1st Metastasis 1200x5= 6000 Feb 2015 2nd metastasis 1900x3= 5700
June 2015 Last follow up NED (8 year survivor) No chemo since 2012 Metastasis treated with radiosurgery
Editorial oligometastasis
There are tumors states intermediate between purely localized lesions and those widely metastatic We propose the existence of a clinical state of oligometastasis to a single or a limited number of organs
Journal of Clinical Oncology 1995
positron emission tomography scanning has resulted in occult metastases being determined in ~20 of patients with non-small-cell lung cancer
bull Local control is or may be an important element of a curative treatment strategy to treat oligometastases ie metastases limited in number and location
Nature Clinical Practice Oncology Importance of Local Control in an Era of Systemic Therapy
S Hellman RR Weichselbaum
Nat Clin Pract Oncol 20052(2)60-61
bull revolution in tumor imaging that has resulted in better delineation of the primary lesion and earlier detection of metastases
PET is going to allow us to see many oligometastasis
bull Successful colonization of a distant site or metastasis is a complex interaction between the tumor cells tumor microenvironment and host For a tumor cell to acquire the ability to colonize a distant organ genetic and epigenetic changes in expression are required to enable the tumor cell to overcome physical boundaries survive in circulation evade the immune system and colonize the distant organ The tumor microenvironment
bull Wuttig et al60published an evaluation of pulmonary metastases isolated from patients with clear-cell renal cell cancer and demonstrated differential genetic signatures between samples isolated from patients with few or many metastases
bull Improved imaging techniques might exclude patients with apparent limited metastases through the detection of additional disease or confirm the oligometastatic state
bull role for molecular classifiers of oligometastasis to be used with clinical and imaging data
Biology and phenotype of metastasis Kimberly S Corwin
At this time we cannot predict tumors that will produce oligometastasis Possibly in the future
Surgery for oligometastasis
Ann Thorac Surg 1984 Oct38(4)323-30 Surgery for pulmonary metastasis a 20-year experience Mountain CF McMurtrey MJ Hermes KE bull 772 resections at MD Anderson bull selection criteria it is important that only patients in whom all known disease can be
completely removed with the planned resection and who have full control of the primary site are treated
bull The overall survival for the group was 35 For patients with carcinoma survival ranged from 24 for those with primary uterine cervix tumors to approximately 54 for urinary tract male genital tract and corpus of uterus primary tumors In the group with sarcoma patients with skeletal tumors had a 464 survival rate (507) for those with osteogenic sarcoma) and 33 of the patients with soft tissue tumors had long-term survival
bull The outcome for patients with melanoma was poor only 121 survived 5 years bull If the original criteria apply multiple and bilateral lesions can be successfully managed
Different prognosis with different histologies Location might be important (lung skeleton)
Help with surgery in oligomatastasis already known in 1984 Unexpected good survival
2014 by American Society of Clinical Oncology Are We Expanding Oligometastatic NonndashSmall-Cell Lung Cancer Using Advanced Radiotherapeutic Modalities Salma K JabbouruArr bull it has been demonstrated that the reduction of disease burden through local treatment in
some disease settings does improve overall survival and can lead to long-term disease control examples include the use of radical nephrectomy in patients with diffuse renal cell carcinoma1ndash3 surgical extirpation of hepatic metastases from colorectal cancer45 and resection of lung metastases from a variety of primary tumor sites6
Before radiosurgery surgery was the main way to reduce tumor burden
Kathy Boltz PhD September 23 2015 Colorectal cancer with liver metastases Synchronous vs sequential resection bull Analyzing data from patients within specific risk categories the study also found that major
complications after synchronous liver and colorectal resections vary and are related to the extent of liver resection performed and the type of colorectal surgery performed
bull Synchronous resection of primary colorectal tumors and metastatic liver tumors is safe and effective in patients who require only minor liver resections
Synchronous surgery better than metachronous Less morbidity one versus several operations Radiosurgery no need to operate We can treat several either in a synchronous or metachronous way
Ann Surg 1999 Sep230(3)309-18 discussion 318-21 Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer analysis of 1001 consecutive cases Fong Y1 Fortner J Sun RL Brennan MF Blumgart LH bull Seven factors were found to be significant and independent predictors of poor long-term
outcome by multivariate analysis bull positive margin (p = 0004) extrahepatic disease (p = 0003) node-positive primary (p =
002) disease-free interval from primary to metastases lt12 months (p = 003) number of hepatic tumors gt1 (p = 00004) largest hepatic tumor gt5 cm (p = 001) and carcinoembryonic antigen level gt200 ngml (p = 001) When the last five of these criteria were used in a preoperative scoring system assigning one point for each criterion
bull the total score was highly predictive of outcome (p lt 00001) No patient with a score of 5 was a long-term survivor
Number or lesions less better than more Size of tumors smaller better than larger
bull Although lung and liver resections are the largest and most frequently reported surgical interventions for oligometastasis more-limited series for metastases removal in other organs have also revealed long-term survivors with select examples listed in Table 1
copy 2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
bull The most frequently reported tumor histologies in surgical series for oligometastasis are colorectal cancer and sarcoma however a clinically limited metastastic state is supported for other histologies bull The largest database of surgical resection for pulmonary metastases includes 43 epithelial 7 germ cell and 6 melanoma histologies28
bull Additionally natural history studies have suggested that a proportion of esophageal38lung3940 breast41 and other histologies4243 will present with limited sites of failure bull early metastases may be of limited nature and therapy before acquisition of required genetic changes could prevent future spread of malignancy bull The therapeutic outcomes of the surgical treatment of oligometastases suggest that
oligometastases exist they but do not estimate the frequency of occurrence
Surgery for oligometastasis
Review of multiple sites and multiple histologies Attach oligometastasis before genetic changes make them more aggressive
2013 by American Society of Clinical Oncology
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
Surgery thousands of patients from 1995 Mostly colorectal AlsoNSCLC and Melanona
5 year survival 20rsquos to 40rsquos
Big body of evidence about surgery for metastasis
Can we do better than surgery with SBRT
History of radiosurgery Can we replace surgery
Use of orthovoltage tube Leksell Sweden neurosurgeon ( 1967)
History of Gamma Knife Radiosurgery Milestones 1951 Leksell professor in Neurosurgery in Sweden introduces the concept Radiosurgery ( it took 15 years to treat the first patient) 1967 the first Gamma Knife prototype is made and the first patient treated at Studsvik nuclear plant 1968 the first patient treated at the Karolinska Sophiahemmet Hospital in Stockholm Sweden 1974 introduction of the first computer assisted dose planning program for the Gamma Knife 1987 the first Gamma Knife model for serial production installed in Pittsburgh USA 1988 Gamma Knife series B installed at the Karolinska Hospital Sweden 1989 the first publication on gamma knife surgery for cerebral metastases 1990 introduction of the Leksell Gamma Plan dose planning program 1995 International Stereotactic Radiosurgery Society (ISRS) Fabrikant Award to Drs Larsson and Backlund for work with the Gamma Knife 1997 ISRS Fabrikant Award to Dr Lunsford 1996 Image fusion between CT and MRI available in the Leksell Gamma Plan 1998 Semiautomatic outlining of target volumes available in the Leksell Gamma Plan 1999 ISRS Fabrikant Award to Dr Lindquist of the Cromwell Hospital
More than 20 years experience in intracranial radiosurgery
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Editorial oligometastasis
There are tumors states intermediate between purely localized lesions and those widely metastatic We propose the existence of a clinical state of oligometastasis to a single or a limited number of organs
Journal of Clinical Oncology 1995
positron emission tomography scanning has resulted in occult metastases being determined in ~20 of patients with non-small-cell lung cancer
bull Local control is or may be an important element of a curative treatment strategy to treat oligometastases ie metastases limited in number and location
Nature Clinical Practice Oncology Importance of Local Control in an Era of Systemic Therapy
S Hellman RR Weichselbaum
Nat Clin Pract Oncol 20052(2)60-61
bull revolution in tumor imaging that has resulted in better delineation of the primary lesion and earlier detection of metastases
PET is going to allow us to see many oligometastasis
bull Successful colonization of a distant site or metastasis is a complex interaction between the tumor cells tumor microenvironment and host For a tumor cell to acquire the ability to colonize a distant organ genetic and epigenetic changes in expression are required to enable the tumor cell to overcome physical boundaries survive in circulation evade the immune system and colonize the distant organ The tumor microenvironment
bull Wuttig et al60published an evaluation of pulmonary metastases isolated from patients with clear-cell renal cell cancer and demonstrated differential genetic signatures between samples isolated from patients with few or many metastases
bull Improved imaging techniques might exclude patients with apparent limited metastases through the detection of additional disease or confirm the oligometastatic state
bull role for molecular classifiers of oligometastasis to be used with clinical and imaging data
