Pancreatic adenocarcinoma represents the fourth-leading cause of cancer-related mortality in the United States. The vast majority of patients are diagnosed at advanced stages of the disease when surgery is no longer an option. For these patients, systemic therapy remains the mainstay of care. Although single-agent gemcitabine has remained the standard of care since its approval in 1997, improvements in patient outcomes may potentially be realized by (1) applying pharmacokinetic principles to optimize drug delivery, such as the administration of gemcitabine at a “fixed-dose rate” infusion; (2) combining gemcitabine with other cytotoxic agents for which evidence of synergy exists, such as platinum compounds; and (3) integrating novel targeted agents such as bevacizumab, erlotinib, and cetuximab into treatment paradigms, based on an increasing understanding of the molecular pathways that govern pancreatic tumor growth and maintenance. This article provides the evidence to support each of these approaches and highlights future directions in the management of metastatic pancreatic cancer.
Andrew H. Ko and Margaret A. Tempero
Pelin Cinar and Andrew H. Ko
The best treatment strategy for patients with locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC) remains the subject of considerable debate. This report presents a case of a 58-year-old woman with locally advanced unresectable PDAC who was treated with sequential FOLFIRINOX for 8 cycles followed by chemoradiation, and continues to show durable disease control 18 months later. The respective roles of systemic therapy and chemoradiation for locally advanced PDAC are discussed, including optimal sequencing of these modalities, recent improvements in chemotherapy, and the question of whether radiotherapy improves survival outcomes in this disease context.
Andrew H. Ko and Christopher H. Crane
It is well established that the development of distant metastatic disease represents the dominant pattern of tumor recurrence/progression among patients with operable and locally advanced pancreatic cancer. However, the contribution of localized or locoregional tumor burden to pancreatic cancer–associated morbidity and mortality may be underappreciated, and therefore balancing competing considerations of systemic versus local disease control becomes important in therapeutic decision-making. The role of local therapies, particularly radiation therapy, has remained somewhat controversial in this disease context. Several phase II and III trials have sought to address the relative importance and role of radiation in both the localized and locally advanced settings, including the sequencing of this modality relative to systemic therapy and its optimal means of administration. However, differences and limitations in study design have produced mixed results, particularly in terms of the contribution of radiation to overall survival benefit. An emerging paradigm that makes conceptual sense and remains the subject of active investigation is to start with a defined period of systemic treatment, thus limiting radiation to the subset of patients who do not manifest with metastatic disease during initial therapy and are therefore most likely to benefit from local control.
Margaret A. Tempero, Mokenge P. Malafa, Mahmoud Al-Hawary, Horacio Asbun, Andrew Bain, Stephen W. Behrman, Al B. Benson III, Ellen Binder, Dana B. Cardin, Charles Cha, E. Gabriela Chiorean, Vincent Chung, Brian Czito, Mary Dillhoff, Efrat Dotan, Cristina R. Ferrone, Jeffrey Hardacre, William G. Hawkins, Joseph Herman, Andrew H. Ko, Srinadh Komanduri, Albert Koong, Noelle LoConte, Andrew M. Lowy, Cassadie Moravek, Eric K. Nakakura, Eileen M. O'Reilly, Jorge Obando, Sushanth Reddy, Courtney Scaife, Sarah Thayer, Colin D. Weekes, Robert A. Wolff, Brian M. Wolpin, Jennifer Burns, and Susan Darlow
Ductal adenocarcinoma and its variants account for most pancreatic malignancies. High-quality multiphase imaging can help to preoperatively distinguish between patients eligible for resection with curative intent and those with unresectable disease. Systemic therapy is used in the neoadjuvant or adjuvant pancreatic cancer setting, as well as in the management of locally advanced unresectable and metastatic disease. Clinical trials are critical for making progress in treatment of pancreatic cancer. The NCCN Guidelines for Pancreatic Adenocarcinoma focus on diagnosis and treatment with systemic therapy, radiation therapy, and surgical resection.
