Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

Authors:
Margaret A. Tempero UCSF Helen Diller Family Comprehensive Cancer Center;

Search for other papers by Margaret A. Tempero in
Current site
Google Scholar
PubMed
Close
 MD
,
Mokenge P. Malafa Moffitt Cancer Center;

Search for other papers by Mokenge P. Malafa in
Current site
Google Scholar
PubMed
Close
 MD
,
Mahmoud Al-Hawary University of Michigan Rogel Cancer Center;

Search for other papers by Mahmoud Al-Hawary in
Current site
Google Scholar
PubMed
Close
 MD
,
Stephen W. Behrman The University of Tennessee Health Science Center;

Search for other papers by Stephen W. Behrman in
Current site
Google Scholar
PubMed
Close
 MD
,
Al B. Benson III Robert H. Lurie Comprehensive Cancer Center of Northwestern University;

Search for other papers by Al B. Benson III in
Current site
Google Scholar
PubMed
Close
 MD
,
Dana B. Cardin Vanderbilt-Ingram Cancer Center;

Search for other papers by Dana B. Cardin in
Current site
Google Scholar
PubMed
Close
 MD
,
E. Gabriela Chiorean Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;

Search for other papers by E. Gabriela Chiorean in
Current site
Google Scholar
PubMed
Close
 MD
,
Vincent Chung City of Hope National Medical Center;

Search for other papers by Vincent Chung in
Current site
Google Scholar
PubMed
Close
 MD
,
Brian Czito Duke Cancer Institute;

Search for other papers by Brian Czito in
Current site
Google Scholar
PubMed
Close
 MD
,
Marco Del Chiaro University of Colorado Cancer Center;

Search for other papers by Marco Del Chiaro in
Current site
Google Scholar
PubMed
Close
 MD, PhD
,
Mary Dillhoff The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;

Search for other papers by Mary Dillhoff in
Current site
Google Scholar
PubMed
Close
 MD
,
Timothy R. Donahue UCLA Jonsson Comprehensive Cancer Center;

Search for other papers by Timothy R. Donahue in
Current site
Google Scholar
PubMed
Close
 MD
,
Efrat Dotan Fox Chase Cancer Center;

Search for other papers by Efrat Dotan in
Current site
Google Scholar
PubMed
Close
 MD
,
Cristina R. Ferrone Massachusetts General Hospital Cancer Center;

Search for other papers by Cristina R. Ferrone in
Current site
Google Scholar
PubMed
Close
 MD
,
Christos Fountzilas Roswell Park Comprehensive Cancer Center;

Search for other papers by Christos Fountzilas in
Current site
Google Scholar
PubMed
Close
 MD
,
Jeffrey Hardacre Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;

Search for other papers by Jeffrey Hardacre in
Current site
Google Scholar
PubMed
Close
 MD
,
William G. Hawkins Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;

Search for other papers by William G. Hawkins in
Current site
Google Scholar
PubMed
Close
 MD
,
Kelsey Klute Fred & Pamela Buffett Cancer Center;

Search for other papers by Kelsey Klute in
Current site
Google Scholar
PubMed
Close
 MD
,
Andrew H. Ko UCSF Helen Diller Family Comprehensive Cancer Center;

Search for other papers by Andrew H. Ko in
Current site
Google Scholar
PubMed
Close
 MD
,
John W. Kunstman Yale Cancer Center/Smilow Cancer Hospital;

Search for other papers by John W. Kunstman in
Current site
Google Scholar
PubMed
Close
 MD, MHS
,
Noelle LoConte University of Wisconsin Carbone Cancer Center;

Search for other papers by Noelle LoConte in
Current site
Google Scholar
PubMed
Close
 MD
,
Andrew M. Lowy UC San Diego Moores Cancer Center;

Search for other papers by Andrew M. Lowy in
Current site
Google Scholar
PubMed
Close
 MD
,
Cassadie Moravek Pancreatic Cancer Action Network;

Search for other papers by Cassadie Moravek in
Current site
Google Scholar
PubMed
Close
,
Eric K. Nakakura UCSF Helen Diller Family Comprehensive Cancer Center;

Search for other papers by Eric K. Nakakura in
Current site
Google Scholar
PubMed
Close
 MD
,
Amol K. Narang The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;

Search for other papers by Amol K. Narang in
Current site
Google Scholar
PubMed
Close
 MD
,
Jorge Obando Duke Cancer Institute;

Search for other papers by Jorge Obando in
Current site
Google Scholar
PubMed
Close
 MD
,
Patricio M. Polanco UT Southwestern Simmons Comprehensive Cancer Center;

Search for other papers by Patricio M. Polanco in
Current site
Google Scholar
PubMed
Close
 MD
,
Sushanth Reddy O’Neal Comprehensive Cancer Center at UAB;

Search for other papers by Sushanth Reddy in
Current site
Google Scholar
PubMed
Close
 MD
,
Marsha Reyngold Memorial Sloan Kettering Cancer Center;

Search for other papers by Marsha Reyngold in
Current site
Google Scholar
PubMed
Close
 MD, PhD
,
Courtney Scaife Huntsman Cancer Institute at the University of Utah;

Search for other papers by Courtney Scaife in
Current site
Google Scholar
PubMed
Close
 MD
,
Jeanne Shen Stanford Cancer Institute;

Search for other papers by Jeanne Shen in
Current site
Google Scholar
PubMed
Close
 MD
,
Charles Vollmer Jr. Abramson Cancer Center at the University of Pennsylvania;

Search for other papers by Charles Vollmer Jr. in
Current site
Google Scholar
PubMed
Close
 MD
,
Robert A. Wolff The University of Texas MD Anderson Cancer Center;

Search for other papers by Robert A. Wolff in
Current site
Google Scholar
PubMed
Close
 MD
,
Brian M. Wolpin Dana-Farber/Brigham and Women’s Cancer Center;

Search for other papers by Brian M. Wolpin in
Current site
Google Scholar
PubMed
Close
 MD, MPH
,
Beth Lynn National Comprehensive Cancer Network.

Search for other papers by Beth Lynn in
Current site
Google Scholar
PubMed
Close
 RN, BS, CMSRN
, and
Giby V. George National Comprehensive Cancer Network.

Search for other papers by Giby V. George in
Current site
Google Scholar
PubMed
Close
 MD
Full access

Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients’ advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.

Overview

During the year 2021 in the United States, an estimated 60,430 people will be diagnosed with pancreatic cancer, and approximately 48,220 people are expected to die of the disease.1 Pancreatic cancer is the fourth most common cause of cancer-related death among US men (after lung, prostate, and colorectal cancer) and women (after lung, breast, and colorectal cancer).1 Although the incidence is roughly equal in both sexes, African Americans have a higher incidence of pancreatic cancer than white Americans.2,3 The incidence of pancreatic cancer in the United States increased from 1999 to 2008, possibly because of the increasing prevalence of obesity, an aging population, and other unknown factors.35 Mortality rates have remained largely unchanged.6,7

In the NCCN Guidelines for Pancreatic Adenocarcinoma, the diagnosis and management of adenocarcinomas of the exocrine pancreas are discussed; neuroendocrine tumors are not included (see the NCCN Guidelines for Neuroendocrine Tumors, available at NCCN.org). These NCCN Guidelines are intended to assist with clinical decision-making, but they cannot incorporate all possible clinical variations and are not intended to replace good clinical judgment or individualization of treatments. Exceptions to the rule were discussed among the panel members during the process of developing and updating these guidelines. A 5% rule (omitting clinical scenarios that comprise less than 5% of all cases) was used to eliminate uncommon clinical occurrences or conditions from these guidelines. A study of 3,706 patients treated for pancreatic cancer in large California hospitals showed that compliance with these NCCN Guidelines for Pancreatic Adenocarcinoma, defined very permissively, improves survival.8

As an overall guiding principle of these guidelines, the panel believes that decisions about diagnostic management and resectability of pancreatic cancer should involve multidisciplinary consultation at high-volume centers with use of appropriate imaging studies. In addition, the panel believes that increasing participation in clinical trials (only 4.6% of patients enroll in a pancreatic cancer trial9) is critical to making progress in this disease. Thus, the panel unanimously endorses participation in a clinical trial over standard or accepted therapy.

Literature Search Criteria and Guidelines Update Methodology

Prior to the update of this version of the NCCN Guidelines for Pancreatic Adenocarcinoma, an electronic search of the PubMed database was performed to obtain key literature in the field of pancreatic cancer using the following search terms: (pancreatic cancer) OR (pancreatic adenocarcinoma) OR (pancreas adenocarcinoma) OR (pancreas cancer). The PubMed database was chosen because it remains the most widely used resource for medical literature and indexes only peer-reviewed biomedical literature.10

The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Practice Guideline; Guidelines; Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation Studies.

The potential relevance of the PubMed search citations over the past year was examined. The data from key PubMed articles and articles from additional sources deemed as relevant to these Guidelines and discussed by the panel have been included in this version of the “Discussion” section (eg, e-publications ahead of print, meeting abstracts). Recommendations for which high-level evidence is lacking are based on the panel’s review of lower-level evidence and expert opinion.

The complete details of the Development and Update of the NCCN Guidelines are available on NCCN.org.

Risk Factors and Genetic Predisposition

Although the increase in risk is small, pancreatic cancer is firmly linked to cigarette smoking.1116 Exposure to chemicals and heavy metals such as beta-naphthylamine, benzidine, pesticides, asbestos, benzene, and chlorinated hydrocarbons is associated with increased risk for pancreatic cancer,17,18 as is heavy alcohol consumption.11,13,1921 Periodontal disease is associated with pancreatic cancer, even when controlling for other risk factors such as gender, smoking, body mass index (BMI), diabetes, and alcohol consumption.22

An increased BMI is associated with an increased risk for pancreatic cancer,19,2325 with BMI during early adulthood being associated with increased pancreatic cancer mortality.26 A meta-analysis including 22 cohort studies with 8,091 patients with pancreatic cancer showed that those who engage in low levels of physical activity have an increased risk for pancreatic cancer, relative to those who engage in high levels of physical activity (relative risk [RR], 0.93; 95% CI, 0.88–0.98).27 Regarding diet, there is some evidence that increased consumption of red/processed meat and dairy products is associated with an elevation in pancreatic cancer risk,28,29 although other studies have failed to identify dietary risk factors for the disease.15,30,31 The association between tea consumption and pancreatic cancer risk has been examined, with mostly null associations being found.

Studies examining the association between vitamin D and risk for pancreatic cancer have shown contradictory results. Some data suggest that low plasma 25-hydroxyvitamin D levels may increase the risk for pancreatic cancer.32 A pooled analysis of 9 case-control studies, including 2,963 patients with pancreatic cancer and 8.527 control subjects, showed a positive association between vitamin D intake and pancreatic cancer risk (odds ratio [OR], 1.13; 95% CI, 1.07–1.19; P<.001).33 This association may be stronger in those with low retinol/vitamin A intake.

