3.3 SRS / neurochirurgische resectie met of zonder WBRT hfdst... · increase of steroid medication,...

3.3 SRS / neurochirurgische resectie met of zonder WBRT I Study ID II Method III Patient

Characteristics IV Interventions V Results primary

outcome VI Results secondary and other outcome

VII Critical appraisal

1. Andrews DW et al, Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial, The Lancet, 2004

1. RCT 2. Supported by grant number (RTOG U10 CA21661, CCOP U10CA37422, Stat U10 CA32115) from the National Cancer Institute 3. 20 RTOG 4. 333-->331Patients 5. October 1999-December 2003

1. Inclusion 18 yrs or older with no previous cranial radiation. A contrast enhanced MRI scan showing one to three brain metastases with a maximum diameter of 4cm for the largest lesion and additional lesions not exceeding 3 cm in diameter. Metastases were deemed unresectable if they were located in deep gray matter or in eloquent cortex. Postoperative patients with either residual or distal brain metastases were eligible if the total number of metastases remained three or fewer, patients with newly diagnosed cancer presenting with brain metastases, patients with unknown primaries Exclusion KPS < 70, haemoglobin concentration < 80g/L, absolute neutrophil count of less than 1000 cellsµL, platelet count less than 50 000 cells/µL, metastases in the brain stem, or within 1 cm of the optic apparatus, patients who had received treatment for systemic cancer within one month of enrolment 2. Age, gender, size of metastasis, RPA class, KPS score, primary site, histology status, metastases (incl number), MMSE

1. WBRT with stereotactic radiosurgery boost. All WBRT was given daily 2,5 Gy fractions to a total of 37,5 GY over 3 weeks 2. WBRT allone. All WBRT was given daily 2,5 Gy fractions to a total of 37,5 GY over 3 weeks

1. Mean survival did not differ much between groups. No survival benifit between groups in patients with mulitple metastases. Patients with single metastasis in the stereotactic radiosurgery group had significantly better survival than those who were not allocated with boost treatment

1+2. No significant differences between treatment groups with respect to overall time to intracranial tumour progression or neuroplogical death rates. There was a statistical sign improvement in KPS and decreased steroid use at 6 months in the stereotacticradiosurgery boost treatment group, but no difference in mental status was noted between groups

1. A2. 2. Not reported 3. Multicentre study but relative small sample size. Description of randomisation available





3. WBRT+stereotact surg: mean age=58,8 (19-82) 52% male, KPS 70-80= 43%.. WBRT allone. mean age=59,9% (24-90), 53% male, KPS 70-80= 37%

1. Aoyama H et al,Stereotactic Radiosurgery Plus Whole-Brain Radiation Therapy vs Stereotactic Radiosurgery Alone for Treatment of Brain Metastases A Randomized Controlled Trial, JAMA, 2006

1. RCT 2. Not reported 3. 11 Hospitals in Japan 4. 132 Patients 5. October 1999-December 2003

1. 18yr Old or older with 1-4 brain metastases, each with a maximum diameter of no more than 3 cm on contrastenhanced MRI scans, derived from a histologically confirmed systemic cancer. Patients had a Karnofski score of 70 or higher. 2. Age, sex, primary tumor site, primary tumor status, RPA, KPS score, Chemotherapy after brain treatment. 3. SRS allone; age mean(range) 62,5 (36-78), men 71%, KPS score 90-100= 52% SRS+WBRT; age mean(range) 62,1 (33-86), men 79%, KPS score 90-100= 53%

1.WBRT with SRS. WBRT dosage schedule was 30 Gy in 10 fractions over 2 to 2,5 weeks.SRS dosage was prescribed to tumor margin. Metastases with a maximum diameter of up to 2 cm were treated with doses of 22 to 25 Gy and those larger than 2 cm were treated with doses of 18 to 20 Gy. 2. SRS allone. SRS dosage was prescribed to tumor margin. Metastases with a maximum diameter of up to 2 cm were treated with doses of 22 to 25 Gy and those larger than 2 cm were treated with doses of 18 to 20 Gy.

1. The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT_SRS group. And 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P=.42).

1+2. The 12-month brain tumor recurrence rate was 46.8% in the WBRT_SRS group and 76.4%for SRS alone group (P_.001). Salvage brain treatment was less frequently required in the WBRT_SRS group (n = 10) than with SRS alone (n = 29) (P_.001)

1. A2. 2. Not reported 3. Not blinded, description of randomisation process, relative small sample size. Multicenter study





1. Chang et al, Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial, The Lancet Oncology, 2009

1. RCT 2. No external funding was received 3. Departments of Radation Oncology and Neurosurgery and the Brain and Spine Center, MD Anderson Cancer Centre, Houston Texas USA 4. 119-->58 5. Jan 2, 2001 - Sept 14, 2007

1. Inclusion age 18 years or greater; RPA class one or two, KPS ≥70; 1 to 3 newly diagnosed brain metastases eligible for SRS; brain MRI within 1 month of enrolment; and signed written informed consent. Exclusion undergone prior brain surgery, SRS, or WBRT; diagnosed with leukaemia, lymphoma, germ-cell tumour, small-cell lung cancer, leptomeningeal disease, or unknown primary tumour; if they were RPA class three (KPS <70); and if they were pregnant.2. Gender, ethnic origin, Number of BM, Recursive partitioning analysis class, Graded prognostic assessment, Primary Site, Liver metastasis, Bone metastasis, Adrenal metastasis.

1. SRS dose was prescribed in accordance to the RTOG 90-05 guidelines. WBRT was prescribed to a total dose of 30 Gy given in 12 daily fractions of 2*5Gy per day. 2. WBRT was prescribed to a total dose of 30 Gy given in 12 daily fractions of 2*5Gy per day.

1. SRS plus WBRT were signifi cantly more likely to show a decline in learning and memory function (mean posterior probability of decline 52%) at 4 months than patients assigned to receive SRS alone (mean posterior probability of decline 24%). In the SRS plus WBRT group, 1 case of grade 3 toxicity was attributed to radiation treatment. In the SRS group, one case of grade 3 toxicity was attributed to radiation treatment. Two cases of grade 4 toxicity in the group that received SRS alone were diagnosed as radiation necrosis.

1+2. 73% Of patients in the SRS plus WBRT group were free from CNS recurrence at 1 year, compared with 27% of patients who received SRS alone (p=0•0003) At month 4 there were 4 deaths (13%) in the group that received SRS allone, and 8 deaths (29%) in the group that received SRS+WBRT

1. A2. 2. 1 Lost to FU. 3. The trial was stopped according to early stopping rules on the basis that there was a high probability that patients randomly assigned to receive SRS+WBRT were sign. More likely to show a decline in learning and memory function at 4 months that the other group. Investigators remained blinded tot the trial except for treatment assignment, which was monitored on an annual basis by the data monitoring committee

1. Do L et al, Resection followed by stereotactic radiosurgery to resection cavity for intracranial metastases, International Journal of Radiation Oncology Biology Physics, 2009

1. Retrospective review 2. Not reported 3. City Hope Nation Cancer Centre 4. 30 5. December 1999 - December 2006

1. Newly diagnosed BM treated with resection followed by SRS/SRT to resection cavity. 2. Gender, Age, RPA class, KPS, Primary tumor site, Lesions, SRS/SRT dose 3. Not described

1. SRS dose range was 15–18 Gy. For the larger lesions, SRT to 24–27.5 Gy in four to six equal fractions of 5.5–6 Gy/fraction were given. For lesions that were not resected, SRS/SRT was used alone to the 80–90% isodose lines, with the dose prescription dependent on the size and site of the brain metastases. 2. Not reported

