Neoadjuvant treatment of pancreatic adenocarcinoma: a systematic review and meta-analysis of 5520 patients

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Abstract

Background

Recent years have seen standardization of the anatomic definitions of pancreatic adenocarcinoma, and increasing utilization of neoadjuvant therapy (NAT). The aim of the current review was to summarize the evidence for NAT in pancreatic adenocarcinoma since 2009, when consensus criteria for resectable (R), borderline resectable (BR), and locally advanced (LA) disease were endorsed.

Methods

PubMed search was undertaken along with extensive backward search of the references of published articles to identify studies utilizing NAT for pancreatic adenocarcinoma. Abstracts from ASCO-GI 2014 and 2015 were also searched.

Results

A total of 96 studies including 5520 patients were included in the final quantitative synthesis. Pooled estimates revealed 36% grade ≥ 3 toxicities, 5% biliary complications, 21% hospitalization rate and low mortality (0%, range 0–16%) during NAT. The majority of patients (59%) had stable disease. On an intention-to-treat basis, R0-resection rates varied from 63% among R patients to 23% among LA patients. R0 rates were > 80% among all patients who were resected after NAT. Among R and BR patients who underwent resection after NAT, median OS was 30 and 27.4 months, respectively.

Conclusions

The current study summarizes the recent literature for NAT in pancreatic adenocarcinoma and demonstrates improving outcomes after NAT compared to those historically associated with a surgery-first approach for pancreatic adenocarcinoma.

Electronic supplementary material

The online version of this article (10.1186/s12957-017-1240-2) contains supplementary material, which is available to authorized users.

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Most cited references 112

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Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial.

Helmut Oettle, Peter Neuhaus, Andreas Hochhaus … (2013)

The prognosis for patients with pancreatic cancer is poor, even after resection with curative intent. Gemcitabine-based chemotherapy is standard treatment for advanced pancreatic cancer, but its effect on survival in the adjuvant setting has not been demonstrated. To analyze whether previously reported improvement in disease-free survival with adjuvant gemcitabine therapy translates into improved overall survival. CONKO-001 (Charité Onkologie 001), a multicenter, open-label, phase 3 randomized trial to evaluate the efficacy and toxicity of gemcitabine in patients with pancreatic cancer after complete tumor resection. Patients with macroscopically completely removed pancreatic cancer entered the study between July 1998 and December 2004 in 88 hospitals in Germany and Austria. Follow-up ended in September 2012. After stratification for tumor stage, nodal status, and resection status, patients were randomly assigned to either adjuvant gemcitabine treatment (1g/m2 d 1, 8, 15, q 4 weeks) for 6 months or to observation alone. The primary end point was disease-free survival. Secondary end points included treatment safety and overall survival, with overall survival defined as the time from date of randomization to death. Patients lost to follow-up were censored on the date of their last follow-up. A total of 368 patients were randomized, and 354 were eligible for intention-to-treat-analysis. By September 2012, 308 patients (87.0% [95% CI, 83.1%-90.1%]) had relapsed and 316 patients (89.3% [95% CI, 85.6%-92.1%]) had died. The median follow-up time was 136 months. The median disease-free survival was 13.4 (95% CI, 11.6-15.3) months in the treatment group compared with 6.7 (95% CI, 6.0-7.5) months in the observation group (hazard ratio, 0.55 [95% CI, 0.44-0.69]; P < .001). Patients randomized to adjuvant gemcitabine treatment had prolonged overall survival compared with those randomized to observation alone (hazard ratio, 0.76 [95% CI, 0.61-0.95]; P = .01), with 5-year overall survival of 20.7% (95% CI, 14.7%-26.6%) vs 10.4% (95% CI, 5.9%-15.0%), respectively, and 10-year overall survival of 12.2% (95% CI, 7.3%-17.2%) vs 7.7% (95% CI, 3.6%-11.8%). Among patients with macroscopic complete removal of pancreatic cancer, the use of adjuvant gemcitabine for 6 months compared with observation alone resulted in increased overall survival as well as disease-free survival. These findings provide strong support for the use of gemcitabine in this setting. isrctn.org Identifier: ISRCTN34802808.

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Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial.

John Neoptolemos, Deborah Stocken, Claudio Bassi … (2010)

Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer. To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer. The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up. Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m(2), intravenous bolus injection, followed by fluorouracil, 425 mg/m(2) intravenous bolus injection given 1-5 days every 28 days) (n = 551) or gemcitabine (1000 mg/m(2) intravenous infusion once a week for 3 of every 4 weeks) (n = 537) for 6 months. Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life. Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (chi(1)(2) = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P < .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups. Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer. clinicaltrials.gov Identifier: NCT00058201.

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1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience.

