In this issue of ONCOLOGY, Dr. Wisinski and her colleagues at the Robert H. Lurie Comprehensive Cancer Center provide a valuable review of the therapeutic approaches to unresectable pancreatic cancer. They are thorough in their approach, and their review outlines the use of chemoradiation as well as the studies of chemotherapy, from fluorouracil(Drug information on fluorouracil) to gemcitabine(Drug information on gemcitabine) (Gemzar) and finally to combinations of chemotherapy. In doing so, they provide a valuable catalog of the work performed to date. They might have emphasized more, however, the conceptual challenges to the definition of unresectable pancreatic cancer itself.
What defines a pancreatic cancer as "unresectable"? It is a difficult question, as the answer is slowly evolving with advances in imaging technology, refinements in chemotherapy and radiation, and novel strategies toward the disease. Oncologists now realize that not all "unresectable" cancers are created equal, and the increasing use of neoadjuvant therapy reflects this understanding.
What we define as unresectable should reflect an important reality. That is, only patients who undergo a margin-negative (R0) resection are likely to derive benefit from surgery. The literature consistently demonstrates median survival times of 8 to 12 months among patients with positive surgical margins. Survival times improve to as much as 26 to 28 months after R0 resections. Thus, the definition of unresectability should reflect the likelihood that our current treatments for pancreatic cancer could achieve the goal of negative margins. Encasement of major vessels such as the superior mesenteric artery (SMA) or celiac axis, portal vein occlusion, and the presence of celiac or para-aortic lymphadenopathy are universally acknowledged as findings that preclude R0 surgery. We label these as "locally advanced" cancers.
One of the weaknesses frequently encountered in the pancreatic cancer literature is the lack of clear distinction between cancers that are truly locally advanced and those that might be made resectable with neoadjuvant therapy. In fairness, these distinctions are evolving as surgical technique and neoadjuvant therapies improve. However many of the trials cited by Wisinski were conducted during an era of intraoperative staging, inferior imaging, and at a time when the subtle differences between truly locally advanced cancers and borderline resectable disease would not have been appreciated.
Indeed, many studies spanning the 1980s (Eastern Cooperative Oncology Group [ECOG], Gastrointestinal Tumor Study Group [GITSG]) through the 1990s to the present time (Burris, Moore) grouped together patients with either locally advanced or metastatic disease. The inclusion of variable numbers of locally advanced with metastatic cases complicates comparison across trials and, more importantly, precludes the identification of patients for whom neoadjuvant therapy might make an R0 resection possible.
Improvements in preoperative imaging now allow for more refined staging of patients. The dramatic improvements in computed tomography (CT) imaging techniques and specific imaging protocols to visualize the relationship between the pancreas, its surrounding vasculature, and the liver can reduce the number of patients incorrectly staged as having resectable disease. One study by Vargas and others at Stanford found that, using multidetector CT, 20 of 23 patients identified on imaging as resectable were indeed able to undergo margin-negative resections. These authors note that while earlier technology incorrectly staged 21% to 47% of patients as resectable, their rate was 13% with multidetector CT scanning. Only one patient had a positive margin, which was actually anticipated by the CT scan. Conversely, in a study by Bao and colleagues, venous involvement of > 180° seen on CT was universally predictive of an R1 resection.
Thus, with increasing resolution of preoperative CT scanning, with more narrowly spaced images, and with optimal timing of contrast, many tumors that would previously have been labeled "locally advanced" might be appreciated as being more amenable to neoadjuvant treatment. Likewise, improved imaging will identify more subtle findings that may suggest unresectable features or metastatic disease, reducing the number of futile surgical procedures.