LA RADIOTERAPIA DEL CARCINOMA DEL PANCREAS - Dott... · LA RADIOTERAPIA DEL CARCINOMA DEL PANCREAS...

LA RADIOTERAPIA DEL

CARCINOMA DEL PANCREAS

Paolo AntognoniPaolo AntognoniU.O. RADIOTERAPIA

Ospedale di Circolo e Fondazione MacchiVARESE

Nadia Di Muzio Nadia Di Muzio U.O. RADIOTERAPIA

IRCCS Ospedale San RaffaeleMILANO

ROLE OF RADIATION THERAPY IN THE MANAGEMENT OF PANCREATIC CANCER:

NEW CHALLENGES FOR AN OLD PARADIGM

• Literature Review and Clinical Controversial Issues(P. Antognoni)

• Advances in Radiation Therapy Techniques and The Contribution of Novel Technologies

(N. Di Muzio)

LA RADIOTERAPIA DEL


RADIOTHERAPY IN THE MANAGEMENT RADIOTHERAPY IN THE MANAGEMENT

OF PANCREATIC CANCER OF PANCREATIC CANCER

BACKGROUND

5-year overall survival for all stages combined: 5%

Only mild improvement of trend in 5-yr relative survival rates (U.S. data): from 3% (1975-1986) to 6% (1999-2005)

At autopsy 30% of pts died with locally destructive pancreatic cancer: local failure is still a major cause of death and a main component of disease progression

The incorporation of systemic chemotherapy into the management of this disease is standard of care at all stages

The role of radiation therapy is less clear and represents a still controversial issue

J. Surg. Oncol. 2012 Wiley Periodicals, Inc

DOI 10.1002/jso.23137

• Adjuvant CHT-RT for resectable disease

• Neoadjuvant CHT-RT forresectable/borderline resectable disease

• “Radical” RT±CHT for locally advancedunresectable pancreatic cancer (LAPC)

• Palliative RT±CHT for LAPC

• RT for isolated local recurrence


DOI 10.1002/jso.23137 RADIOTHERAPY IN THE MANAGEMENT RADIOTHERAPY IN THE MANAGEMENT

OF PANCREATIC CANCER OF PANCREATIC CANCER SEVERAL CLINICAL SETTINGS (MOSTLY IN

CONJUNCTION WITH CHEMOTHERAPY)


DOI 10.1002/jso.23137

RADIOTHERAPY IN THE MANAGEMENT OF PANCREATIC CANCER

ADJUVANT CHT-RT: RANDOMIZED TRIALS(RCT)

The largest RCT

Established adjuvant CHT-RT as new

standard of resectable PC in the US:

the highest median survival

Survival detriment in

CHT-RT arm

Trend for surv. benefit

PARADOXICAL RESULTS IN TERMS OF SURVIVAL IMPROVEMENT WITH ADJUVANT CHEMO-RT!

• The GITSG, EORTC and ESPAC-1 studies utilized what isnow known to be an inferior radiation treatment schedule, asit is now believed that the treatment break in split-courseschedules allows for tumor repopulation and subsequentlypoorer outcomes

• These studies also failed to include quality assurance for the radiation treatments, a factor we now know to be associatedwith treatment deviations and poorer outcomes in numerousdisease sites including pancreatic cancer

• Finally, the radiation delivered in these trials utilizedsignificantly larger fields and target volumes than are currently used (more toxicity).

