Contemporary ry Evid idence-Based Surgical Management of P - - PowerPoint PPT Presentation

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
• f 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† (95% CI) 5 year† (95% CI) Size Grade Lymph Nodes Margins Adjuvant Tx ≤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

• f 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
• ver 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 HR (CI, p-value) Multivariable* 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 OR (CI, p-value) Multivariable 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

• f 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

29

Median Survival by Group:

• Surgery + Chemo: 25.6 months
• Chemo + Surgery: 27.6 months
• Surgery only:

15.2 months

• Chemo only:

10.5 months

Test of equality: p <0.001

COX REGRESSION ANALYSIS BY STAGE

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Stage 1 Stage 2 HR CI (95%) P-value HR CI (95%) P-value Surgery Only Ref.

• Ref.
• Surgery + Chemo

0.68 0.64 – 0.72 <0.001 0.50 0.44 – 0.56 <0.001 Chemo + Surgery 0.68 0.61 – 0.75 <0.001 0.45 0.38 – 0.55 <0.001 Chemo Only 1.89 1.68 – 2.12 <0.001 1.18 0.98 – 1.43 0.08 Model adjusted for: age, sex, race, insurance status, geographic location, income, metropolitan area, facility type, tumor grade, LN status, Charleson-Deyo score, year, tumor site, tumor size, TNM T, TNM N, and stage

Received Treatment 13,426 Start with Surgery 8,490 (63.2%) Start with Chemotherapy 4,936 (36.8%) Chemotherapy Only 3,818 (77.3%) Surgery + Chemo 5,684 (66.9%) Surgery Only 2,806 (33.1%) Preop Chemo + Surgery 1,118 (22.7%)

INTENTION TO TREAT ANALYSIS

DISCUSSION

• Similar survival for patients who complete surgery plus chemotherapy,

regardless of order

• Surgical resection is fundamental to achieve long-term survival in patients with

pancreatic cancer.

• Upfront surgical resection could be considered for early resectable pancreatic

cancer

• Majority of patients who start with chemotherapy, do not receive surgical

resection (~ 77%).

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• UofP
• 522 patients, 2008 to 2015
• Number of chemotherapy cycles received (0, 1–5, and 6 cycles)
• Sequence (NAC, AC, or NAC /AC)
• 6 cycles in any sequence was associated with optimal survival
• Sequence not associated with survival
• Conclusions- Receipt of 6 or more perioperative cycles of

chemotherapy, regardless of sequence, is ideal

Imminently Resectable

• Upfront surgery
• pT3, pN1 (1/10), 1.3 cm in

greatest dimension, well differentiated, R0

• Postop FOLFRINOX

Hospital Volume and Surgical Mortality

• Over last two decades hospital

volume has been linked to mortality for high-risk surgeries

• Pancreatic
• Esophageal
• Gastrectomy
• Nephrectomy
• Cardiac surgery
• Vascular surgery
• Colorectal
• Bariatric

• ECU

– 1996 to July 2012 – In 2008 two surgical oncologists with HPB expertise recruited and established a multidisciplinary tumor board and clinic

• Three cohorts

– Early 1996-2007 – Transition 2008-2009 – Mature 2010-2012

Pancreatic Resections per Year

10 20 30 40 50 60 70 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

Transition Mature

Year

Early

Results

Quality Indicator

1996-2007 (Early) 2008-2009 (Transition) 2010-2012 (Mature) if cancer directed surgery; appropriate documentation 82.4% 84.6% 82.4% if patients stage I or II; resection or documentation 46.2 68.3 64.9 if cancer-directed surgery ; chemotherapy with

• r without radiation or documented

45.1% 88% 94.9% if stage IV no surgery 97.9 97.6 97.7 if no resection; chemotherapy/ chemo XRT or documentation 36.4 47.3 47.0 if undergoing treatment; time to treatment < 2 months 97.8% 100% 100% if resection; margins negative 86.4% 100% 91.4% if resection > 10 lymph nodes 44.2% 7.7% 46.6% mortality < 5% 4.3% 11.5% 3.9% hospital volume > 12 7.5 25.5 39 Total 3 4 6

Enhanced Recovery After Surgery

• Multimodal, evidence based, perioperative care pathway designed to improve

recovery after major surgery

• Kehlet, Copenhagen
• “Fast-track”
• ERAS group of academic European surgeons
• Entire perioperative period
• Carb loading
• Goal directed fluid resuscitation and intraoperative normothermia
• Multimodal pain management (avoidance of narcotics)
• Prevention of postoperative ileus, early enteral nutrition
• Avoidance of nasogastric tubes and drains
• Early convalesce

• Purpose
• To better understand the barriers and feasibility in designing

an optimal perioperative pathway for a single surgeon performing a variety abdominal procedures

Factor ERAS % (no.) No ERAS %(no.) P value Gender Male Female 46.0 (40) 54.0 (47) 46.7(43) 53.3 (49) 0.92 Age 61.4 (13.9) 63.1 (13.9) 0.41 Race White Black 62.1 (54) 34.5 (30) 60.9 (56) 34.8 (32) 0.95 Charlson comorbidities 0-2 3-5 >5 43.7 (38) 36.8 (32) 19.5 (17) 47.8 (44) 28.3 (26) 23.9 (22) 0.46 Surgery Pancreatectomy Colectomy Hepatic resection Gastrectomy Intestinal resection 27.6 (24) 12.6 (11) 12.6 (11) 4.6 (4) 16.1 (14) 14.1 (13) 12.0 (11) 20.7 (19) 12.0 (11) 21.7 (20) 0.064 Postoperative LOS 6.2 (4.9) 9.6 (9.3) 0.024 Complications Grade 0-I Grade II-V 67.8(59) 32.2(28) 54.4(50) 42.6 42) 0.064 Cost 21,674 (12,118) 30,380 (25,723) 0.029 Readmissions 11.5 (10) 21.4 (19) 0.076 Mortality 0 (0) 3.3 (3) 0.044

Summary

• ERAS perioperative protocols improve patient outcomes
• ERAS protocols can be implemented in a wide range of patients

undergoing complex abdominal surgery

• Need not to be procedure specific but can incorporate the general principles
• f ERAS in a single perioperative program
• Benefits from such a program include decrease LOS, cost, and

mortality

Perioperative Surgical Home

• ACA
• Volume to quality
• Coordinate care surgical patient
• From decision to do surgery to

recovery

• Evidence based practice
• Minimize variation

Next Steps

• Patient cohorts
• E6- Complex GI, Colorectal,

Thoracic, Head and Neck, and Urology

• High-preforming teams
• iPace
• MMC One of only eight US hospitals
• New Pathway Innovators initiative,

focused on improving

• Improve the quality and safety
• fully integrating medical education in

interprofessional setting

Summary

• Not all pancreatic cancer is the same
• Personalize approach should be considered
• Locally advanced
• Borderline
• Imminently resectable
• High-risk

Summary

• Volume is only part to the story
• ERAS
• Peri-operative surgical home
• Patient education, ERAS, care management, navigation
• Cohorting and high-performing teams
• iPace
• Culture