Pancreatic Adenocarcinoma ranks as the most challenging of human malignancies, with overall 5-year survivorship being measured in a couple of percent. Major progress has occurred regarding the molecular underpinnings and pathogenesis of pancreatic adenocarcinoma, definition of the epidemiology and genetics of this disease, identification of individuals at risk, and in 2008, the preliminary description of the pancreatic genome. However, clinical developments over the past decade have been modest and incremental at most. The core drug and the backbone of treatment in all settings of pancreatic adenocarcinoma— adjuvant, locally advanced, and metastatic—remains gemcitabine.
The past decade of research focused initially on combining cytotoxic therapies with gemcitabine, and more recently, on combining newer “targeted agents.” Some success has been observed by combining the platinum analogs and the fluoropyrimidines with gemcitabine in the advanced pancreatic cancer setting. Three- and four-drug combinations have also been assessed, but the data are limited and the major trade-off becomes a toxicity-benefit equation. In relative terms, more limited incremental gains have been observed by combining erlotinib with gemcitabine, while other randomized phase III trials of targeted agents combined with gemcitabine have essentially shown no benefit. Several of the newer generation anti-vascular agents (VEGF-trap, axitinib) are being evaluated in ongoing phase III trials.
In the short-term, expectations for advances in pancreatic adenocarcinoma therapy are reserved, with most progress likely to be made in therapy refinement and patient selection. However, it is reasonable to surmise that major progress will evolve as the molecular biology of pancreatic adenocarcinoma continues to be unraveled, as the infrastructure for translational research is strengthened with new preclinical models, and with recognition of the prerequisite requirement for intensive cross-disciplinary collaboration.
Estimates are that nearly 38,000 individuals were diagnosed with pancreatic adenocarcinoma in the United States in 2008. For the majority, the disease is both locally advanced and unrespectable or de novo metastatic at the time of diagnosis, conferring median survival durations of 3 to 18 months. Approximately 15% of patients present with localized disease and undergo a potentially curative surgical intervention; however, even in this most select of patient subgroups, the anticipated 5-year survival rates range from 12% to 20%.
TARGETED THERAPY FOR PANCREATIC ADENOCARCINOMA
The expectations and hope for the value of new biologic agents have, unfortunately, exceeded the reality of the challenges of pancreatic cancer. However, results of a randomized phase III trial comparing gemcitabine and erlotinib vs. gemcitabine in patients with untreated advanced disease provided a small but real hint of activity. A modest but statistically significant difference in median survival was noted, along with an improved progression-free survival (PFS) and a more compelling, approximate 40% improvement in 1-year survival (from 17% with gemcitabine to 23% with the combination). Moreover, there was an association between rash severity and survival in this trial, as has been observed in studies in other malignancies where anti-epidermal growth factor receptor (EGFR)-based therapies have had utility. Patients with rash grade ≥ 2 had a near-doubling of their survival to 10.5 months, compared with 5.3 months for patients with no rash.
The challenge will be to identify the patients most likely to benefit from treatment in advance of a therapeutic trial. Information on molecular correlates was available from only approximately 21% (n = 117) of the study patients. There was a suggestion that patients with wild-type ras tumors may have had increased benefit from erlotinib; however, the small sample size limited the conclusions that could be made in this post-hoc K-ras mutational analysis.For now, the rash and ras story is evolving and there are no specific implications regarding patient care. In contrast to the data on gemcitabine combined with erlotinib, results of a phase III randomized trial comparing gemcitabine and cetuximab vs. gemcitabine in untreated, advanced pancreatic cancer patients have indicated no advantage with the addition of cetuximab (median survival, 5.4 months for the combination and 5.9 months for gemcitabine, hazard ratio [HR] 1.09). Of note, the absolute difference in survival for both erlotinib and cetuximab were similar at 0.5 months; however, one study was “positive” and the other “negative,” raising the question of whether there is a difference between a small molecule tyrosine kinase inhibitor and a monoclonal antibody in this disease.