RADIOTHERAPY IN THE MANAGEMENT OF

PANCREATIC CANCER

ADJUVANT CHT-RT: CRITICISM OF RCT


DOI 10.1002/jso.23137 RADIOTHERAPY IN THE MANAGEMENT OF PANCREATIC CANCER

ADJUVANT CHT-RT: NON-RANDOMIZED TRIALS

SOME ADDITIONAL BENEFIT TO THE POTENTIAL BENEFIT OF ADJUVANT CHEMO-RT (45-50.4 Gy continuous course)

1.092 PTS

• To avoid delays in adjuvant therapies by administering treatment before surgery

• Higher chances of delivering full-dose chemo and/or RT

• Avoid major surgery in pts who show local/systemic PD duringneoadjuvant treatment

• Potential downstaging of borderline resectable disease and increased rate of R0 resection

• Preoperatve treatment less toxic (less small bowel inside RT fields, higher tumor oxygenation and increased drug delivery than in postoperative setting)


RATIONALE OF NEOADJUVANT CHT-RT


DOI 10.1002/jso.23137

NEOADJUVANTNEOADJUVANT APPROACH MAY BE APPROACH MAY BE BENEFICIALBENEFICIAL FOR A SUBSET OF THE FOR A SUBSET OF THE

PATIENT POPULATION, AND PARTICULARLY PATIENT POPULATION, AND PARTICULARLY FOR THOSE WITH BORDERLINE FOR THOSE WITH BORDERLINE

RESECTABLE DISEASE:RESECTABLE DISEASE: BUT THER ARE NO RANDOMIZED STUDIES!BUT THER ARE NO RANDOMIZED STUDIES!


DOI 10.1002/jso.23137


PANCREATIC CANCER NEOADJUVANT CHT-RT: the MDACC Phase II Trials of

Preoperative Concurrent Chemo-RT for resectable PC

First phase II trials of neoadjuvant 5FU-based chemoRT ± IORT (1992-

2006)

Rapid-fractionation preoperative chemoRT: promising results in

resectable pts (3-yr OS: 23%)

No advantages to paclitaxel-based preoperative treatment


DOI 10.1002/jso.23137 RADIOTHERAPY IN THE MANAGEMENT OF

PANCREATIC CANCER NEOADJUVANT CHT-RT: NON-RCT FOR

BORDERLINE RESECTABLE PC

33%-64% of pts with borderline resectable cancers underwent surgical resection

Rate of R0 resections: 87%-100%

Small numbers of pts, but good potential for down staging of borderline resectabletumors to achieve R0 resection with CHT+RT tot. doses of 45-56 Gy or equivalent.

2001-2011 selected non-randomized trials


ONGOING AND RECENTLY COMPLETED

ADJUVANT/NEOADJUVANT TRIALS (CHT± RT)

Subset analyses of RTOG 0848 may provide additional

data that may help stratify patients who could benefit

from adjuvant radiation, leading to more personalized

treatment regimens;

NEED OF PERSONALIZED TREATMENT REGIMENS!


ADJUVANT RT: ONGOING Phase III RTOG 0848 TRIAL EVALUATING BOTH ERLOTINIB AND CHEMO-RT

RTOG 0848 will provide additional prospective randomized

data to help clarify whether adjuvant radiation adds benefit to

patients undergoing pancreaticoduodenectomy

• Adjuvant and Neoadjuvant chemoRT regimens usually

demand daily RT treatment for 5-6 wks, a significantburden on pts with life expectancies typically <1yr

• Neoadjuvant therapy can delay the only potentiallycurative procedure for pts with resectable lesions



PANCREATIC CANCER ADJUVANT & NEOADJUVANT CHEMO-RT:

Drawbacks

Potential for “short-course” chemoRT like those experimentedin the MDACC trials, but with more effective radiations: the case for Neoadjuvant Hypofractionated Proton Therapy!

A proton radiotherapy schedule consisting of 5 fraction of 5 CGE as part of neoadjuvant therapyfor adenocarcinoma of the pancreas seems

dosimetrically feasible, providing excellent

target volume coverage, dose homogeneity, and normal tissue sparing.

Hypofractionated Proton Radiotherapy in thissetting merits Phase I clinical trial investigation.