Chronic pancreatitis has been identified as a risk factor for pancreatic cancer,3437 with one study demonstrating a 7.2-fold increased risk for pancreatic cancer for patients with a history of pancreatitis.38 A meta-analysis including 2 case-control studies and one cohort study (1,636 patients with pancreatic cancer) showed that hepatitis B infection is associated with pancreatic cancer (OR, 1.50; 95% CI, 1.21–1.87).39 Patients with systemic lupus erythematosus are also suggested to be at an increased risk for pancreatic cancer. In a meta-analysis of 11 cohort studies, patients with systemic lupus erythematosus were found to be an increased risk for developing pancreatic cancer (CI 1.32–1.53, hazard ratio [HR], 1.43).40 However, further epidemiologic studies involving careful evaluation of these possible risk factors with adjustments for potential confounders are needed to clarify their impact on pancreatic cancer risk.

Diabetes and Pancreatic Cancer

The association between diabetes mellitus and pancreatic cancer is particularly complicated. A population-based study of 2,122 patients with diabetes found that approximately 1% of patients diagnosed with diabetes who are aged 50 years or younger will be diagnosed with pancreatic cancer within 3 years.41 Prediabetes may also be associated with increased risk for pancreatic cancer.42 A systematic review and dose-response meta-analysis including 9 prospective studies (n=2,408) showed that every 0.56 mmol/L increase in fasting blood glucose is associated with a 14% increase in pancreatic cancer incidence.43

Numerous studies have shown an association between new-onset non-insulin–dependent diabetes and the development of pancreatic cancer,41,4447 especially in those who are elderly, have a lower BMI, experience weight loss, or do not have a family history of diabetes.48 In these short-onset cases of diabetes diagnosed prior to pancreatic cancer diagnoses, diabetes is thought to be caused by the cancer, although the physiologic basis for this effect is not yet completely understood.49

Long-term diabetes, conversely, appears to be a risk factor for pancreatic cancer, as some studies have shown an association of pancreatic cancer with diabetes of 2- to 8-year duration.50 However, certain risk factors such as obesity, associated with both diabetes and pancreatic cancer, may confound these analyses.51 A meta-analysis including 44 studies showed that the strength of the association between diabetes and pancreatic cancer risk decreases with duration of diabetes, potentially due to the effects of long-term treatment of diabetes.52

The use of diabetic medications such as insulin and sulfonylureas has been found to be associated with an increased risk for pancreatic cancer.5355 On the other hand, metformin may be associated with a reduced risk for pancreatic and other cancers,5358 though a retrospective cohort study (n=980) showed that metformin did not significantly improve survival in diabetic patients diagnosed with pancreatic cancer.59

In addition, diabetes and diabetic medication may affect outcomes in patients with pancreatic cancer. Metformin use has been reported to result in higher pancreatic cancer survival in patients with diabetes. A retrospective analysis of 302 patients with pancreatic cancer and diabetes treated at The University of Texas MD Anderson Cancer Center found that metformin use was associated with increased survival at 2 years (30.1% vs 15.4%; P=.004) and increased overall survival (OS; 15.2 vs 11.1 months; P=.009).60 The OS difference was significant only in patients without distant metastases and remained significant when insulin users were excluded. In contrast, data from a meta-analysis of more than 38,000 patients show that those with pancreatic cancer and diabetes have a significantly lower OS than those without diabetes (14.4 vs 21.7 months; P<.001).46 A similar result was seen in a prospective cohort study, in which the survival of 504 patients with and without diabetes who developed pancreatic cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was compared.61 After multivariable adjustment, mortality was significantly higher in participants with diabetes compared with those without (HR, 1.52; 95% CI, 1.14–2.04; P<.01).

Genetic Predisposition

Pancreatic cancer is thought to have a familial component in approximately 10% of cases, and familial excess of pancreatic cancer is associated with high risk.15,6265 A retrospective review of 175 families in which a family history of pancreatic cancer was present showed that a genetic mutation was present in 28% of families.66 A prospective registry-based study of 5,179 individuals from 838 kindreds found that having just 1 first-degree relative with pancreatic cancer raises the risk for pancreatic cancer by 4.6-fold, whereas having 2 affected first-degree relatives raises the risk by about 6.4-fold.67 An analysis of 9,040 family members of 1,718 kindreds with pancreatic cancer showed that a family history of early-onset pancreatic cancer (ie, <50 years) was associated with greater risk of pancreatic cancer (standardized incidence ratio, 9.31; 95% CI, 3.42–20.28; P<.001), and lifetime risk of pancreatic cancer increases as the age of onset decreases (HR, 1.55; 95% CI, 1.19–2.03 per year).68 The genetic basis of this inherited predisposition is not known in most cases, and as many as 80% of patients with a family history of pancreatic cancer have no known genetic cause.62 The genes most commonly associated with pathogenic germline alterations are BRCA1, BRCA2, ATM, PALB2, MLH1, MSH2, MSH6, PMS2, CDKN2A, and TP53.69 Germline mutations in the STK11 gene result in Peutz-Jeghers syndrome, in which individuals have gastrointestinal polyps and an increased risk for colorectal cancer.7072 These individuals also have a highly elevated risk for developing pancreatic cancer, reported to be increased by as much as 132-fold.73,74 Furthermore, STK11 undergoes somatic mutation in approximately 5% of pancreatic cancers.75

As with nonhereditary forms of pancreatitis, familial pancreatitis is also associated with an increased risk for pancreatic cancer.76 Several genes are associated with the familial form of pancreatitis, including PRSS1, SPINK1, and CFTR.77 The increased risk for the development of pancreatic cancer in these individuals is estimated to be 26-fold to as high as 87-fold.35,7880

Familial malignant melanoma syndrome (also known as melanoma-pancreatic cancer syndrome or familial atypical multiple mole melanoma [FAMMM]) syndrome is caused by germline mutation of the CDKN2A (p16INK4a/p14ARF) gene.81 This syndrome is associated with a 20- to 47-fold increased risk for pancreatic cancer.82,83 In addition, patients with Melanoma-Pancreatic Cancer syndrome may experience an earlier onset of pancreatic cancer than the general population.84

Lynch syndrome is the most common form of genetically determined colorectal cancer predisposition and is caused by germline mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2).8590 Patients with Lynch syndrome also have an estimated 9- to 11-fold elevated risk for pancreatic cancer.91,92 In a sample of 96 patients with pancreatic cancer, 2 mutations were found in the MSH6 MMR gene.93

Microsatellite instability (MSI) is also a prognostic factor for survival in many cancers, notably for colon cancer although rare in pancreatic adenocarcinoma. Microsatellites are regions of coding and noncoding DNA where short sequences or single nucleotides of DNA are repeated. MSI is caused by a loss of DNA MMR activity. Mutations in germline MMR genes result in a lack of repair of any errors, such as destabilizing errors introduced during DNA replication that shorten or lengthen microsatellites, which then persist in somatic cells. Tumor samples can be assessed for the sizes of microsatellite markers and classified as MSI high (MSI-H), low (MSI-L), and stable (MSS).87,90 The NCCN Panel recommends MSI testing and/or MMR testing on available tumor tissue for patients with locally advanced or metastatic pancreatic adenocarcinoma.

An excess of pancreatic cancer is also seen in families harboring BRCA1/2 (breast cancer susceptibility gene-1 and -2) mutations, although the link with BRCA2 is better established.93100 Studies of unselected patients with pancreatic cancer have detected BRCA1/2 mutations at a frequency of 4%–7%.101,102 The risk for pancreatic cancer is elevated 2- to 6-fold in these patients, and the age of onset is younger than average in the general population.94,98,99 Patients with pancreatic cancer who have Ashkenazi Jewish ancestry may have a greater likelihood of testing positive for a BRCA1/2 mutation, with prevalence of detected mutations in this group ranging from 5.5% to 19%, with mutations being more common for BRCA2.96,102104

BRCA1/2 is also involved in the Fanconi DNA anemia/BRCA pathway. This pathway is responsible for the repair of DNA interstrand cross-links, and particular mutations in other Fanconi anemia/BRCA pathway genes, including in PALB2, FANCC, and FANCG, have also been identified as increasing pancreatic cancer susceptibility.100,105107

Whole-genome sequencing allowed for the identification of germline mutations in ATM, a DNA damage response gene, in 2 kindreds with familial pancreatic cancer.108 Further analyses then revealed ATM mutations in 4 of 166 individuals with familial pancreatic cancer. In a sample of 96 patients with pancreatic cancer, 4% had a mutation in ATM.93

Patients with pancreatic cancer for whom a hereditary cancer syndrome is suspect should be considered for genetic counseling.109 The panel emphasizes the importance of taking a thorough family history when seeing a new patient with pancreatic cancer. In particular, a family history of pancreatitis, melanoma, and cancers of the pancreas, colorectum, breast, and ovaries should be noted. A free online pancreatic cancer risk prediction tool, called PancPRO, is available and may help determine risk.65 Referral for genetic counseling may be considered for patients diagnosed with pancreatic cancer, especially those who have a family history of cancer or who are young, as well as those of Ashkenazi Jewish ancestry. The panel recommends germline testing in any patient with confirmed pancreatic cancer and in those in whom there is a clinical suspicion for inherited susceptibility (see the NCCN Guidelines for Genetic/Familial High-Risk Assessment, Breast, Ovarian, and Pancreatic, available at NCCN.org). The panel currently does not identify a specific age to define early-onset pancreatic cancer, though age 50 has been used in previous studies of familial pancreatic cancer.68 If a cancer syndrome is identified, at-risk relatives should be offered genetic counseling. With or without a known syndrome, individuals with a suspicious family history should be advised on risk-reducing strategies including smoking cessation and weight loss. In addition, the possibility of screening for pancreatic (see subsequent section) and other cancers should be discussed. For patients with locally advanced or metastatic disease who are candidates for anticancer therapy, the NCCN Panel recommends testing for actionable somatic mutations, including but not limited to fusions (ALK, NRG1, NTRK, ROS1), mutations (BRAF, BRCA 1/2, HER2, KRAS, PALB2), and MMR deficiency.

Premalignant Tumors of the Pancreas

Mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are cystic lesions that can be small and asymptomatic and are often discovered incidentally; MCNs have an ovarian-like stroma.110112 IPMNs can occur in the main duct and/or in the branch ducts. Lesions involving the main duct have a higher malignant potential than those in the branches, with the risk of malignancy at around 62%.113 The risk of malignancy in MCNs is <15%.113

An international group of experts has established guidelines for the management of pancreatic IPMNs and MCNs,114 as has a European group.115 The international group strongly recommends resection in fit patients with main duct IPMNs ≥ 10 mm.113 For branch-duct IPMNs, surveillance is considered an appropriate option in patients who are older or unfit or for cysts lacking high-risk stigmata. Branch-duct IPMNs that have an enhancing mural nodule ≥ 5 mm, or are in the head of the pancreas causing obstructive jaundice should be considered for resection.113 Patients with resected IPMNs are followed with imaging studies to identify recurrences. For MCNs, the international group recommends resection for all fit patients, and recurrences are not observed.113 The European group gives similar recommendations.115

Systemic Therapy Approaches for Locally Advanced or Metastatic Disease

The data supporting the regimens used in pancreatic cancer are described in subsequent sections (also summarized in Table 2, available in these guidelines at NCCN.org).

