Contemporary ry Evid idence-Based Surgical Management of P Pancreatic Cancer Timothy L. Fitzgerald, MD Director of Surgical Oncology Maine Medical Center Professor of Surgery Tufts University School of Medicine-Maine Medical Center Associate Medical Director of Surgical Oncology MaineHealth
Outline • Not all pancreatic cancer is the same • Subtypes of resectable cancer • Locally advanced • Borderline resectable • High-risk • Imminently resectable • Optimizing care peri-operative
Adenocarcinoma of the Pancreas • A majority of patients with pancreatic carcinoma die within two years of diagnosis • Curative surgical resection is the only strategy that results in long-term durable survival
Treatment of Metastatic Pancreatic Cancer • FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer • 342 pts FOLFIRINOX vs. Gem • Median survival 11.1 vs. 6.8 mo. • Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine • 861 pts nab-paclitaxel/gem vs. gem • 8.5 vs. 6.7 mo. N Engl J Med 3798:25 and N Engl J Med 369;18
• Survival after pancreatectomy • Age • Tumor size • Grade/differentiation • Lymph node (LN) metastases • Adjuvant treatment • Clinical factors
Survival (conditional) probability Age ≤ 65 3 Year † 5 year † Size Grade Lymph Nodes Margins Adjuvant Tx (95% CI) (95% CI) ≤2cm I/II Negative (-) Negative (-) No .55 (.53-.56) .40 (.38-.42) Yes .65 (.64-.67) .52 (.51-.54) Positive (+) No .39 (.37-.42) .25 (.22-.27) Yes .52 (.49-.54) .37 (.35-.39) Positive (+) Negative (-) No .40 (.38-.42) .25 (.23-.27) Yes .52 (.50-.54) .37 (.36-.39) Positive (+) No .24 (.22-.26) .12 (.10-.13) Yes .36 (.34-.39) .22 (.20-.24) ≤2cm III/IV Negative (-) Negative (-) No .50 (.47-.52) .33 (.31-.35) Yes .56 (.54-.58) .42 (.40-.44) Positive (+) No .29 (.26-.31) .15 (.13-.17) Yes .41 (.39-.44) .26 (.24-.29) Positive (+) Negative (-) No .29 (.27-.31) .16 (.14-.17) Yes .42 (.40-.44) .27 (.25-.29) Positive (+) No .15 (.13-.17) .06 (.05 -.07) Yes .26 (.24-.28) .13 (.11-.15) >2cm I/II Negative (-) Negative (-) No .45 (.44-.47) .31 (.29-.32) Yes .57 (.56-.58) .43 (.42-.45) Positive (+) No .30 (.28-.31) .16 (.15-.17) Yes .42- (.40-.44) .27 (.25-.29) Positive (+) Negative (-) No .30 (.29-.31) .16 (.15-.18) Yes .43 (.41-.44) .28 (.26-.29) Positive (+) No .16 (.14-.17) .06 (.05-.07) Yes .27 (.25-.28) .14 (.13-.15) >2cm III/IV Negative (-) Negative (-) No .35 (.33-.37) .20 (.19-.22) Yes .47 (.46-.49) .32 (.31-.34) Positive (+) No .20 (.18-.21) 0.09 (.07-.10) Yes .31 (.30-.33) .18 (.16-.19) Positive (+) Negative (-) No .20 (.19-.21) .09 (.08-.10) Yes .32 (.31-.33) .18 (.17-.19) Positive (+) No .08 (.07-.09) .024 (.020-.028) Yes .17 (.16-.18) .07 (.06-.08)
Case: Locally advanced • 69 y.o. female stomach upset and dyspepsia • CT - ill-defined 3 cm mass in the head of the pancreas with occlusion of the SMV and involvement of the SMA • EUS 2.9 cm mass in the head/uncinate process of the pancreas with involvement of superior mesenteric artery and likely peripancreatic lymphadenopathy, duodenal invasion • Pathology- adenocarcinoma
• 96 patients • 49% were taken to surgery • Type A - 62% • Type B- 24% • RO resection- 80% • Median survival 26 mo.
• 254 patients who underwent resection attempts after TNT • 9% patients explored but not ultimately resected • 91 % resection • RFS and OS rates were 23.5 and 58.8 months
• 3 factors associated with RFS and OS • Extended duration chemotherapy, > 6 cycles (10.3 vs 27.3 months; 23.9 vs 60.1 months, P < 0.001) • CA19-9 response (10.5 vs 29.3 months; 30.2 vs 60.5 months) • Major pathologic response (12.1 vs NYR months, 34.5 vs 72.1 months, P < 0.001) • Not associated • Anatomic classification (BR vs LA), chemotherapy regimen/switch, or radiologic downstaging
• The use of neoadjuvant systemic therapy for pancreatic cancer has increased over the last decade • Neoadjuvant multiagent chemotherapy has become the standard of care for locally advanced and borderline resectable tumors • The role of radiation therapy as a part of multi-modality treatment regimens remains poorly defined
: : Neoadju juvant Radia iation versus no Neoadju juvant Radiation Tumor Stage Univariable Multivariable* HR (CI, p-value ) HR (CI, p-value ) T3 0.96 (0.85 – 1.09, p=0.504) 0.98 (0.86 – 1.11, p= 0.701) T4 0.82 (0.67 – 1.01, p=0.059) 0.83 (0.67 – 1.04, p= 0.106) Combined (T3/T4) 0.93 (0.84 – 1.04, p=0.202) 0.94 (0.85 – 1.05, p= 0.301) Adjusted for age, sex, race, ethnicity, insurance type, geographic location, income, Charlson- Deyo Score, facility type, type of surgery performed, TNM node and tumor classifications, and surgical margin status.