Biology and phenotype of metastasis Kimberly S Corwin
At this time we cannot predict tumors that will produce oligometastasis Possibly in the future
Surgery for oligometastasis
Ann Thorac Surg 1984 Oct38(4)323-30 Surgery for pulmonary metastasis a 20-year experience Mountain CF McMurtrey MJ Hermes KE bull 772 resections at MD Anderson bull selection criteria it is important that only patients in whom all known disease can be
completely removed with the planned resection and who have full control of the primary site are treated
bull The overall survival for the group was 35 For patients with carcinoma survival ranged from 24 for those with primary uterine cervix tumors to approximately 54 for urinary tract male genital tract and corpus of uterus primary tumors In the group with sarcoma patients with skeletal tumors had a 464 survival rate (507) for those with osteogenic sarcoma) and 33 of the patients with soft tissue tumors had long-term survival
bull The outcome for patients with melanoma was poor only 121 survived 5 years bull If the original criteria apply multiple and bilateral lesions can be successfully managed
Different prognosis with different histologies Location might be important (lung skeleton)
Help with surgery in oligomatastasis already known in 1984 Unexpected good survival
2014 by American Society of Clinical Oncology Are We Expanding Oligometastatic NonndashSmall-Cell Lung Cancer Using Advanced Radiotherapeutic Modalities Salma K JabbouruArr bull it has been demonstrated that the reduction of disease burden through local treatment in
some disease settings does improve overall survival and can lead to long-term disease control examples include the use of radical nephrectomy in patients with diffuse renal cell carcinoma1ndash3 surgical extirpation of hepatic metastases from colorectal cancer45 and resection of lung metastases from a variety of primary tumor sites6
Before radiosurgery surgery was the main way to reduce tumor burden
Kathy Boltz PhD September 23 2015 Colorectal cancer with liver metastases Synchronous vs sequential resection bull Analyzing data from patients within specific risk categories the study also found that major
complications after synchronous liver and colorectal resections vary and are related to the extent of liver resection performed and the type of colorectal surgery performed
bull Synchronous resection of primary colorectal tumors and metastatic liver tumors is safe and effective in patients who require only minor liver resections
Synchronous surgery better than metachronous Less morbidity one versus several operations Radiosurgery no need to operate We can treat several either in a synchronous or metachronous way
Ann Surg 1999 Sep230(3)309-18 discussion 318-21 Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer analysis of 1001 consecutive cases Fong Y1 Fortner J Sun RL Brennan MF Blumgart LH bull Seven factors were found to be significant and independent predictors of poor long-term
outcome by multivariate analysis bull positive margin (p = 0004) extrahepatic disease (p = 0003) node-positive primary (p =
002) disease-free interval from primary to metastases lt12 months (p = 003) number of hepatic tumors gt1 (p = 00004) largest hepatic tumor gt5 cm (p = 001) and carcinoembryonic antigen level gt200 ngml (p = 001) When the last five of these criteria were used in a preoperative scoring system assigning one point for each criterion
bull the total score was highly predictive of outcome (p lt 00001) No patient with a score of 5 was a long-term survivor
Number or lesions less better than more Size of tumors smaller better than larger
bull Although lung and liver resections are the largest and most frequently reported surgical interventions for oligometastasis more-limited series for metastases removal in other organs have also revealed long-term survivors with select examples listed in Table 1
copy 2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
bull The most frequently reported tumor histologies in surgical series for oligometastasis are colorectal cancer and sarcoma however a clinically limited metastastic state is supported for other histologies bull The largest database of surgical resection for pulmonary metastases includes 43 epithelial 7 germ cell and 6 melanoma histologies28
bull Additionally natural history studies have suggested that a proportion of esophageal38lung3940 breast41 and other histologies4243 will present with limited sites of failure bull early metastases may be of limited nature and therapy before acquisition of required genetic changes could prevent future spread of malignancy bull The therapeutic outcomes of the surgical treatment of oligometastases suggest that
oligometastases exist they but do not estimate the frequency of occurrence
Surgery for oligometastasis
Review of multiple sites and multiple histologies Attach oligometastasis before genetic changes make them more aggressive
2013 by American Society of Clinical Oncology
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
Surgery thousands of patients from 1995 Mostly colorectal AlsoNSCLC and Melanona
5 year survival 20rsquos to 40rsquos
Big body of evidence about surgery for metastasis
Can we do better than surgery with SBRT
History of radiosurgery Can we replace surgery
Use of orthovoltage tube Leksell Sweden neurosurgeon ( 1967)
History of Gamma Knife Radiosurgery Milestones 1951 Leksell professor in Neurosurgery in Sweden introduces the concept Radiosurgery ( it took 15 years to treat the first patient) 1967 the first Gamma Knife prototype is made and the first patient treated at Studsvik nuclear plant 1968 the first patient treated at the Karolinska Sophiahemmet Hospital in Stockholm Sweden 1974 introduction of the first computer assisted dose planning program for the Gamma Knife 1987 the first Gamma Knife model for serial production installed in Pittsburgh USA 1988 Gamma Knife series B installed at the Karolinska Hospital Sweden 1989 the first publication on gamma knife surgery for cerebral metastases 1990 introduction of the Leksell Gamma Plan dose planning program 1995 International Stereotactic Radiosurgery Society (ISRS) Fabrikant Award to Drs Larsson and Backlund for work with the Gamma Knife 1997 ISRS Fabrikant Award to Dr Lunsford 1996 Image fusion between CT and MRI available in the Leksell Gamma Plan 1998 Semiautomatic outlining of target volumes available in the Leksell Gamma Plan 1999 ISRS Fabrikant Award to Dr Lindquist of the Cromwell Hospital
More than 20 years experience in intracranial radiosurgery
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
positron emission tomography scanning has resulted in occult metastases being determined in ~20 of patients with non-small-cell lung cancer
bull Local control is or may be an important element of a curative treatment strategy to treat oligometastases ie metastases limited in number and location
Nature Clinical Practice Oncology Importance of Local Control in an Era of Systemic Therapy
S Hellman RR Weichselbaum
Nat Clin Pract Oncol 20052(2)60-61
bull revolution in tumor imaging that has resulted in better delineation of the primary lesion and earlier detection of metastases
PET is going to allow us to see many oligometastasis
bull Successful colonization of a distant site or metastasis is a complex interaction between the tumor cells tumor microenvironment and host For a tumor cell to acquire the ability to colonize a distant organ genetic and epigenetic changes in expression are required to enable the tumor cell to overcome physical boundaries survive in circulation evade the immune system and colonize the distant organ The tumor microenvironment
bull Wuttig et al60published an evaluation of pulmonary metastases isolated from patients with clear-cell renal cell cancer and demonstrated differential genetic signatures between samples isolated from patients with few or many metastases
bull Improved imaging techniques might exclude patients with apparent limited metastases through the detection of additional disease or confirm the oligometastatic state
bull role for molecular classifiers of oligometastasis to be used with clinical and imaging data
Biology and phenotype of metastasis Kimberly S Corwin
At this time we cannot predict tumors that will produce oligometastasis Possibly in the future
Surgery for oligometastasis
Ann Thorac Surg 1984 Oct38(4)323-30 Surgery for pulmonary metastasis a 20-year experience Mountain CF McMurtrey MJ Hermes KE bull 772 resections at MD Anderson bull selection criteria it is important that only patients in whom all known disease can be
completely removed with the planned resection and who have full control of the primary site are treated
bull The overall survival for the group was 35 For patients with carcinoma survival ranged from 24 for those with primary uterine cervix tumors to approximately 54 for urinary tract male genital tract and corpus of uterus primary tumors In the group with sarcoma patients with skeletal tumors had a 464 survival rate (507) for those with osteogenic sarcoma) and 33 of the patients with soft tissue tumors had long-term survival
bull The outcome for patients with melanoma was poor only 121 survived 5 years bull If the original criteria apply multiple and bilateral lesions can be successfully managed
Different prognosis with different histologies Location might be important (lung skeleton)
Help with surgery in oligomatastasis already known in 1984 Unexpected good survival
2014 by American Society of Clinical Oncology Are We Expanding Oligometastatic NonndashSmall-Cell Lung Cancer Using Advanced Radiotherapeutic Modalities Salma K JabbouruArr bull it has been demonstrated that the reduction of disease burden through local treatment in
some disease settings does improve overall survival and can lead to long-term disease control examples include the use of radical nephrectomy in patients with diffuse renal cell carcinoma1ndash3 surgical extirpation of hepatic metastases from colorectal cancer45 and resection of lung metastases from a variety of primary tumor sites6
Before radiosurgery surgery was the main way to reduce tumor burden
Kathy Boltz PhD September 23 2015 Colorectal cancer with liver metastases Synchronous vs sequential resection bull Analyzing data from patients within specific risk categories the study also found that major