FOLFIRINOX and Modified FOLFIRINOX

In 2003, a French group reported the results of an open phase I study to assess the feasibility of a combination therapy consisting of 5-FU/leucovorin plus oxaliplatin and irinotecan (FOLFIRINOX) for the treatment of patients with metastatic solid tumors.116 Their study included 2 patients with pancreatic cancer, and the regimen showed antitumor activity. A subsequent multicenter phase II trial specifically for patients with advanced pancreatic adenocarcinoma demonstrated promising response rates.117 A later randomized phase II trial showed a response rate of >30% to FOLFIRINOX in patients with metastatic pancreatic cancer.118

Results from the randomized phase III PRODIGE trial evaluating FOLFIRINOX versus gemcitabine in patients with metastatic pancreatic cancer and good performance status showed dramatic improvements in both median progression-free survival (PFS) (6.4 vs 3.3 months; P<.001) and median OS (11.1 vs 6.8 months; P<.001), in favor of the group receiving FOLFIRINOX.119 Eligibility criteria for this trial, however, were stringent, limiting real-world generalizability.120 For example, patients with abnormal bilirubin levels were excluded from participating.

A systematic review including 11 studies and 315 patients with locally advanced pancreatic cancer showed a pooled median OS of 24.2 months (95% CI, 21.7–26.8).121 An observational study including 101 patients with locally advanced unresectable disease who were treated with FOLFIRINOX as induction therapy showed that 29% of the sample (20% without administration of chemoradiation) had a reduction in tumor size of greater than 30%, and half of the patients who experienced a reduction in tumor size underwent resection.122 Out of the patients who underwent resection, 55% achieved an R0 resection.

Because of the strong results from the PRODIGE trial, FOLFIRINOX is included as a preferred, category 1 recommendation for first-line treatment of patients with good performance status (ie, ECOG 0-1) with metastatic pancreatic cancer. It is listed as a category 2A recommendation for patients with locally advanced disease by extrapolation. The panel also lists this regimen as an acceptable option in the neoadjuvant/borderline resectable setting.

There are some concerns about the toxicity of the FOLFIRINOX regimen. In the PRODIGE trial, some of the grade 3-4 toxicity rates that were significantly greater in the FOLFIRINOX group than in the gemcitabine group were 45.7% for neutropenia, 12.7% for diarrhea, 9.1% for thrombocytopenia, and 9.0% for sensory neuropathy.119 Despite the high levels of toxicity, no toxic deaths have been reported.117119 Furthermore, the PRODIGE trial determined that, despite this toxicity, fewer patients in the FOLFIRINOX group than in the gemcitabine group experienced a degradation in their quality of life at 6 months (31% vs 66%, P<.01).119 A more detailed analysis of the quality of life of patients in this trial was published and showed that FOLFIRINOX maintained and even improved quality of life more so than gemcitabine.123

The panel appreciates that the toxicity of FOLFIRINOX can be managed with a variety of approaches. For example, a group from Memorial Sloan Kettering Cancer Center reported good activity and acceptable toxicity of first-line FOLFIRINOX at 80% dose intensity with routine growth factor support in carefully selected patients with metastatic or locally advanced disease.124 Median OS was 12.5 months in the metastatic setting and 13.7 months in patients with locally advanced disease.

The efficacy and toxicity of a modified FOLFIRINOX regimen in which the initial dosing of bolus 5-FU and irinotecan were each reduced by 25% were assessed in a phase II single-arm prospective trial (n=75).125 In patients with metastatic disease, the efficacy of the modified regimen was comparable to that of the standard regimen (median OS, 10.2 months). In patients with locally advanced disease, the median OS was 26.6 months. Patients who received the modified regimen experienced significantly less neutropenia, fatigue, and vomiting, relative to patients who received the standard FOLFIRINOX regimen. Thus, to reduce the toxicity associated with FOLFIRINOX and improve its tolerability, the modified FOLFIRINOX regimen is also included as a preferred treatment option.

Gemcitabine Monotherapy

For patients with locally advanced or metastatic disease, gemcitabine has been established as providing clinical benefit and a modest survival advantage over treatment with bolus 5-FU.126 The panel recommends gemcitabine monotherapy as one option for front-line therapy for patients with locally advanced or metastatic disease (category 1) disease and a good performance status. Because the approved indications for gemcitabine include the relief of symptoms, the panel also recommends gemcitabine monotherapy as a reasonable first-line and second-line option for symptomatic patients with locally advanced or metastatic disease with poor performance status (category 1).

Gemcitabine monotherapy also has category 1 evidence supporting its use in the adjuvant setting. In the large phase III CONKO-001 trial, in which 368 patients without prior chemotherapy or radiation therapy were randomly assigned to adjuvant gemcitabine versus observation after macroscopically complete resection, an intention-to-treat analysis of the data showed that the primary endpoint of increased DFS was met (13.4 vs 6.9 months; P<.001, log rank).127 Final results from this study showed median OS to be improved significantly for patients in the gemcitabine arm (22.8 vs 20.2 months; HR, 0.76; 95% CI, 0.61–0.95; P=.01).128 An absolute survival difference of 10.3% was observed between the 2 groups at 5 years (20.7% vs 10.4%).128

Gemcitabine Response: hENT1

Human equilibrative nucleoside transporter 1 (hENT1) is a nucleoside transporter that has been studied as a predictor for response to gemcitabine.129 Preliminary clinical data showed that hENT1 expression may in fact predict response to gemcitabine.130135

hENT1 was validated as a predictive biomarker for benefit from gemcitabine in the adjuvant setting. A meta-analysis including 7 studies with 770 patients with resected pancreatic cancer showed that hENT1 expression was associated with DFS (HR, 0.58; 95% CI, 0.42–0.79) and OS (HR, 0.52; 95% CI, 0.38–0.72) in patients who received adjuvant gemcitabine, but not in patients who received adjuvant fluoropyrimidine-based therapy.136 Two retrospective analyses from ESPAC-3 and RTOG-9704 found the same results, although results from the adjuvant CONKO-001 trial and the AIO-PK0104 trial were unable to confirm these results using a different antibody for the immunohistochemical analysis (SP120).137,138

Unfortunately, hENT1 could not be validated in the metastatic setting in the LEAP trial, which also used the SP120 assay to determine hENT1 expression.

Further studies based on hENT1 expression using the 10D7G2 assay are limited by the fact that no commercial source of the antibody and no CLIA-approved testing are available.

Fixed-Dose-Rate Gemcitabine

Studies have suggested that the infusion rate of gemcitabine may be important for its efficacy. Gemcitabine is a prodrug, which must be phosphorylated for antitumor activity. Clinical studies have shown that administering gemcitabine at a fixed dose rate (FDR) maximizes intracellular concentrations of the phosphorylated forms of gemcitabine.139 In a randomized phase II trial of patients with locally advanced or metastatic pancreatic cancer, the infusion of gemcitabine at an FDR led to better survival compared with gemcitabine delivered at a higher dose, over 30 minutes.140 In the phase III randomized ECOG-6201 trial of patients with advanced pancreatic cancer, median survival was increased in the group receiving FDR gemcitabine versus standard gemcitabine (6.2 vs 4.9 months; P=.04), although this outcome did not satisfy the protocol-specified criteria for superiority.141 When gemcitabine is considered for the treatment of advanced pancreatic cancer, the NCCN Panel views FDR gemcitabine (10 mg/m2/min) as a reasonable alternative to the standard infusion of gemcitabine over 30 minutes (category 2B).

FDR gemcitabine is incorporated into some commonly used gemcitabine-based regimens (eg, GEMOX [gemcitabine and oxaliplatin]; GTX [gemcitabine, docetaxel, and capecitabine]). See “Gemcitabine Combinations,” next section.142,143 The combination of FDR gemcitabine and capecitabine has also been found to be active and well-tolerated.144

Gemcitabine Combinations

The NCCN Panel acknowledges that, historically, combination chemotherapy did not appear to be superior to monotherapy in the era of 5-FU–based therapy. However, because gemcitabine is superior to bolus 5-FU in the advanced setting when efficacy endpoints of survival and relief from symptoms are used, it is now often combined with other chemotherapeutic agents for patients with good performance status. Gemcitabine has been investigated in combination with potentially synergistic agents (such as cisplatin, oxaliplatin, capecitabine, 5-FU, and irinotecan) or in a multidrug combination (eg, cisplatin, epirubicin, gemcitabine, 5-FU).141143,145155 Two meta-analyses of randomized controlled trials (RCTs) found that gemcitabine combinations give a marginal benefit in OS over gemcitabine monotherapy in the advanced setting, with a significant increase in toxicity.156,157

Combinations recommended in the advanced setting are discussed subsequently. The panel does not consider the combination of gemcitabine plus docetaxel158 or gemcitabine plus irinotecan155,158,159 to meet the criteria for inclusion in the guidelines. In addition, gemcitabine plus sorafenib is not recommended. The multicenter, double-blind, placebo-controlled, randomized phase III BAYPAN trial compared gemcitabine plus either sorafenib or placebo in chemotherapy-naïve patients with advanced or metastatic disease.160 This trial did not meet its primary endpoint of PFS in its 104 patients (5.7 vs 3.8 months; P=.90). Gemcitabine combinations are currently being used and studied in the adjuvant setting.

Of note, results from several studies have indicated that the benefit of gemcitabine combination chemotherapy is predominantly seen in patients with good performance status.149,150,152

Gemcitabine Plus Albumin-Bound Paclitaxel

Albumin-bound paclitaxel is a nanoparticle form of paclitaxel. In a publication of a phase I–II trial, 67 patients with advanced pancreatic cancer received gemcitabine plus albumin-bound paclitaxel. At the maximum tolerated dose, the partial response rate was 48%, with an additional 20% of patients demonstrating stable disease for 16 or more weeks. The median OS at this dose was 12.2 months.161

Based on these results, the large, open-label, international, randomized, phase III MPACT trial was initiated in 861 patients with metastatic pancreatic cancer and no prior chemotherapy.162 Participants were randomized to receive gemcitabine plus albumin-bound paclitaxel or gemcitabine alone. The trial met its primary endpoint of OS (8.7 vs 6.6 months; P<.0001; HR, 0.72).162 The addition of albumin-bound paclitaxel also improved other endpoints, including 1-year survival, 2-year survival, response rate, and PFS. OS was associated with a decrease in CA 19-9 (HR, 0.53; 95% CI, 0.36–0.78; P=.001).163 Tumor response was validated with PET imaging.164 The most common grade 3 or higher adverse events attributable to albumin-bound paclitaxel were neutropenia, fatigue, and neuropathy. Development of peripheral neuropathy was associated with longer treatment duration and greater treatment efficacy.165 Updated results of the MPACT trial show that long-term survival is possible with gemcitabine plus albumin-bound paclitaxel, as 3% of patients from that arm were alive at 42 months, whereas no patients were alive from the control arm at that time.166 Factors associated with survival in this trial include Karnofsky performance status score and absence of liver metastases.167

