Combined-Modality Treatment for Operable Pancreatic Adenocarcinoma

Pisters and colleagues from the M. D. Anderson Cancer Center offer a state-of-the-art discussion of the staging and treatment of pancreatic cancer. Their treatise addresses most of the current issues of controversy surrounding this disease from a largely nonparochial standpoint, and should serve as a primer for the multidisciplinary approach to the treatment of pancreatic ductal cancer. Their call for and justification of regionalization of treatment in patients with potentially resectable disease rings true with virtually all national and international studies that have examined this topic from the aspect of morbidity, mortality (and thus survival), duration of hospitalization, and of course in our current economic climate, cost.[1-7] This topic should no longer be considered controversial. But now to the meat. Most pancreatic surgeons believe that more (surgery) is not necessarily better for pancreatic cancer. Studies addressing the ultimate in more surgery"-ie, regional pancreatectomy (first advocated by Fortner[8] at Memorial Sloan-Kettering Cancer Center), extended lymphadenectomy (removal of second-, third-, and/or fourth-order nodal stations),[9,10] and routine resection of the superior mesenteric/ portal venous axis[11]-have been repeatedly unsuccessful in making a substantial or statistically meaningful dent in the still-dismal survival data after an ostensibly curative resection. Neoadjuvant Chemoradiation Therapy
The M. D. Anderson group,[12] and for an even longer time the group from the Fox-Chase Cancer Center,[ 13] have been the pioneers of upfront (neoadjuvant) therapy for potentially resectable pancreatic cancer and continue to be outspoken advocates of this concept. Pisters and coauthors present and discuss a compelling argument for the theoretic benefit of neoadjuvant chemoradiation therapy directed at both the primary site of disease and systemic, microscopic metastatic disease before initiating the operative "trauma" of curative resection. Pisters and colleagues argue several salient points: (1) Neoadjuvant therapies for colon and breast cancer serve as precedents for the efficacy of neoadjuvant intervention (the authors do, however, fully acknowledge that pancreatic ductal cancer is less chemoresponsive); (2) they maintain that pancreatic cancer is a systemic disease at diagnosis, as supported by the incidence of recurrent, distant (residual) metastatic disease; (3) with adjuvant (postoperative) chemoradiation therapy, treatment of the unresected micrometastatic disease is delayed (at the least, assuming no complication) for about 6 weeks, including 2 weeks for hospitalization postresection, and an additional 4 to 6 weeks for satisfactory convalescence until adjuvant therapy is safe to initiate; and finally, (4) when chemoradiation therapy is planned for the postoperative period, a substantial number of patients (about 25%) never receive the adjuvant therapy because of either surgical complications or inappropriate performance status. In addition, a not insignificant percentage of patients (about 20%-40%) develop progressive, distant metastatic disease during neoadjuvant therapy that only becomes evident at the time of restaging after completion of such therapy. These patients are thus spared what would (likely) have been a nontherapeutic, noncurative pancreatectomy had they not undergone neoadjuvant therapy (and been given the additional month to 6 weeks for this occult metastatic disease to become evident with current state-ofthe- art imaging). This overall argument remains a very compelling justification of neoadjuvant therapy. However, others raise arguments against the concept of neoadjuvant therapy for pancreatic cancer that are not as well-discussed in this treatise. Total costs increase with upfront, preresection chemoradiation therapy. Most of these patients also need some form of biliary enteric drainage procedure, usually an endoscopic and/or bilioenteric stent, because of their obstructive jaundice. Such endoscopic stents have their own potential (albeit rare) complications (bleeding, infection, perforation).[14] In addition, institution of neoadjuvant therapy requires biopsy proof of malignancy, and therefore some form of a pancreatic biopsy is required (see below, Preresection Pancreatic Biopsy). Finally, arguments can be raised that because pancreatic ductal cancer is a relatively chemoresistant neoplasm, delaying resection for the obligate 4 to 6 weeks of neoadjuvant chemoradiation therapy potentially allows the development of two problems related to the neoplasm-either local tumor extension, preventing ultimate resection after neoadjuvant therapy is completed, or the establishment of distant metastatic disease during the neoadjuvant therapy that would make the eventual pancreatectomy noncurative. Which argument is correct? Unfortunately, no one knows, because a prospective, randomized study has not been conducted. Probably one of the most important points raised by this excellent review is the need for a prospective, randomized trial of neoadjuvant vs adjuvant therapy for pancreatic cancer-an ideal trial for the American College of Surgeons Oncology Group or another multicenter group to undertake. Rather than trying ever-new chemotherapeutic agents, a change in our paradigm of approach would seem the most hopeful means of having a real impact on the depressing outcome of this disease. Preresection Pancreatic Biopsy
Use of routine neoadjuvant therapy requires histologic proof of malignancy. While we understand that no card-carrying oncologist will pro- provide neoadjuvant chemoradiation therapy without biopsy proof of cancer, we have considerable concerns about the potential misinterpretation of this "need" for biopsy proof prior to surgical intervention. Most pancreatic surgeons believe that "if it looks like, acts like, feels like, and smells like a periampullary malignancy," it should be treated like one (ie, with resection), even if attempts at preoperative biopsy proof are "negative" (or possibly better termed "inconclusive"). We fear that the requirement of histologic proof may delay intervention unless the protocol for treatment includes an arm undergoing "resection without neoadjuvant treatment" if the attempts at biopsy are inconclusive. Without this understanding, the need for histologic confirmation will do a disservice in up to 10%-20% of patients with potentially resectable pancreatic cancers. Retroperitoneal Margin
Finally, we want to underscore and emphasize the importance of a periadventitial SMA dissection, which may help to include one of the most frequent sites of nodal and perineural metastases. However, this medial (perivascular retroperitoneal) margin and the posterior uncinate margin continue to represent the weak links of state-of-the-art pancreaticoduodenectomy. Indeed, our inability to reliably obtain a true R0 resection in up to 20%-30% of patients lends support to the need for something other than "more surgery."