There is a common theme in all the guidelines. The goal is high-quality and cost-effective care. Clinical trials are always the ‘standard of care’ and should be offered in all stages.— Ramesh K. Ramanathan, MD
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The 5-year survival rate of those diagnosed with pancreatic cancer remains stubbornly fixed around 5%. Even in the 20% of cases in which surgical resection is undertaken for curative intent, the 5-year survival rate after surgery is 20% to 30%. As we make progress in other cancers with decreasing incidence and mortality rates, pancreatic cancer is the outlier, and by 2020, it is expected to move from number 4 to number 2, overtaking breast and colorectal cancer deaths per year.1
There still exists therapeutic nihilism in pancreatic cancer. In fact, a significant number of patients who otherwise would benefit from surgical resection are not referred to an experienced surgical team and do not receive a multimodality consultation from medical/radiation oncologists and gastroenterologists.2,3 Some patients with metastatic disease do not receive optimal systemic therapy or, at the other end of the spectrum, are overtreated. Symptom management is not optimal, and palliative care services are underutilized. Few patients (5%) participate in clinical trials, thus slowing the movement of promising agents into daily practice.1
Excellent guidelines are available from the National Comprehensive Cancer Network® (www.NCCN.org) and the European Society for Medical Oncology,4 and the recently published ASCO guidelines5-7—summarized in this issue of The ASCO Post (ASCO Guideline on Potentially Curable Pancreatic Cancer, ASCO Guideline on Treatment of Locally Advanced, Unresectable Pancreatic Cancer, and ASCO Guideline on Metastatic Pancreatic Cancer)—will supplement and aid the practicing physician to formulate an appropriate treatment plan. The ASCO guidelines are evidence-based, with recommendations based on analysis of phase III randomized controlled trials whenever available. Detailed information about the methods used to develop these guidelines are available in the methodology supplement of each article and at www.asco.org/guidelines/PCPC: www.asco.org/guidelines/LAPC and www.asco.org/guidelines/MetPC.
The ASCO guidelines are published as three separate articles for the management of resectable, locally advanced, and metastatic disease. Each guideline addresses the pertinent clinical and management questions faced by the treating physician.
Potentially Curable Pancreatic Cancer
The ASCO guidelines seek to address the following key issues: (1) initial assessment; (2) which patients should undergo a potentially curative strategy; (3) which patients should be offered preoperative therapy followed by surgery; (4) adjuvant therapy following surgery; (5) the role of palliative care services; and (6) frequency of follow-up care or surveillance after surgery.
The goal when dealing with a potentially resectable pancreatic cancer is speedy, cost-efficient initial workup and then determination of suitability for immediate surgery or preoperative therapy. There is increasing enthusiasm for the use of upfront chemotherapy and/or chemoradiation in most cases. However, we still do not have evidence that this approach is beneficial, and patients with clearly defined resectable pancreatic cancer should be surgically explored. Clearly, entering this group of patients in a clinical trial is of the utmost importance. The radiologic criteria for “borderline resectable cancer” are observer-dependent, and interpretation is difficult.
These guidelines recommend a practical solution: For tumors that are not clearly resectable or at high risk of rapid recurrence after surgery, preoperative therapy can be considered. We should not overlook that pancreatectomy is a major operation, especially in the elderly and for tumors of the head of the pancreas (Whipple procedure). To ensure a rapid recovery and increase the percentage of patients who can go on to receive adjuvant therapy, supportive care, physical therapy, and dietary changes are all needed. We would all agree that surveillance is needed due to the high risk of recurrence after surgery; however, there is a lack of data on survival improvement or benefit of scheduled assessments, and extrapolation and expert consensus are thus utilized in this situation.
Locally Advanced Pancreatic Cancer
The issues addressed in this guideline are: (1) initial assessment; (2) initial treatment approach for locally advanced pancreatic cancer; (3) the role of chemotherapy, chemoradiotherapy, and stereotactic body radiation therapy; (4) the role of chemotherapy when there is clinical or radiologic disease progression of locally advanced pancreatic cancer; (5) introduction of palliative care; and (6) frequency of follow-up care/surveillance.
The goals of therapy for patients with locally advanced pancreatic cancer differ from those for potentially resectable patients, as surgical resection is very unlikely, even with current combination systemic therapy and the addition of radiation therapy. Patients with locally advanced pancreatic cancer generally have or will develop difficult-to-control symptoms such as pain, gastric outlet obstruction, and gastroparesis, leading to early satiety and weight loss. Although treatment strategies for locally advanced pancreatic cancer are similar to those for metastatic disease, one-third of patients with locally advanced pancreatic cancer do not develop systemic disease, and death results from complications caused by the primary tumor; they can be difficult to manage, and early involvement of palliative care services is recommended.
Metastatic Pancreatic Cancer
The questions addressed in this guideline are: (1) initial assessment; (2) appropriate first-line treatment; (3) appropriate second-line line therapy for patients with disease progression or intolerable toxicity; (4) introduction of palliative care; (5) recommended strategies for relief of pain and symptoms; and (6) follow-up care/surveillance.
We have seen improvements in metastatic pancreatic cancer, with prolongation of median and 1- and 2-year survival with the introduction of FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) and nanoparticle albumin-bound (nab)-paclitaxel (Abraxane)/gemcitabine regimens as first-line therapy. Physicians need to be familiar with these regimens and select patients appropriately based on performance status, age, and comorbidity to optimize outcome and minimize toxicity. Interestingly erlotinib, approved by the U.S. Food and Drug Administration for first-line therapy in combination with gemcitabine, has fallen out of favor and is minimally used in practice due to its borderline clinical benefit, which comes at the expense of some toxicity and cost.
Only recently, second-line therapy was found to improve survival; 5-FU/oxaliplatin (OFF/FOLFOX) and 5-FU/MM-398 regimens in the second-line setting after gemcitabine showed an approximately 2-month improved median survival over 5-FU.8,9 The optimal regimen for second-line therapy is a moving target. We do not have phase III data on the benefit of second-line therapy after FOLFIRINOX or nab-paclitaxel/gemcitabine used as first-line therapy.
The effectiveness of second-line OFF or FOLFOX (commonly used in the United States) and 5-FU/MM-398 is based on studies done predominantly in patients treated with single-agent gemcitabine. The data for second-line OFF was based on a small study; a survival benefit, however, was not confirmed in a Canadian study (with FOLFOX) reported only in abstract form.10 MM-398 (nanoliposomal irinotecan) has the advantage of not causing neurotoxicity, which is likely after treatment in the first-line setting, and may be a preferable second-line regimen. The ASCO guidelines can aid physicians to select the “ best” second-line regimen based on patient characteristics. Targeted therapy and molecular profiling are still in their infancy, and patients should be encouraged to participate in clinical trials.
There is a common theme in all the guidelines. The goal is high-quality and cost-effective care. Clinical trials are always the “standard of care” and should be offered in all stages. Early involvement of palliative care services must be encouraged. Increasing involvement of the public, advocacy groups, and health-care professionals in research and clinical care will aid us to make progress against this disease. ■
Disclosure: Dr. Ramanathan has received research grants from Merrimack, Celegene, AbbVie, Plexxicon, Tahio, Super Lab, Berg Biosystems, and honoraria from Pharmacyclics, and Cerulean.
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