Gemcitabine plus albumin-bound paclitaxel is a category 1 recommendation for the treatment of patients with metastatic disease and good performance status based on these results, and is listed as a preferred option in this setting. Good performance status for this regimen is defined as ECOG 0-2, since the clinical trial used Karnofsky performance status ≥70 as an eligibility criterion.162,166 Therefore, some patients with an ECOG score of 2 may be eligible to receive this regimen.168,169 By extrapolation of the data, the panel recommends this combination in the locally advanced, good performance status setting as well (category 2A). The panel also notes that this combination is an acceptable option in the neoadjuvant/borderline resectable setting

Gemcitabine Plus Cisplatin

Data regarding the survival impact of combining gemcitabine with a platinum agent are conflicting, and results of RCTs have not provided support for use of gemcitabine plus cisplatin in the treatment of patients with advanced pancreatic cancer. Three phase III trials evaluating the combination of gemcitabine with cisplatin versus gemcitabine alone in patients with advanced pancreatic cancer failed to show a significant survival benefit for the combination over the single agent.146,147,150

Nevertheless, selected patients may benefit from this regimen because patients with breast and ovarian cancers who are carriers of a BRCA mutation170172 and selected patients with inherited forms of pancreatic cancer96 may have disease that is particularly sensitive to a platinum agent. A retrospective study from Johns Hopkins University School of Medicine of patients with metastatic pancreatic cancer and a family history of breast, ovarian, or pancreatic cancers suggested that response to gemcitabine and cisplatin was superior even with one affected relative.173 Patients with a family history of pancreatic cancer alone demonstrated a large survival advantage when treated with platinum-based chemotherapy (6.3 vs 22.9 months; HR, 0.34; 95% CI, 0.15–0.74; P<.01).173 Furthermore, a report of 5 of 6 patients with known BRCA mutations and metastatic pancreatic adenocarcinoma treated with a platinum-based regimen at Memorial Sloan Kettering Cancer Center showed a radiographic partial response.174 Thus, gemcitabine plus cisplatin may be a good choice in selected patients with disease characterized by hereditary risk factors (eg, BRCA or PALB2 mutations). The panel recommends gemcitabine plus cisplatin for patients with metastatic or locally advanced disease, only for known BRCA1/2 or PALB2 mutations. FOLFIRINOX and modified FOLFIRINOX are also possible treatment options for patients with BRCA 1/2 and PALB2 mutations.

Gemcitabine Plus Erlotinib and Other Targeted Therapeutics

Results of phase III studies of combinations of gemcitabine with a biologic agent have indicated that only the combination of gemcitabine plus erlotinib is associated with a statistically significant increase in survival when compared with gemcitabine alone.175179 In the phase III, double-blind, placebo-controlled NCIC CTG PA.3 trial of 569 patients with advanced or metastatic pancreatic cancer randomly assigned to receive erlotinib (which is an inhibitor of epidermal growth factor receptor tyrosine kinase) plus gemcitabine versus gemcitabine alone, patients in the erlotinib arm showed statistically significant improvements in OS (HR, 0.82; P=.038) and PFS (HR, 0.77; P=.004) when compared with patients receiving gemcitabine alone.175 Median survival was 6.24 months and 1-year survival was 23%, compared with 5.91 months and 17% in the control arm. Adverse events, such as rash and diarrhea, were increased in the group receiving erlotinib, but most were grade 1 or 2.175 This trial, other trials, and community experience show that occurrence of grade 2 or higher skin rash is associated with better response and OS of patients receiving erlotinib.175,180,181

The NCCN Panel recommends the gemcitabine-erlotinib combination therapy as a treatment option, under other recommended regimens, for patients with locally advanced or metastatic disease and good performance status, with this combination being a category 1 recommendation for patients with metastatic disease. However, the panel notes that although this combination significantly improved survival, the actual benefit was small, suggesting that only a small subset of patients benefit.

Gemcitabine Plus Capecitabine

A number of randomized trials have investigated the combination of gemcitabine with capecitabine, a fluoropyrimidine, in patients with advanced pancreatic cancer. A randomized study in 533 patients with advanced disease found that PFS and objective response rates were significantly improved in patients receiving gemcitabine plus capecitabine when compared with gemcitabine alone, although a trend toward an improvement in OS for the combination arm did not reach statistical significance.148 Similarly, results from another smaller phase III trial evaluating this combination did not demonstrate an OS advantage for overall study population receiving the combination of gemcitabine with capecitabine, although a posthoc analysis showed OS to be significantly increased in the subgroup of patients with good performance status.152 Results from a third randomized phase III trial also showed that gemcitabine with capecitabine did not significantly improve OS, compared with gemcitabine alone, though patients who received gemcitabine with capecitabine had a greater overall response rate (ORR), compared with patients who received gemcitabine only (43.7% vs 17.6%, respectively; P=.001).182 In a meta-analysis of 8 RCTs, OS was better in patients receiving gemcitabine plus capecitabine than in patients receiving gemcitabine alone (HR, 0.87; P=.03).183 Although there are concerns about dosing and toxicity of capecitabine in a US population, a biweekly regimen of fixed-dose gemcitabine in combination with capecitabine may be both effective and well-tolerated in patients with advanced disease.144

The panel includes the combination of gemcitabine, docetaxel, and capecitabine (GTX regimen) as a category 2B recommendation for the treatment of patients with metastatic or locally advanced disease and good performance status. In a report of 35 patients with metastatic pancreatic cancer treated with this regimen, the authors reported an ORR of 29% (all had partial responses), with an additional 31% of patients exhibiting a minor response or stable disease.143 The median survival was 11.2 months for all patients and 13.5 months for patients exhibiting a partial response. This regimen demonstrated significant toxicities, however, with 14% of patients having grade 3-4 leukopenia, 14% having grade 3-4 thrombocytopenia, and 9% having grade 3/4 anemia. A retrospective case-review study at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins found similar results, with a median OS of 11.6 months and grade 3 or greater hematologic and nonhematologic toxicity rates of 41% and 9%, respectively.184

Gemcitabine combined with capecitabine and oxaliplatin (GEMOXEL) was recently assessed in a randomized phase II trial (n=67) for the metastatic setting.185 Disease control rate (P=.004), PFS (P<.001), and OS (P<.001) were all superior in patients randomized to receive the GEMOXEL regimen, compared with patients randomized to receive gemcitabine alone.

The NCCN Panel considers gemcitabine-based combination therapy with capecitabine to be a reasonable option (category 2A) for patients with locally advanced or metastatic disease and a good performance status who are interested in pursuing more aggressive therapy outside a clinical trial.

Gemcitabine and Other Fluoropyrimidine-Based Therapies

Gemcitabine has been examined in combination with other fluoropyrimidine-based therapies. A recent meta-analysis of 8 RCTs, including more than 2,000 patients, found that OS was significantly improved when a fluoropyrimidine was added to gemcitabine.183 In a phase II randomized trial, the effects of the FIRGEM regimen [irinotecan delivered before and after infusion of 5-FU/leucovorin (FOLFIRI.3), alternating with FDR gemcitabine] were assessed in 98 patients with metastatic pancreatic cancer.186 Patients were randomized to receive the FIRGEM regimen or FDR gemcitabine monotherapy. The primary objective of a 45% PFS rate at 6 months was reached, and PFS was a median of 5.0 months in those randomized to receive the FIRGEM regimen, while those randomized to receive only gemcitabine had a median PFS of 3.4 months (HR, 0.59; 95% CI, 0.38–0.90). Rates of hematologic toxicity were higher in those who received the FIRGEM regimen, relative to those who received gemcitabine only. Study investigators deemed FIRGEM to be effective and feasible in the metastatic setting.

The ECOG E2297 trial compared gemcitabine monotherapy with gemcitabine and bolus 5-FU/leucovorin in patients with advanced pancreatic cancer; no statistically significant survival advantage was observed for patients receiving the combination regimen.145

Recent randomized trials from Asia show that gemcitabine combined with the oral fluoropyrimidine S-1 may improve response and survival in patients with locally advanced pancreatic cancer, though trial results are inconsistent regarding whether outcomes are improved over gemcitabine monotherapy.187189

Capecitabine and Continuous Infusion 5-FU

The panel lists capecitabine monotherapy and continuous infusion 5-FU as first-line and second-line treatment options for patients with locally advanced disease (category 2B), and for patients with poor performance status and metastatic disease (category 2B). They are also recommended as options in the adjuvant settings (category 2A for continuous infusion 5-FU and category 2B for capecitabine). The capecitabine recommendation is supported by a randomized phase III trial from the Arbeitsgemeinschaft Internistische Onkologie (AIO) group in which OS was similar in patients with advanced pancreatic cancer receiving capecitabine plus erlotinib followed by gemcitabine monotherapy or gemcitabine plus erlotinib followed by capecitabine monotherapy.190

Note that the capecitabine dose recommended by the panel (1,000 mg/m2 by mouth twice daily) is less than the dose described by Cartwright et al, because the higher dose has been associated with increased toxicity (eg, diarrhea, hand and foot syndrome).191

Fluoropyrimidine Plus Oxaliplatin

The combination of a fluoropyrimidine (5-FU/leucovorin or capecitabine) with oxaliplatin is listed as a possible first-line treatment of metastatic or locally advanced disease (category 2B). The panel bases these recommendations on the randomized phase III CONKO-003 trial (5-FU/leucovorin/oxaliplatin [OFF] vs best supportive care) and on a phase II study (CapeOx).192,193 Both of these studies only enrolled patients who had received 1 prior chemotherapy regimen, but the panel feels the extrapolation to first-line therapy is appropriate (category 2B).

Maintenance Therapy in Advanced Disease

With the success of more effective regimens in patients with advanced disease, questions have been raised about how best to manage the treatment-free interval prior to disease progression. Options include continuing systemic therapy, stopping treatment, dropping the most toxic agents, and using different agents for maintenance therapy.

Based on the fact that the BRCA genes encode for proteins involved in homologous recombination repair and that cells with mutations are sensitive to poly (ADP ribose) polymerase (PARP) inhibitors, the efficacy of olaparib, a PARP inhibitor, was investigated. In a phase II trial assessing its efficacy and safety, the tumor response rate for patients with metastatic pancreatic cancer and a germline BRCA1/2 mutation (n=23) was 21.7% (95% CI, 7.5–43.7).194 Following this, in the randomized, double-blind, placebo-controlled phase 3 POLO trial, olaparib was found to be an effective maintenance therapy agent for patients with metastatic pancreatic cancer and germline BRCA 1/2 mutations and no disease progression following at least 16 weeks of first-line platinum-based therapy. A total of 154 patients were randomized to receive either olaparib or placebo. In the olaparib arm, the median PFS was 7.4 months compared with 3.8 months in the placebo arm (95% CI 0.35-0.82, P=.004). At interim, however, there was found to be no difference in OS between the olaparib and placebo groups (18.9 vs 16.1 months, 95% CI 0.56-1.46, P=.68). Adverse events, such as those grade 3 or higher, were found to be higher in the olaparib arm than in the placebo arm (40% vs 23%).195 Based on this data, olaparib is recommended by the NCCN Panel as a preferred targeted maintenance therapy for patients with germline BRCA-mutated metastatic disease and no disease progression after 4 to 6 months of first-line platinum-based therapy. Other maintenance therapy options for patients include clinical trial enrollment; gemcitabine-based therapy for patients who received previous first-line gemcitabine and nab-paclitaxel; or capecitabine, 5-FU with or without irinotecan, or FOLFOX for patients who received previous FOLFIRINOX. The NCCN Panel has included 5-FU with or without irinotecan for patients who exhibited oxaliplatin-related progressive neuropathy or allergy. Finally, if irinotecan-related gastrointestinal toxicity is of concern, then FOLFOX may be a suitable maintenance therapy.