Pathologic Response Univariable Multivariable OR (CI, p-value) OR (CI, p-value) Complete Pathologic Response T3 3.18 (1.73 – 5.83, p<0.001) 2.58 (1.38 – 4.82, p=0.003) T4 3.66 (1.47 – 9.12, p=0.005) 4.02 (1.54 – 10.46, p=0.004) Combined (T3/T4) 3.58 (2.18 – 5.89, p<0.001) 2.89 (1.73 – 4.83, p<0.001) R0 resection T3 1.52 (1.19 – 1.95, p=0.001) 1.45 (1.13 – 1.88, p=0.004) T4 3.17 (2.11 – 4.75, p<0.001) 3.37 (2.17 – 5.24, p<0.001) Combined (T3/T4) 1.80 (1.46 – 2.22, p<0.001) 1.79 (1.44 – 2.23, p<0.001) Tumor Downstaging T3 2.90 (2.30 – 3.66, p<0.001) 2.77 (2.17 – 3.53, p<0.001) T4 2.29 (1.44 – 3.67, p=0.001) 2.15 (1.28 – 3.62, p=0.004) Combined (T3/T4) 2.89 (2.43 – 3.45, p<0.001) 2.79 (2.32 – 3.35, p<0.001) *Multivaiable model controlling for: age, sex, race, ethnicity, insurance type, geographic location, income, Charlson-Deyo Score, facility type, TNM node, year, and tumor classifications. ** Includes control for type of surgery performed.
Conclusions • The use of multiagent of chemotherapy for locally advanced pancreatic cancer increased by 33% from 2006 to 2014 • Use of neoadjuvant radiation remained stable • Administration of radiation is associated with: • Tumor downstaging • R0-resection rates • Complete pathologic response • Not associated with improved survival
• Prospective consecutive surgical BR or LA PAC patients after induction FOLFIRINOX • 23 French centers between 2010 - 2015 • Treated with or without preoperative additional XRT • 203 pts • 106 BR and 97 LA • Overall survival (OS) and disease-free survival, 45.4 months and 16.2 months • XRT • higher R0 resection rate (89.2% vs 76.3%; P = 0.017) • ypN0 rate (76.2% vs 48.5%) • Pathologic major response (33.3% vs 12.9%; P = 0.001) • Longer OS (57.8 vs 35.5 months; P = 0.007).
Case: Locally advanced • 8 cycles FOLFRINOX • Long course XRT • ?
Borderline Resectable • 64 yo patient developed painless jaundice • ERCP and EUS with placement of stent after a mass was seen involving the GDA with complete interface loss and possible invasion of the portal vein • Biopsy confirmed adenocarcinoma
Definition: Borderline Resectable Tumors Lopez NE et al . Borderline resectable pancreatic cancer
• 884 pts BRPC, chemotherapy gemzar, S-1 • Lower resection rates for NAT (75.1 vs. 93.3%) • Higher R0 resection rates (84 vs 70%) • Improved survival (25.7 vs. 19) • No difference in survival with addition of XRT
Background • ALLIANCE trial (A021501) - Phase 2, randomized trial comparing the use of neoadjuvant chemotherapy and chemotherapy plus radiation in borderline resectable pancreatic ductal adenocarcinomas
Borderline Resectable • 8 Cycles of FOLFRINOX • CA 19-9 from 960 to 188.6. • Whipple with portal vein resection • T2NO, 3.5 cm • Scattered cells, 50% tumor response
High-risk pancreatic cancer • 61 y.o. female with back pain that was lasting for several days • CT 3 cm mass that abuts the splenic vein and SMV • EUS FNA demonstrated adenocarcinoma
High-risk pancreatic cancer • 4 Cycles of FOLFRINOX • Extended distal pancreatectomy with resection and reconstruction of portal vein at confluence • T1cN0, tumor spread over 4 cm, largest 1.1 cm • R0, tumor regression 60%
Imminently Resectable • 68 y.o. male is with jaundice workup with an ERCP with stent placement • CT- Obvious dilatation of the pancreatic duct but no evidence of a mass in the head of the pancreas. • EUS- a small pancreatic head cancer with biopsies consistent with adenocarcinoma
• PRODIGE 24/CCTG PA.6 Trial • 493 patients • Randomized phase III trial • Pancreatic adenocarcinoma curative surgery • mFOLFIRINOX vs. gemcitabine • Median survival mFOLFIRINOX- 54.4 months vs. gemcitabine- 35.0 months • ASCO • If up front surgery recommend 6 mo. postop chemo Preferred mFOLRIRINOX • Similar trial with gemcitabine/nab-paclitaxel vs. gemcitabine (APACT) was negative
NEOADJUVANT vs. ADJUVANT CHEMOTHERAPY FOR T1/T2 PANCREATIC CANCER Roberto J. Vidri, William T. Olsen, David E. Clark, Timothy L. Fitzgerald Division of Surgical Oncology Tufts University School of Medicine-Maine Medical Center Portland, ME 27
BACKGROUND • Neoadjuvant vs. adjuvant • Neoadjuvant treatment assures receipt of chemotherapy • Neoadjuvant therapy may lead to complications that prevent surgical resection • A many as 30% never undergo resection 28
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