Neoadjuvant therapy for localized pancreatic cancer: support is growing?

N eoadjuvant therapy for localized resectable pancreatic cancer (PC) was first considered (almost recommended? ) at the Massachusetts General Hospital (MGH) more than 2 decades ago based on the observation by Drs Willett, Warshaw, and colleagues that local control (and peritoneal dissemination) was a problem with a surgery first treatment strategy.1 Now, in the era of more effective systemic therapies, neoadjuvant therapy is being reconsidered (almost advocated? ) by Ferrone et al from the same institution based on their observation that patients with more advanced disease (borderline resectable or locally advanced PC) who had been declined for upfront surgery by experienced surgeons and therefore treated with systemic therapy, usually followed by chemoradiation, were not only still standing after induction therapy but also appeared to demonstrate tumor response.2 The objective responses seen radiographically and biochemically (CA19-9) then prompted reconsideration of surgery—the tumors were removed in most patients—and those patients who completed all therapy, including surgery, had an improved survival duration even when compared to patients with earlier stage (resectable) disease treated with surgery first. The authors fall short of advocating a neoadjuvant approach for all patients with localized PC, but we enthusiastically support the partial endorsement of neoadjuvant therapy and feel confident that more comprehensive advocacy will develop long before another 2 decades have passed. One of the first papers reporting the results of a prospective trial of preoperative/neoadjuvant therapy for patients with localized PC was published by Evans, Rich, and colleagues.3 This trial was based on the following clinical observations: (1) A subset of patients who underwent surgery first experienced early postoperative disease recurrence and such patients, if treated with a neoadjuvant approach, may be identified at the time of posttreatment (preoperative) restaging and thereby be spared an unnecessary, ineffective therapy (operation) with its associated risks for morbidity and mortality. Ferrone and colleagues applied this strategy to patients with borderline resectable PC for good reason—as the magnitude of the operation increased, the desire to prevent early recurrence also increased. A big operation in a poorly selected patient may result in both short survival duration and a life seriously compromised by surgical morbidity prior to death. (2) Chemoradiation delivered before surgery may be more effective (than when given postoperatively) and may potentially prevent/decrease local, regional, and peritoneal recurrence. Indeed, a concept first proposed at MGH is confirmed in the current report where only 4 (10%) of 40 patients with borderline resectable/locally advanced PC treated neoadjuvantly experienced local/regional recurrence and 3 (8%) of 40 developed peritoneal recurrence; even though not all patients received radiation and important relevant details of radiation delivery (fractionation, technique, concomitant chemotherapy dose and schedule, etc.) were not provided. (3) The delivery of adjuvant therapy after a large pancreatic operation is difficult for many patients. We appreciated this in the early 1990s and, despite advances in the surgical care of patients with PC, many treated with a surgery first strategy today do not recover sufficiently to go on to receive intended postoperative adjuvant therapy.4 To the extent that systemic therapies would improve in the future (as now has occurred and is discussed in the Ferrone manuscript), a surgery first approach will prevent many patients from receiving effective systemic therapies. Clearly, when the 1992 manuscript was conceived3, now more than 2 decades ago, the hope was that a neoadjuvant treatment strategy would avoid operation in those patients with aggressive tumor biology for whom surgery would be ineffective and also allow us to develop the tools needed to provide more complicated combined modality therapy such as techniques for pretreatment biopsy, biliary decompression, and supportive care measures. However, until very recently, most physicians have been unwilling to consider a delay in potentially curative surgery despite the knowledge that immediate surgery would benefit only a small minority of operated patients and the delivery of postoperative adjuvant therapy would frequently be unsuccessful.