1. Of the 33 lesions treated by resection followed by SRS/SRT 12% developed local recurrence. Of the 20 leasions treated by SRS/SRT alone 20% had local recurrence. Overall 70% had brain tumor recurrences. Recurrence in lesions treated with SRS/SRT only occurred in 63%. Recurrence was symptomatic in 23% and was associated with neurologic deficit in 30%. Symptomes were:

1+2. At the last follow up visit, 14 of the 30 patients had died. The 12 month overall survival rate was 51%. 23% of the patients had died of progressive neurologic disease or with severe intercurrent central nervous system symptoms. The 12 monthly neurologic specific survival rate was 75%

1. C. 2. Not reported 3. Small sample size, descriptive.





headaches, nausea/vomiting and dizziness

1. Fahrig A et al, Hypofractionated stereotactic radiotherapy for brain metastases--results from three different dose concepts, Strahlenther Onkologie, 2007

1. Prospective Clinical Trial 2. Not reported 3. Two German Novalis, BrainLAB AG, Heimstetten, Germany 4. 163-->150 5. June 2000 - June 2005

1. Exclusion Location in the brainstem, mesencephalon, basal ganglia, capsula interna, total volume of one or more metastases > 3 cm3, patients with more than 4 metastases were admitted to WBRT, small cell lung cancer patients. 2. Age, Gender, RPA class, Number of metastases, PTV, Primary tumour, Localization 3. Not described

1. 3 different dose concepts for stereotactic radiosurgery: 1. (n=72) 5x 6-7Gy 2. (n=59) 10x4Gy 3. (n=97) 7x5Gy 2. Not reported

1. 6 Months and 12 months were 83% and 66% respectively. Median survival of all patients was 16 months. This was significantly better in patients treated with 10x4Gy and 7x5Gy vs the 5x6-7 Gy group 17 vs 11 months respectively. The only sign influence factor on tumor specific and brain specific survival was RPA class in 42% patients. No early toxicity during treatment, requiring the increase of steroid medication, occurred. 10% of all patients experienced toxicity. side effects occured significantly more often after 5x6-7 Gy and 7x5Gy. None of the patients treated with 10x4Gy as affected by adverse effects.

1+2. Not reported 1. B. 2. Not reported 3. There is a possible conflict of interest as it is not clear how Novartis is involved with this research. No patient characteristics for the different groups. no randomisation and blinding.

1. Fuentes R et al, Surgery versus radiosurgery for patients with a solitary brain metastasis from non-small cell lung cancer, Cochrane Database of Systematic Reviews, 2006

1. Cochrane systematic review 2. Not reported 3. 1966 - 2009 4. CENTRAL/MEDLINE/EMBASE/CINAHL 5. Randomized or controled trials, prospective or retrospective cohort studies 6. 686-->47finally used

1. Histologically proven NSCLC, adults of more than 18 yrs old and have their primary tumour in complete remission when the diagnosis of a solitary brain metastasis was made. Also mandatory that the included patients had a MRI or a contrast enhanced CT scan as part of their initial evaluation. 2. Not reported

1. Surgery (megavoltage stereotactic radiotherapy) with of without whole brain irradiation. 2. all types of radiosurgery with or withou whole brain irradiation for solitary brain metastasis from NSCLC, independently of the chemotherapy treatment that has been administered.

1. No article was relavant for the review

1+2. No article was relavant for the review

1. A1 2. No studies that matched the inclusion creteria. No RCT's that compared chirurgy and radiochirurgy for patients with a single brain MT resulting out of NSCLC





1. Gaspar L et al, Recursive partitioning analyses (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials, International Journal of Radiation Oncology Biology Physics, 1997

1. Review 2. Not reported 3. RTOG 79-16, 85-28 and 89-05 4. 1276-->1200 out of 3 RTOG consecutive databases 5. 1979 - 1993

1. Eligitibility criteria: study 1) KPS was 40 or more study 2) KPS was more than 60 study 3) KPS was 70 or more. 2. Age, KPS, tumor related characteristics

1. See protocols RTOG RTOG 79-16; 30 Gy 10/6 fractions in 2/3 weeks and RTOG 85-28; 1,6Gy 2x a day seperated 4-8hrs 5x a week, boost 16Gy to 38,4Gy. RTOG 89-05; 37,5Gy in 15 daily fractions with or withour BUdR continuous 96hrs in the weeks prior and during radiation. 2. Not reported

1. The results indicates a survival difference according to KPS, age, number of BM, status and site of origin of primary lesion and the time of interval between presentation of primary and BM. The only treatment related variable associated with better survival was a delivered dose of 52 Gy or more.

1+2. The median survival time (MST) of the entire group was 4,4 months. The MST for the patiens with a KPS > 70 was 4,9 months. The MST for the patients with a KPS < 70 was 2,3 months. The MST for patients with controlled primary lesion was 5,5 months and 3,9 for patients with uncontrolled primary lesion. Patients <65 years was 6.1 months and 4,0 months for patients >65 years. The MST was 4,8 and 7,1 months for the patients with and without other systemic metastases, respectively

1. B. 2. Not reported 3. Very old data over a long period, difference in patient characteristics not transparant, therefore unable to see the balance between the different groups after using the decision tree, large sample size

1. Hart MG et al, Surgical resection and whole brain radiation therapy versus whole brain radiation therapy alone for single brain metastases, Cochrane Database of Systematic Reviews, 2005

1. Cochrane systematic review 2. Internal source. Dr. Hart was the repient of a Cochrane Geneacological Cancer Review group Grant 3. Updated till 2007 4. CENTRAL, Medline, Embase, Cancerlit, Biosis and the Science Citation Index. 5. RCT's with low risk for bias 6. 860 studies with 3 RCT's

1. Patients with systemic cancer (primary site confirmed by histology) and a suspected single brain metastasis were included. 2. Age, sex, KPS

1. Surgical resection plus WBRT 2. WBRT allone.

1. The analysis did not demonstrate a statistically significant difference in survival between the two treatments. 1 trial had enough data and fount that those treated by surgery and WBRT maintained their functional independence longer that those by WBRT allone. There was a trend that those treated by surgery were less likely to die from neurological causes. No statistical heterogeneity was found between the trials.

1+2. The results do not demonstrate that either treatment was more likely to to cause adverse events

1. A1 2. Included studies where critically reviewed using the inclusion criteria. Only studies with a low risk for bias were included. Blinding was not always possible in case of surgery

1. Kocher et al, Adjuvant Whole-Brain Radiotherapy Versus Observation after Radiosurgery or Surgical Resection of one to three Cerebral Metastases:

1. RCT 2. Supported by grant No. 2U10 CA11488-25 through 5U10 CA011488-40 from the NCI (Bethesda, MD) and by

1. Inclusion criteria Age ≥ 18 years, WHO performance status ≤2, 1-3 brain metastases, Radiosurgery: single metastasis ≤ 3.5 cm,

1. Patients treated with complete surgery or radiosurgery and adjuvant WBRT (30 Gy in 10 fractions), five fractions per week.

1. Duration of functional indepence: no difference in median time till first report of deterioration to WHO PS of more than 2 (Observation = 10 months

1+2. Overall intracranial progression was sign more frequent in the OBS arm (78%) than the WBRT arm (48%). Median progress free survival was

1. A2. 2. 6 patients ineligible 3. Unknown if study is performed in single centre or multiple centres. No explanation about the





Results of the EORTC 22952-26001 Study, Journal of clinical Oncology, 2011

donation from Deutsche Krebshilfe from Germany through the EORTC Charitable Trust 3. Not described 4. 359 5. Patients were included between November 1996 to November 2007

multiple metastases ≤ 2.5 cm diameter, Surgery: complete surgical resection, Radiosurgery; histologic confirmation of primary tumor or other metastases ≤ 4 years ago, stereotactic biopsy of the brain metastasis otherwise, Stable systemic cancer for ≥ 3 months and/or asymptomatic synchronous primary tumor without metastases outside the CNS or unknown primary tumor. Exclusion criteria Brain metastasis of small-cell lung cancer, lymphoma, leukemia, myeloma, germ cell tumors, Brain stem metastases, Leptomeningeal metastases, Recurrent brain metastases after surgery and/or radiosurgery and/or brain irradiation, Inability to interrupt chemotherapy during whole-brain radiotherapy. 2. Age, Sex, WHO performance status, Neurologic status, Localization of primary tumor, Macroscopic tumor outside the brain. 3. WBRT (180) versus Observation (179): patient and lesion characteristics were well ballanced.

