Neoadjuvant chemotherapy for localized pancreatic cancer: too little or too long?

For a ‘‘systemic’’ disease such as pancreatic cancer, neoadjuvant chemotherapy is a logical approach that thus far has been limited largely by a lack of effective systemic agents. For example, when considering treatment sequencing for patients with resectable disease, the concept of offering a treatment with an objective response rate of less than 10 % (as for gemcitabine alone) has been unacceptable to most clinicians. (Chemo)radiation has therefore been the backbone of most neoadjuvant approaches, with the goal of improving local/regional disease control (preventing local recurrence) and avoiding operation in those with progressive disease found on post-treatment, preoperative restaging. A few neoadjuvant studies to date have included relatively short courses of chemotherapy—without any obvious improvement in outcomes compared with chemoradiation alone. To further complicate treatment sequencing controversy, surgeons have cautioned that many patients (and referring physicians) want their tumors resected tomorrow and can find a surgeon who will accommodate them. Concerns about increased perioperative morbidity (following neoadjuvant therapy) still exist but have been allayed by several studies, including a recent NSQIP analysis. Importantly, an ‘‘effective’’ neoadjuvant chemotherapy regimen could theoretically improve longterm outcomes by successfully treating (possibly even eradicating) micrometastatic disease in the setting of an immune-competent host who is not attempting to recover from a large operation. The duration of neoadjuvant chemotherapy is a critical variable. If the right drug is selected for the right patient, treatment will need to be long enough to effectively treat micrometastatic disease. If the wrong drug(s) is selected (we only learn this in retrospect when restaging is performed), treatment should be short enough to avoid losing a window of resectability due to local disease progression. This is an important consideration in patients with resectable and borderline resectable disease (in contrast to those patients with locally advanced pancreatic cancer—thus the importance of accurate pretreatment staging). At present, there is little evidence to support any specific neoadjuvant treatment duration, although opinions exist that are based largely on personal experience, extrapolation from other solid tumor sites, and translational laboratory science. Rose and coauthors from Virginia Mason Medical Center are to be commended for demonstrating that patients are willing and able to undergo almost 6 months (on average) of neoadjuvant chemotherapy with good results, both shortterm and long-term . To what degree this was the result of the well-known experience and talent of this multidisciplinary group will be reflected in the ability of others to duplicate these results. Although patients were not treated on a clinical trial, they were maintained in a prospective registry, which is a practice that should be encouraged. The major strength of the study was the relatively large (n = 64) and homogeneously staged patient population, all radiographically ‘‘borderline resectable’’ by the SSO/AHPBA consensus criteria and with no evidence of metastatic disease by pretreatment staging that included laparoscopy with peritoneal washings—which did introduce an added selection bias as most such reports have not included laparoscopic staging. The outcomes in this study are not entirely due to increased ‘‘selection’’ provided by the extended duration of therapy. There clearly was a treatment effect demonstrated at the site of the primary tumor. Almost half of patients underwent resection of the primary, with R0 Society of Surgical Oncology 2014