Michael and Moore provide an excellent review of the frustrating history of drug development for pancreatic cancer. These frustrations have been accompanied by the knowledge that pancreatic adenocarcinoma has almost always metastasized systemically, most often to the liver, by the time the patient comes to a physician. Thus, local treatment, while important, will ultimately cure only a few patients in the absence of effective concomitant or sequential systemic therapy.
Clinical Benefit Concept Evolves
Until recently, it could be argued that no effective therapy existed for patients with metastatic pancreatic adenocarcinoma. However, with the development of gemcitabine(Drug information on gemcitabine) (Gemzar) that has changed. We now have an intervention for a subset of patients that has a positive effect on pain and performance status. How was this accomplished? Michael and Moore describe the astute clinical observations made by Ephraim Casper, Mark Green, and other clinical investigators during the initial phase II testing of gemcitabine in patients with advanced pancreatic cancer. These researchers clearly documented that some patients experienced marked symptomatic improvement during therapy with gemcitabine, sometimes in the absence of clear objective (radiographic) responses. It was these observations that led to the development of the clinical benefit concept (a novel way of determining response based on assessment of a combination of pain, performance status, and weight gain). Clinical benefit response then became the primary end point of the pivotal trials leading to the approval of gemcitabine in pancreatic cancer.[3,4]
There is little question that when faced with a difficult and highly symptomatic disease like pancreatic cancer, evidence that a well-tolerated agent can affect, even slightly, the well-being of patients is an important advance. The article also provides an excellent, well-referenced overview of the plasma and cellular biochemistry and mechanism of action of gemcitabine, and contrasts these data with its closely related cousin, cytarabine(Drug information on cytarabine) (ara-C). As second and third generation trials combining gemcitabine with other agents and modalities develop, an understanding of the cellular events that take place in tumor and normal cells will be important. This understanding has already led to rational combinations of gemcitabine with other agents, such as cisplatin(Drug information on cisplatin) (Platinol)[,5] and with radiation.
New Focus on Pancreatic Cancer Research
An interesting collateral outcome of the relatively rapid approval of gemcitabine for pancreatic cancer has been the increased attention that many pharmaceutical companies now direct toward pancreatic cancer. This disease is currently viewed as one with important opportunities to gain accelerated approval for innovative therapeutics. This by-product of the approval of gemcitabine for the treatment of advanced pancreatic cancer can only increase the number of options that may one day be available for patients with this devastating malignancy.
Finally, a word of caution, lest we lose sight of the overriding importance of maintaining our momentum. It is paramount that we continue to explore new therapeutic ideas through well-designed clinical trials in pancreatic cancer. While there is little question that the development of gemcitabine represents an important achievement for patients with pancreatic cancer, we must not lose sight of the most important goals of systemic therapy: induction of complete remissions, significant extensions of survival, and ultimately, cure. Objectively, gemcitabine produces radiographically measurable responses in only a small number of patients and a slight improvement in median survival. When measured in this manner, gemcitabines impact is much more modest than that suggested by clinical benefit response.
It is important, then, for practitioners and investigators alike not to view the introduction of gemcitabine as a resting- or stopping-place for drug development in pancreatic cancer. The success of gemcitabine must not slow the pace of innovation in this disease. Continued investigative momentum is critical, particularly when the molecular and biochemical events central to pancreatic cancer carcinogenesis are rapidly being discovered.[7,8] These insights are already identifying many new and exciting targets for therapeutic development. It will remain paramount that our first thought for a patient diagnosed with advanced pancreatic cancer be: Is there a trial for which this patient will qualify?