2007 dosimetric study

2011 Phase I study


PANCREATIC CANCER NEOADJUVANT RT: Short-course Proton Therapy (PRT)

Neoadjuv. short-course PRT+Capecitabine is feasible:

a phase II study is underway

R0 resection rate: 82%

15 pts, with localized

resectable PC of the head

Preoperative chemoRT with1wk PRT+Capecitabinefollowed by early surgery (1-3 wks)


DOI 10.1002/jso.23137

RADIOTHERAPY IN THE MANAGEMENT OF PANCREATIC

CANCER

“RADICAL” RT ± CHT FOR UNRESECTABLE LAPC:

Prospective Randomized Trials

Rationale for chemoRT in LAPC: only option when the chances of negative margins after surgery are low

Few randomized studies with low number of pts over a long time

Combined treatment with chemoRT increases median survival to approx. 9-13 months, but rarely resultsin long-term survival: many pts develop metastatic disease soon after diagnosis and receive little benefit

Initial Chemotherapy followed by restaging and then ChemoRT only for those pts with no evidenceof metastatic progression: promising approach!


DOI 10.1002/jso.23137


BRACHYTHERAPY & IORT FOR LAPC

•• IntraoperativeIntraoperative BrachyBrachy (I(I--125, AU125, AU--198, Pd198, Pd--103):103): manysmall studies, low median survivals (7-15 wks), LC in the range of 65%, but…”complication rates felt to beunacceptably high”!

•• IORT: IORT: no clear survival benefit added by IORT in the setting of resectable PC. In the US it is still used in ptswith unresectable disease without demonstrated benefitsin survival or disease-free progression.

VERY LIMITED INDICATIONS IN THE ERA OF HIGHVERY LIMITED INDICATIONS IN THE ERA OF HIGH--DOSE DOSE

CONFORMAL STEREOTACTIC BODY RT AND IGCONFORMAL STEREOTACTIC BODY RT AND IG--IMRT! IMRT!


PANCREATIC CANCER

PALLIATIVE IRRADIATION OF LAPC


DOI 10.1002/jso.23137

• In the palliative setting the median survival time is notsignificantly affected by a higher RT dose

• Compared with higher doses given over 5-6 wks, chemoRT (30 Gy/10 fract./2 wks + concurrent infusion5FU) results in similar median survival and local disease-progression rates

• Higher RT doses can lead to increased acute treatment-related morbidity

RECOMMENDED SCHEDULE:

30 Gy in 10 fractions + i.v. 5FU

• Chemoradiotherapy (3DCRT: 45 Gy in 25 fractions of 1.8 Gy/day + 5FU) is feasibleand may be an effective treatment optionalso in those patients who present withisolated local metastasis after primarysurgery for pancreatic cancer.

Wilkowski R, Thoma M, Bruns C, et al.: Combined chemoradiotherapy for isolated

local recurrence after primary resection of pancreatic cancer. JOP 2006;7:34–40.


RT FOR ISOLATED LOCAL RECURRENCE


DOI 10.1002/jso.23137



PANCREATIC CANCER

“RADICAL” STEREOTACTIC BODY RT (SBRT) FOR LAPC

SEVERAL TRIALS BUT NO

ESTABLISHED STANDARD FOR SBRT

DOSE/FRACTIONATION FOR LAPC.

MORE COMMON RANGE: 25 Gy single

fraction / 45 Gy in 3 fract. DOSE-RESPONSE EFFECT AND INCREASED LOCAL CONTROL

RIGOROUS QUALITY CONTROL TO MINIMIZE TOXICITY to OARs: (duodenum and stomach)



PANCREATIC CANCER

IMRT FOR LAPC

Several studies have demonstrated the feasibility of IMRT in pancreatic cancer and have shown promising results especially withIG-IMRT: potential for dose-escalation with less toxicity!


PANCREATIC CANCERNEW RESEARCH STRATEGIES AND REMAINING

CHALLENGES WITH RADIATION THERAPY

Pancreatic cancer is in general a tumour with a large stromal component and therefore less likelyto shrink radiologically, despite a possibleresponse from cancer cells. Functional imaging may be more appropriate tomeasure response for LAPC.