2. Patients treated with complete surgery or radiosurgery and observation.

versus WBRT = 9,5 months).

slightly longer in patients receiving WBRT(4.6 months) to OBS(3.4 months). No difference was found between the two arms in overall survival.13 late toxicity events were reported in the WBRT arm and 3 in the OBS arm. Progression-free survival Median progression-free survival slightly longer in patients receiving WBRT (4,6 months) versus observation group (3,4 months) Overall survival no difference between WBRT and observation group (10,7 vs. 10,9 months) Late toxicities in WBRT group 1 patient probably died of toxicity, neurologic death was more frequent in the observational arm (44%) than in WBRT arm (28%) Quality of life acute toxicity of WBRT was mild.

reason for differentiating in assigning moments for the different treatment groups.





1. Kondziolka D et al, Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases, International Journal of Radiation Oncology Biology Physics, 1999

1. RCT 2. Dr. Kondziolka is supported by NIH Grant K09-NS01723 3. Not reported 4. 27 5. Not reported

1. Eligible criteria: histologic confirmation of the tumor type either at the primary site or at a site of metastatic disease; All BM were ≤25 mm in mean diameter and more than 5 mm from the optic chiasm; patients had only 2, 3, or 4 tumors on contrast-enhanced MRI scan prior to randomization; patients had a KPS of ≥70. Histologic tumor types could include lung, breast, colon, renal cell, melanoma, bladder, ovarian, and uterine carcinomas. Patients considered ineligible either did not meet one or more of the above criteria or could not undergo MR scanning. 2. Age, gender. Tumor histology, Systemic disease, number of tumors 3. Not described

1. WBRT: megavoltage beams with a source axis distance no less than 80 cm. Fraction sizes of 2.5 Gy. Midplane dose 30 Gy in 12 fractions Radiosurgery: performed within the time course of WBRT. Time interval between WBRT and radiosurgery in patients randomized to radiosurgery, was 1 month. Patients randomized to undergo radiosurgery had Gamma Knife radiosurgery administered using stereotactic MR guidance. Patients received a tumour margin dose of 16 Gy. Patients with symptomatic cerebral edema were got dexamethasone 24 mg per day in divided doses or less. All patients received a single 40 mg intravenous dose of methylprednisolone. 2. Not reported

1. Local failure at 1 year was 100% after WBRT alone but only 8% in patients who had boost radiosurgery. The medain time to local failure was 6 months after WBRT alone in comparison to 36 months after WBRT plus radiosurgery. Patients who received WBRT alone lived a median of 7,5 months, while those who received WBRT plus radiosurgery liver 11 months.

1+2. There was no neurologic or systemic morbidity related to steriotactic radiosurgery. Survival did not depend on histology or number of tumours, but was related to extent of extracranial disease

1. B. 2. Not reported 3. The study was randomized but had a very small sample size (the trial was stopped at 60% accrual mark due to benefit in stereotactic radiosurgery group). Methods are well described. There is a possible conflict of interest





1. Lagerwaard FJ et al, Identification of prognostic factors in patients with brain metastases: a review of 1292, International Journal of Radiation Oncology Biology Physics patients, 1999

1. Retrospective cohort study 2. Not reported 3. Department of Radiation Oncology, Daniel den Hoed Cancer Center, Rotterdam 4. 1333-->1298 5. January 1981 - December 1990

1. Documented brain metastases from solid tumors. Only patients with CT diagnoses of BM. Patients with mere clinical suspicion or isotop scanning of the brain were excluded. 2. Sex, Age, Site of primary, ECOG, Systemic tumor activity, Number of brain metastases 3. Not described

1. All patients were treated with high doses of steroids dexamethasone (dose range 4–16 mg/day, mean 14.6 mg/day). The majority of patients were treated with steroids and WBRT, using lateral opposed fields with a 4 MV or 6 MV linear accelerator, fractionation schedules (76%) 30 Gy in 10 fractions or 20 Gy in 5 fractions (dose range 8–56 Gy, mean 31.5 Gy; SD 5 6.9 Gy). One hundred and forty-eight patients with single brain metastasis received an additional boost dose (range 5–20 Gy; mean 11.5 Gy; SD 5 3.4 Gy). In 95 patients with single brain metastasis were treated with surgery followed by radiotherapy (dose range 20–55 Gy; mean 38.7 Gy; SD 5 8.5 Gy), started within 6 weeks after operation. 118 (9.1%) were treated with steroids only after diagnosis of brain metastases. 2. Brain tumour management with WBRT alone

1. The overall survival 3.4 months, with 6 months, and 2 year survival percentages of 36%, 12%, and 4 respectively. Survival was statistically sign, different between patients treated with steroids only (1.3 months), patients treated with radiotherapy (3,6 months)and patients treated with radiosurgery followed by radiotherapy (8,9 months)

1+2. Analysis within primary tumour groups showed interval between primary tumour and BM, measured at 2 years, to be a prognostic factor in patients with breast primaries (p=0,03). In pulmonary and renal primaries no statistical sign could be found according to interval. Primary tumours other than breast, renal and unknown primaries showed no significant difference with respect to survival, tested against lung primaries. Within the subgroup of patiens treated with radiotherapy only, three prognostic subgroups could be constructed: 1: Good prognosis: ECOG 0 or 1 and no or limited systemic tumor activity and good response to steroids. 2: Poor prognosis: ECOG 2 or 3 and systemic tumor activity limited or extensive and little response to steroids. 3: Moderate prognosis: All other patients treated with radiotherapy

1. B. 2. 6 Patients lost to FU 3. Old data, big sample size, retrospective





1. Le Pechoux CD et al, Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial, The Lancet Oncology, 2009

1. RCT 2. Unrestricted grants from Institut Gustave-Roussy, Association pour la Recherche sur le Cancer (2001), Programme Hospitalier de Recherche Clinique (2007). The EORTC contribution to this trial was supported by grants 5U10 CA11488-30 through 5U10 CA011488-38 from the National Cancer Institute 3. 157 Centres in 22 countries, Mostly EU and North USA 4. 720 / 4 Patients lost to FU 5. 1 September 1999 - 31 December 2005

1. Histologically proven limited stage SCLC in complete remission after initial treatment were eligible for inclusion in the trial. Patients had to have a WHO performance status of less or equal to 22. Sex, Age 3. Standard dose; age yrs= 60 (38-83), sex= 234 males. Higher dose, age yrs= 60 (34-78), sex= 226 males.

1. PCI at higher dose (36 Gy in 18 daily fractions of 2 Gy (conventional fractioning) or 24 twice daily fractions of 1,5 Gy (hyperfractionated accelerated radiotherapy)) 2. PCI at standard dose (25Gy in 10 daily fractions of 2,5 Gy)

1. 2 Year incidence of total brain metastases are 29% (95%CI 24-35) in the standard group and 23% (95%CI 18-29) in the higher dose group.

