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Mark M. Zalupski, M.D . University of Michigan

Neoadjuvant Therapy for Pancreatic Cancer. Mark M. Zalupski, M.D . University of Michigan Ascension Michigan GI Conference Multidisciplinary Management of the GI Cancer Patient March 30, 2019. Disclosures – None

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Mark M. Zalupski, M.D . University of Michigan

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  1. Neoadjuvant Therapy for Pancreatic Cancer Mark M. Zalupski, M.D. University of Michigan Ascension Michigan GI Conference Multidisciplinary Management of the GI Cancer Patient March 30, 2019

  2. Disclosures – None Off Label Use - Yes

  3. Definition of neoadjuvant treatment Pancreas Cancer – Background, Multi-modality and Adjuvant Therapy Neoadjuvant Trials Ongoing Efforts and Conclusions

  4. What is neoadjuvanttreatment? “Treatmentgiven as a first step to shrink a tumor before the main treatment, which is usually surgery” 1st treatment sometime called induction Can be chemotherapy and/or radiation Use often has defined value in post-op setting Main treatment = curative intent = surgery No need to “shrink” tumor in operable disease Target of systemic Tx includes micrometastaticdz

  5. Pancreatic Cancer - Scope of the Problem • 56,440 cases expected 20181 • 5 year survival 7.7% • By 2030, pancreas Ca expected to surpass breast, prostate and CRC to become 2nd leading cause of cancer death2 • Small minority (~15%) with operable dz (includes resectable and borderline resectable disease) • Older patient population with co-morbidities and disease associated complications • 1CA Cancer J Clin. 2018;68(1):7-302Can Res 2014:74;2913

  6. CT Criteria for Resection • No extra pancreatic disease • No extension to celiac/SMA • Patent SMV/PV • Encasement / reconstructable SMV/PV • Contact on SMA / celiac (<=180o) Resectable

  7. Resectable adenocarcinoma of the pancreatic head Kitts 527268 Resectable tumor, RRHA

  8. Borderline resectableadenocarcinoma of pancreatic head

  9. Resectable Pancreas Cancer Patterns of Treatment Failure • Early Spread to Regional Nodes • Subclinical Liver Metastasis in Majority • In Resected Pts Loco-regional Failure > 85% without Adjuvant Treatment • Liver Metastasis in > 75% Patients with Improved Local Control • Poor Prognostic Factors + LN, + margins (R1 - R2 resections)

  10. Localized Pancreatic CancerMulti-Modality Treatment Surgical Treatment - Necessary but not sufficient for cure Goal is R0resection Morbidity and difficult recovery following surgery Radiation Therapy - Enhances local control in resected pts As neoadjuvanttx, increases R0 resection rate Underutilized (?) Systemic Chemotherapy - Increases survival Combinations enhance benefits Majority of patients still suffer distant recurrence

  11. Resectable Pancreatic CA – Adjuvant Treatment 1NEJM 2004:350;1200 2JAMA 2007:297;267 3Lancet 2017:389;1011 4NEJM 2018:379;2395

  12. Resectable Pancreatic CAReceipt and Timing of Multimodality Therapy1 NCDB 2004-2011 39,441 pts stage I and II • 22.8% received no treatment • 18.5% chemotherapy only • 23.0% surgery only • 35.8% multimodality treatment • Age is a barrier to multimodality treatment OR as compared to < 55 yo56-64 - 0.83, 65-75 – 0.60, >76 - 0.17 • Multimodality tx increased over time (31.3  37.9%) 1J Gastrointestinal Surg 2016;20:93

  13. Resectable Pancreatic Cancer Surgery  Adjuvant Therapy m-FOLFIRINOX Gemcitabine/Capecitabine +/- RT / Capecitabine Single agent chemotherapy Neoadjuvant Therapy  Surgery Chemotherapy (same) as in adjuvant +/- RT Surgery if no progression, metastatic disease

  14. Rationale for preop therapy • Provides early treatment of micrometastaticdisease • Treating an intact patient • Delayed recovery may prevent the delivery of postoperative adjuvant therapy • Patients with rapidly progressive disease will not be subjected to surgery • A logical strategy for the high incidence of positive margins

  15. Potential Barriers to Neoadjuvant Therapy • Need for biopsy EUS – FNA • Biliary decompression and a continuing risk of cholangitis • Patient / Family • Concern for localized disease progression

