Gastroenterology

Gastroenterology

Volume 144, Issue 6, May 2013, Pages 1316-1326
Gastroenterology

Disease and Therapy of Pancreatic Disorder
Review
Therapeutic Advances in Pancreatic Cancer

https://doi.org/10.1053/j.gastro.2013.01.078Get rights and content

Despite our improved understanding of pancreatic cancer biology and ability to perform more complex pancreatic cancer surgeries that produce better short-term outcomes, major progress toward increasing survival times has been painstakingly slow. Through the often-repeated, dismal survival statistics, it is easy to lose sight of real progress that has been made in pancreatic cancer therapy. It is particularly interesting to observe the extent to which these advances are interdependent and the effects they have had on practice. For example, during the past 5–10 years, we have seen widespread adoption of pancreatic imaging protocols that allow for objectively defined criteria of resectability. This has led to the definition of “borderline resectable pancreatic cancer”—a new clinical category that has affected the design of clinical trials. A major change in our surgical approach has been the move to minimally invasive pancreatectomy, which continues to gain broader acceptance and use, particularly for left-sided lesions. Although many new agents have been developed aimed at putative molecular targets, recent breakthroughs in therapy for advanced disease have arisen from our ability to safely give patients combination cytotoxic chemotherapy. We are now faced with the challenge of combining multidrug, cytotoxic chemotherapies with newer-generation agents. Ultimately, the hope is that drug combinations will be selected based on biomarkers, and strategies for pancreatic cancer therapy will be personalized, which could prolong patients' lives and reduce toxicity. We review the major advances in pancreatic cancer therapy during the last 5 years, and discuss how these have set the stage for greater progress in the near future.

Section snippets

Resectable Cancer

Pancreatic ductal adenocarcinoma (PDAC) is usually detected at a late stage, when <20% of patients are eligible for potentially curative resection; most of these patients have disease recurrence. Although mortality from PDAC has decreased significantly, particularly among patients treated at high-volume centers, pancreatectomy continues to cause significant morbidities that can affect physicians' ability to deliver adjuvant therapy. It is therefore important to optimize surgical techniques in

Borderline Resectable Pancreatic Cancer

A major development in the clinical management of pancreatic cancer over the last several years has been the recognition of a subset of tumors that cannot be clearly categorized as resectable or locally unresectable. These borderline resectable pancreatic tumors might technically be resectable, but have a high likelihood for positive margins with upfront surgery. A consistent, objective, and standardized definition of borderline resectable pancreatic cancer is required to design and conduct

Locally Advanced and Metastatic Disease

Most patients (80%) present with advanced tumors that cannot be removed by surgery; their management is a significant unmet challenge. More than 50% of patients come to clinical attention with metastatic disease, and an additional 30%–40% present with locally advanced tumors.32, 33 The prognosis for these patients is poor. Patients with locally advanced disease have a median survival time of 8–12 months, and patients with distant metastases have significantly worse outcomes, with a median

Advances in Chemotherapy for Metastatic Disease

The development of improved systemic treatments is a high priority for pancreatic cancer. In 1997, gemcitabine monotherapy was established as standard of care because it was shown to have greater clinical benefit than weekly 5-FU therapy.35 Since then, gemcitabine chemotherapy combinations have been intensely evaluated. Despite frequently encouraging early-phase data, phase III trials of such combinations have yet to demonstrate a statistically significant survival benefit over gemcitabine

Advances in Targeted Therapy

Our increased understanding of the molecular and genetic changes associated with tumorigenesis has led to the development of agents that specifically target these alterations. Targets have included KRAS and downstream factors, such as mitogen-activated protein kinase, epidermal growth factor receptor, vascular endothelial growth factor A, and type I receptor for insulin-like growth factor.60 The characteristically dense stroma and desmoplastic reaction surrounding most pancreatic

Locally Advanced Disease

There are few data from randomized, controlled trials to indicate the best treatment approaches for patients with locally advanced disease. A number of trials have been performed during the past 30 years, often assessing some combination of chemotherapy and radiation. However, it has been difficult to draw conclusions from these studies because of variations in the dose and methods of radiation, use of radiosensitizers, and chemotherapy controls. Combined chemoradiotherapy clearly prolongs

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    Conflicts of interest The authors disclose no conflicts.

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