1+2. There was a lower overall survival in the higher dose group

1. B. 2. 4 Lost to follow up 3. Multicentre and multicountry study. Relative big sample size. Lost to follow up described. No description of randomisation

1. Lester JFM et al, Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small-cell lung cancer: A Cochrane review, Cochrane Database of Systematic Reviews, 2005

1. Cochrane systematic review 2. Not reported 3. Between 1966 and December 2004 4. MEDLINE, EMBASE, LILACS, Cancerlit 5. RCT's 6. 4 RCT's

1. Patients with histologically or cytologically confirmed NSCLC treated with radical intent and no radiological evidence of brain metastasis prior to randomisation. 2. 187 patients adenocarcinoma or large-cell carcinoma confined to the chest 254 patients Stage III inoperable NSCLC and 97 patients NSCL 13% Stage I/II, 87% stage III and 281 male patients inoperable NSCLC

1. Using PCI 2. Not using PCI

1. Incidence of brain metastases: PCI did significantly reduce the incidence of brain metastases in three trials. The incidence of brain metastases was sign lower in the PCI arm compared to the control arm. Time to brain metastases: The VALG trial, median time to development of brainmetastases was 34 weeks in the PCI group and 29 weeks in the control group, not sign. The Umsawasdi trial, PCI was also reported to significantly prolong the median time to CNS metastases (50.5 weeks vs 23 weeks, P=0.002,

1+2. Toxicity: Two trials reported no late complication of PCI. One trial reported no excexxive neurological toxicity with PCI compared to the control arm. Quality of life: Quality of life measures were not carried uit in any of the studies

1. A2 2. Small population and no meta-analyses done. Rondimizing method unclear for two included studies.





Cox’s regression model). The prevalence of brain metastases at 12 and 24 months for PCI versus observation in RTOG 84-03 was not significant (15% vs 17% and 15% vs 31%). Survival: No trial reported a survival advantage with PCI over observation.

1. Li J et al, Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function, Journal of Clinical Oncology, 2007

1. Prospective study 2. Not reported 3. Multicenter study 4. 208-->135 5. Not reported

1. Adult patients were eligible to participate if they had radiologically demonstrated BM from histologically proven solid tumor, required WBRT, and had a KPS of 70 or more. 2. Not reported 3. Not described

1. All patients received 10 daily fractions of 3Gy WBRT 2. Not reported

1. Patients with greater tumour shrinkage after WBRT survive longer. The one year survival in the good responding patients was 28% aginst 16% in the poor responding patients

1+2. Tumor shrinkage is associated with better preservation of specific NCF functions, especially executive function and fine motor coordination.

1. B. 2. Not reported. 3. Scans were reviewed blinded, relative big sample size, multicentre but there is a conflict of interest. The two groups do have almost the same number of participants. However the group differences are not showed and makes it difficult to interpret the results.

1. Mintz AHK et al, A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis, Cancer, 1996

1. Randomized trial 2. Funded by the NCI of Canada and Ontario Oncology groep 3. Not reported 4. 162 -->143 5. 1 September 1989-4 March 1993

1. Patients younger than 80 yrs and had a lesion consistent with a single brain metastasis on CT and pathologic confirmation of cancer within the previous 5 years. KPS over 50. 2. Age, sex, KPS, location primary, extend of disease3. Radiation allone; Mean age yrs/SD = 58 (9.86) Sex (M/F)= 22/21 Surgery and Radiation; Mean age yrs/SD = 58,9 (8,98) Sex (M/F)= 24/17

1. Surgergy + radiation craniotomy under general asesthesia to achive gross total removal of the metastases or lobectomy. (300 cGy x10 fractions of radiation over 2 weeks) 2.Radiation alone (300 cGy x10 fractions of radiation over 2 weeks)

1. Median survival for radio ther allone= 6,28 mnths (95% CI 3-11,4) Median survival for radio ther + surg= 5,62 mnths (95% CI 3,9-7,2)

1+2. Quality of life not significant different for both diff. KPS ≥70 (mean 0,32 SD=0.30 P=0.98)

1. B. 2. 0 3. Blinded multicentre study, relative small sample size. Relative low KPS to still be included. Heterogenous group of patient group when primary malignancy is considered





1. Muacevic A et al, Microsurgery plus whole brain irradiation versus Gamma Knife surgery alone for treatment of single metastases to the brain: a randomized controlled multicentre phase III trial, Journal of Neuro-Oncology, 2008

1. Randomized trial 2. This study was granted by Elekta Research Foundation 3. Multicentre 4. 70-->64 5. October 1999-16 October 2003

1. Single untreated brain metastasis with a diameter of similar or more than 3cm in an operable site, were aged between 18 and 80 years, had a historically proven cancer at a site ouside the CNS, presented with a KPS greater or equal to 70 and were thought to have a stable systemicdisease with a life expectancy of at least 4 months. For patients with an unknown primary tumor, a confirmatory stereotactic biopsy was required 2. Sex, age, KPS, RPA 3. - Surgery only; Sex (male/female)= 15/18, Age year Mean/median/range= 58,3/59/32-75 KPS(mean/median/range)= 76,4/80/70-100 - WBRT and surgery; Sex (male/female)= 12/19, Age year Mean/median/range= 54,3/55/35-78 KPS(mean/median/range)= 79,4/80/70-100

1.WBRT and Surgery WBRT: dose of 40Gy over 4 weeks (2Gy x 20 fractions). Gamma knife surgery was administered using stereotactic MRI guidance. The treatment was performed on an outpatient basis. The mean dose applied to the tumor margin (prescribed tumor dose) was 21 Gy (range: 14–27 Gy). The prescribed tumor dose was in the range of 20–27 Gy for radio-resistant tumors (such as melanoma, hypernephroma) and in the range of 14–20 Gy for more radio-sensitive tumors (such as breast cancer). The mean maximum dose was 41 Gy (range: 28–54 Gy), and on average, the 50% isodose (range: 35–85%) was used to irradiate the tumor margin. Conformal multiple isocenter Gamma Knife surgery (mean number of isocenters per patient: 7) was performed in all patients 2.WBRT 40Gy over 4 weeks (2Gy x 20 fractions).

1. Length of survival did not differ between the treatment groups, median survival was 9.5 months after surgery plus WBRT and 10.3months after radiosurgery allone

1+2. The 1-year neurological death rate was higher in the surgery group than in the radiosurgery group (29% vs 11%); the difference, however, was statistically not significant (P = 0.3). The 1-year systemic death rate was in the range of 53% in both treatment groups (P = 0.8). Early and late Grade 1 or 2 complications occurred significantly more often after surgery plus WBRT than after radiosurgery alone (P\0.01), whereas no significant differences could be detected for early or late grade 3 or grade 4 toxicities HRQL scores and disease status was assessed 6 weeks and 6 months after treatment. Generally, HRQL scores were maintained at baseline levels prior to tumor progression and significantly decreased thereafter mostly due to systemic disease progression. Improved scores for the domains ‘‘role functioning’’ and ‘‘QOL’’ were seen 6 weeks after radiosurgery (P\0.05). However, this difference was lost 6 months after treatment

1. B. 2. 0 3. Multicentre study not finished due to losing patients. Small sample size, no blinding





1. Nieder CA et al, The role of postoperative radiotherapy after resection of a single brain metastasis: Combined analysis of 643 patients, Strahlentherapie und Onkologie, 2007

1. Systematic literature review 2. Not reported 3. Up to June 2007 4. Medline 5. Up to June 2007 6. 10

1. Key words: "resection or neurosurgery", "brain metastases, cerebral metastases or secondary brain tumo(u)r", reference list of all articles --> all publications reporting on patient groups with single brain metastases + clearly defined radiation doses and evaluation of the brain relapse pattern. 2. Median age (range), median time after diagnose, sex, WHO performance scale.