complications after synchronous liver and colorectal resections vary and are related to the extent of liver resection performed and the type of colorectal surgery performed
bull Synchronous resection of primary colorectal tumors and metastatic liver tumors is safe and effective in patients who require only minor liver resections
Synchronous surgery better than metachronous Less morbidity one versus several operations Radiosurgery no need to operate We can treat several either in a synchronous or metachronous way
Ann Surg 1999 Sep230(3)309-18 discussion 318-21 Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer analysis of 1001 consecutive cases Fong Y1 Fortner J Sun RL Brennan MF Blumgart LH bull Seven factors were found to be significant and independent predictors of poor long-term
outcome by multivariate analysis bull positive margin (p = 0004) extrahepatic disease (p = 0003) node-positive primary (p =
002) disease-free interval from primary to metastases lt12 months (p = 003) number of hepatic tumors gt1 (p = 00004) largest hepatic tumor gt5 cm (p = 001) and carcinoembryonic antigen level gt200 ngml (p = 001) When the last five of these criteria were used in a preoperative scoring system assigning one point for each criterion
bull the total score was highly predictive of outcome (p lt 00001) No patient with a score of 5 was a long-term survivor
Number or lesions less better than more Size of tumors smaller better than larger
bull Although lung and liver resections are the largest and most frequently reported surgical interventions for oligometastasis more-limited series for metastases removal in other organs have also revealed long-term survivors with select examples listed in Table 1
copy 2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
bull The most frequently reported tumor histologies in surgical series for oligometastasis are colorectal cancer and sarcoma however a clinically limited metastastic state is supported for other histologies bull The largest database of surgical resection for pulmonary metastases includes 43 epithelial 7 germ cell and 6 melanoma histologies28
bull Additionally natural history studies have suggested that a proportion of esophageal38lung3940 breast41 and other histologies4243 will present with limited sites of failure bull early metastases may be of limited nature and therapy before acquisition of required genetic changes could prevent future spread of malignancy bull The therapeutic outcomes of the surgical treatment of oligometastases suggest that
oligometastases exist they but do not estimate the frequency of occurrence
Surgery for oligometastasis
Review of multiple sites and multiple histologies Attach oligometastasis before genetic changes make them more aggressive
2013 by American Society of Clinical Oncology
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
Surgery thousands of patients from 1995 Mostly colorectal AlsoNSCLC and Melanona
5 year survival 20rsquos to 40rsquos
Big body of evidence about surgery for metastasis
Can we do better than surgery with SBRT
History of radiosurgery Can we replace surgery
Use of orthovoltage tube Leksell Sweden neurosurgeon ( 1967)
History of Gamma Knife Radiosurgery Milestones 1951 Leksell professor in Neurosurgery in Sweden introduces the concept Radiosurgery ( it took 15 years to treat the first patient) 1967 the first Gamma Knife prototype is made and the first patient treated at Studsvik nuclear plant 1968 the first patient treated at the Karolinska Sophiahemmet Hospital in Stockholm Sweden 1974 introduction of the first computer assisted dose planning program for the Gamma Knife 1987 the first Gamma Knife model for serial production installed in Pittsburgh USA 1988 Gamma Knife series B installed at the Karolinska Hospital Sweden 1989 the first publication on gamma knife surgery for cerebral metastases 1990 introduction of the Leksell Gamma Plan dose planning program 1995 International Stereotactic Radiosurgery Society (ISRS) Fabrikant Award to Drs Larsson and Backlund for work with the Gamma Knife 1997 ISRS Fabrikant Award to Dr Lunsford 1996 Image fusion between CT and MRI available in the Leksell Gamma Plan 1998 Semiautomatic outlining of target volumes available in the Leksell Gamma Plan 1999 ISRS Fabrikant Award to Dr Lindquist of the Cromwell Hospital
More than 20 years experience in intracranial radiosurgery
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
bull Successful colonization of a distant site or metastasis is a complex interaction between the tumor cells tumor microenvironment and host For a tumor cell to acquire the ability to colonize a distant organ genetic and epigenetic changes in expression are required to enable the tumor cell to overcome physical boundaries survive in circulation evade the immune system and colonize the distant organ The tumor microenvironment
bull Wuttig et al60published an evaluation of pulmonary metastases isolated from patients with clear-cell renal cell cancer and demonstrated differential genetic signatures between samples isolated from patients with few or many metastases
bull Improved imaging techniques might exclude patients with apparent limited metastases through the detection of additional disease or confirm the oligometastatic state
bull role for molecular classifiers of oligometastasis to be used with clinical and imaging data
Biology and phenotype of metastasis Kimberly S Corwin
At this time we cannot predict tumors that will produce oligometastasis Possibly in the future
Surgery for oligometastasis
Ann Thorac Surg 1984 Oct38(4)323-30 Surgery for pulmonary metastasis a 20-year experience Mountain CF McMurtrey MJ Hermes KE bull 772 resections at MD Anderson bull selection criteria it is important that only patients in whom all known disease can be
completely removed with the planned resection and who have full control of the primary site are treated
bull The overall survival for the group was 35 For patients with carcinoma survival ranged from 24 for those with primary uterine cervix tumors to approximately 54 for urinary tract male genital tract and corpus of uterus primary tumors In the group with sarcoma patients with skeletal tumors had a 464 survival rate (507) for those with osteogenic sarcoma) and 33 of the patients with soft tissue tumors had long-term survival
bull The outcome for patients with melanoma was poor only 121 survived 5 years bull If the original criteria apply multiple and bilateral lesions can be successfully managed
Different prognosis with different histologies Location might be important (lung skeleton)
Help with surgery in oligomatastasis already known in 1984 Unexpected good survival
2014 by American Society of Clinical Oncology Are We Expanding Oligometastatic NonndashSmall-Cell Lung Cancer Using Advanced Radiotherapeutic Modalities Salma K JabbouruArr bull it has been demonstrated that the reduction of disease burden through local treatment in
some disease settings does improve overall survival and can lead to long-term disease control examples include the use of radical nephrectomy in patients with diffuse renal cell carcinoma1ndash3 surgical extirpation of hepatic metastases from colorectal cancer45 and resection of lung metastases from a variety of primary tumor sites6
Before radiosurgery surgery was the main way to reduce tumor burden
Kathy Boltz PhD September 23 2015 Colorectal cancer with liver metastases Synchronous vs sequential resection bull Analyzing data from patients within specific risk categories the study also found that major
complications after synchronous liver and colorectal resections vary and are related to the extent of liver resection performed and the type of colorectal surgery performed
bull Synchronous resection of primary colorectal tumors and metastatic liver tumors is safe and effective in patients who require only minor liver resections
Synchronous surgery better than metachronous Less morbidity one versus several operations Radiosurgery no need to operate We can treat several either in a synchronous or metachronous way
Ann Surg 1999 Sep230(3)309-18 discussion 318-21 Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer analysis of 1001 consecutive cases Fong Y1 Fortner J Sun RL Brennan MF Blumgart LH bull Seven factors were found to be significant and independent predictors of poor long-term
outcome by multivariate analysis bull positive margin (p = 0004) extrahepatic disease (p = 0003) node-positive primary (p =
002) disease-free interval from primary to metastases lt12 months (p = 003) number of hepatic tumors gt1 (p = 00004) largest hepatic tumor gt5 cm (p = 001) and carcinoembryonic antigen level gt200 ngml (p = 001) When the last five of these criteria were used in a preoperative scoring system assigning one point for each criterion
bull the total score was highly predictive of outcome (p lt 00001) No patient with a score of 5 was a long-term survivor
Number or lesions less better than more Size of tumors smaller better than larger
bull Although lung and liver resections are the largest and most frequently reported surgical interventions for oligometastasis more-limited series for metastases removal in other organs have also revealed long-term survivors with select examples listed in Table 1
copy 2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
bull The most frequently reported tumor histologies in surgical series for oligometastasis are colorectal cancer and sarcoma however a clinically limited metastastic state is supported for other histologies bull The largest database of surgical resection for pulmonary metastases includes 43 epithelial 7 germ cell and 6 melanoma histologies28
bull Additionally natural history studies have suggested that a proportion of esophageal38lung3940 breast41 and other histologies4243 will present with limited sites of failure bull early metastases may be of limited nature and therapy before acquisition of required genetic changes could prevent future spread of malignancy bull The therapeutic outcomes of the surgical treatment of oligometastases suggest that
oligometastases exist they but do not estimate the frequency of occurrence
Surgery for oligometastasis
Review of multiple sites and multiple histologies Attach oligometastasis before genetic changes make them more aggressive
2013 by American Society of Clinical Oncology
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
Surgery thousands of patients from 1995 Mostly colorectal AlsoNSCLC and Melanona