Subsequent Therapy in the Advanced Setting

A systematic review of clinical trials that assessed the efficacy of subsequent therapy after gemcitabine in pancreatic cancer concluded that, while data are very limited, evidence suggests an advantage of additional chemotherapy over best supportive care.196 For patients with advanced disease who have received prior gemcitabine-based therapy, fluoropyrimidine-based chemotherapy regimens are acceptable subsequent options.192,193,197,198 Gemcitabine-based therapy can be given to those previously treated with fluoropyrimidine-based therapy.

Results from the phase III CONKO-003 trial showed significant improvements in both median PFS (13 vs 9 weeks; P=.012) and median OS (20 vs 13 weeks; P=.014) when oxaliplatin was added to 5-FU/leucovorin,199,200 making this regimen the standard approach for subsequent therapy for patients without prior exposure to fluoropyrimidine-based therapy at that time. Final results of the trial were published in 2014.201 The median OS in the OFF arm was 5.9 months (95% CI, 4.1–7.4), whereas it was 3.3 months (95% CI, 2.7–4.0) in the 5-FU/leucovorin arm, for a significant improvement in the HR (0.66; 95% CI, 0.48–0.91; P=.01).

However, results from the open-label phase III PANCREOX trial show that the addition of oxaliplatin to 5-FU/leucovorin (OFF) in subsequent treatment may be detrimental.202 In this trial, 108 patients with advanced pancreatic cancer who progressed on gemcitabine-based treatment were randomized to receive second-line mFOLFOX6 or infusional 5-FU/ leucovorin. No difference was seen in median PFS (3.1 vs 2.9 months; P=.99), but median OS was worse in those in the FOLFOX arm (6.1 vs 9.9 months; P=.02). Furthermore, the addition of oxaliplatin resulted in increased toxicity, with rates of grade 3/4 adverse events of 63% in the FOLFOX arm and of 11% in the 5-FU/ leucovorin arm. However, this trial was limited by imbalances in PS 2 proportion between the study arms and possible crossover in treatment delivered following progression.203 The randomized phase II SWOG S1115 trial showed that patients with metastatic disease that failed to respond to gemcitabine-based therapy (n=62) who received mFOLFOX (fluorouracil and oxaliplatin) had a median OS of 6.7 months, which is comparable to the median OS rates found in the CONKO-003 and PANCREOX trials.204

In the NAPOLI-1 phase III randomized trial, the effects of nanoliposomal irinotecan were examined in patients with metastatic pancreatic cancer who previously received gemcitabine-based therapy.205 Patients were randomized to receive nanoliposomal irinotecan monotherapy, 5-FU/leucovorin, or both (n=417). Median PFS (3.1 vs 1.5 months; HR, 0.56; 95% CI, 0.41–0.75; P<.001) was significantly greater for patients who received nanoliposomal irinotecan with 5-FU/leucovorin, compared with patients who did not receive irinotecan. Updated analyses showed that median OS (6.2 vs 4.2 months; HR, 0.75; P=.042) was significantly greater for patients who received nanoliposomal irinotecan with 5-FU/leucovorin, compared with patients who received 5-FU/leucovorin without irinotecan.206 Grade 3 or 4 adverse events that occurred most frequently with this regimen were neutropenia (27%), fatigue (14%), diarrhea (13%), and vomiting (11%).205 Irinotecan liposomal injection, combined with 5-FU/leucovorin, was later approved by the FDA to be used as a subsequent treatment option after gemcitabine-based therapy in patients with metastatic disease. The panel recommends this regimen as a subsequent treatment option for patients with good performance status and disease progression.

Another subsequent therapy option in patients with good performance status and locally advanced or metastatic disease is 5-FU + leucovorin + irinotecan (FOLFIRI). A phase II trial found comparable efficacy and safety in patients treated with mFOLFOX (n=30) and modified FOLFIRI-3 (n=21) regimens whose disease had failed previous gemcitabine treatment; OS was 14.9 and 16.6 weeks, respectively.207 Another phase II trial studied 63 patients with metastatic disease and failure in 1 to 3 lines of gemcitabine- and platinum-based chemotherapies, who received FOLFIRI (in 2 different schedules reported together; FOLFIRI-1 and -3).208 The median OS was 6.6 months (95% CI, 5.3–8.1 months). Patients who had grade 3-4 toxicities (23.8%) experienced mainly hematologic or digestive toxicities. A GISCAD multicenter phase II study of locally advanced or metastatic disease evaluated the FOLFIRI-2 regimen in patients previously treated with gemcitabine with or without platinum-based therapies.209 The OS was 5 months and the toxicity was manageable; patients experienced grade 3–4 neutropenia (20%) and diarrhea (12%).

The AIO-PK0104 trial also assessed subsequent therapy in a randomized crossover trial and found capecitabine to be efficacious after progression on gemcitabine/erlotinib in patients with advanced disease.210 In this trial, capecitabine/erlotinib followed by gemcitabine gave similar outcomes to the aforementioned sequence.

Advances in research have revealed that human immune-checkpoint–inhibitor antibodies that inhibit the interactions between immune cells and antigen-presenting cells may also do so in tumor cells.211 There is evidence that PD-1 blockade with pembrolizumab may be effective in tumors with MMR deficiency (dMMR).212 Pembrolizumab is an anti-PD-1 receptor antibody and blocks its interaction with PD-L1 and PD-L2, releasing the PD-1–mediated inhibition of the immune response, which improves antitumor immunity. The results of a phase II study in patients with 12 different dMMR advanced cancers, including pancreas, found that treatment with pembrolizumab resulted in durable responses (ORR in 53% of patients, with 21% complete response).213 There were 6 patients with pancreatic cancer with an ORR in 62% of patients (2 had complete response and 3 had progressive disease). Adverse events were experienced by 74% of all patients receiving pembrolizumab; most were low grade (20% experienced grade 3 or 4 adverse events, such as diarrhea/colitis, pancreatitis/hyperamylasemia, fatigue, arthritis/arthralgias, or anemia).213 Adverse events, however, for immune checkpoint inhibitors can be significant; see the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities, available at NCCN.org.

Based on these data, pembrolizumab was granted accelerated FDA approval in 2017 for patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. Similar results were reported from the phase II KEYNOTE-158 study. Among 27 noncolorectal tumor types, including pancreatic cancer, with a median follow-up of 13.4 months, the ORR was reported to be 34.3% (95% CI 28.3%–40.8%), the median PFS was 4.1 months (95% CI 2.4-4.9 months), and the median OS was 23.5 months.214 Pembrolizumab is recommended by the NCCN Panel for the advanced disease setting for first-line and subsequent treatment as appropriate.

Finally, neurotrophin receptor kinase (NTRK) gene fusions, although rare, have been implicated in the oncogenesis of pancreatic cancer. In 3 multicenter, open-label, single-arm trials (a phase 1 study with adults, a phase I-II study with children, and a phase II study with adolescents and adults), the efficacy and safety of larotrectinib, an NTRK inhibitor, was investigated.215,216 The primary endpoint was set to be ORR and the secondary endpoints were determined to be PFS, duration of response, and safety. Among 17 tumor types, the ORR during independent review was 75% (95% CI, 61–85). After 9.4 months, 86% of participants had either underwent curative surgery or were continuing treatment. At 1 year, 55% of patients were progression-free and the toxicity profile of the agent was found to be minimal.215 Based on this data, larotrectinib was approved by the FDA in 2018 for the treatment of NTRK gene fusion positive solid tumors in adult and pediatric patients with known acquired resistance and advanced or morbid disease that has progressed despite treatment.216 Updated data published in 2020 reported that the percentage of patients with an objective response was 79% (95% CI 72-85) with 16% of patients showing a complete response.217 Similarly, entrectinib is another NTRK inhibitor approved in 2019 by the FDA for adult and pediatric patients (ages 12 years and older) with advanced, morbid, or unresectable NTRK gene fusion positive solid tumors with acquired resistance to standard treatment.218 Data from 3 phase I-II trials (ALKA-372-001, STARTRK-1, and STARTRK-2) revealed that entrectinib had an ORR of 57.4% and a median duration of response (DOR) of 10.4 months. Like its predecessor, it had a tolerable safety profile.219,220 Thus the NCCN Panel recommends larotrectinib and entrectinib as first-line and subsequent treatment options for patients with NTRK gene fusion positive locally advanced or metastatic pancreatic adenocarcinoma.

To summarize, subsequent treatment options for patients with good performance status and previously treated with gemcitabine-based therapy include: 5-FU/leucovorin/liposomal irinotecan (category 1 for metastatic disease), FOLFIRI, FOLFIRINOX or modified FOLFIRINOX, 5-FU/leucovorin/oxaliplatin (OFF), FOLFOX, CapeOx, capecitabine, or continuous infusion 5-FU.Options for patients with good performance status and previously treated with fluoropyrimidine-based therapy include: 5-FU/leucovorin/nanoliposomal irinotecan (if no prior irinotecan administered), gemcitabine/albumin-bound paclitaxel, gemcitabine/cisplatin, gemcitabine/erlotinib, or gemcitabine monotherapy. Chemoradiation may be a subsequent treatment option in select patients (see “Management of Locally Advanced Disease,” in these NCCN Guidelines at NCCN.org). For MSI-H or dMMR tumors, pembrolizumab is an option, whereas for NTRK gene fusion positive disease, larotrectinib or entrectinib may be considered. Subsequent treatment options for patients with poor performance status include gemcitabine (standard infusion as a category 1 and fixed-dose-rate as a category 2B recommendation), capecitabine (category 2B recommendation), and continuous infusion 5-FU (category 2B recommendation).

F1
F2
F3
F4

References

  • 1.

    Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin 2021;71:733.

  • 2.

    Arnold LD, Patel AV, Yan Y, et al. Are racial disparities in pancreatic cancer explained by smoking and overweight/obesity? Cancer Epidemiol Biomarkers Prev 2009;18:23972405.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Simard EP, Ward EM, Siegel R, et al. Cancers with increasing incidence trends in the United States: 1999 through 2008. CA Cancer J Clin 2012;62:118128.

  • 4.

    Eheman C, Henley SJ, Ballard-Barbash R, et al. Annual Report to the Nation on the status of cancer, 1975-2008, featuring cancers associated with excess weight and lack of sufficient physical activity. Cancer 2012;118:23382366.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Smith BD, Smith GL, Hurria A, et al. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol 2009;27:27582765.

  • 6.

    StatBite. StatBite. U.S. pancreatic cancer rates. J Natl Cancer Inst 2010;102:1822.