1. WBRT and different types of local “partial-brain” radiotherapy 2. Not reported

1.after surgery alone (n=94) 38 patients developed a local relapse at the original site. After additional radiotherapy (n=224) 28 patients developed a local relapse at the original site. 18% ofwas the total local relapse rate. Postoperative radiotherapy at least doubles the local control rate compared to surgery alone

1+2. Not reported 1. B 2. A small amount of studies included for results. The included studies are difficult to compare as they are testing and measuring different subjects. No clear insight view into the results of the different studies as all results are combined while this seems not possible.

1. Slotman B et al, Prophylactic cranial irradiation in extensive small-cell lung cancer, New England Journal of Medicine, 2007

1. Randomized trial 2. Supported by grants (5U10-CA11488-29 through 5U10-CA1148837) from the National Cancer Institute and by funds from the Dutch Cancer Society for local data management. Dr. Postmus reports receiving consulting fees from Astra-Zeneca, GlaxoSmithKline, Transgene, and Transave; lecture fees from Roche, GlaxoSmithKline, Eli Lilly, and Abraxis; and grant support from Actelion, Roche, and GlaxoSmithKline. No other potential conflict of interest relevant to this article was reported. 3. Multicentre 4. 266 patients 5. February 2001-March 2006

1. Cytologically or histologically confirmed, extensive small-cell lung cancer, defined as disease beyond the hemithorax and supraclavicular nodes or pleural effusion containing tumor cells. All patients had to have had a response to systemic chemotherapy, as judged by the standard treatment policy of each participating center. 2. Median age (range), median time after diagnose, sex, WHO performance scale. 3. Prophylactic Cranial Irradiation; median age= 62 (range 37-75), Median time after diagnose = 4,2 mo, Sex = 67,8% (n=97) male. WHO perf scale = 0; 36,4%, 1; 55,9% 2; 7,7%. Control; median age= 63 (range 39-75), Median

1. Prophylactic Cranial Irradiation Radiation to the intracranial content was administered with the use of two opposed lateral fields with a linear accelerator (4 to 18 MV) or cobalt unit. Each field was treated daily on a schedule of four to five fractions per week. The dose was specified to the midline. The following schedules for cranial irradiation could be used: 20 Gy in 5 or 8 fractions, 24 Gy in 12 fractions, 25 Gy in 10 fractions, or 30 Gy in 10 or 12 fractions. The biologically equivalent doses for these schedules range from 25 to 39 Gy.Radiotherapy had to start 4 to 6 weeks after chemotherapy. 2. No further therapy

1. Symptomatic brain metastases were observed in 24 of the 143 patients in the irradiation group (16,8%) and 59 of the 143 in the control group (41,3%). The cummulative risk of symptomatic brain metastases at 6 and 12 months were 4,4% and 14,6% in the irradiation group and 32,0% and 40,4% in the control group.

1+2. Survival without disease progression was sign. Longer in the irradiation group than the control group with a median of 14,7 weeks vs 12,0 weeks.. At six months the surv. Rate without disease progr. Was 23,4% (95%CI, 16.6 to 30.9) in the irradiation group and 15,5% (95% CI, 10,1 to 22,0) in the control group. The irradiation group had also 1+2 sign longer overall survival than the control group 6.7 mocompared to 5,4mo. The rate of compliance with the quality of life assessment was 93,7% at baseline but decreased to 46,3% at 9 mo. From baseline to month 9, there was no statistical or clinically significant difference in global health status between the study groups

1. B. 2. Not reported 3. Multicentre study with relative big sample size





time after diagnose = 4,2 mo, Sex = 57,3% (n=82) male. WHO perf scale = 0; 36,4%, 1; 53,1% 2; 10,5%.

1. Stafinski T et al, Effectiveness of stereotactic radiosurgery alone or in combination with whole brain radiotherapy compared to conventional surgery and/or whole brain radiotherapy for the treatment of one or more brain metastases: a systematic review and meta-analysis, Cancer Treatment Reviews, 2006

1. Systematic review 2. Not reported 3. Not reported 4. Not reported 5. Randomised or controlled (e.g., pseudo-randomised or quasi-randomised in which allocation was not truly randomised) trials and prospective or retrospective cohort studies with concurrent comparison groups. 6. 4

1. 18 yrs of age or older who had been diagnosed through CT, MRI or PET with more one or more brain metastases less than 4 cm in diameter and had not received prior cranial irradiation, regardless of primary tumour histology and status or the presence of extracranial metastases. 2. Not reported

1. SRS allone or in combination with WBRT 2. conventional surgery and / or WBRT

1. -Based on the trend observed across studies it appears that the addition of WBRT to SRS does not improve survival. -None of the reviewed studies assessed health related quality of life. -Only one trial compared the functional independence following treatment between patients who received WBRT+SRS and those who received WBRT only. At 6 mo the WBRT+SRS was faring better

1+2. WBRT + SRS versus WBRT: In two trials, a statistically significant difference in local tumour control at 24 months was found (pooled HR (95% CI): 0.49 (0.33–0.74) p < 0.005)). Specifically, patients who received. One trial reported about the number of patients within each treatment arm whose cause of death was related to uncontrolled metastatic brain disease. The relative risk of neurologic death was indicating that there was no difference in the risk of neurologic death between treatment arms. Information on adverse events was collected in two trials. Andrews: no statistically significant difference in the incidence of acute or late toxicities between treatment arms. Kondziolka: concluded that there was ‘no neurologic or systemic morbidity related to SRS’. WBRT + SRS were 51% less likely to have lost local tumour control 24 months after treatment. WBRT + SRS and SRS alone were 91% and 62%, respectively. WBRT + SRS versus SRS: Local

1. B 2. No blinding used in the included studies





tumour control was not considered in the cohort study. The statistical significant difference in 12 month local tumour control between treatment arms in the trial led by Chougule et al. was not provided. Neurologic death. Neither Chougule et al. nor the cohort study reported the incidence of neurologic death.

1. Tsao MN et al, Whole brain radiotherapy for the treatment of multiple brain metastases, Cochrane Database of Systematic Reviews, 2006

1. Cochrane systematic review 2. Not reported 3. 1966-2007 4. CENTRAL, ,MEDLINE, EMBASE, CANCERLIT, CINAHL 5. Trials 6. 30

1. Adult participants receiving whole brain radiotherapy for multiple metastases to the brain from any primary cancer.2. Patient characteristics were extracted based on age, KPS and status of extracranial disease from the trials. Treatment characteristics were also extracted. If patient populations or treatment characteristics were deemed to be heterogeneous, we did not pool data for meta-analysis.

1. Altered whole brain radiotherapy dose fractioned schedules vs conventional WBRT fractioned schedules (3000cGy in 10 frac OR 2000 cGy in 5 frac) WBRT and systemic therapy WBRT plus radiosensitizers vs brain radiotherapy WBRT plus radiosurgery vs WBRT Radiosurgery alone or radiosurgery and WBRT Steroids alone vs Whole brain radiotherapy 2. for all groups except the first group of interventions the last named therapy is used as the control arm

1. No difference in survival at 6 mo was found. No significant difference was found in response rate between patients receiving only WBRT and those receiving treatment with WBRT and radiosensitizers. No sign. difference in tumor progression of brain specific quality of life was found. A higher proportion of participants in the efaproxiral arm had stable or improving quality of life scores and KPS as compared to participants treated with whole brain radiotherapy alone

1+2. All six studies that assessed the addition of radiosensitizers to whole brain radiotherapy reported serious adverse effects

1. A1 2. SWOT analysis done. Large sample size.

1. Varlotto et al, Analysis of tumor control and toxicity in patients who have survived at least on year after radiosurgery for brain metastases, International Journal of

1. Retrospective study 2. Not reported 3. University of Pittsburgh Medical Center 4. 844-->137 5. 1987 - 2001

1. Patients were eligible for radiosurgery if they had a KPS of 50 or more and if the metastasis had an avarage tumor diameter of 3,5cm or more.

