SBRT in Pancreas Cancer Role of The Radiosurgery Society Anand Mahadevan MD FRCS FRCR Chairman Division of Radiation Oncology Geisinger Health System, Danville, PA, USA. Past President and Chairman: The Radiosurgery SocIety
Objectives Current role of radiation in Pancreas Cancer Role of local control SBRT for pancreas cancer Clinical scenarios for exploring future role
Clinical Scenarios in Pancreas Cancer Resectable Pancreas cancer Neoadjuvant SBRT Adjuvant SBRT Borderline resectable Pancreas Cancer Locally advanced Metastatic Pancreas Cancer Oligometastatic Pancreas Cancer Local recurrence
Resected Pancreas Cancer ChemoRT vs. Observation ChemoRT Improves Overall Survival vs Observation GITSIG Study Significant Increase in Med Survival (20m vs 11m) Significant increase in 5-yr Survival (18% vs 8%)
R1 resection = Poor Survival
Post OP R1 Resection Fiducials placed at surgery One planning CT with oral and IV contrast 1000cGy to +ve margins 3-4 weeks post OP 5040cGy 5-6 field IMRT6-8 weeks postop Concurrent Xeloda Adjuvant Gemcitabine
Negative Margins vs. Positive Margins + SBRT Boost Median Survival 27m vs. 29.5m 2yr Survival 51.3% vs.50.4% 4yr Survival 37% vs. 42% p=0.7881
P=0.0002 Local Control
Results Summary Cohort N Median Survival (months) 2-Year Survival (Actuarial) 5-Year Survival (Actuarial) Overall 157 22 45% 24% Negative Margins (R0) 95 27 51% 28% Positive Margins (R1) 62 19.5 36% 17% Untreated 20 14 16% Chemo/RT 19 19.5 36% Chemo/RT + CK 23 29.5 50%
ESPAC 4 Adjuvant Gem vs GemCAP Primary endpoint OS 2008-2014, 730 pts, Med age 65yrs 60%R1, 80% N=, 40% Poorly differentiated Med OS: 28m v 25.5m p=0.032 5% yr Survival: 29% vs 16 % No diff in Grade ¾ Toxicity.
ESPAC4 Patterns of Failure
High Risk Post OP R1 +ve margin T3/4 (size) N+ Poorly differentiated Post OP CA19-9 > 92.5
RSS Multi Institutional Study Phase II III study Phase II single arm ESPAC4 + SBRT (5 treataments) If >70% survive 1 year then move to Phase III ESPAC4 +/- SBRT 6 Cycles Gem/Cape with SBRT between Cycles 1 and 2
Adjuvant Post Op SBRT 1 Cycles of Gem-Cape Plan SBRT during cycle 1 5 Fractions in week off between cycles 1-2 5Gyx5 to Tumor bed (7Gy dose painting to R1) Continue systemic therapy upto 6 cycles
Total Neoadjuvant Therapy Total Neoadjuvant Therapy (TNT) Neoadjuvant Chemo and Surgery (NeoC-S) Neoadjuvant Chemo and SBRT (NeoC-SBRT) Chemo Chemo Chemo SBRT Surgery Surgery SBRT
Results Overall Survival Treatment Group Number Median Overall Survival (Months) TNT 25 36.5 NeoC-SBRT 49 19.3 NeoC- Surgery 6 22.2 p=0.1 7 p=0.03 p=0.98
Neoadjuvant PreOp SBRT Short course 5 treatments 5Gyx5 with Dose painting 7Gy to vascular margins Surgery within 4 weeks after SBRT Radiation naive tissue in reconstruction Continue standard of care systemic therapy Room for salvage RT at recurrence
Locally Advanced Pancreas Cancer
Classic Trials: RT vs. ChemoRT and Chemo vs. ChemoRT
Modern Chemo-radiation Trials Trial Treatment No of Pts Med OS RTOG 9812 50.4Gy+Taxol 122 11.3m RTOG 0020 50.4Gy+Taxol/Gem 154 11.7m RTOG0411 50.4Gy+Xeloda/Avastin 94 11.9m FFCD-SSRO 60Gy+5FU/Cisplat 59 8.6m ECOG 4201 50.4Gy+Gem 34 11.0m
FFCD-SFRO
Would Better systemic therapy made a difference Gem Abraxane, FOLFIRINOX Would earlier Radiation help? Shorter radiation (SBRT) without interrupting systemic therapy?
