Pancreatic cancer constitutes only 3% of cancer diagnoses yet it is the 4th leading cause of cancer death in women and the 5th in men with a 5-year survival of just 5%. While the Whipple procedure is potentially curative, only a small minority of patients are candidates.
What can we do for the vast majority of patients with advanced disease who aren’t candidates for surgery or radiation? As it turns out, there is quite a lot.
CANCER BIOLOGY We now know that pancreatic cancer has unique features, among them its anatomy, placing it in the middle of many vital organs. Its genetic makeup is also unique with oncogenes like K-ras, p16 and p53 commonly mutated. BRCA mutations (found in familial breast & ovary cancer) and mismatch repair deficiencies (associated with Lynch syndrome) have also been found. Unfortunately, immunotherapies (PD1, PDL1 & CTLA4) and the new “targeted agents” have had little impact on this disease. In 2015 cytotoxic chemotherapy remains the principal modality for the management of advanced pancreatic cancer. HISTORY OF TREATMENTS Following decades of slow progress with chemotherapy, Gemcitabine, introduced in the 1990’s became a favored agent with Platin (Cisplatin, Oxaliplatin), Taxane (Taxol, Docetaxel), Erlotinib & Irinotecan combinations added into the mix. With FOLFIRINOX and a response rate of 31.6% (NEJM, 2012), a new benchmark was established. But this and other combinations came with toxicities that often decreased the patient’s quality of life. Although the doublet of Nab-Paclitaxel (Abraxane) & Gemcitabine not unlike the earlier GTX (Gemcitabine& Taxotere& Xeloda) offer lower toxicity, the objective response rate of only 23% (Von Hoff, J Clin Oncol, 2012) leaves much to be desired. More recently infusional combinations of Irinotecan, Cisplatin, Taxotere, Gemcitabine & 5-FU have offered additional options. But how are patients and their physicians to choose? Pancreatic cancer cells isolated into microspheroids and maintained in a 3-D environment.Pancreatic cancer cells exposed to Trimetrexate – no effect.Pancreatic cancer cells undergoing programmed cell death following exposure to Mitomycin C plus Irinotecan. PATIENTS NEED PERSONALIZED CANCER THERAPY In our laboratory, we find that pancreatic cancer patients fall into several broad categories. {{cta('8abe8785-a4a0-40ee-b960-71ebb51d4a37','justifyright')}} The first are a group of truly drug sensitive patients who respond to many treatments. These fortunate few can benefit from the mildest of drug combinations. A small minority of patients reveal sensitivity to “targeted agents” like Erlotinib (Tarceva) offering them a comparatively simple, oral intervention. A much larger group reveals a more distinct pattern of sensitivity. For these patients it becomes critical to select between “Platinum-based” (GemOx, Cisplatin & Gemcitabine); “Taxane-based” (GTX, Abraxane/Gemcitabine) or “Irinotecan-based” (Folfirinox, Folfiri) regimens as their profiles are uniquely different. A final group of patients are resistant to standard chemotherapeutics and should consider experimental therapies early in their course. This was the subject of our recent collaboration with Brazilian investigators reported in Chicago this past June (Nagourney RA, et al, Proceedings ASCO 2015). PROMISING RESULTS Using our laboratory functional profiling analysis, we were the first to identify Cisplatin & Gemcitabine in this disease. Indeed one of our early patients responded so dramatically that he became the subject of a July, 1998 Scientific American report. Our longest surviving metastatic pancreatic cancer patient was eleven years and a current one now approaches 7 years. What concerns us now is that patients are being shuttled onto treatments, not based upon drug responsiveness but instead upon physician experience, ease of administration or cost. Not every patient is sensitive and not every patient’s response is durable, but intelligent application of laboratory-directed therapies offers a uniquely effective approach to this otherwise difficult malignancy. We are encouraged by our good experiences in this disease and believe that patients with advanced pancreatic cancer can benefit from both conventional and experimental drug combinations. Not only is a diagnosis of pancreatic cancer not a death sentence, there are definite reasons to be optimistic.