1. Radiosurgery was performed with a gamma knife in all patients. The mean, peripheral, radiosurgical tumor dose was 16 Gy (range 12–25). The maximal doses varied

1. The actuarial rate of distal failure was 23% and 67,1% at one and 5 years respectively. The longest interval between radiosurgery and distal failure was 50 months.

1+2. Overall, local failure developed in 37 of the 208 tumours. Of the 137 patients, 17 experienced local failure alone, 48 experienceddistal intracranial recurrence

1. C. 2. Not reported. 3. Long inclusion period started a long time ago, small sample size as the total has been split up in the different subgroups.





Radiation Oncology Biology Physics, 2003

2. Age, KPS, Gender 3. Not described

between 24 and 50 Gy (mean maximal dose 32). Of the lesions, 151 were treated with the 50% isodose and 1, 2, 19, 1, 20, 13, and 1 were treated with the 45%, 55%, 60%, 65%, 70%, 80%, and 90% isodose line, respectively. 2. Not reported

Age, NSCLC and concomitant WBRT and SRS were factors correlated with distant intecranial relapse. The actuarial incidence of adverse events at 1 and 5 years was 2,8% and 11,4%.

alone and 3 experienced both local and distal failure. At 1 and 5 years, the actuarial local control rate was 89,6% and 62.8% respectively. No local recurrences developed after 37 months.

1. Weltman E et al, Radiosurgery for brain metastases: a score index for predicting prognosis, International Journal of Radiation Oncology Biology Physics, 2000

1. Retrospective study 2. Not reported 3. Hospital Isrealita Albert Einstein, Sao Paulo, Brazil. 4. 65 5. July 1993 - December 1997

1. Exclusion more than 5 lesions, any lesion larger than 30cm3, KPS less than 50, clinical evidence requiring urgent neurological intervention, or a very poor overall prognosis due to progressive systemic disease. 2. Sex, Primary tumours, KPS, age, Systemic disease status. 3. Not described

1. WBI was a 3000cGy total dose administred over 2 weeks (300 cGy/day, 5 days/week) for patients with KPS<70 and 4000cGy adminstred over 4 weeks (200cGy/day, 5days/week). The radiosurgery procedures followed the F. L. Fisher stereotactic treatment planning systemversions 2.21 and 3.1X, and were performed with a 6 MV linear accelerator (36, 38). One to 5 lesions were treated per patient, per treatment. The median prescribed dose was 18 Gy, calculated at 80% of the maximum dose in the grid calculation 2. Not reported

1. Survival ranged from less than 1 month to more than 65 months. Overall actuarial median survival was 6.8 months, with two living patients living 30 and 65 months after radiosurgery. Survival curves for WBI, metastatic brain lesion site, age, prim tumour histology did not demonstrate sign difference among subsets by log rank test. However the number of lesions and the largest brain lesion volume subset curves differed signif. Actuarial median survival was 10.29 months for patiens with KPS ≥ 80 and 3.46 months for those with KPS ≤ 70

1+2. RPA Kaplan Meier survival curve showed significant a difference between the three classes with the expected median survival for class 1 which is 20.19 months, 7.75 months for class 2 and 3.38 months for class 3. The actuarial median survival for the low SIR group is 2,91 months, 7 months for the intermediate SIR group and 31,38 months for the high SIR group

1. C. 2. Not reported 3. Small sample size, old data but not too long period, People were not per definition seperated in homogenous classes. The influences of other possible prognostic facors is not tested

3.3 SRS / neurochirurgische resectie met of zonder WBRT

I Study ID II Method III Patient characteristics IV Interventions V Results primary

outcome VI Results secondary and other outcome(s)

VII Critical appraisal of study quality





1. Fife KM et al, Determinants of outcome in melanoma patients with cerebral metastases. Journal of Clinical Oncology, 2004

1. Retrospective 2. Not reported 3. Multi-centre 4. 1137 patients 5. 1952 - 2000 (follow-up until 2003)

1. Presence of cerebral metastases, treated at the Sydney Melanoma Unit from 1952 to 2000 2. Age, sex, date of primary melanoma diagnosis, Breslow thickness, presence of extracranial metastases, number of cerebral metastases, radiotherapy dose, details of surgery 3. Cohort 1952-1984 vs. cohort 1985-2000

1. Surgery (craniotomy with macroscopically complete excision, subtotal resection or biopsy), postoperative radiotherapy, (palliative) WBRT --> dose range = 4 - 60 Gy in 5 or 10 daily fractions 2. Not reported

1. Cohort 1952-1984 - 12 Pts (3%) had surgery and radiotherapy; - Median survival = 11.5 months; Cohort 1985-2000 - 158 Pts (24%) had surgery and radiotherapy;- median survival = 8.9 months

1+2. Treatment modality, systemic disease activity, performance status

1. B 2. Not reported 3. Retrospective, small sample size pts concerning group who received radiotherapy in cohort 1952-1984, did dosage radiotherapy varied over time?

1. Fowler A et al, Survival of patients following neurosurgical treatment of colorectal adenocarcinoma metastasis in the Northern Sydney-Central Coast area. Journal of Clinical Neuroscience, 2008

1. Retrospective 2. The authors acknowledge the support of Sydney Neuro-Oncology group in preparation of this study 3. Northern Sydney / Central Coast Area Health Service 4. 32 Patients 5. 1999 - 2007 (follow-up until first of May, 2007)

1. Patients with diagnosis of craniotomy for metastasis from colorectal adenocarcinoma (histopathological diagnosis) from 1999 onwards; either admitted by a neurosurgeon or had an inpatient referral and care of a neurosurgeon with a therapeutic intent; patients who were admitted to the neurosurgical unit with an established diagnosis or a likely diagnosis of CNS colorectal metastasis on clinical grounds and not specifically undergoing resective surgery; patients undergoing cerebrospinal fluid (CSF) diversion or tumor cyst drainage 2. Age, sex, location primary tumor, KPS, multiplicity, diameter of lesion, neurosurgical intervention, WBRT 3. Treated with WBRT vs. untreated with WBRT

1. Not reported 2. Not reported

1. 16 Patients received radiotherapy after surgical intervention --> 13 pts had WBRT only, 1 pt WBRT combined with stereotactic radiosurgery and 2 pts WBRT combined with localised field radiotherapy; median survival of pts who had WBRT = 10.6 months as compared to pts without adjunct radiotherapy (5.2 months)

1+2. Not reported 1. C 2. 16/32 Patients received WBRT after surgery 3. Small sample size, treatment primary tumors (and/or stage) in other institutions (no correction possible), no description about the dosage of WBRT (reproducibility?)