5 year survival 20rsquos to 40rsquos
Big body of evidence about surgery for metastasis
Can we do better than surgery with SBRT
History of radiosurgery Can we replace surgery
Use of orthovoltage tube Leksell Sweden neurosurgeon ( 1967)
History of Gamma Knife Radiosurgery Milestones 1951 Leksell professor in Neurosurgery in Sweden introduces the concept Radiosurgery ( it took 15 years to treat the first patient) 1967 the first Gamma Knife prototype is made and the first patient treated at Studsvik nuclear plant 1968 the first patient treated at the Karolinska Sophiahemmet Hospital in Stockholm Sweden 1974 introduction of the first computer assisted dose planning program for the Gamma Knife 1987 the first Gamma Knife model for serial production installed in Pittsburgh USA 1988 Gamma Knife series B installed at the Karolinska Hospital Sweden 1989 the first publication on gamma knife surgery for cerebral metastases 1990 introduction of the Leksell Gamma Plan dose planning program 1995 International Stereotactic Radiosurgery Society (ISRS) Fabrikant Award to Drs Larsson and Backlund for work with the Gamma Knife 1997 ISRS Fabrikant Award to Dr Lunsford 1996 Image fusion between CT and MRI available in the Leksell Gamma Plan 1998 Semiautomatic outlining of target volumes available in the Leksell Gamma Plan 1999 ISRS Fabrikant Award to Dr Lindquist of the Cromwell Hospital
More than 20 years experience in intracranial radiosurgery
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Surgery for oligometastasis
Ann Thorac Surg 1984 Oct38(4)323-30 Surgery for pulmonary metastasis a 20-year experience Mountain CF McMurtrey MJ Hermes KE bull 772 resections at MD Anderson bull selection criteria it is important that only patients in whom all known disease can be
completely removed with the planned resection and who have full control of the primary site are treated
bull The overall survival for the group was 35 For patients with carcinoma survival ranged from 24 for those with primary uterine cervix tumors to approximately 54 for urinary tract male genital tract and corpus of uterus primary tumors In the group with sarcoma patients with skeletal tumors had a 464 survival rate (507) for those with osteogenic sarcoma) and 33 of the patients with soft tissue tumors had long-term survival
bull The outcome for patients with melanoma was poor only 121 survived 5 years bull If the original criteria apply multiple and bilateral lesions can be successfully managed
Different prognosis with different histologies Location might be important (lung skeleton)
Help with surgery in oligomatastasis already known in 1984 Unexpected good survival
2014 by American Society of Clinical Oncology Are We Expanding Oligometastatic NonndashSmall-Cell Lung Cancer Using Advanced Radiotherapeutic Modalities Salma K JabbouruArr bull it has been demonstrated that the reduction of disease burden through local treatment in
some disease settings does improve overall survival and can lead to long-term disease control examples include the use of radical nephrectomy in patients with diffuse renal cell carcinoma1ndash3 surgical extirpation of hepatic metastases from colorectal cancer45 and resection of lung metastases from a variety of primary tumor sites6
Before radiosurgery surgery was the main way to reduce tumor burden
Kathy Boltz PhD September 23 2015 Colorectal cancer with liver metastases Synchronous vs sequential resection bull Analyzing data from patients within specific risk categories the study also found that major
complications after synchronous liver and colorectal resections vary and are related to the extent of liver resection performed and the type of colorectal surgery performed
bull Synchronous resection of primary colorectal tumors and metastatic liver tumors is safe and effective in patients who require only minor liver resections
Synchronous surgery better than metachronous Less morbidity one versus several operations Radiosurgery no need to operate We can treat several either in a synchronous or metachronous way
Ann Surg 1999 Sep230(3)309-18 discussion 318-21 Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer analysis of 1001 consecutive cases Fong Y1 Fortner J Sun RL Brennan MF Blumgart LH bull Seven factors were found to be significant and independent predictors of poor long-term
outcome by multivariate analysis bull positive margin (p = 0004) extrahepatic disease (p = 0003) node-positive primary (p =
002) disease-free interval from primary to metastases lt12 months (p = 003) number of hepatic tumors gt1 (p = 00004) largest hepatic tumor gt5 cm (p = 001) and carcinoembryonic antigen level gt200 ngml (p = 001) When the last five of these criteria were used in a preoperative scoring system assigning one point for each criterion
bull the total score was highly predictive of outcome (p lt 00001) No patient with a score of 5 was a long-term survivor
Number or lesions less better than more Size of tumors smaller better than larger
bull Although lung and liver resections are the largest and most frequently reported surgical interventions for oligometastasis more-limited series for metastases removal in other organs have also revealed long-term survivors with select examples listed in Table 1
copy 2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
bull The most frequently reported tumor histologies in surgical series for oligometastasis are colorectal cancer and sarcoma however a clinically limited metastastic state is supported for other histologies bull The largest database of surgical resection for pulmonary metastases includes 43 epithelial 7 germ cell and 6 melanoma histologies28
bull Additionally natural history studies have suggested that a proportion of esophageal38lung3940 breast41 and other histologies4243 will present with limited sites of failure bull early metastases may be of limited nature and therapy before acquisition of required genetic changes could prevent future spread of malignancy bull The therapeutic outcomes of the surgical treatment of oligometastases suggest that
oligometastases exist they but do not estimate the frequency of occurrence
Surgery for oligometastasis
Review of multiple sites and multiple histologies Attach oligometastasis before genetic changes make them more aggressive
2013 by American Society of Clinical Oncology
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
Surgery thousands of patients from 1995 Mostly colorectal AlsoNSCLC and Melanona
5 year survival 20rsquos to 40rsquos
Big body of evidence about surgery for metastasis
Can we do better than surgery with SBRT
History of radiosurgery Can we replace surgery
Use of orthovoltage tube Leksell Sweden neurosurgeon ( 1967)
History of Gamma Knife Radiosurgery Milestones 1951 Leksell professor in Neurosurgery in Sweden introduces the concept Radiosurgery ( it took 15 years to treat the first patient) 1967 the first Gamma Knife prototype is made and the first patient treated at Studsvik nuclear plant 1968 the first patient treated at the Karolinska Sophiahemmet Hospital in Stockholm Sweden 1974 introduction of the first computer assisted dose planning program for the Gamma Knife 1987 the first Gamma Knife model for serial production installed in Pittsburgh USA 1988 Gamma Knife series B installed at the Karolinska Hospital Sweden 1989 the first publication on gamma knife surgery for cerebral metastases 1990 introduction of the Leksell Gamma Plan dose planning program 1995 International Stereotactic Radiosurgery Society (ISRS) Fabrikant Award to Drs Larsson and Backlund for work with the Gamma Knife 1997 ISRS Fabrikant Award to Dr Lunsford 1996 Image fusion between CT and MRI available in the Leksell Gamma Plan 1998 Semiautomatic outlining of target volumes available in the Leksell Gamma Plan 1999 ISRS Fabrikant Award to Dr Lindquist of the Cromwell Hospital
More than 20 years experience in intracranial radiosurgery
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Ann Thorac Surg 1984 Oct38(4)323-30 Surgery for pulmonary metastasis a 20-year experience Mountain CF McMurtrey MJ Hermes KE bull 772 resections at MD Anderson bull selection criteria it is important that only patients in whom all known disease can be
completely removed with the planned resection and who have full control of the primary site are treated
bull The overall survival for the group was 35 For patients with carcinoma survival ranged from 24 for those with primary uterine cervix tumors to approximately 54 for urinary tract male genital tract and corpus of uterus primary tumors In the group with sarcoma patients with skeletal tumors had a 464 survival rate (507) for those with osteogenic sarcoma) and 33 of the patients with soft tissue tumors had long-term survival
bull The outcome for patients with melanoma was poor only 121 survived 5 years bull If the original criteria apply multiple and bilateral lesions can be successfully managed
Different prognosis with different histologies Location might be important (lung skeleton)
Help with surgery in oligomatastasis already known in 1984 Unexpected good survival
2014 by American Society of Clinical Oncology Are We Expanding Oligometastatic NonndashSmall-Cell Lung Cancer Using Advanced Radiotherapeutic Modalities Salma K JabbouruArr bull it has been demonstrated that the reduction of disease burden through local treatment in
some disease settings does improve overall survival and can lead to long-term disease control examples include the use of radical nephrectomy in patients with diffuse renal cell carcinoma1ndash3 surgical extirpation of hepatic metastases from colorectal cancer45 and resection of lung metastases from a variety of primary tumor sites6
Before radiosurgery surgery was the main way to reduce tumor burden
Kathy Boltz PhD September 23 2015 Colorectal cancer with liver metastases Synchronous vs sequential resection bull Analyzing data from patients within specific risk categories the study also found that major
complications after synchronous liver and colorectal resections vary and are related to the extent of liver resection performed and the type of colorectal surgery performed
bull Synchronous resection of primary colorectal tumors and metastatic liver tumors is safe and effective in patients who require only minor liver resections
Synchronous surgery better than metachronous Less morbidity one versus several operations Radiosurgery no need to operate We can treat several either in a synchronous or metachronous way