  • 7.

    Worni M, Guller U, White RR, et al. Modest improvement in overall survival for patients with metastatic pancreatic cancer: a trend analysis using the surveillance, epidemiology, and end results registry from 1988 to 2008. Pancreas 2013;42:11571163.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Visser BC, Ma Y, Zak Y, et al. Failure to comply with NCCN Guidelines for the management of pancreatic cancer compromises outcomes. HPB (Oxford) 2012;14:539547.

  • 9.

    Hoos WA, James PM, Rahib L, et al. Pancreatic cancer clinical trials and accrual in the United States. J Clin Oncol 2013;31:34323438.

  • 10.

    U.S. National Library of Medicine-Key MEDLINE® Indicators. Accessed July 24, 2014. Available at: http://www.nlm.nih.gov/bsd/bsd_key.html

    • PubMed
    • Export Citation
  • 11.

    Anderson MA, Zolotarevsky E, Cooper KL, et al. Alcohol and tobacco lower the age of presentation in sporadic pancreatic cancer in a dose-dependent manner: a multicenter study. Am J Gastroenterol 2012;107:17301739.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Bosetti C, Lucenteforte E, Silverman DT, et al. Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4). Ann Oncol 2012;23:18801888.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Hassan MM, Bondy ML, Wolff RA, et al. Risk factors for pancreatic cancer: case-control study. Am J Gastroenterol 2007;102:26962707.

  • 14.

    Lynch SM, Vrieling A, Lubin JH, et al. Cigarette smoking and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. Am J Epidemiol 2009;170:403413.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Raimondi S, Maisonneuve P, Lowenfels AB. Epidemiology of pancreatic cancer: an overview. Nat Rev Gastroenterol Hepatol 2009;6:699708.

  • 16.

    Vrieling A, Bueno-de-Mesquita HB, Boshuizen HC, et al. Cigarette smoking, environmental tobacco smoke exposure and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2010;126:23942403.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Mancuso TF, el-Attar AA. Cohort study of workers exposed to betanaphthylamine and benzidine. J Occup Med 1967;9:277285.

  • 18.

    Antwi SO, Eckert EC, Sabaque CV, et al. Exposure to environmental chemicals and heavy metals, and risk of pancreatic cancer. Cancer Causes Control 2015;26:15831591.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Alsamarrai A, Das SL, Windsor JA, Petrov MS. Factors that affect risk for pancreatic disease in the general population: a systematic review and meta-analysis of prospective cohort studies. Clin Gastroenterol Hepatol 2014;12:16351644.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Lucenteforte E, La Vecchia C, Silverman D, et al. Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4). Ann Oncol 2012;23:374382.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Bagnardi V, Rota M, Botteri E, et al. Alcohol consumption and site-specific cancer risk: a comprehensive dose-response meta-analysis. Br J Cancer 2015;112:580593.

  • 22.

    Maisonneuve P, Amar S, Lowenfels AB. Periodontal disease, edentulism, and pancreatic cancer: a meta-analysis. Ann Oncol 2017;28:985995.

  • 23.

    Larsson SC, Orsini N, Wolk A. Body mass index and pancreatic cancer risk: A meta-analysis of prospective studies. Int J Cancer 2007;120:19931998.

  • 24.

    Li D, Morris JS, Liu J, et al. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA 2009;301:25532562.

  • 25.

    Patel AV, Rodriguez C, Bernstein L, et al. Obesity, recreational physical activity, and risk of pancreatic cancer in a large U.S. Cohort. Cancer Epidemiol Biomarkers Prev 2005;14:459466.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Genkinger JM, Kitahara CM, Bernstein L, et al. Central adiposity, obesity during early adulthood, and pancreatic cancer mortality in a pooled analysis of cohort studies. Ann Oncol 2015;26:22572266.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Behrens G, Jochem C, Schmid D, et al. Physical activity and risk of pancreatic cancer: a systematic review and meta-analysis. Eur J Epidemiol 2015;30:279298.

  • 28.

    Larsson SC, Wolk A. Red and processed meat consumption and risk of pancreatic cancer: meta-analysis of prospective studies. Br J Cancer 2012;106:603607.

  • 29.

    Thiébaut AC, Jiao L, Silverman DT, et al. Dietary fatty acids and pancreatic cancer in the NIH-AARP diet and health study. J Natl Cancer Inst 2009;101:10011011.

  • 30.

    Genkinger JM, Wang M, Li R, et al. Dairy products and pancreatic cancer risk: a pooled analysis of 14 cohort studies. Ann Oncol 2014;25:11061115.

  • 31.

    Rohrmann S, Linseisen J, Nöthlings U, et al. Meat and fish consumption and risk of pancreatic cancer: results from the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 2013;132:617624.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Wolpin BM, Ng K, Bao Y, et al. Plasma 25-hydroxyvitamin D and risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2012;21:8291.

  • 33.

    Waterhouse M, Risch HA, Bosetti C, et al. Vitamin D and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Case-Control Consortium. Ann Oncol 2015;26:17761783.

  • 34.

    Duell EJ, Lucenteforte E, Olson SH, et al. Pancreatitis and pancreatic cancer risk: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4). Ann Oncol 2012;23:29642970.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Lowenfels AB, Maisonneuve P, Cavallini G, et al. Pancreatitis and the risk of pancreatic cancer. N Engl J Med 1993;328:14331437.

  • 36.

    Malka D, Hammel P, Maire F, et al. Risk of pancreatic adenocarcinoma in chronic pancreatitis. Gut 2002;51:849852.

  • 37.

    Munigala S, Kanwal F, Xian H, et al. Increased risk of pancreatic adenocarcinoma after acute pancreatitis. Clin Gastroenterol Hepatol 2014;12:11431150.e1.

  • 38.

    Bracci PM, Wang F, Hassan MM, et al. Pancreatitis and pancreatic cancer in two large pooled case-control studies. Cancer Causes Control 2009;20:17231731.

  • 39.

    Majumder S, Bockorny B, Baker WL, et al. Association between HBsAg positivity and pancreatic cancer: a meta-analysis. J Gastrointest Cancer 2014;45:347352.

  • 40.

    Seo MS, Yeo J, Hwang IC, et al. Risk of pancreatic cancer in patients with systemic lupus erythematosus: a meta-analysis. Clin Rheumatol 2019;38:31093116.

  • 41.

    Chari ST, Leibson CL, Rabe KG, et al. Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology 2005;129:504511.

  • 42.

    Huang Y, Cai X, Qiu M, et al. Prediabetes and the risk of cancer: a meta-analysis. Diabetologia 2014;57:22612269.

  • 43.

    Liao WC, Tu YK, Wu MS, et al. Blood glucose concentration and risk of pancreatic cancer: systematic review and dose-response meta-analysis. BMJ 2015;350:g7371.

  • 44.

    Gullo L, Pezzilli R, Morselli-Labate AM.; Italian Pancreatic Cancer Study Group. Diabetes and the risk of pancreatic cancer. N Engl J Med 1994;331:8184.

  • 45.

    Gupta S, Vittinghoff E, Bertenthal D, et al. New-onset diabetes and pancreatic cancer. Clin Gastroenterol Hepatol 2006;4:13661372., quiz 1301.

  • 46.

    Raghavan SR, Ballehaninna UK, Chamberlain RS. The impact of perioperative blood glucose levels on pancreatic cancer prognosis and surgical outcomes: an evidence-based review. Pancreas 2013;42:12101217.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Rosa JA, Van Linda BM, Abourizk NN. New-onset diabetes mellitus as a harbinger of pancreatic carcinoma. A case report and literature review. J Clin Gastroenterol 1989;11:211215.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Lee JH, Kim SA, Park HY, et al. New-onset diabetes patients need pancreatic cancer screening? J Clin Gastroenterol 2012;46:e58e61.

  • 49.

    Sah RP, Nagpal SJ, Mukhopadhyay D, et al. New insights into pancreatic cancer-induced paraneoplastic diabetes. Nat Rev Gastroenterol Hepatol 2013;10:423433.

  • 50.

    Elena JW, Steplowski E, Yu K, et al. Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. Cancer Causes Control 2013;24:1325.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Pezzilli R, Casadei R, Morselli-Labate AM. Is type 2 diabetes a risk factor for pancreatic cancer? JOP 2009;10:705706.

  • 52.

    Song S, Wang B, Zhang X, et al. Long-term diabetes mellitus is associated with an increased risk of pancreatic cancer: a meta-analysis. PLoS One 2015;10:e0134321.

  • 53.

    Bodmer M, Becker C, Meier C, et al. Use of antidiabetic agents and the risk of pancreatic cancer: a case-control analysis. Am J Gastroenterol 2012;107:620626.

  • 54.

    Li D, Yeung S-CJ, Hassan MM, et al. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 2009;137:482488.

  • 55.

    Singh S, Singh PP, Singh AG, et al. Anti-diabetic medications and risk of pancreatic cancer in patients with diabetes mellitus: a systematic review and meta-analysis. Am J Gastroenterol 2013;108:510519., quiz 520.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56.

    Franciosi M, Lucisano G, Lapice E, et al. Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. PLoS One 2013;8:e71583.

  • 57.

    Soranna D, Scotti L, Zambon A, et al. Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis. Oncologist 2012;17:813822.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58.

    Wang Z, Lai ST, Xie L, et al. Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Res Clin Pract 2014;106:1926.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59.

    Chaiteerakij R, Petersen GM, Bamlet WR, et al. Metformin use and survival of patients with pancreatic cancer: a cautionary lesson. J Clin Oncol 2016;34:18981904.

  • 60.

    Sadeghi N, Abbruzzese JL, Yeung SC, et al. Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res 2012;18:29052912.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61.

    Toriola AT, Stolzenberg-Solomon R, Dalidowitz L, et al. Diabetes and pancreatic cancer survival: a prospective cohort-based study. Br J Cancer 2014;111:181185.

  • 62.

    Hruban RH, Canto MI, Goggins M, et al. Update on familial pancreatic cancer. Adv Surg 2010;44:293311.

  • 63.

    Humphris JL, Johns AL, Simpson SH, et al. Clinical and pathologic features of familial pancreatic cancer. Cancer 2014;120:36693675.

  • 64.

    Lynch HT, Smyrk T, Kern SE, et al. Familial pancreatic cancer: a review. Semin Oncol 1996;23:251275.

  • 65.

    Wang W, Chen S, Brune KA, et al. PancPRO: risk assessment for individuals with a family history of pancreatic cancer. J Clin Oncol 2007;25:14171422.

  • 66.

    Catts ZA, Baig MK, Milewski B, et al. Statewide retrospective review of familial pancreatic cancer in Delaware, and frequency of genetic mutations in pancreatic cancer kindreds. Ann Surg Oncol 2016;23:17291735.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67.

    Klein AP, Brune KA, Petersen GM, et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res 2004;64:26342638.

  • 68.

    Brune KA, Lau B, Palmisano E, et al. Importance of age of onset in pancreatic cancer kindreds. J Natl Cancer Inst 2010;102:119126.

  • 69.