1. Korinth MC et al, Prognostic Factors for Patients with Microsurgically Resected Brain Metastases. Onkologie, 2002

1. Retrospective 2. Not reported 3. Department of neurosurgery of the University Hospital Aachen 4. 187 Patients 5. July 1989 - September 1996 (duration follow-up 3 months to 7 years after inclusion)

1. Surgical resection of brain metastasis 2. Sex, age, localisation primary tumor, duration neurological symptoms, preoperative KPS, extra-cerebral tumor progression 3. Not reported

1. Mean total dose = 32 (16-61) Gy, administered in single doses of 2 (1.3-3) Gy 2. Not reported

1. 111/187 Pts = postoperative WBRT; - Actuarial survival = 11.2 months (compared to 5.6 months (no postoperative WBRT) and 11.8 months (unknown whether postoperative WBRT

1+2. Localisation metastasis, primary tumor, KPS, absence extracerebral tumor progression, stable disease

1. C 2. No loss to follow up reported 3. Retrospective, old data

1. Nieder C et al, The Role of Postoperative Radiotherapy after Resection of a Single Brain Metastasis; combined Analysis of 643 Patients. Stahlentherapie und Onkologie, 2007

1. Systematic review 2. Not reported 3. Multi-centre 4. 10 Publications, 643 pooled patients 5. 1990 - 2006 (follow-up until June 1, 2007)

1. Key words: "resection or neurosurgery", "brain metastases, cerebral metastases or secondary brain tumo(u)r", reference list of all articles --> all publications reporting on patient groups with single brain metastases + clearly defined radiation doses and evaluation of the brain relapse pattern 2. Not reported

1. Relapse after (in)complete resection with WBRT vs. relapse after (in)complete resection without WBRT 2. Not reported

1. After additional radiotherapy (224 patients from 3 studies, all had complete resection) = 28 pts developed local relapse

1+2. No significant dose-response relationship

1. B 2. No information about patient characteristics (can patients be pooled?), quality assessment separate studies not described, most studies included are observational

1. Paek SH et al, Reevaluation of surgery for the treatment of brain metastases: review of 208 patients with single or multiple brain metastases treated at one institution with modern neurosurgical techniques. Neurosurgery, 2005

1. Retrospective 2. Not reported 3. Department of Neurosurgery at Thomas Jefferson University Hospital, Philadelphia 4. 208 Patients 5. March 1995 - December 2002 (duration follow-up until May 2003)

1. Single or multiple brain metastases, underwent craniotomies 2. Age, sex, location primary cancer, systemic disease, symptoms (presenting), preoperative treatments, KPS, RTOG 9508-eligibility, brain tumor location, tumor size3. Not reported

1. Surgery 2. Not reported

1. 146 Pts / 208 pts were treated with radiation therapy (WBRT and/or stereotactic radiosurgery (SRS))

1+2. - Median survival time of surgery = 8 months; - Treatment with postoperative radiotherapy =survival time of 9.1 months versus no postoperative radiotherapy (0.8 months)

1. B 2. No lost to follow up reported 3. Moderate sample size, no blinding at outcome assessment

1. Patchell RA et al, Postoperative Radiotherapy in the Treatment of Single Metastases to the Brain: A Randomized Trial. JAMA, 1998

1. Prospective randomised trial 2. Not reported 3. Multi-centre, university-affiliated cancer treatment facilities 4. 146 Eligible patients of whom 51 were not randomised due to refusal and physician preference

1. Inclusion at least 18 years old who had a tissue-proven diagnosis of metastatic brain tumor obtained from a complete resection of a single brain metastasis exclusion patients with incomplete removed brain metastases by surgery,

1. RT was started within 28 days after surgery; 50.4 Gy / 5.5 weeks (1.8 Gy x 28 fractions) 2. No RT

1. Recurrence rate of tumor anywhere in the brain in radiation group = 18% vs 70% in observation group; recurrence rate at original BM was lower in radiation group than in observation group (10% vs. 46%); - Time to any brain

1+2. - Survival times were not significantly different between both groups - Time between diagnosis of primary tumor and development of BM was increased with increased survival - Postoperative radiotherapy prevented

1. A2 2. None were lost to follow-up 3. Old dataset, high quality study design, reproducibility study high, small sample size





for specific treatment --> 95 patients in study 5. September 1989 - March 1997 (follow-up until November 1, 1997)

evidence of leptomeningeal metastases, history of previous cranial radiotherapy, need for immediate treatment to prevent acute neurologic deterioration, concomitant second malignancies, KPS < 70%, presence of radiosensitive primary tumors 2. Sex, age, KPS, primary tumor location, extent of disease, time between diagnosis primary tumor and development BM, location BM 3. Observation (surgery only) group versus radiation group (surgery + WBRT).

recurrence or to original BM site was longer in radiation group vs observation group

death due to neurologic causes (14% vs 44%) - No difference between the two groups in maintaining functional independence

1. Rades D et al, A matched-pair analysis comparing whole-brain radiotherapy plus stereotactic radiosurgery versus surgery plus whole-brain radiotherapy and a boost to the metastatic site for one or two brain metastases. International Journal of Radiation Oncology, Biology and Physiology, 2009

1. Retrospective 2. Not reported 3. Not reported 4. 94 Patients 5. 1996 - 2007 (duration follow-up time not described)

1. One or two brain metastases (diameter ≤ 4 cm) treated with either WBRT+SRS or OP+WBRT+boost, RPA-class 1 and 2, no prior radiotherpay or surgery to the brain, confirmation of metastases by CT or MRI, administration of dexamethasone (12-32 mg/d) during WBRT 2. Age, sex, WBRT schedule, ECOG performance score, primary tumor, nr of brain metastases, extracerebral metastases, RPA-class, interval first diagnosis of tumor to WBRT 3. WBRT+SRS versus OP+WBRT+boost

1. WBRT: either 10x3 Gy in 2 weeks or 20x2 Gy in 4 weeks; SRS: linear accelerator-basedSRS or as Gamma Knife SRS --> 15-25 Gy in a single fraction 2. Not reported

1. - Survival: WBRT+SRS = 15 months versus OP+WBRT+boost = 25 months; mulitvariate analyses: ECOG-PS, extracerebral metastases, RPA-class, interval from tumor diagnosis to WBRT = prognostic values - No statistical difference in intracerebral and local control beween WBRT+SRS and OP+WBRT+boost

1+2. Not reported 1. B 2. No lost to follow-up reported 3. Matched-pair analyses used for decreasing selection bias, retrospective, good performance patient group (external validity?)





1. Roos DE et al, Whole brain irradiation following surgery or radiosurgery for solitary brain metastases: Mature results of a prematurely closed randomized Trans-Tasman Radiation Oncology Group trial (TROG 98.05). Radiotherapy and Oncology, 2006

1. Phase III, prospective controlled trial 2. Not reported 3. Multi-centre (6 centres)4. 19 Patients 5. 7 August 1998 - 5 April 2000 (follow-up until 24 November 2005)

1. Inclusion MRI prior to surgery or radiosurgery showing a solitary (presumed) brain metastases from an extra-cranial primary malignancy with complete surgical excision or RS within 6 weeks of registration; post surgery/RS WHO performance status ≤ 2 and age ≥ 18 exclusion primary brain tumor, small cell lung cancer, seminoma, lymphoma, myeloma or leukaemia, macroscopic residual disease following surgery, meningeal disease, life expectancy due to extra-cranial disease predicted to be less than 6 months, prior brain radiation 2. Sex, age, primary cancer, site of BM, WHO performance status, RTOG recursive partitioning analysis class, overall health/QOL, mini-mental state score 3. Whole Brain Irradiation vs observation group

1. RT was to commence within 2 weeks of randomisation; 36 Gy in 18 fractions (3 Gy/fraction and 5 fractions per week) --> 11 months after trial activation the fractionation was amended to 30 Gy in 10 fractions over 2 weeks 2. No RT

1. Median failure-free survival = 5.7 versus 4.5 months in WBI and observation group (not statistical signifcant); - 3/10 Patients (WBI group) CNS relapse vs 7/9 patients (observation group) - Median progression-free survival = 4.3 versus 4.5 months and median overall survival = 9.2 verus 6.2 months in WBI versus observational (not statistical significant)

1+2. 2 Probable cases of late CNS toxicity in WBI-arm

1. B 2. None were lost to follow-up 3. Small sample size due to unacceptable low accrual rate, randomisation method not described, external validity ↓

1. Salvati M et al, Solitary brain metastases from non-oat cell lung cancer: clinical and prognostic features. Neurosurgery reviews, 1996

1. Case serie 2. Not reported 3. Neurosurgical Division of Rome 'La Sapienza' University 4. 91 Patients 5. 1975 - 1990 (duration follow-up not described)