Ann Surg 1999 Sep230(3)309-18 discussion 318-21 Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer analysis of 1001 consecutive cases Fong Y1 Fortner J Sun RL Brennan MF Blumgart LH bull Seven factors were found to be significant and independent predictors of poor long-term
outcome by multivariate analysis bull positive margin (p = 0004) extrahepatic disease (p = 0003) node-positive primary (p =
002) disease-free interval from primary to metastases lt12 months (p = 003) number of hepatic tumors gt1 (p = 00004) largest hepatic tumor gt5 cm (p = 001) and carcinoembryonic antigen level gt200 ngml (p = 001) When the last five of these criteria were used in a preoperative scoring system assigning one point for each criterion
bull the total score was highly predictive of outcome (p lt 00001) No patient with a score of 5 was a long-term survivor
Number or lesions less better than more Size of tumors smaller better than larger
bull Although lung and liver resections are the largest and most frequently reported surgical interventions for oligometastasis more-limited series for metastases removal in other organs have also revealed long-term survivors with select examples listed in Table 1
copy 2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
bull The most frequently reported tumor histologies in surgical series for oligometastasis are colorectal cancer and sarcoma however a clinically limited metastastic state is supported for other histologies bull The largest database of surgical resection for pulmonary metastases includes 43 epithelial 7 germ cell and 6 melanoma histologies28
bull Additionally natural history studies have suggested that a proportion of esophageal38lung3940 breast41 and other histologies4243 will present with limited sites of failure bull early metastases may be of limited nature and therapy before acquisition of required genetic changes could prevent future spread of malignancy bull The therapeutic outcomes of the surgical treatment of oligometastases suggest that
oligometastases exist they but do not estimate the frequency of occurrence
Surgery for oligometastasis
Review of multiple sites and multiple histologies Attach oligometastasis before genetic changes make them more aggressive
2013 by American Society of Clinical Oncology
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
Surgery thousands of patients from 1995 Mostly colorectal AlsoNSCLC and Melanona
5 year survival 20rsquos to 40rsquos
Big body of evidence about surgery for metastasis
Can we do better than surgery with SBRT
History of radiosurgery Can we replace surgery
Use of orthovoltage tube Leksell Sweden neurosurgeon ( 1967)
History of Gamma Knife Radiosurgery Milestones 1951 Leksell professor in Neurosurgery in Sweden introduces the concept Radiosurgery ( it took 15 years to treat the first patient) 1967 the first Gamma Knife prototype is made and the first patient treated at Studsvik nuclear plant 1968 the first patient treated at the Karolinska Sophiahemmet Hospital in Stockholm Sweden 1974 introduction of the first computer assisted dose planning program for the Gamma Knife 1987 the first Gamma Knife model for serial production installed in Pittsburgh USA 1988 Gamma Knife series B installed at the Karolinska Hospital Sweden 1989 the first publication on gamma knife surgery for cerebral metastases 1990 introduction of the Leksell Gamma Plan dose planning program 1995 International Stereotactic Radiosurgery Society (ISRS) Fabrikant Award to Drs Larsson and Backlund for work with the Gamma Knife 1997 ISRS Fabrikant Award to Dr Lunsford 1996 Image fusion between CT and MRI available in the Leksell Gamma Plan 1998 Semiautomatic outlining of target volumes available in the Leksell Gamma Plan 1999 ISRS Fabrikant Award to Dr Lindquist of the Cromwell Hospital
More than 20 years experience in intracranial radiosurgery
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
2014 by American Society of Clinical Oncology Are We Expanding Oligometastatic NonndashSmall-Cell Lung Cancer Using Advanced Radiotherapeutic Modalities Salma K JabbouruArr bull it has been demonstrated that the reduction of disease burden through local treatment in
some disease settings does improve overall survival and can lead to long-term disease control examples include the use of radical nephrectomy in patients with diffuse renal cell carcinoma1ndash3 surgical extirpation of hepatic metastases from colorectal cancer45 and resection of lung metastases from a variety of primary tumor sites6
Before radiosurgery surgery was the main way to reduce tumor burden
Kathy Boltz PhD September 23 2015 Colorectal cancer with liver metastases Synchronous vs sequential resection bull Analyzing data from patients within specific risk categories the study also found that major
complications after synchronous liver and colorectal resections vary and are related to the extent of liver resection performed and the type of colorectal surgery performed
bull Synchronous resection of primary colorectal tumors and metastatic liver tumors is safe and effective in patients who require only minor liver resections
Synchronous surgery better than metachronous Less morbidity one versus several operations Radiosurgery no need to operate We can treat several either in a synchronous or metachronous way
Ann Surg 1999 Sep230(3)309-18 discussion 318-21 Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer analysis of 1001 consecutive cases Fong Y1 Fortner J Sun RL Brennan MF Blumgart LH bull Seven factors were found to be significant and independent predictors of poor long-term
outcome by multivariate analysis bull positive margin (p = 0004) extrahepatic disease (p = 0003) node-positive primary (p =
002) disease-free interval from primary to metastases lt12 months (p = 003) number of hepatic tumors gt1 (p = 00004) largest hepatic tumor gt5 cm (p = 001) and carcinoembryonic antigen level gt200 ngml (p = 001) When the last five of these criteria were used in a preoperative scoring system assigning one point for each criterion
bull the total score was highly predictive of outcome (p lt 00001) No patient with a score of 5 was a long-term survivor
Number or lesions less better than more Size of tumors smaller better than larger
bull Although lung and liver resections are the largest and most frequently reported surgical interventions for oligometastasis more-limited series for metastases removal in other organs have also revealed long-term survivors with select examples listed in Table 1
copy 2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
bull The most frequently reported tumor histologies in surgical series for oligometastasis are colorectal cancer and sarcoma however a clinically limited metastastic state is supported for other histologies bull The largest database of surgical resection for pulmonary metastases includes 43 epithelial 7 germ cell and 6 melanoma histologies28
bull Additionally natural history studies have suggested that a proportion of esophageal38lung3940 breast41 and other histologies4243 will present with limited sites of failure bull early metastases may be of limited nature and therapy before acquisition of required genetic changes could prevent future spread of malignancy bull The therapeutic outcomes of the surgical treatment of oligometastases suggest that
oligometastases exist they but do not estimate the frequency of occurrence
Surgery for oligometastasis
Review of multiple sites and multiple histologies Attach oligometastasis before genetic changes make them more aggressive
2013 by American Society of Clinical Oncology
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
Surgery thousands of patients from 1995 Mostly colorectal AlsoNSCLC and Melanona
5 year survival 20rsquos to 40rsquos
Big body of evidence about surgery for metastasis
Can we do better than surgery with SBRT
History of radiosurgery Can we replace surgery
Use of orthovoltage tube Leksell Sweden neurosurgeon ( 1967)
History of Gamma Knife Radiosurgery Milestones 1951 Leksell professor in Neurosurgery in Sweden introduces the concept Radiosurgery ( it took 15 years to treat the first patient) 1967 the first Gamma Knife prototype is made and the first patient treated at Studsvik nuclear plant 1968 the first patient treated at the Karolinska Sophiahemmet Hospital in Stockholm Sweden 1974 introduction of the first computer assisted dose planning program for the Gamma Knife 1987 the first Gamma Knife model for serial production installed in Pittsburgh USA 1988 Gamma Knife series B installed at the Karolinska Hospital Sweden 1989 the first publication on gamma knife surgery for cerebral metastases 1990 introduction of the Leksell Gamma Plan dose planning program 1995 International Stereotactic Radiosurgery Society (ISRS) Fabrikant Award to Drs Larsson and Backlund for work with the Gamma Knife 1997 ISRS Fabrikant Award to Dr Lunsford 1996 Image fusion between CT and MRI available in the Leksell Gamma Plan 1998 Semiautomatic outlining of target volumes available in the Leksell Gamma Plan 1999 ISRS Fabrikant Award to Dr Lindquist of the Cromwell Hospital
More than 20 years experience in intracranial radiosurgery
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Kathy Boltz PhD September 23 2015 Colorectal cancer with liver metastases Synchronous vs sequential resection bull Analyzing data from patients within specific risk categories the study also found that major
complications after synchronous liver and colorectal resections vary and are related to the extent of liver resection performed and the type of colorectal surgery performed
bull Synchronous resection of primary colorectal tumors and metastatic liver tumors is safe and effective in patients who require only minor liver resections
Synchronous surgery better than metachronous Less morbidity one versus several operations Radiosurgery no need to operate We can treat several either in a synchronous or metachronous way
Ann Surg 1999 Sep230(3)309-18 discussion 318-21 Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer analysis of 1001 consecutive cases Fong Y1 Fortner J Sun RL Brennan MF Blumgart LH bull Seven factors were found to be significant and independent predictors of poor long-term
outcome by multivariate analysis bull positive margin (p = 0004) extrahepatic disease (p = 0003) node-positive primary (p =