    Rainone M, Singh I, Salo-Mullen EE, et al. An emerging paradigm for germline testing in pancreatic ductal adenocarcinoma and immediate implications for clinical practice: a review. JAMA Oncol 2020;6:764771.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70.

    Hemminki A, Markie D, Tomlinson I, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 1998;391:184187.

  • 71.

    Jenne DE, Reimann H, Nezu J, et al. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 1998;18:3843.

  • 72.

    Korsse SE, Harinck F, van Lier MG, et al. Pancreatic cancer risk in Peutz-Jeghers syndrome patients: a large cohort study and implications for surveillance. J Med Genet 2013;50:5964.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 73.

    Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000;119:14471453.

  • 74.

    van Lier MG, Wagner A, Mathus-Vliegen EM, et al. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol 2010;105:12581264., author reply 1265.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 75.

    Su GH, Hruban RH, Bansal RK, et al. Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am J Pathol 1999;154:18351840.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 76.

    Weiss FU. Pancreatic cancer risk in hereditary pancreatitis. Front Physiol 2014;5:70.

  • 77.

    Pagon RA, Adam MP, Ardinger HH, et al., (eds), Pancreatitis Overview. in GeneReviews(R). Seattle (WA). University of Washington, Seattle. 2014.

  • 78.

    Howes N, Lerch MM, Greenhalf W, et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol 2004;2:252261.

  • 79.

    Lowenfels AB, Maisonneuve P, DiMagno EP, et al. Hereditary pancreatitis and the risk of pancreatic cancer. J Natl Cancer Inst 1997;89:442446.

  • 80.

    Rebours V, Lévy P, Ruszniewski P. An overview of hereditary pancreatitis. Dig Liver Dis 2012;44:815.

  • 81.

    Whelan AJ, Bartsch D, Goodfellow PJ. Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N Engl J Med 1995;333:975977.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 82.

    de Snoo FA, Bishop DT, Bergman W, et al. Increased risk of cancer other than melanoma in CDKN2A founder mutation (p16-Leiden)-positive melanoma families. Clin Cancer Res 2008;14:71517157.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 83.

    Vasen HF, Gruis NA, Frants RR, et al. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer 2000;87:809811.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 84.

    Lynch HT, Brand RE, Hogg D, et al. Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome. Cancer 2002;94:8496.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 85.

    Aaltonen LA, Salovaara R, Kristo P, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med 1998;338:14811487.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 86.

    Lindor NM, Petersen GM, Spurdle AB, et al. Pancreatic cancer and a novel MSH2 germline alteration. Pancreas 2011;40:11381140.

  • 87.

    Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003;348:919932.

  • 88.

    Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005;352:18511860.

  • 89.

    Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 2008;26:57835788.

  • 90.

    Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010;138:20732087.e3.

  • 91.

    Kastrinos F, Mukherjee B, Tayob N, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA 2009;302:17901795.

  • 92.

    Win AK, Young JP, Lindor NM, et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol 2012;30:958964.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 93.

    Hu C, Hart SN, Bamlet WR, et al. Prevalence of pathogenic mutations in cancer predisposition genes among pancreatic cancer patients. Cancer Epidemiol Biomarkers Prev 2016;25:207211.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 94.

    Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 1999;91:13101316.

  • 95.

    Al-Sukhni W, Rothenmund H, Borgida AE, et al. Germline BRCA1 mutations predispose to pancreatic adenocarcinoma. Hum Genet 2008;124:271278.

  • 96.

    Ferrone CR, Levine DA, Tang LH, et al. BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma. J Clin Oncol 2009;27:433438.

  • 97.

    Hahn SA, Greenhalf B, Ellis I, et al. BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst 2003;95:214221.

  • 98.

    Iqbal J, Ragone A, Lubinski J, et al. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer 2012;107:20052009.

  • 99.

    van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, et al. Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet 2005;42:711719.

  • 100.

    Zhen DB, Rabe KG, Gallinger S, et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med 2015;17:569577.

  • 101.

    Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol 2004;22:735742.

  • 102.

    Holter S, Borgida A, Dodd A, et al. Germline BRCA mutations in a large clinic-based cohort of patients with pancreatic adenocarcinoma. J Clin Oncol 2015;33:31243129.

  • 103.

    Lucas AL, Frado LE, Hwang C, et al. BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts. Cancer 2014;120:19601967.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 104.

    Salo-Mullen EE, O’Reilly EM, Kelsen DP, et al. Identification of germline genetic mutations in patients with pancreatic cancer. Cancer 2015;121:43824388.

  • 105.

    Couch FJ, Johnson MR, Rabe K, et al. Germ line Fanconi anemia complementation group C mutations and pancreatic cancer. Cancer Res 2005;65:383386.

  • 106.

    Slater EP, Langer P, Niemczyk E, et al. PALB2 mutations in European familial pancreatic cancer families. Clin Genet 2010;78:490494.

  • 107.

    van der Heijden MS, Yeo CJ, Hruban RH, et al. Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res 2003;63:25852588.

  • 108.

    Roberts NJ, Jiao Y, Yu J, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov 2012;2:4146.

  • 109.

    Syngal S, Brand RE, Church JM, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 2015;110:223262., quiz 263.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 110.

    Clores MJ, Thosani A, Buscaglia JM. Multidisciplinary diagnostic and therapeutic approaches to pancreatic cystic lesions. J Multidiscip Healthc 2014;7:8191.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 111.

    Farrell JJ, Fernández-del Castillo C. Pancreatic cystic neoplasms: management and unanswered questions. Gastroenterology 2013;144:13031315.

  • 112.

    Law JK, Hruban RH, Lennon AM. Management of pancreatic cysts: a multidisciplinary approach. Curr Opin Gastroenterol 2013;29:509516.

  • 113.

    Tanaka M, Fernández-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012;12:183197.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 114.

    Tanaka M, Fernández-Del Castillo C, Kamisawa T, et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology 2017;17:738753.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 115.

    Del Chiaro M, Verbeke C, Salvia R, et al. European experts consensus statement on cystic tumours of the pancreas. Dig Liver Dis 2013;45:703711.

  • 116.

    Ychou M, Conroy T, Seitz JF, et al. An open phase I study assessing the feasibility of the triple combination: oxaliplatin plus irinotecan plus leucovorin/ 5-fluorouracil every 2 weeks in patients with advanced solid tumors. Ann Oncol 2003;14:481489.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 117.

    Conroy T, Paillot B, François E, et al. Irinotecan plus oxaliplatin and leucovorin-modulated fluorouracil in advanced pancreatic cancer--a Groupe Tumeurs Digestives of the Federation Nationale des Centres de Lutte Contre le Cancer study. J Clin Oncol 2005;23:12281236.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 118.

    Ychou M, Desseigne F, Guimbaud R, et al. Randomized phase II trial comparing folfirinox (5FU/leucovorin [LV], irinotecan [I] and oxaliplatin [O]) vs gemcitabine (G) as first-line treatment of metastatic pancreatic adenocarcinoma (MPA). First results of the ACCORD 11 trial [abstract]. J Clin Oncol 2007;25 (June 20 Suppl):4516.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 119.

    Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:18171825.

  • 120.

    Peixoto RD, Ho M, Renouf DJ, et al. Eligibility of metastatic pancreatic cancer patients for first-line palliative intent nab-paclitaxel plus gemcitabine versus FOLFIRINOX. Am J Clin Oncol 2015.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 121.

    Suker M, Beumer BR, Sadot E, et al. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol 2016;17:801810.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 122.

    Sadot E, Doussot A, O’Reilly EM, et al. FOLFIRINOX induction therapy for stage 3 pancreatic adenocarcinoma. Ann Surg Oncol 2015;22:35123521.

  • 123.

    Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, et al. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol 2013;31:2329.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 124.

    Lowery MA, Yu KH, Adel NG, et al. Activity of front-line FOLFIRINOX (FFX) in stage III/IV pancreatic adenocarcinoma (PC) at Memorial Sloan-Kettering Cancer Center (MSKCC) [abstract]. ASCO Meeting Abstracts 2012;30:4057.

    • Crossref
    • PubMed
    • Export Citation
  • 125.

    Stein SM, James ES, Deng Y, et al. Final analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer. Br J Cancer 2016;114:737743.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 126.

    Burris HA III, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997;15:24032413.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 127.

    Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007;297:267277.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 128.

    Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 2013;310:14731481.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 129.

    Mackey JR, Mani RS, Selner M, et al. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res 1998;58:43494357.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 130.

    Farrell JJ, Elsaleh H, Garcia M, et al. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology 2009;136:187195.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 131.

    Greenhalf W, Ghaneh P, Neoptolemos JP, et al. Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial. J Natl Cancer Inst 2014;106:djt347.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 132.

    Liu ZQ, Han YC, Zhang X, et al. Prognostic value of human equilibrative nucleoside transporter1 in pancreatic cancer receiving gemcitabin-based chemotherapy: a meta-analysis. PLoS One 2014;9:e87103.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 133.

    Marechal R, Bachet JB, Mackey JR, et al. Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma. Gastroenterology 2012;143:664674 e661-666.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 134.

    Saif MW, Lee Y, Kim R. Harnessing gemcitabine metabolism: a step towards personalized medicine for pancreatic cancer. Ther Adv Med Oncol 2012;4:341346.

  • 135.

    Zhu Y, Qi M, Lao L, et al. Human equilibrative nucleoside transporter 1 predicts survival in patients with pancreatic cancer treated with gemcitabine: a meta-analysis. Genet Test Mol Biomarkers 2014;18:306312.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 136.

    Bird NT, Elmasry M, Jones R, et al. Immunohistochemical hENT1 expression as a prognostic biomarker in patients with resected pancreatic ductal adenocarcinoma undergoing adjuvant gemcitabine-based chemotherapy. Br J Surg 2017;104:328336.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 137.

    Ormanns S, Heinemann V, Raponi M, et al. Human equilibrative nucleoside transporter 1 is not predictive for gemcitabine efficacy in advanced pancreatic cancer: translational results from the AIO-PK0104 phase III study with the clone SP120 rabbit antibody. Eur J Cancer 2014;50:18911899.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 138.

    Sinn M, Riess H, Sinn BV, et al. Human equilibrative nucleoside transporter 1 expression analysed by the clone SP 120 rabbit antibody is not predictive in patients with pancreatic cancer treated with adjuvant gemcitabine - Results from the CONKO-001 trial. Eur J Cancer 2015;51:15461554.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 139.

    Grunewald R, Abbruzzese JL, Tarassoff P, et al. Saturation of 2′,2′-difluorodeoxycytidine 5′-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine. Cancer Chemother Pharmacol 1991;27:258262.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 140.

    Tempero M, Plunkett W, Ruiz Van Haperen V, et al. Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 2003;21:34023408.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 141.

    Poplin E, Feng Y, Berlin J, et al. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2009;27:37783785.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 142.

    Demols A, Peeters M, Polus M, et al. Gemcitabine and oxaliplatin (GEMOX) in gemcitabine refractory advanced pancreatic adenocarcinoma: a phase II study. Br J Cancer 2006;94:481485.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 143.

    Fine RL, Fogelman DR, Schreibman SM, et al. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol 2008;61:167175.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 144.