A major methodological flaw of preoperativechemoRT studies is that none of them israndomized and they all report the results ofthe subset of patients who actuallyunderwent a resection, rather then reportingby intention to treat

Despite the aforementioned methodological shortcomings,

literature appears to indicate that preoperative chemoRT in

borderline resectable and presumably also primarily resectablepancreatic cancer may improve resection rate, R0 resection rate

and possibly overall survival.This hypothesis is valid and should be tested in randomizedprospective studies.

• Conflicting results from randomized studies• No general standard of care• Optimal treatment both curative and palliative is complex and needs a

multidisciplinary team• Adjuvant and Neoadjuvant treatments in pts with resectable PC need

more prospective trials• Newer RT techniques may increase the therapeutic benefit by higher RT

doses that may improve local control• Need of further studies focusing on the molecular pathways involved in

the carcinogenesis and progression of this disease• Molecular markers will begin to be used routinely as prognosticators and

may guide personalized therapeutic decisions


PANCREATIC CANCER

CONCLUSION FROM THE LITERATURE ANALYSIS ON

THE ROLE OF RADIATION THERAPY


DOI 10.1002/jso.23137


PANCREATIC CANCER

CONTROVERSIAL CLINICAL ISSUES:

CTV DELINEATION & OARs DOSE-CONSTRAINTS


PANCREATIC CANCER:

PROBLEMS WITH CTV CONTOURING

Computed tomography scans significantly under-

represent pancreatic cancer tumor size compared

with pathologic specimens in resectable cases

PITFALLS IN CTV

CONTOURING

We found that nearly 60% of all tumors in the proximal pancreas (head, neck, or

uncinate process) had pathologic invasion into the duodenum, despite rare evidence

of duodenal invasion on preoperative CT and no cases seen on EUS


PANCREATIC CANCER:


The high rate of pathologic duodenal invasion suggests a riskof duodenal undercoverage with highly conformal radiotherapy

CTV primary expansion formulaA linear regression analysis was performed to relate

primary tumor size on preoperative CT scan to size on

pathologic specimen.


PANCREATIC CANCER:


CTV primary expansion formula

A linear regression analysis was performed to relate primary

tumor size on preoperative CT scan to size on pathologic

specimen.

16 mm+(0:75 x CT maximum tumor size in

millimeters) = Pathologic maximum tumor

size in millimeters

97.5% of pathologic tumor covered!


PANCREATIC CANCER

OARs DOSE-CONSTRAINTS FOR PANCREAS RT

Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC).

IJROBP, Volume: 76, Issue: 3, Supplement March 1, 2010

The current dose-constraints to OARs are defined according to the QUANTEC document and are related to specificclinical toxicity endpoints, depending also on the irradiation technique & dose fractionation (3D-CRT/IMRT/SBRT).

OO

AA

RR


PANCREATIC CANCER

CTV & OARs DELINEATION

CONTOURING

ATLASES AND LIBRARIES FOR

OARs

SEGMENTATION

A Whipple procedure was performed, the pathology showed a 1.3 cm moderately differentiated invasive adenocarcinoma in the pancreatic head with lymphovascular invasion. The marginswere negative; however, 1 of the 15 lymph nodes sampled waspositive. His CA19-9 was less than 3 preoperatively, indicatingthat he quite likely did not produce this marker.• He was staged as pT1N1M0 (AJCC Stage IIB)• The patient was referred for adjuvant chemoradiation


PANCREATIC CANCER

CTV & OARs DELINEATION

SEVERAL CTVs

ACCORDING TO

SURGICAL

PROCEDURE AND

DISEASE STAGE

Nadia Di Muzio

ADVANCES IN RADIATION THERAPY

TECHNIQUES AND THE CONTRIBUTION OF

NOVEL TECHNOLOGIES:

EXPERIENCE OF THE IRCCS SAN RAFFAELE

LA RADIOTERAPIA DEL


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