002) disease-free interval from primary to metastases lt12 months (p = 003) number of hepatic tumors gt1 (p = 00004) largest hepatic tumor gt5 cm (p = 001) and carcinoembryonic antigen level gt200 ngml (p = 001) When the last five of these criteria were used in a preoperative scoring system assigning one point for each criterion
bull the total score was highly predictive of outcome (p lt 00001) No patient with a score of 5 was a long-term survivor
Number or lesions less better than more Size of tumors smaller better than larger
bull Although lung and liver resections are the largest and most frequently reported surgical interventions for oligometastasis more-limited series for metastases removal in other organs have also revealed long-term survivors with select examples listed in Table 1
copy 2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
bull The most frequently reported tumor histologies in surgical series for oligometastasis are colorectal cancer and sarcoma however a clinically limited metastastic state is supported for other histologies bull The largest database of surgical resection for pulmonary metastases includes 43 epithelial 7 germ cell and 6 melanoma histologies28
bull Additionally natural history studies have suggested that a proportion of esophageal38lung3940 breast41 and other histologies4243 will present with limited sites of failure bull early metastases may be of limited nature and therapy before acquisition of required genetic changes could prevent future spread of malignancy bull The therapeutic outcomes of the surgical treatment of oligometastases suggest that
oligometastases exist they but do not estimate the frequency of occurrence
Surgery for oligometastasis
Review of multiple sites and multiple histologies Attach oligometastasis before genetic changes make them more aggressive
2013 by American Society of Clinical Oncology
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
Surgery thousands of patients from 1995 Mostly colorectal AlsoNSCLC and Melanona
5 year survival 20rsquos to 40rsquos
Big body of evidence about surgery for metastasis
Can we do better than surgery with SBRT
History of radiosurgery Can we replace surgery
Use of orthovoltage tube Leksell Sweden neurosurgeon ( 1967)
History of Gamma Knife Radiosurgery Milestones 1951 Leksell professor in Neurosurgery in Sweden introduces the concept Radiosurgery ( it took 15 years to treat the first patient) 1967 the first Gamma Knife prototype is made and the first patient treated at Studsvik nuclear plant 1968 the first patient treated at the Karolinska Sophiahemmet Hospital in Stockholm Sweden 1974 introduction of the first computer assisted dose planning program for the Gamma Knife 1987 the first Gamma Knife model for serial production installed in Pittsburgh USA 1988 Gamma Knife series B installed at the Karolinska Hospital Sweden 1989 the first publication on gamma knife surgery for cerebral metastases 1990 introduction of the Leksell Gamma Plan dose planning program 1995 International Stereotactic Radiosurgery Society (ISRS) Fabrikant Award to Drs Larsson and Backlund for work with the Gamma Knife 1997 ISRS Fabrikant Award to Dr Lunsford 1996 Image fusion between CT and MRI available in the Leksell Gamma Plan 1998 Semiautomatic outlining of target volumes available in the Leksell Gamma Plan 1999 ISRS Fabrikant Award to Dr Lindquist of the Cromwell Hospital
More than 20 years experience in intracranial radiosurgery
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Ann Surg 1999 Sep230(3)309-18 discussion 318-21 Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer analysis of 1001 consecutive cases Fong Y1 Fortner J Sun RL Brennan MF Blumgart LH bull Seven factors were found to be significant and independent predictors of poor long-term
outcome by multivariate analysis bull positive margin (p = 0004) extrahepatic disease (p = 0003) node-positive primary (p =
002) disease-free interval from primary to metastases lt12 months (p = 003) number of hepatic tumors gt1 (p = 00004) largest hepatic tumor gt5 cm (p = 001) and carcinoembryonic antigen level gt200 ngml (p = 001) When the last five of these criteria were used in a preoperative scoring system assigning one point for each criterion
bull the total score was highly predictive of outcome (p lt 00001) No patient with a score of 5 was a long-term survivor
Number or lesions less better than more Size of tumors smaller better than larger
bull Although lung and liver resections are the largest and most frequently reported surgical interventions for oligometastasis more-limited series for metastases removal in other organs have also revealed long-term survivors with select examples listed in Table 1
copy 2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
bull The most frequently reported tumor histologies in surgical series for oligometastasis are colorectal cancer and sarcoma however a clinically limited metastastic state is supported for other histologies bull The largest database of surgical resection for pulmonary metastases includes 43 epithelial 7 germ cell and 6 melanoma histologies28
bull Additionally natural history studies have suggested that a proportion of esophageal38lung3940 breast41 and other histologies4243 will present with limited sites of failure bull early metastases may be of limited nature and therapy before acquisition of required genetic changes could prevent future spread of malignancy bull The therapeutic outcomes of the surgical treatment of oligometastases suggest that
oligometastases exist they but do not estimate the frequency of occurrence
Surgery for oligometastasis
Review of multiple sites and multiple histologies Attach oligometastasis before genetic changes make them more aggressive
2013 by American Society of Clinical Oncology
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
Surgery thousands of patients from 1995 Mostly colorectal AlsoNSCLC and Melanona
5 year survival 20rsquos to 40rsquos
Big body of evidence about surgery for metastasis
Can we do better than surgery with SBRT
History of radiosurgery Can we replace surgery
Use of orthovoltage tube Leksell Sweden neurosurgeon ( 1967)
History of Gamma Knife Radiosurgery Milestones 1951 Leksell professor in Neurosurgery in Sweden introduces the concept Radiosurgery ( it took 15 years to treat the first patient) 1967 the first Gamma Knife prototype is made and the first patient treated at Studsvik nuclear plant 1968 the first patient treated at the Karolinska Sophiahemmet Hospital in Stockholm Sweden 1974 introduction of the first computer assisted dose planning program for the Gamma Knife 1987 the first Gamma Knife model for serial production installed in Pittsburgh USA 1988 Gamma Knife series B installed at the Karolinska Hospital Sweden 1989 the first publication on gamma knife surgery for cerebral metastases 1990 introduction of the Leksell Gamma Plan dose planning program 1995 International Stereotactic Radiosurgery Society (ISRS) Fabrikant Award to Drs Larsson and Backlund for work with the Gamma Knife 1997 ISRS Fabrikant Award to Dr Lunsford 1996 Image fusion between CT and MRI available in the Leksell Gamma Plan 1998 Semiautomatic outlining of target volumes available in the Leksell Gamma Plan 1999 ISRS Fabrikant Award to Dr Lindquist of the Cromwell Hospital
More than 20 years experience in intracranial radiosurgery
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
bull Although lung and liver resections are the largest and most frequently reported surgical interventions for oligometastasis more-limited series for metastases removal in other organs have also revealed long-term survivors with select examples listed in Table 1
copy 2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
bull The most frequently reported tumor histologies in surgical series for oligometastasis are colorectal cancer and sarcoma however a clinically limited metastastic state is supported for other histologies bull The largest database of surgical resection for pulmonary metastases includes 43 epithelial 7 germ cell and 6 melanoma histologies28
bull Additionally natural history studies have suggested that a proportion of esophageal38lung3940 breast41 and other histologies4243 will present with limited sites of failure bull early metastases may be of limited nature and therapy before acquisition of required genetic changes could prevent future spread of malignancy bull The therapeutic outcomes of the surgical treatment of oligometastases suggest that
oligometastases exist they but do not estimate the frequency of occurrence
Surgery for oligometastasis
Review of multiple sites and multiple histologies Attach oligometastasis before genetic changes make them more aggressive
2013 by American Society of Clinical Oncology
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
Surgery thousands of patients from 1995 Mostly colorectal AlsoNSCLC and Melanona
5 year survival 20rsquos to 40rsquos
Big body of evidence about surgery for metastasis
Can we do better than surgery with SBRT
History of radiosurgery Can we replace surgery
Use of orthovoltage tube Leksell Sweden neurosurgeon ( 1967)
History of Gamma Knife Radiosurgery Milestones 1951 Leksell professor in Neurosurgery in Sweden introduces the concept Radiosurgery ( it took 15 years to treat the first patient) 1967 the first Gamma Knife prototype is made and the first patient treated at Studsvik nuclear plant 1968 the first patient treated at the Karolinska Sophiahemmet Hospital in Stockholm Sweden 1974 introduction of the first computer assisted dose planning program for the Gamma Knife 1987 the first Gamma Knife model for serial production installed in Pittsburgh USA 1988 Gamma Knife series B installed at the Karolinska Hospital Sweden 1989 the first publication on gamma knife surgery for cerebral metastases 1990 introduction of the Leksell Gamma Plan dose planning program 1995 International Stereotactic Radiosurgery Society (ISRS) Fabrikant Award to Drs Larsson and Backlund for work with the Gamma Knife 1997 ISRS Fabrikant Award to Dr Lunsford 1996 Image fusion between CT and MRI available in the Leksell Gamma Plan 1998 Semiautomatic outlining of target volumes available in the Leksell Gamma Plan 1999 ISRS Fabrikant Award to Dr Lindquist of the Cromwell Hospital
More than 20 years experience in intracranial radiosurgery
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
2013 by American Society of Clinical Oncology