    Ko AH, Espinoza AM, Jones KA, et al. Optimizing the administration of fixed-dose rate gemcitabine plus capecitabine using an alternating-week schedule: a dose finding and early efficacy study in advanced pancreatic and biliary carcinomas. Am J Clin Oncol 2012;35:411417.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 145.

    Berlin JD, Catalano P, Thomas JP, et al. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 2002;20:32703275.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 146.

    Colucci G, Giuliani F, Gebbia V, et al. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell’Italia Meridionale. Cancer 2002;94:902910.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 147.

    Colucci G, Labianca R, Di Costanzo F, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol 2010;28:16451651.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 148.

    Cunningham D, Chau I, Stocken DD, et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 2009;27:55135518.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 149.

    Heinemann V, Boeck S, Hinke A, et al. Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer 2008;8:8282.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 150.

    Heinemann V, Quietzsch D, Gieseler F, et al. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 2006;24:39463952.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 151.

    Heinemann V, Labianca R, Hinke A, et al. Increased survival using platinum analog combined with gemcitabine as compared to single-agent gemcitabine in advanced pancreatic cancer: pooled analysis of two randomized trials, the GERCOR/GISCAD intergroup study and a German multicenter study. Ann Oncol 2007;18:16521659.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 152.

    Herrmann R, Bodoky G, Ruhstaller T, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol 2007;25:22122217.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 153.

    Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005;23:35093516.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 154.

    Reni M, Cordio S, Milandri C, et al. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol 2005;6:369376.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 155.

    Rocha Lima CM, Green MR, Rotche R, et al. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 2004;22:37763783.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 156.

    Ciliberto D, Botta C, Correale P, et al. Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials. Eur J Cancer 2013;49:593603.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 157.

    Sun C, Ansari D, Andersson R, et al. Does gemcitabine-based combination therapy improve the prognosis of unresectable pancreatic cancer? World J Gastroenterol 2012;18:49444958.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 158.

    Kulke MH, Tempero MA, Niedzwiecki D, et al. Randomized phase II study of gemcitabine administered at a fixed dose rate or in combination with cisplatin, docetaxel, or irinotecan in patients with metastatic pancreatic cancer: CALGB 89904. J Clin Oncol 2009;27:55065512.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 159.

    Stathopoulos GP, Syrigos K, Aravantinos G, et al. A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. Br J Cancer 2006;95:587592.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 160.

    Gonçalves A, Gilabert M, François E, et al. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol 2012;23:27992805.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 161.

    Von Hoff DD, Ramanathan RK, Borad MJ, et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 2011;29:45484554.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 162.

    Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:16911703.

  • 163.

    Chiorean EG, Von Hoff DD, Reni M, et al. CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer. Ann Oncol 2016;27:654660.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 164.

    Ramanathan RK, Goldstein D, Korn RL, et al. Positron emission tomography response evaluation from a randomized phase III trial of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas. Ann Oncol 2016;27:648653.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 165.

    Goldstein D, Von Hoff DD, Moore M, et al. Development of peripheral neuropathy and its association with survival during treatment with nab-paclitaxel plus gemcitabine for patients with metastatic adenocarcinoma of the pancreas: A subset analysis from a randomised phase III trial (MPACT). Eur J Cancer 2016;52:8591.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 166.

    Goldstein D, El-Maraghi RH, Hammel P, et al. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst 2015;107:107.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 167.

    Tabernero J, Chiorean EG, Infante JR, et al. Prognostic factors of survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer. Oncologist 2015;20:143150.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 168.

    Buccheri G, Ferrigno D, Tamburini M. Karnofsky and ECOG performance status scoring in lung cancer: a prospective, longitudinal study of 536 patients from a single institution. Eur J Cancer 1996;32A:11351141.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 169.

    Ma C, Bandukwala S, Burman D, et al. Interconversion of three measures of performance status: an empirical analysis. Eur J Cancer 2010;46:31753183.

  • 170.

    Golan T, Kanji ZS, Epelbaum R, et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer 2014;111:11321138.

  • 171.

    Majdak EJ, Debniak J, Milczek T, et al. Prognostic impact of BRCA1 pathogenic and BRCA1/BRCA2 unclassified variant mutations in patients with ovarian carcinoma. Cancer 2005;104:10041012.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 172.

    Stefansson OA, Jonasson JG, Johannsson OT, et al. Genomic profiling of breast tumours in relation to BRCA abnormalities and phenotypes. Breast Cancer Res 2009;11:R47.

  • 173.

    Oliver GR, Sugar E, Laheru D, et al. Family history of cancer and sensitivity to platinum chemotherapy in pancreatic adenocarcinoma [abstract]. Gastrointestinal Cancers Symposium 2010:180.

    • PubMed
    • Export Citation
  • 174.

    Lowery MA, Kelsen DP, Stadler ZK, et al. An emerging entity: pancreatic adenocarcinoma associated with a known BRCA mutation: clinical descriptors, treatment implications, and future directions. Oncologist 2011;16:13971402.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 175.

    Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:19601966.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 176.

    Philip PA, Benedetti J, Corless CL, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. J Clin Oncol 2010;28:36053610.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 177.

    Kindler HL, Niedzwiecki D, Hollis D, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol 2010;28:36173622.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 178.

    Kindler HL, Ioka T, Richel DJ, et al. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol 2011;12:256262.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 179.

    Van Cutsem E, Vervenne WL, Bennouna J, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol 2009;27:22312237.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 180.

    Aranda E, Manzano JL, Rivera F, et al. Phase II open-label study of erlotinib in combination with gemcitabine in unresectable and/or metastatic adenocarcinoma of the pancreas: relationship between skin rash and survival (Pantar study). Ann Oncol 2012;23:19191925.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 181.

    Stepanski EJ, Reyes C, Walker MS, et al. The association of rash severity with overall survival: findings from patients receiving erlotinib for pancreatic cancer in the community setting. Pancreas 2013;42:3236.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 182.

    Lee HS, Chung MJ, Park JY, et al. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore) 2017;96:e5702.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 183.

    Li Q, Yan H, Liu W, et al. Efficacy and safety of gemcitabine-fluorouracil combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomized controlled trials. PLoS One 2014;9:e104346.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 184.

    De Jesus-Acosta A, Oliver GR, Blackford A, et al. A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. Cancer Chemother Pharmacol 2012;69:415424.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 185.

    Petrioli R, Roviello G, Fiaschi AI, et al. Gemcitabine, oxaliplatin, and capecitabine (GEMOXEL) compared with gemcitabine alone in metastatic pancreatic cancer: a randomized phase II study. Cancer Chemother Pharmacol 2015;75:683690.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 186.

    Trouilloud I, Dupont-Gossard AC, Malka D, et al. Fixed-dose rate gemcitabine alone or alternating with FOLFIRI.3 (irinotecan, leucovorin and fluorouracil) in the first-line treatment of patients with metastatic pancreatic adenocarcinoma: an AGEO randomised phase II study (FIRGEM). Eur J Cancer 2014;50:31163124.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 187.

    Yanagimoto H, Ishii H, Nakai Y, et al. Improved survival with combined gemcitabine and S-1 for locally advanced pancreatic cancer: pooled analysis of three randomized studies. J Hepatobiliary Pancreat Sci 2014;21:761766.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 188.

    Li Y, Sun J, Jiang Z, et al. Gemcitabine and S-1 combination chemotherapy versus gemcitabine alone for locally advanced and metastatic pancreatic cancer: a meta-analysis of randomized controlled trials in Asia. J Chemother 2015;27:227234.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 189.

    Yamaue H, Shimizu A, Hagiwara Y, et al. Multicenter, randomized, open-label Phase II study comparing S-1 alternate-day oral therapy with the standard daily regimen as a first-line treatment in patients with unresectable advanced pancreatic cancer. Cancer Chemother Pharmacol 2017;79:813823.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 190.

    Boeck S, Vehling-Kaiser U, Waldschmidt D, et al. Erlotinib 150 mg daily plus chemotherapy in advanced pancreatic cancer: an interim safety analysis of a multicenter, randomized, cross-over phase III trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’. Anticancer Drugs 2010;21:94100.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 191.

    Cartwright TH, Cohn A, Varkey JA, et al. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol 2002;20:160164.

  • 192.

    Pelzer U, Schwaner I, Stieler J, et al. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer 2011;47:16761681.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 193.

    Xiong HQ, Varadhachary GR, Blais JC, et al. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer 2008;113:20462052.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 194.

    Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015;33:244250.

  • 195.

    Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 2019;381:317327.

  • 196.

    Rahma OE, Duffy A, Liewehr DJ, et al. Second-line treatment in advanced pancreatic cancer: a comprehensive analysis of published clinical trials. Ann Oncol 2013;24:19721979.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 197.

    Maisey N, Chau I, Cunningham D, et al. Multicenter randomized phase III trial comparing protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin in inoperable pancreatic cancer. J Clin Oncol 2002;20:31303136.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 198.

    Chiorean EG, Von Hoff DD, Tabernero J, et al. Second-line therapy after nab-paclitaxel plus gemcitabine or after gemcitabine for patients with metastatic pancreatic cancer. Br J Cancer 2016;115:e13.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 199.

    Pelzer U, Kubica K, Stieler J, et al. A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study [abstract]. J Clin Oncol 2008;26 (May 20 suppl):4508.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 200.

    Saif MW. New developments in the treatment of pancreatic cancer. Highlights from the “44th ASCO Annual Meeting”. Chicago, IL, USA. May 30 - June 3, 2008. JOP 2008;9:391397.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 201.

    Oettle H, Riess H, Stieler JM, et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol 2014;32:24232429.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 202.

    Gill S, Ko YJ, Cripps C, et al. PANCREOX: a randomized phase III study of 5-fluorouracil/leucovorin with or without oxaliplatin for second-line advanced pancreatic cancer in patients who have received gemcitabine-based chemotherapy. J Clin Oncol 2016;34:39143920.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 203.

    Uccello M, Moschetta M, Arkenau HT. Second-line combination therapies in pancreatic cancer: where are we now? J Clin Oncol 2017;35:13701371.

  • 204.

    Chung V, McDonough S, Philip PA, et al. Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial. JAMA Oncol 2017;3:516522.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 205.

    Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet 2016;387:545557.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 206.

    Wang-Gillam A, Li C-P, Bodoky G, et al. Updated overall survival (OS) analysis of NAPOLI-1: Phase 3 study of nanoliposomal irinotecan (nal-IRI, MM-398), with or without 5-fluorouracil and leucovorin (5-FU/LV), vs 5-FU/LV in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine (gem)-based therapy. ASCO Meeting Abstracts 2016;34:4126.

    • Crossref
    • PubMed
    • Export Citation
  • 207.

    Yoo C, Hwang JY, Kim JE, et al. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer 2009;101:16581663.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 208.

    Neuzillet C, Hentic O, Rousseau B, et al. FOLFIRI regimen in metastatic pancreatic adenocarcinoma resistant to gemcitabine and platinum-salts. World J Gastroenterol 2012;18:45334541.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 209.

    Zaniboni A,