Margaret A. Tempero, Mokenge P. Malafa, Stephen W. Behrman, Al B. Benson III, Ephraim S. Casper, E. Gabriela Chiorean, Vincent Chung, Steven J. Cohen, Brian Czito, Anitra Engebretson, Mary Feng, William G. Hawkins, Joseph Herman, John P. Hoffman, Andrew Ko, Srinadh Komanduri, Albert Koong, Andrew M. Lowy, Wen Wee Ma, Nipun B. Merchant, Sean J. Mulvihill, Peter Muscarella II, Eric K. Nakakura, Jorge Obando, Martha B. Pitman, Sushanth Reddy, Aaron R. Sasson, Sarah P. Thayer, Colin D. Weekes, Robert A. Wolff, Brian M. Wolpin, Jennifer L. Burns, and Deborah A. Freedman-Cass
The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize major discussion points from the 2014 NCCN Pancreatic Adenocarcinoma Panel meeting. The panel discussion focused mainly on the management of borderline resectable and locally advanced disease. In particular, the panel discussed the definition of borderline resectable disease, role of neoadjuvant therapy in borderline disease, role of chemoradiation in locally advanced disease, and potential role of newer, more active chemotherapy regimens in both settings.
Featured Updates to the NCCN Guidelines
Margaret A. Tempero, Mokenge P. Malafa, E. Gabriela Chiorean, Brian Czito, Courtney Scaife, Amol K. Narang, Christos Fountzilas, Brian M. Wolpin, Mahmoud Al-Hawary, Horacio Asbun, Stephen W. Behrman, Al B. Benson III, Ellen Binder, Dana B. Cardin, Charles Cha, Vincent Chung, Mary Dillhoff, Efrat Dotan, Cristina R. Ferrone, George Fisher, Jeffrey Hardacre, William G. Hawkins, Andrew H. Ko, Noelle LoConte, Andrew M. Lowy, Cassadie Moravek, Eric K. Nakakura, Eileen M. O’Reilly, Jorge Obando, Sushanth Reddy, Sarah Thayer, Robert A. Wolff, Jennifer L. Burns, and Griselda Zuccarino-Catania
The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights discuss important updates to the 2019 version of the guidelines, focusing on postoperative adjuvant treatment of patients with pancreatic cancers.
Featured Updates to the NCCN Guidelines
Margaret A. Tempero, J. Pablo Arnoletti, Stephen W. Behrman, Edgar Ben-Josef, Al B. Benson III, Ephraim S. Casper, Steven J. Cohen, Brian Czito, Joshua D. I. Ellenhorn, William G. Hawkins, Joseph Herman, John P. Hoffman, Andrew Ko, Srinadh Komanduri, Albert Koong, Wen Wee Ma, Mokenge P. Malafa, Nipun B. Merchant, Sean J. Mulvihill, Peter Muscarella II, Eric K. Nakakura, Jorge Obando, Martha B. Pitman, Aaron R. Sasson, Anitra Tally, Sarah P. Thayer, Samuel Whiting, Robert A. Wolff, Brian M. Wolpin, Deborah A. Freedman-Cass, and Dorothy A. Shead
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pancreatic Adenocarcinoma discuss the workup and management of tumors of the exocrine pancreas. These NCCN Guidelines Insights provide a summary and explanation of major changes to the 2012 NCCN Guidelines for Pancreatic Adenocarcinoma. The panel made 3 significant updates to the guidelines: 1) more detail was added regarding multiphase CT techniques for diagnosis and staging of pancreatic cancer, and pancreas protocol MRI was added as an emerging alternative to CT; 2) the use of a fluoropyrimidine plus oxaliplatin (e.g., 5-FU/leucovorin/oxaliplatin or capecitabine/oxaliplatin) was added as an acceptable chemotherapy combination for patients with advanced or metastatic disease and good performance status as a category 2B recommendation; and 3) the panel developed new recommendations concerning surgical technique and pathologic analysis and reporting.
Margaret A. Tempero, Mokenge P. Malafa, Mahmoud Al-Hawary, Stephen W. Behrman, Al B. Benson III, Dana B. Cardin, E. Gabriela Chiorean, Vincent Chung, Brian Czito, Marco Del Chiaro, Mary Dillhoff, Timothy R. Donahue, Efrat Dotan, Cristina R. Ferrone, Christos Fountzilas, Jeffrey Hardacre, William G. Hawkins, Kelsey Klute, Andrew H. Ko, John W. Kunstman, Noelle LoConte, Andrew M. Lowy, Cassadie Moravek, Eric K. Nakakura, Amol K. Narang, Jorge Obando, Patricio M. Polanco, Sushanth Reddy, Marsha Reyngold, Courtney Scaife, Jeanne Shen, Charles Vollmer Jr., Robert A. Wolff, Brian M. Wolpin, Beth Lynn, and Giby V. George
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.