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
Surgery thousands of patients from 1995 Mostly colorectal AlsoNSCLC and Melanona
5 year survival 20rsquos to 40rsquos
Big body of evidence about surgery for metastasis
Can we do better than surgery with SBRT
History of radiosurgery Can we replace surgery
Use of orthovoltage tube Leksell Sweden neurosurgeon ( 1967)
History of Gamma Knife Radiosurgery Milestones 1951 Leksell professor in Neurosurgery in Sweden introduces the concept Radiosurgery ( it took 15 years to treat the first patient) 1967 the first Gamma Knife prototype is made and the first patient treated at Studsvik nuclear plant 1968 the first patient treated at the Karolinska Sophiahemmet Hospital in Stockholm Sweden 1974 introduction of the first computer assisted dose planning program for the Gamma Knife 1987 the first Gamma Knife model for serial production installed in Pittsburgh USA 1988 Gamma Knife series B installed at the Karolinska Hospital Sweden 1989 the first publication on gamma knife surgery for cerebral metastases 1990 introduction of the Leksell Gamma Plan dose planning program 1995 International Stereotactic Radiosurgery Society (ISRS) Fabrikant Award to Drs Larsson and Backlund for work with the Gamma Knife 1997 ISRS Fabrikant Award to Dr Lunsford 1996 Image fusion between CT and MRI available in the Leksell Gamma Plan 1998 Semiautomatic outlining of target volumes available in the Leksell Gamma Plan 1999 ISRS Fabrikant Award to Dr Lindquist of the Cromwell Hospital
More than 20 years experience in intracranial radiosurgery
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Can we do better than surgery with SBRT
History of radiosurgery Can we replace surgery
Use of orthovoltage tube Leksell Sweden neurosurgeon ( 1967)
History of Gamma Knife Radiosurgery Milestones 1951 Leksell professor in Neurosurgery in Sweden introduces the concept Radiosurgery ( it took 15 years to treat the first patient) 1967 the first Gamma Knife prototype is made and the first patient treated at Studsvik nuclear plant 1968 the first patient treated at the Karolinska Sophiahemmet Hospital in Stockholm Sweden 1974 introduction of the first computer assisted dose planning program for the Gamma Knife 1987 the first Gamma Knife model for serial production installed in Pittsburgh USA 1988 Gamma Knife series B installed at the Karolinska Hospital Sweden 1989 the first publication on gamma knife surgery for cerebral metastases 1990 introduction of the Leksell Gamma Plan dose planning program 1995 International Stereotactic Radiosurgery Society (ISRS) Fabrikant Award to Drs Larsson and Backlund for work with the Gamma Knife 1997 ISRS Fabrikant Award to Dr Lunsford 1996 Image fusion between CT and MRI available in the Leksell Gamma Plan 1998 Semiautomatic outlining of target volumes available in the Leksell Gamma Plan 1999 ISRS Fabrikant Award to Dr Lindquist of the Cromwell Hospital
More than 20 years experience in intracranial radiosurgery
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
History of radiosurgery Can we replace surgery
Use of orthovoltage tube Leksell Sweden neurosurgeon ( 1967)
History of Gamma Knife Radiosurgery Milestones 1951 Leksell professor in Neurosurgery in Sweden introduces the concept Radiosurgery ( it took 15 years to treat the first patient) 1967 the first Gamma Knife prototype is made and the first patient treated at Studsvik nuclear plant 1968 the first patient treated at the Karolinska Sophiahemmet Hospital in Stockholm Sweden 1974 introduction of the first computer assisted dose planning program for the Gamma Knife 1987 the first Gamma Knife model for serial production installed in Pittsburgh USA 1988 Gamma Knife series B installed at the Karolinska Hospital Sweden 1989 the first publication on gamma knife surgery for cerebral metastases 1990 introduction of the Leksell Gamma Plan dose planning program 1995 International Stereotactic Radiosurgery Society (ISRS) Fabrikant Award to Drs Larsson and Backlund for work with the Gamma Knife 1997 ISRS Fabrikant Award to Dr Lunsford 1996 Image fusion between CT and MRI available in the Leksell Gamma Plan 1998 Semiautomatic outlining of target volumes available in the Leksell Gamma Plan 1999 ISRS Fabrikant Award to Dr Lindquist of the Cromwell Hospital
More than 20 years experience in intracranial radiosurgery
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Use of orthovoltage tube Leksell Sweden neurosurgeon ( 1967)
History of Gamma Knife Radiosurgery Milestones 1951 Leksell professor in Neurosurgery in Sweden introduces the concept Radiosurgery ( it took 15 years to treat the first patient) 1967 the first Gamma Knife prototype is made and the first patient treated at Studsvik nuclear plant 1968 the first patient treated at the Karolinska Sophiahemmet Hospital in Stockholm Sweden 1974 introduction of the first computer assisted dose planning program for the Gamma Knife 1987 the first Gamma Knife model for serial production installed in Pittsburgh USA 1988 Gamma Knife series B installed at the Karolinska Hospital Sweden 1989 the first publication on gamma knife surgery for cerebral metastases 1990 introduction of the Leksell Gamma Plan dose planning program 1995 International Stereotactic Radiosurgery Society (ISRS) Fabrikant Award to Drs Larsson and Backlund for work with the Gamma Knife 1997 ISRS Fabrikant Award to Dr Lunsford 1996 Image fusion between CT and MRI available in the Leksell Gamma Plan 1998 Semiautomatic outlining of target volumes available in the Leksell Gamma Plan 1999 ISRS Fabrikant Award to Dr Lindquist of the Cromwell Hospital
More than 20 years experience in intracranial radiosurgery
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
History of Gamma Knife Radiosurgery Milestones 1951 Leksell professor in Neurosurgery in Sweden introduces the concept Radiosurgery ( it took 15 years to treat the first patient) 1967 the first Gamma Knife prototype is made and the first patient treated at Studsvik nuclear plant 1968 the first patient treated at the Karolinska Sophiahemmet Hospital in Stockholm Sweden 1974 introduction of the first computer assisted dose planning program for the Gamma Knife 1987 the first Gamma Knife model for serial production installed in Pittsburgh USA 1988 Gamma Knife series B installed at the Karolinska Hospital Sweden 1989 the first publication on gamma knife surgery for cerebral metastases 1990 introduction of the Leksell Gamma Plan dose planning program 1995 International Stereotactic Radiosurgery Society (ISRS) Fabrikant Award to Drs Larsson and Backlund for work with the Gamma Knife 1997 ISRS Fabrikant Award to Dr Lunsford 1996 Image fusion between CT and MRI available in the Leksell Gamma Plan 1998 Semiautomatic outlining of target volumes available in the Leksell Gamma Plan 1999 ISRS Fabrikant Award to Dr Lindquist of the Cromwell Hospital
More than 20 years experience in intracranial radiosurgery
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Table 1 Results of Recently Published Larger Series After Gamma Knife Radiosurgery of Cerebral Metastases Single or Multiple Number of Patients Local Tumour Control () Mathieu et al 2007 Melanoma Both 244 862 Gaudy-Marqueste et al 2006 Various Both 106 837 Pan et al 2005 Lung Both 191 84ndash94 (volume-dependent) Gerosa et al 2005 Lung Both 504 94One-year local control 94 Simonovaacute et al 2003 Various Both 400 90 Hasegawa et al 2003 Various Both 172 87 Sheehan et al 2002 Lung Both 273 84 Chen et al 1999 Various Both 190 89
From BE lippitz Karolinska Stockolm
( European Neurological Review 2011)
Excellent local control even with melanoma
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
1987 The CyberKnife System is developed ( 20 years later than gammaknife) 1990 Accuray Incorporated is founded 1996 Japan approves the CyberKnife System for tumors in the head and neck 1999 Food and Drug Administration (FDA) clears the CyberKnife System for the treatment of tumors in the head and base of skull 2001 FDA clears enhancements to the CyberKnife System for tumors anywhere in the body ( 15 years after initial development) Korea and Taiwan approve the CyberKnife System for tumors in the head and neck 2002 Europe approves the CyberKnife System for tumors anywhere in the body 2003 Korea approves the CyberKnife System for tumors anywhere in the body 2004 FDA clears Accurayrsquos Synchronyreg Respiratory Tracking System Taiwan approves the CyberKnife System for tumors anywhere in the body 2005 FDA clears Xsighttrade Spine Tracking System Accuray introduces its fourth-generation CyberKnife System which delivers faster treatment with greater flexibility making extracranial radiosurgery easier China approves the CyberKnife System for tumors in the head and neck 2006 Accuray opens new manufacturing and RampD facility FDA clears Xsighttrade Lung Tracking System and 4D Treatment Optimization and Planning System 2007 Accuray common stock begins trading on The NASDAQ Stock Market under the symbol ARAY
Accuray company milestones
Extracraneal radiosurgery is no more than 15 years old ( since 2001)
Experience of radiosurgery is now more than 45 years old Others companies claim to have SRS technology
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
TABLE 1 Local Control in Early Stage Non-small Cell Lung Cancer AuthorRef Treatment Local Single Fraction Control Equivalent Dose (Gy) North AmericaEurope Timmerman et al (2006)37 20ndash22 Gy x 3 95 (2 + yr) 56ndash62 Bauman et al (2006)42 15 Gy x 3 80 (3 yr) 41 Fritz et al (2006)43 30 Gy x 1 80 (3 yr) 30 Nyman et al (2006)44 15 Gy x 3 80 (crude) 41 Zimmerman et al (2005)45 125 Gy x 3 87 (3 yr) 435 Timmerman et al (2003)35 18ndash24 Gy x 3 90 (2 yr) 50ndash68 McGarry et al (2005)36 Asia Xia et al (2006)46 5 Gy x 10 95 (3 yr) 32 Hara et al (2006)47 2006 30ndash34 Gy x 1 80 (3 yr) 30ndash34 Nagata et al (2005)41 12 Gy x 4 94 (3 yr) 42
R Timmerman J Thor Onc July 2007
Comment short follow up 2-3 years
Much better than fractionated XRT
Radiosurgery
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients By Caroline Helwick The ASCO POST September 1 2014 Volume 5 Issue 14 bull Japanese investigators conducted a retrospective review of 87 stage I patients who declined surgery
and were treated with stereotactic radiotherapy bull They found local control rates for T1 and T2 tumors at 5 years to be 92 and 73 respectively Five-