  16. Neoadjuvant Gemcitabine-based Therapy in Resectable Pancreas Cancer - MDAH Experience 1 Gem 400 mg/m2wkly x 7 + 30 Gy RT wk 1-2 or 2 Gem 750 mg/m2 + Cis 30 mg/m2qow x 4  Gem 400 mg/m2wkly x 4 + 30 Gy RT wk 1-2 followed by surgery in those that remain resectable Note: only 1 of 176 pts had isolated local progression 1 J ClinOncol 26:3496, 2008 2 J ClinOncol 26:3487, 2008

  17. Localized / ResectablePancreatic Cancer Adjuvant 100 Surgery Neoadjuvant 100 Chemo +/- RT 20 20 80 Explored 80 Resected 20 20 60 Resected 60 Chemo +/- RT

  18. Preop vs Postop No. Patients Benefit Morbidity Med S of of (Resected) Chemo XRT Surg Neoadj 100 60 > 20 mo Adj. 60 80 < 20 mo

  19. Neoadjuvant Gemcitabine-based Therapy in Resectable Pancreas Cancer - MDAH Experience Comp/ Med Surv Med Surv n Resected Resectednot Oper Gem/RT1 86 74% 34.0 mos 7.1 mos Gem-Cis 90 66% 31.0 mos 10.1 mos Gem/RT2 Most failures systemic More difficult to complete longer preop course 1 J Clin Oncol 26:3496, 2008 2 J Clin Oncol 26:3487, 2008

  20. Resectable/Resected Pancreatic CANationwide Trends and Results with Neoadjuvant TX1 NCDB 1998-2011 18,243 resections • Post-op adjuvant tx (58% che, 39% RT) • 7.5% received neoadjtx (>99% che, 82% RT) • Use increased over time (4.3%  17%) • Neoadjuvant treatment associated with • R0 resection 85.5% vs 77.8% • Negative lymph nodes 59.3% vs 42.9% • Lower 30 day mortality 2.0% vs. 4.6% • Lower 30 day readmission rate 7.4% vs 9.5% • Median survival 24.3 mos vs. 18.7 mos 1J SurgOncol. 2017;116:127

  21. Phase II Full Dose Gemcitabine with RT Week 1 Week 2 Week 4 Week 5 Week 6 Week 7 Week 8 M T W T F S S M T W T F S S M T W T F S S M T W T F S S M T W T F S S M T W T F S S M T W T F S S XRT XRT XRT G G G G G G G G Gemcitabine: 1000 mg/m2 30 min IV infusion XRT 36 Gy in 15 fractions

  22. Phase II Full Dose Gemcitabine with RT n=41 8 (19.5%) ≥ grade 3 non-heme toxicity1 20 pts entered as resectable2 20 explored, 17 resected Clear margins in 16/17 Uninvolved LN in 11/17 One Path CR , 3 microscopic foci only Average LOS 13.5 days No 30-day mortality Median f/u 12 mos - 10/17 alive without recurrence 1J Clin Oncol 2008, 26(6):942 2Ann SurgOncol 2006, 13(2):150

  23. PREOPANC-1 Preoperative chemo/RT vs surgery for resectable/borderline resectable pancreatic cancer - Phase III trial Surgery  6 mos Gemcitabine Preop Gem/RT  Surgery  Adj Gem x 4 mos CMT – RT 36 Gy in 15 fractions + Gem 1 g/m2 R J Clin Oncol 36, 2018 (suppl; abstr LBA4002)

  24. PREOPANC-1 Preoperative chemo/RT vs surgery for resectable/borderline resectable pancreatic cancer - Phase III trial Accrual April 2013–July 2017 Results • J Clin Oncol 36, 2018 (suppl; abstr LBA4002)

  25. UMCC 6-25 Phase II Trial Neoadjuvant Gemcitabine, Oxaliplatin and RT Treatment Schema SURGERY ? Week 7 Week 1 Week 2 Week 3 Week 5 Week 6 M T W T F S S M T W T F S S M T W T F S S M T W T F S S M T W T F S S M T W T F S S XRT XRT XRT G G G G G G O O O O 30 Gy in 15 fractions XRT Gemcitabine: 1 g/m2, 30 minutes G Oxaliplatin: 85 mg/m2 O

