Neoadjuvant Chemotherapy forResectable Pancreatic Cancer:Where We StandManav S. Sharma, MDWalter G. Park, MD, MSShyam J. Thakkar, MD

WHY?Data from the NIH/SEER program

WHY?Data from the NIH/SEER program

Rationale for Neoadjuvantchemotherapy1. Chemotherapy administered before surgery to nondissected, well-oxygenated tissue may maximize anypotential benefit compared to post op tissue2. May decrease tumor volume, thus improving R0resectability and completion of multimodal treatment3. Minimize regional nodal disease/micrometastasis,hence reducing the risk of loco-regional recurrence.

Rationale for Neoadjuvantchemotherapy 40- 50% of patients having undergone curative resectiondo not receive the adjuvant treatment planned due tosurgical complications, poor performance status,comorbidity, patient refusal, and/or early diseaserecurrence Identifying aggressive tumors; avoiding futile surgery

Data from AHN Argument for neoadjuvant chemotherapy for resectablepancreatic cancer– 70 PDA patients deemed resectable– 64 patients underwent surgery 37 (58%) started adjuvant chemotherapy Only 16 (25%) completed treatment. Patients who completed their adjuvant chemotherapy had asignificantly prolonged survival time versus those who did notcomplete all cycles (36.9 months vs. 18.8 months, P 0.014). ).Each additional cycle of chemotherapy conferred a relative survivaladvantage

Argument against neoadjuvant Since surgery is the only potential cure, toxicneoadjuvant regimen may be harmful as these couldhamper the surgical outcome Risk of disease progression under therapy Lack of randomized controlled data- most of theliterature on neoadjuvant treatment is from patients withborderline or locally advanced (unresectable) pancreaticcancer without concrete evidence

Data thus far 1992: Single arm single center data from MD Anderson in astudy by Evans et al. Multitude of studies but most combine resectable andborderline resectable (some with locally advanced) forneoadjuvant chemotherapy and radiation therapy. Low strength data- Systematic review and metanalysis byBradley et al. in 2019: 452 studies reviewed; 9 offeredcomparison between NAT and surgery followed by adj fortreatment of RPC; only 1 RCT (which was terminated early) Mixed results without conclusive evidence to change currentguideline

Data thus far Difficult to interpret:––––No standardization of definition of resectable diseaseNo standardization of neoadjuvant chemotherapy regimenNeo adjuvant chemo vs chemoradiation?Selection bias: patients who did not undergo surgery afterNeoadj were not included in survival analysis– Selection bias based on patient preference– Bias based on surgical team preference: location of tumor andease of surgery

Major studies underway Randomized phase II/III trial of neoadjuvantchemotherapy with gemcitabine and S-1 versus upfrontsurgery for resectable pancreatic cancer (includesBRPA)- Study Group of Preoperative Therapy forPancreatic Cancer (Prep) and Japanese Study Group ofAdjuvant Therapy for Pancreatic cancer (JSAP)

Major studies underway Neoadjuvant chemotherapy versus surgery first forresectable pancreatic cancer (Norwegian PancreaticCancer Trial - 1 (NorPACT-1)) - a national multicentrerandomized controlled trial.– Panc head cancers only– Primary end point is overall mortality in patient who undergoresection– Secondary endpoint is overall survival after randomization withITT analysis

Major studies underway Resectable pancreatic adenocarcinoma neo-adjuvantFOLF(IRIN)OX-based chemotherapy- a multicenter, noncomparative, randomized, phase II trial (PANACHE01PRODIGE48 study)– French study– evaluating the safety and efficacy of two regimens of neoadjuvant chemotherapy (4 cycles of mFOLFIRINOX orFOLFOX) relative to upfront surgery and adjuvant chemotherapyin patients with resectable PDAC

Neoadjuvant chemo for resectablePDA MDPC started neoadjuvant protocol for resectable headand neck PDA per NCCN criteria Tail cancers not included--- Onc Surgery consensus--easy resectablility with distal pancreatectomy which haslow morbidity. Ongoing prospective data collection since Nov 2018 as aQuality improvement study

Performance status good/Age 65- Modified FOLFIRINOXPerformance status poor/Age 65- Gemcitabine Abraxane4 cycles: Once/week X 3 weeks 1 week drug holidayRestaging at 2 months and 4 monthsCT abdomen pancreatic protocol CA 19-9SurgeryAdjuvant chemotherapy

End points Primary– Survival at 1, 2 and 5 years Secondary– Tolerability of neoadjuvant chemotherapy– Patients undergoing surgery– R0 resection margins

Preliminary results 9 resectable patients thus far– 3 patients received neoadjuvant therapy and underwent resection– 2 patients received neoadjuvant therapy and did not undergoresection– 4 patients are receiving neoadjuvant therapy and will probablyundergo resection– 9/9 100% neoadjuvant therapy tolerance– 3/5 60% neoadjuvant therapy with successful resection– 3/3 100% R0 resection margin

Where do we stand? Standard of care for resectable pancreatic cancerremains surgery adjuvant chemotherapy Increasing evidence regarding improved outcomes withNeoadjuvant treatment are emerging (however, withdebatable and conflicting results) underlining the needfor robust randomized controlled trials in the field Until then, regional and institutional protocols based onmultidivisional consensus and patient preference dictatethe care pathway followed

References Fuyuhiko et al. Study Group of Preoperative Therapy for Pancreatic Cancer (Prep) and Japanese Study Group of AdjuvantTherapy for Pancreatic cancer (JSAP), Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP05), Japanese Journal of Clinical Oncology, Volume49, Issue 2, February 2019, Pages 190–194Schwatz et al. Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy - a multicenter,non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study) BMC Cancer. 2018; 18: 762.Mokdad et al. Neoadjuvant Therapy Followed by Resection Versus Upfront Resection for Resectable Pancreatic Cancer:A Propensity Score Matched Analysis. J Clin Oncol. 2017 Feb 10;35(5):515-522Evans DB et al. Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. ArchSurg. 1992 Nov;127(11):1335-9Heinrich H et al. Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer withoutincreasing morbidity: results of a prospective phase II trial. Ann Surg. 2008 Dec;248(6):1014-22.Clyod JM et al.Chemotherapy Versus Chemoradiation as Preoperative Therapy for Resectable PancreaticDuctal Adenocarcinoma:A Propensity Score Adjusted Analysis. Pancreas. 2019 Feb;48(2):216-222Bradley A et al. Upfront Surgery versus Neoadjuvant Therapy for Resectable Pancreatic Cancer: SystematicReview and Bayesian Network Meta-analysis. Sci Rep. 2019 Mar 13;9(1):4354.Ielpo, B. et al. Preoperative treatment with gemcitabine plus nab-paclitaxel is a safe and effective chemotherapy forpancreatic adenocarcinoma. Eur J Surg Oncol. 42, 1394–1400 (2016).Roland, C. L. et al. Neoadjuvant therapy is associated with a reduced lymph node ratio in patients with potentially resectablepancreatic cancer. Annals of surgical oncology. 22(4), 1168–1175 (2015).Tzeng, C. W. et al. Treatment sequencing for resectable pancreatic cancer: influence of early metastases and surgicalcomplications on multimodality therapy completion and survival. J Gastrointest Surg. 18, 16–24 (2014).

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