SBRT Stanford Phase I Stanford EBRT+ Boost Stanford Gem SBRT Danish Phase II UPMC Sinai, Baltimore BIDMC Upfront SBRT BIDMC Gem SBRT Tampa Hopkins/Stanford/Memorial
Toxicity
Total Neoadjuvant Therapy Total Neoadjuvant Therapy (TNT) Neoadjuvant Chemo and Surgery (NeoC-S) Neoadjuvant Chemo and SBRT (NeoC-SBRT) Chemo Chemo Chemo SBRT Surgery Surgery SBRT
Results Overall Survival Treatment Group Number Median Overall Survival (Months) TNT 25 36.5 NeoC-SBRT 49 19.3 NeoC- Surgery 6 22.2 p=0.1 7 p=0.03 p=0.98
Results Local Regional Recurrence
FOLFIRINOX SBRT
Locally advanced Pancreatic CA FOLFIRINOX vs. Gemcitabine/Abraxane with SBRT Randomized Phase II Primary Outcomes: Toxicity/Tolerability (QOL) Progression free (PFS) Overall survival Conversion to resectable disease
Schema Patients will be randomized to receive gem/abraxane vs. FOLFIRINOX for six months All patients without metastatic dz at 3 monthswill receive SBRT between cycles 4 and 5. Patients to be restaged in 6 months for resectability Maintainance systemic therapy vs observation at patient tolerance/physician discretion
Schema for Locally Advanced Pancreatic Ca Patient will be randomized to receive mfolfirin OX vs. Gemciatbine abraxane x3 months restaging SBRT second line chemo restaging No distant metastasis Assess resectability after 6 cycles of Chemo
Inclusion: Histologically or cytopathological confirmed adenocarcinoma of the pancreas. Locally advanced, unresectable pancreatic cancer as defined on CT as having tumor abutment of >180 (> 50%) of the circumference of the superior mesenteric artery (SMA) or celiac axis, unreconstructable superior mesenteric vein (SMV) or portal vein (PV) involvement. No evidence of distant metastasis either prior to or after chemotherapy. ECOG 0-1. Good organ and marrow function as defined below:
Exclusion ECOG >1 Patients who have had prior abdominal radiotherapy. Patients receiving any investigational agents.
Quality of Life (QOL) physical symptoms physical functioning and emotional well-being at baseline, during treatment, and after treatment. QOL measures will be assessed prior to therapy, 14 days prior to SBRT, 10-12 weeks after SBRT, 6 months after SBRT. 1 year after completion of therapy.
Locally recurrent Pancreas Cancer and Oligometastatic If unresectable Phase II stratified by MSI status FOLFIRINOX +/- SBRT if MSI low Pembrolizumab +/- SBRT if MSI High
Oligometastasis/Local Recurrence Phase II Trial Patients with Oligometastasis/Local Recurrence ECOG performance 1 No contraindication for systemic therapy Reasonable Life expectancy Lesions treatable with SBRT
Schema Registration 2 cycles of systemic therapy Restage. If non metastatic Randomize SBRT and further systemic therapy vs Continue Systemic therapy until progression or Tolerance
RadioImmunotherapy Symposium - SRS/SBRT Scientific Meeting 2016
Multicenter Studies RadioImmunotherapy Symposium - SRS/SBRT Scientific Meeting 2016
Multi-Institutional Studies Accrual of Large number of patients Improved statistical power Generalizability of results Ability to test Cross-Platform Facilitates institutional co-operation Protocol base for smaller institutions to treat unusual diseases
Hurdles Regulatory Issues Regional IRB requirements Statistical Issues Logistical problems Responsibility of overseeing and conduct Collection and maintenance of data Communication during conduct of trial Cost $$$$
The Radiosurgery Society International Society of professionals dedicated to the advance of stereotactic radiation Enthusiastic to forge collaborations to advance cancer care Consortium of state of the art radiation therapy user base and beneficiaries Link to clinical trials, efficacy and quality of life outcomes RSSearch Largest SRS/SBRT registry >20,000 patients
Mission Statement The Radiosurgery Society is a multidisciplinary non-profit organization, consisting of surgeons, radiation oncologists, physicists, and allied professionals, who are dedicated to advancing the science and clinical practice of SRS and SBRT.
Membership by Specialty Total Members - 550
Potential Role of The Radiosurgery Society Provide a central repository of trials Generalize Protocol and Consent forms Expert Group advise and critique of trial design Central Trial Review Committee Statistical Advise Regulatory Overview Logistical Support Data Safety Monitoring Board Central Physics review
Summary Surgery is still the primary curative treatment for Pancreatic cancer Stereotactic Body Radiotherapy is not a substitute but an alternative when indicated Systemic therapy is vital in the curative multidisciplinary management of micro metastatic cancer. Stereotactic Radiosurgery is becoming a component in the multidisciplinary treatment of Pancreatic Cancer and its role needs to be better defined with prospective studies.
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