Since the approval of gemcitabine (Gemzar) a decade ago for advanced pancreatic cancer, a number of studies have been conducted—many of them investing enormous time, effort, and patient resources—to evaluate the benefit of combining gemcitabine with other therapeutic agents. The vast majority of these studies have been disappointingly negative, failing to demonstrate any significant prolongation of survival using a gemcitabine-containing combination. Thus, the PA.3 trial conducted by the National Cancer Institute of Canada was a landmark study of sorts in that it was the first phase III trial in advanced pancreatic cancer to show a survival advantage with the addition of a second drug, in this case the oral epidermal growth factor receptor (EGFR) inhibitor erlotinib (Tarceva), to gemcitabine.
When the data were first presented in 2005, many oncologists responded with a fair degree of skepticism: the median survival difference between the two arms was only 2 weeks (6.4 vs 6.0 months, gemcitabine plus erlotinib vs gemcitabine plus placebo, respectively). However, the hazard ratio for survival—reflecting the difference in survival between the two arms over time, rather than at a predefined static time point—was 0.81, suggesting a 19% reduction in the risk of death for patients receiving combination therapy. Nevertheless, these results led to the obvious question: even if something is statistically significant, is it clinically meaningful?
Survival vs Toxicity
One might argue that in a disease with as poor a prognosis as pancreatic cancer, even a very modest benefit in outcomes can be important to patients. However, the necessary corollary to this argument is to evaluate whether any modest increments in longevity are counterbalanced by the greater toxicities caused by study treatment. Looking at the data from PA.3, it is not surprising that patients receiving gemcitabine plus erlotinib did have side effects more frequently than those receiving gemcitabine monotherapy. These included both expected toxicities (rash, diarrhea) as well as several that were less anticipated (stroke, cardiac events, thromboembolic events, and interstitial lung disease, to name a few). Whether these potential adverse events outweigh the modest benefits in survival is obviously a very subjective decision, based on a patient's threshold for accepting risk and the relative merits (s)he may place on quantity vs quality of life.
The ability to make such a decision might be easier were we to have information regarding the likelihood of a patient's responding, or not responding, to a given therapy a priori. This more individualized, "patient-tailored" strategy to decision-making (as opposed to a one-size-fits-all approach) has already borne fruit in a number of other solid tumors, such as lung and breast cancer,[1,2] in which molecular analysis of tumor tissue for expression of single genes, or expression patterns of a combinatorial set of genes, has shown to be a useful tool in guiding selection of therapeutic agents.
By contrast, one of the great obstacles in pancreatic cancer is the difficulty in obtaining adequate tumor material for such detailed interrogation, as the vast majority of patients have inoperable disease at presentation and are usually diagnosed by fine-needle aspiration or cytologic brushings during endoscopic retrograde cholangiopancreatogram (ERCP). This barrier was illustrated quite clearly in the PA.3 trial, in which only a quarter of study patients had tumor samples available for assessment of EGFR status. Although the numbers were clearly too small to make any definitive conclusions, the fact that benefit derived from erlotinib seemed to be independent of EGFR expression is consistent with other studies assessing this class of agents in certain solid tumors.
K-ras Mutational Status
Besides intratumoral EGFR expression, analysis of the mutational status of the K-ras oncogene represents another possibility that could help decide whether or not to use erlotinib in pancreatic cancer, given the mounting evidence that mutated K-ras predicts for lack of sensitivity to EGFR inhibitors.[4,5] Investigators of the PA.3 trial did examine, post hoc, K-ras mutational status as a predictor for treatment benefit in the subset of study patients in whom tumor tissue was available (n = 117). While a trend toward greater benefit of erlotinib for overall survival was observed in the 21% of evaluable patients with wild-type K-ras (hazard ratio = 0.66), this finding was not statistically significant (P = .34). Again, however, this perhaps reflected inadequate sample size rather than indicating a truly negative result. Going forward, study designs in pancreatic cancer may very well mandate acquisition of tumor material prior to initiation of treatment—the technical challenges of doing so notwithstanding—so that these kinds of analyses can be performed with greater power. Such an approach may in the future lead to more rational selection of therapy for any given individual based on his or her unique tumor characteristics.
In the end, does the US Food and Drug Administration approval of erlotinib for use in combination with gemcitabine in patients with advanced pancreatic cancer establish a new standard of care? Certainly, it is a small positive step in the right direction for a disease in which negative phase III studies had been becoming the norm. Moreover, the approval provides an important proof of concept regarding the use of newer "targeted" therapies in pancreatic cancer.
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