  26. UMCC 6-25 Phase II Trial Neoadjuvant Gemcitabine, Oxaliplatin and RT n=68 pts (4 institutions) 12 resectable, 49 borderline, 7 unresectable 61 (90%) completed neoadjuvant treatment 5 PR, 50 SD (including 19 with MR), 12 PD 5/9 with Primary PD had RO resection 43 (63%) resected; 36/43 RO (84%) (32 whipple, 11 distal, 40% with vascular R&R) Cancer 2013;119:2692

  27. Median OS 18.2 months

  28. Med OS Not Resected 10.9 mos Med OS Resected – 27.1 mos Med OS R0 Resection – 34.6 mos

  29. UMCC 6-25 - Conclusions Radiologic response not necessary for RO resection CA19-9 response associated with RO resection Evidence for downstaging (+LN 49% vs. ~70% post-op) 55% of treated patients received adjuvant therapy Cancer 2013;119:2692

  30. Total Neoadjuvant Therapy (TNT) in Borderline Resectable Pancreatic CA UMCC 11.007 n=25 3 mos m-FOLFIRINOX  5 weeks IMRT/Gem  1 mos Gem  Surgery 21 pts completed 3 mos chemo, 19 all protocol tx Per serial CTs - 44% PR, 44% SD One early death, 4 liver metastasis, 2 pts inoperable 18 explored, 13 resected (all R0), venous resect 9 pts By ITT – med PFS 13.1 mos, med OS 24.4 mosResected pts - PFS 21.6 mos, OS 37.0 mosUnresected pts – PFS 8.9 mos, OS 12.6 mos submitted Int J Rad Onc Biolphys

  31. TNT in Borderline Resectable Pancreatic CA DFCI - Phase II Trial in Borderline ResectableDz4 months of m-FOLFIRINOX then Individualized RT (SBRT or long course IMRT) + Cape n=48 79% received 8 cycles of m-FOLFIRINOX 35% IMRT, 56% SBRT per serial CTs 44% PR, 30% SD R0 Resection in 65% By ITT med PFS 14.7 mos, med OS 37.7 mos Resected pts - PFS 48.6 mos, OS NR Unresected pts – PFS 8.9 mos, OS 12.6 mos JamaOncol. 2018;4(7);963

  32. A021501 – Neoadjuvant FOLFIRINOX +/- SBRT in borderline resectable pancreas cancer If no metastasis, surgical exploration and resection Resected patients receive post-op FOLFOX x 4 Primary: 18 mos OS Secondary: PFS, QOL R0 resection rate, Safety Pancreatic head adenocarcinoma Borderline resectable per intergroup criteria No prior treatment ECOG 0-1 No neuropathy No ca19-9 limit FOLFIRINOX x 8 N=67 R N=67 FOLFIRINOX x 7 then SBRT As of 3/21/19, accrual at 121 of planned 134 SBRT arm closed 8/13/18 when interim data analysis < 11/30 with R0 resection met the protocol specified futility boundary

  33. NeoadjuvantTx - Resectable Pancreas Cancer S1505–FOLFIRINOX vs. Gemcitabine/nab-Paclitaxel Primary Endpoint - 2 Year Overall Survival with a “pick the winner” design • Accrual completed April 2018 with 147 registrations • 39 registered patients ineligible due to > resectable disease on baseline CT scan • Grade 3-4 toxicity ~ 2/3 of patients = with either regimen ________________________________________________ GI Intergroup/NCTN planning randomized trial in Surgery adjuvant FOLFIRINOX vs. Neoadjuvant FOLFIRINOX  Surgery

  34. Neoadjuvant Therapy of Pancreatic Cancer Practical Considerations Chemotherapy m-FOLFIRINOX, gemcitabine/capecitabine standard adjuvant therapies gemcitabine/nab-paclitaxel (?), single agent therapy Radiation Surgeon and institutional preferences Continuing arterial contact SBRT, 3 weeks of 3D conformal, 5 (or more) weeks of IMRT Concurrent chemotherapy – capecitabine (or 5FU), gemcitabine Duration of neoadjuvant treatment 3 to 6 months - shorter for resectable disease, longer for borderline Surgical treatment response not required for operation prepare for vascular resection / reconstruction Post-operative adjuvant treatment target 6 mos of systemic therapy Postoperative RT in R1resections, LN + resections

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