1. Inclusion solitary lesion documented by CT scan without/with contrast enhancement and, more recently, by MRI without/with gadolinium; Karnofsky Performance Status (KPS) rating higher than 60; surgically approachable lesion; presence of a silent or

1. Radiotherapy: varying techniques were used --> Gamma-Knife, Whole brain = 30 Gy in 2 weeks, 40-45 gy in 4/5 weeks 2. Not reported

1. The various techniques of radiotherapy produced different collateral effects

1+2. Not reported 1. C 2. No lost to follow-up reported 3. Retrospective, descriptive, small sample size and long inclusion period, different techniques of radiotherapy --> results valid?, old study





therapeutically controlled systemic tumor in those cases where it was brought to light by immediate clinical staging2. Sex, age, asymptomatic/symptomatic brain metastases, staging primary tumor, KPS 3. -

1. Soltys SG et al, Stereotactic radiosurgery of the postoperative resection cavity for brain metastases. International journal of Radiation Oncology, 2008

1. Retrospective 2. Dr. Adler is a shareholder and member of the board of directors of accuracy, Inc., manufacturer of the Cyberknife radiosurgical system; Dr. Gibbs is a nonpaid member of the Clinical Advisory Board of the same company 3. Stanford University Medical Center 4. 72 Patients 5. 1998 - 2006 (duration follow-up until death)

1. Inclusion brain metastases surgically removed resection cavity subsequently was treated with radiosurgery exclusion receivement of immediate WBI after surgery and postsurgical SRS without indication of cranial progression because of referring physician preference or small-cell lung carcinoma histologic state on final pathologic examination, underwent previous WBI or any other form of cranial external beam irradiation 2. Age, sex, KPS, RPA-class, management primary tumor, presence extracranial metastases, pathologic state, total no. of metastases, extent of surgical resection 3. Not reported

1. SRS: prescribed to a median marginal dose of 18 Gy to the median 79% isodose line 2. Not reported

1. 10/69 Cavities = local failure --> crude overall local tumor control rate = 86% - Conformality index and modified conformality index = significant predictors of local failure - Distant failure = 32/65 pts (49%) - 7 Patients died before first MRI follow-up - 34/72 Pts (47%) had died at last follow-up - Median overall survival 15.1 months

1+2. 7 Pts = symptomatic posttreatment edema

1. C 2. No lost to follow-up reported 3. Multiple treating physicians, descriptive, solely good performance patient group (external validity ↓)

1. Tsao MN et al, Radiotherapeutic management of brain metastases: a systematic review and meta-analysis. Cancer Treatment Reviews, 2005

1. Systematic review 2. Not reported 3. 1966 - 2004 4. MEDLINE, CANCERLIT, CINAHL, EMBASE, Cochrane library

1. Inclusion (design) published randomized or quasi-randomized controlled trials (abstracts also eligible), (population) adult patients with single and multiple brain

1. Single brain metastases - WBRT + surgery versus WBRT alone - Surgery + WBRT versus surgery alone - WBRT alone versus

1. For patients with single brain metastasis, good performance status, and minimal or no evidence of extracranial disease, surgical excision and post-operative WBRT

1+2. Recurrence: 18% of 49 patients in the surgery and radiation group versus 70% of 46 patients in surgery-group alone (p < 0,001)

1. B 2. No lost to follow up reported 3. Assessment study quality moderately performed (complete assessment in article





5. published randomised or quasi-randomised controlled trials 6. 27 Trials

metastases from cancer of any histology, (intervention) external beam radiotherapy or radiosurgery in one study arm, (outcomes) survival, intracranial progression-free duration, response of brain metastases to therapy, quality of life, symptom control, neurological function, toxicity exclusion studies that used prophylactic radiotherapy for brain metastases; phase I or II, bacause of the availibility of randomized controlled trials; published in languages other than English 2. Not reported

WBRT + radiosurgery boost (WBRT: 3000cGY/10 fractions; 4000cGy/20 fractions; 3600 cGy/12 fractions) 2. Not reported

improves survival 'Clinical Practice Guidelines…..of brain metastases'); small sample size subgroup single brain metastases; results heterogeneous, therefore caution for pooling data

1. Wronski M et al, Surgical resection of brain metastases from renal cell carcinoma in 50 patients. Urology, 1996

1. Retropective 2. Not reported 3. Memorial Sloan-Kettering Cancer Centre 4. 709 Consecutive patients with resected brain metastatic brain tumors --> 50 patients with metastatic RCC 5. January 1974 - December 1993 (duration follow-up until December 30, 1994)

1. Metastatic RCC 2. Age, sex, intratumoral hemorrhage diagnosed, onset BM, localisation tumor in kidney, presence lung metastases, nr and location of metastases, median survival time 3. Not reported

1. WBRT: average dose = 3000 cGy (range 2000 to 5700 cGy) and delivered in 10 to 15 fractions 2. Not reported

1. 22/50 Pts received WBRT postoperatively

1+2. Median survival for pts with WBRT (N=22) = 13.3 versus 14.5 months for pts who did not receive WBRT (N=18)

1. C 2. No lost to follow-up reported 3. Descriptive, retrospective, small sample size





1. Wronski M et al, Surgical treatment of brain metastases from melanoma: a retrospective study of 91 patients. Journal of Neurosurgery, 2000

1. Retrospective 2. None reported 3. Single institution 4. 780 Patients with resected brain metastatic brain tumors --> 91 patients 5. January 1974 - December 1994 (duration follow-up: minimum of 24 months)

1. Resection of metastatic brain tumors at MSKCC, presence of parenchymal brain metastases from primary melanoma tumors2. Age, sex, presence lung metastases, nr and location of metastases, diameter metastasis, WBRT, brain recurrence, carcinomatosis meningitis, median survival time 3. Not reported

1. Not reported 2. Not reported

1. Median length of survival was 9.5 months in patients receiving WBRT (N=49) compared with 8.3 months in 29 patients who did not receive WBRT after surgery

1+2. Not reported 1. C 2. No lost to follow-up reported 3. Descriptive, retrospective, two imaging techniques used (misclassification?), small sample size

1. Zacest AC et al, Surgical management of cerebral metastases from melanoma: outcome in 147 patients treated at a single institution over two decades. Journal of Neurosurgery, 2002

1. Retrospective 2. Not reported 3. Department of Neurosurgery at the Royal Prince Alfred Hospital 4. 147 Patients 5. January 1979 - March 1999 (duration follow-up until death of for a minimum of 6 months)

1. Histologicalle proven cerebral metastases from melanoma, surgical treatment 2. Age, sex, primary lesion characteristics, symptoms at presentations, nr and diameter of metastases, location of meteastasis, extracranial metastases and its extent 3. Not reported

1. Craniotomy and tumor excision, WBRT within 2 weeks of surgery (most common WBRT regimen was 30 Gy in 10 fractions, but regimens ranged from 20 Gy in 5 fractions to 45 Gy in 25 fractions) 2. Not reported

1. - 92% Received postoperative WBRT; - 69% Of the patients had postoperative WBRT, 1% had WBRT and SRS and 22% had postoperative WBRT followed by chemotherapy; - Survival postoperative WBRT = 9 months; - Survival postoperatieve WBRT+SRS = 5 months;- Survival postoperative WBRT and chemotherapy = 11 months

1+2. Not reported 1. C 2. No patient was excluded 3. Partly old data, long inclusion period, varied WBRT regimens, heterogeneous patient group when considering primary tumor en treatment regimens

Date post:	08-Mar-2018
Category:	Documents
Upload:	dinhnhi
View:	219 times
Download:	3 times

3.3 SRS / neurochirurgische resectie met of zonder WBRT hfdst... · increase of steroid medication,...

Documents