SBRT in Pancreas Cancer Role of The Radiosurgery Society

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1 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

2 Objectives Current role of radiation in Pancreas Cancer Role of local control SBRT for pancreas cancer Clinical scenarios for exploring future role

3 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

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6 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%)

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12 R1 resection = Poor Survival

13 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

14 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

15 P= Local Control

16 Results Summary Cohort N Median Survival (months) 2-Year Survival (Actuarial) 5-Year Survival (Actuarial) Overall % 24% Negative Margins (R0) % 28% Positive Margins (R1) % 17% Untreated % Chemo/RT % Chemo/RT + CK %

17 ESPAC 4 Adjuvant Gem vs GemCAP Primary endpoint OS , 730 pts, Med age 65yrs 60%R1, 80% N=, 40% Poorly differentiated Med OS: 28m v 25.5m p= % yr Survival: 29% vs 16 % No diff in Grade ¾ Toxicity.

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19 ESPAC4 Patterns of Failure

20 High Risk Post OP R1 +ve margin T3/4 (size) N+ Poorly differentiated Post OP CA19-9 > 92.5

21 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

22 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

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27 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

28 Results Overall Survival Treatment Group Number Median Overall Survival (Months) TNT NeoC-SBRT NeoC- Surgery p=0.1 7 p=0.03 p=0.98

29 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

30 Locally Advanced Pancreas Cancer

31 Classic Trials: RT vs. ChemoRT and Chemo vs. ChemoRT

32 Modern Chemo-radiation Trials Trial Treatment No of Pts Med OS RTOG Gy+Taxol m RTOG Gy+Taxol/Gem m RTOG Gy+Xeloda/Avastin m FFCD-SSRO 60Gy+5FU/Cisplat m ECOG Gy+Gem m

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34 FFCD-SFRO

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38 Would Better systemic therapy made a difference Gem Abraxane, FOLFIRINOX Would earlier Radiation help? Shorter radiation (SBRT) without interrupting systemic therapy?

39 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

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41 Toxicity

42 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

43 Results Overall Survival Treatment Group Number Median Overall Survival (Months) TNT NeoC-SBRT NeoC- Surgery p=0.1 7 p=0.03 p=0.98

44 Results Local Regional Recurrence

45 FOLFIRINOX SBRT

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47 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

48 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

49 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

50 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:

51 Exclusion ECOG >1 Patients who have had prior abdominal radiotherapy. Patients receiving any investigational agents.

52 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, weeks after SBRT, 6 months after SBRT. 1 year after completion of therapy.

53 Locally recurrent Pancreas Cancer and Oligometastatic If unresectable Phase II stratified by MSI status FOLFIRINOX +/- SBRT if MSI low Pembrolizumab +/- SBRT if MSI High

54 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

55 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

56 RadioImmunotherapy Symposium - SRS/SBRT Scientific Meeting 2016

57 Multicenter Studies RadioImmunotherapy Symposium - SRS/SBRT Scientific Meeting 2016

58 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

59 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 $$$$

60 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

61 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.

62 Membership by Specialty Total Members - 550

63 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

64 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.

65 Thank you