Jordan Winter, John L. Cameron, Kurtis A. Campbell … (2006)

Pancreaticoduodenectomy (PD) with the possible addition of neoadjuvant or adjuvant therapy is the standard of care in the United States for adenocarcinoma originating in the pancreatic head, neck, and uncinate process. We reviewed 1423 patients who underwent a PD for a malignancy originating in the pancreas at our institution between 1970 and 2006. We examined 1175 PDs for ductal adenocarcinomas in greater detail. Eighteen different histological types of pancreatic cancer were identified; the most common diagnoses included ductal adenocarcinoma, neuroendocrine carcinoma, and IPMN with invasive cancer. Patients with ductal adenocarcinoma were analyzed in detail. The median age was 66 years, with patients in the present decade significantly older (68 years), on average, than patients in the three prior decades (e.g., 60 years in 1970, P = 0.02). The median tumor diameter was 3 cm; 42% of the resections had positive margins and 78% had positive lymph nodes. The perioperative morbidity was 38%. The median postoperative stay declined over time, from 16 days in the 1980s to 8 days in the 2000s (P < 0.001). The perioperative mortality declined from 30% in the 1970s to 1% in the 2000s (P < 0.001). The median survival for all patients with ductal adenocarcinoma was 18 months (1-year survival = 65 %, 2-year survival = 37%, 5-year survival = 18%). In a Cox proportional hazards model, pathological factors having a significant impact on survival included tumor diameter, resection margin status, lymph node status, and histologic grade. This is the largest single-institution experience with PD for pancreatic cancer. Patients who have cancers with favorable pathological features have a statistically significant improved long-term survival.

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Author and article information

Contributors

Mashaal Dhir: dhirm@upstate.edu

Gautam K. Malhotra: gmalhotra@unmc.edu

Davendra P.S. Sohal: sohald@ccf.org

Nicholas A. Hein: nicholas.hein@unmc.edu

Lynette M. Smith: lmsmith@unmc.edu

Eileen M. O’Reilly: oreillye@mskcc.org

Nathan Bahary: baharyn@upmc.edu

Chandrakanth Are: 402 559 8941 , care@unmc.edu

Journal

Journal ID (nlm-ta): World J Surg Oncol

Journal ID (iso-abbrev): World J Surg Oncol

Title: World Journal of Surgical Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1477-7819

Publication date (Electronic): 10 October 2017

Publication date PMC-release: 10 October 2017

Publication date Collection: 2017

Volume: 15

Electronic Location Identifier: 183

Affiliations

[1 ]ISNI 0000 0000 9159 4457, GRID grid.411023.5, Department of Surgery, , SUNY Upstate Medical University, ; Syracuse, NY 13210 USA

[2 ]ISNI 0000 0001 0666 4105, GRID grid.266813.8, Department of Surgery, , University of Nebraska Medical Center, ; Omaha, NE 98198 USA

[3 ]ISNI 0000 0001 0675 4725, GRID grid.239578.2, Division of Hematology and Oncology, , Taussig Cancer Institute, Cleveland Clinic, ; Cleveland, OH 44195 USA

[4 ]ISNI 0000 0001 0666 4105, GRID grid.266813.8, Department of Biostatistics, , College of Public Health, University of Nebraska Medical Center, ; Omaha, NE 68198 USA

[5 ]ISNI 0000 0001 2171 9952, GRID grid.51462.34, David M. Rubenstein Center for Pancreatic Cancer, Memorial Sloan Kettering Cancer Center, ; New York, NY 10065 USA

[6 ]ISNI 0000 0001 0650 7433, GRID grid.412689.0, Department of Medicine, Division of Hematology and Oncology, , University of Pittsburgh Medical Center, ; Pittsburgh, PA 15232 USA

[7 ]ISNI 0000 0001 0666 4105, GRID grid.266813.8, Department of Surgery, Division of Surgical Oncology, , University of Nebraska Medical Center, ; Omaha, NE 98198 USA

[8 ]ISNI 0000 0001 0666 4105, GRID grid.266813.8, Department of Surgery/Genetics, Cell Biology and Anatomy, , University of Nebraska Medical Center, ; Omaha, NE 68198 USA

Article

Publisher ID: 1240

DOI: 10.1186/s12957-017-1240-2

PMC ID: 5634869

PubMed ID: 29017581

SO-VID: 81a996b2-87d5-4420-a8a3-01d33896ee42

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 11 June 2017

Date accepted : 25 August 2017

Custom metadata

ScienceOpen disciplines: Surgery

Keywords: pancreatic cancer,pancreatic adenocarcinoma,neoadjuvant therapy,outcomes,survival

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ScienceOpen disciplines: Surgery

Keywords: pancreatic cancer, pancreatic adenocarcinoma, neoadjuvant therapy, outcomes, survival

Neoadjuvant treatment of pancreatic adenocarcinoma: a systematic review and meta-analysis of 5520 patients

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

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Most cited references 112

Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial.

Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial.

1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience.

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