year overall survival rates for stage IA and IB subgroups were 72 and 62 respectively bull The researchers concluded that the survival rate for SBRT is ldquopotentially comparable to that of surgeryrdquo bull ----------------------------------------------------------------------------------------------------------------------------
MD
IJRO October 1 2015Volume 93 Issue 2 Pages 361ndash367 Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery Nelson Moussazadeh et al Division of Neurological Surgery Memorial Cancer Center New York New York
Of 278 patients 31 (111) with 36 segments treated for spinal tumors survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 61 years (maximum
Fig 1 Disease progression Kaplan-Meier analysis for local tumor control in patients surviving gt5 years after 24-Gy spinal stereotactic radiosurgery (SRS) delivered in a single fraction (patients at risk n=31)
Not many studies about 5 years local controlHigh Local tumor control seems to be holding after 5 years
Around 90 local control at 5 years
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Radiosurgery for oligometastasis (Mostly review articles)
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
2013 by American Society of Clinical Oncology Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy Kimberly S Corbin Samuel Hellman and Ralph R WeichselbaumuArr
m1 yg2yIj3yf4yh5yo6y
1100 lesions treated High local control moderate survival most follow up 2-3 years
Extracranial Oligometastases A Subset of Metastases Curable With Stereotactic Radiotherapy
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
copy 2014 by American Society of Clinical Oncology Radical Irradiation of Extracranial Oligometastases Joseph K SalamauArr and Michael T Milano + Author Affiliations Joseph K Salama Duke University Durham NC and Michael T Milano University of Rochester Rochester NY Corresponding author Joseph K Salama MD Department of Radiation Oncology Duke University Box 3085 Durham NC 27710 e-mail josephsalamadukeedu
Most complete review article
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
From Joseph Salama
TMC( treated metastatic control) very high( mostly above 75) Still short FU 1-3 years
Multiple countries interested in treating oligometastasis with SBRT
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
From Joseph Salama
Bigger number and bigger size of metastasis decrease the good outcome Most of the patients no more than 5 metastasis
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
JCONovember 2014Volume 26 Issue 11 Pages 713ndash719 Predictive Factors for Local Control in Primary and Metastatic Lung Tumours after Four to Five Fraction Stereotactic Ablative Body Radiotherapy A Single Institutions Comprehensive Experience I Thibault et alt bull 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR
using 48ndash60 Gy in four to five fractions bull The 2 year local control rate was 96 in stage I NSCLC 76 in colorectal cancer (CRC)
metastases and 91 in non-lungnon-CRC metastases Conclusions Lung SABR of 48ndash60 Gyfour to five fractions resulted in high local control rates for all tumours except Colorectal metastases Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control
Histology might make a difference But all had high degree of control Histology might make a difference but all had high degree of control
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
From Joseph Salama
Treating all known metastasis Some studies as high as 8 met per patient High degree of local control even in ldquoresistantrdquo histologies (melanoma) Survival depends on primary( renal prostate highlung low)
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Cancer 2012 Jun 1118(11)2962-70 doi 101002cncr26611 Epub 2011 Oct 21 Stereotactic body radiotherapy for multisite extracranial oligometastases final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease Salama JK Vokes EE Hellman S Weichselbaum RR Et al Department of Radiation Oncology Duke University Durham North Carolina 27710 USA METHODS Patients with 1 to 5 metastatic cancer sites life expectancy of gt3 months received escalating SBRT doses to all known cancer sites RESULTS Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 Median follow-up was 209 months One and 2-year progression-free survival are 333 1-year and 2-year overall survival are 815 (95 CI 711-911) and 567 (95 CI 439-689) Eleven patients (183) have not progressed CONCLUSIONS Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT Further investigation should focus on patient selection Number of lesions important
No much information about treating more than 5 lesions Can we treat many
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic NonndashSmall-Cell Lung Cancer Puneeth Iyengar Robert Timmerman et al Presented in part at American Society of Clinical Oncology Annual Meeting Chicago IL May 31-June 4 2013 Patients and Methods Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression Results 24 patients median age of 67 years median follow-up of 116 months All patients had progressed through platinum-based chemotherapy 52 sites treated Lung parenchyma was most often irradiated Median PFS was 147 months and median OS was 204 months only 3 of 47 ( 6 ) measurable lesions recurring within the SBRT field Conclusion Use of SBRT with erlotinib resulted in high PFS and OS substantially greater than historical values for patients who only received systemic agents
Chemotherapy failures Learn to combine chemo and XRT Good local control high PFS and OS
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
An Individual Patient Data Meta-Analysis of Outcomes and Prognostic Factors after Treatment of Oligometastatic Non-Small Cell Lung Cancer Authors
A Ashworth1 S Senan2 D A Palma3 M Riquet4 Y Ahn5 U Ricardi6 M
B ASTRO meeting 2014
C PurposeObjective(s) Long-term survival has been observed in patients with oligometastatic NSCLC
treated with locally ablative treatments to all sites of metastatic disease D MaterialsMethods After a systematic review of the literature data were obtained on 757 NSCLC
patients from 20 hospitals worldwide with 1-5 synchronous or metachronous metastases treated with surgical metastectomy stereotactic ablative radiotherapy stereotactic radiosurgery or radical external-beam radiotherapy and curative-intent treatment of the primary lung cancer
E Results F Three risk groups were identified on RPA low-risk metachronous metastases (5-year OS 478)
intermediate risk synchronous metastases and N0 disease (5-year OS 362) high risk synchronous metastases and N1N2 disease (5-year OS 138)
G Conclusions Significant OS differences were observed in oligometastatic patients stratified by type of metastatic presentation and N-status
H Long-term survival is common in selected patients with metachronous oligometastases I We propose this risk classification scheme be utilized in guiding selection of patients for clinical trials of
ablative treatment
Three Different levels of risks Metachronus and no positive nodes best prognosis
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Future of SRS for oligometastasis
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Stereotactic Radiation Therapy Combined With Immunotherapy Augmenting the Role of Radiation in Local and Systemic Treatment Review Article | May 15 2015 | Oncology Journal bull By AndrewB Sharabi et al ------------------------------------------------------------------- bull Large radiation fields encompassing significant volumes of bone marrow or blood pool have
been observed to result in decreases in white blood cell counts giving rise to the notion that radiation may be generally immunosuppressive
bull Nonetheless with the application of SRS and SBRT there is the possibility of significantly limiting the volume of bone marrow andor blood pool being irradiated thereby minimizing these potentially consequential immunosuppressive effects
bull Accumulating preclinical data have documented that immunotherapy can augment radiation-mediated local tumor response Similarly radiation can augment the systemic effects of immunotherapy ndash
bull Most preclinical data to date are from studies of high doses of radiation that when translated to the clinic may be best delivered with SBRT
bull carefully designed studies will be required to investigate the effects of radiation combined with immunotherapy on local tumor control in the definitive setting and on systemic tumor control in the metastatic setting
SBRT and Inmunotherapy
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Because the response rate in patients with melanoma was significantly higher than expected on the basis of historical data we believe that the combination and investigation of CD4+ effector memory T cells as a predictor of response warrant further study
SBRT abscopal effect
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Targeted radiation might be more inmmuno-stimulator than surgery
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Abscopal effect found in rats with radiosurgery
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Varian The edge
Cyberknife
Development of new models for SBRT gammaknife
Electa Axesse
SBRT is a growing technology
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Based on PET technologyTreat many lesions
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
Conclusions
1 SRS is producing unexpected high local control over fractionated radiation 2 Histology is not as important as with fractionation ( good response with melanomas renal cell cancer etc) 3 It requires high daily fractions Thus technology is very important to minimize radiation to normal tissues ( ex lung tumors motion) 4 It might replace surgery in many situations ( Ex early lung cancer) 5It is well suited to treat oligometastasis 6 It might increase inmmunity helping the new systemic approaches with this new modality
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
The end
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
How Do We Combine Radical Irradiation of Extracranial Oligometastases With Systemic Therapy As metastasis-directed therapies are offered more often practitioners wonder how to integrate them with standard systemic therapy regimens It is unknown if these treatments should be delivered before systemic therapy concurrently with systemic therapy immediately after systemic therapy or at time of progression if metastases are limited in number
