Surgical Treatment of Resectable and Borderline Resectable Pancreas Cancer: Expert Consensus Statement

Margins in pancreatic cancer resection procedures occur at planes where the specimen is separated from surrounding structures or where the pancreas or bowel are divided. These include duodenal/gastric, common bile duct, proximal jejunal, and pancreatic neck transection margins, as well as margins measured “radially” or “tangentially” (anterior and posterior pancreatic surfaces).42 The most important margin is the plane of abutment of the uncinate process with the SMA. Unlike other margins such as the posterior margin where a buffer of fat and areolar tissue lie between the pancreas and the margin, the uncinate process of the pancreas directly contacts the SMA as well as the neural and lymphatic plexus associated with the celiac trunk.26,44 This margin is variously referred to as the uncinate, posterior pancreatic, mesenteric, or retroperitoneal margin. It should be referred to by the more appropriately descriptive term “SMA margin.” Margins can be described clinically and pathologically by R status, where R represents the degree of residual disease.42 R0 means there is neither gross, nor microscopic evidence of cancer at the margin. R1 indicates grossly negative, but microscopically positive disease at the margin. Finally, R2 indicates that gross tumor remains. There is a paucity of detailed literature regarding margins and their influence on survival following pancreatic resections.45,46 Most papers indicate total numbers or percentage of positive margin cases, yet do not provide R status by margin site.47 Nor is the influence of the distance of the margin from edge of the tumor well understood. Accordingly, some investigators have proposed standardization of the process of margin evaluation. This begins in the preoperative period with expert evaluation of the relationship between the tumor and with critical vasculature using high-quality imaging such as dual-phase CT with three-dimensional (3D) reconstruction. A major goal of this evaluation is to eliminate R2 resections prior to surgery. Next, the margins of resected specimens need to be properly oriented by the surgeon and the specimen inked by the pathologist or by the surgeon in the presence of a pathologist. Most importantly, the SMA margin should be evaluated using perpendicular, rather than en face, sampling which should lead to greater specificity, but possibly less sensitivity. It is critical that the surgeon and pathologist reconcile the R status collaboratively in the postoperative period. These principles have been nicely delineated in the current AJCC cancer staging manual (Sixth Edition).42 Clinical Impact of Positive Margins Overall, positive margin rates are reported to range between 15% and 85% and, when present, these are regularly predictive of decreased survival.26,46,48 Unfortunately, in many papers R2 and R1 margin results are lumped, making determination of the individual effect on survival of each of these outcomes is difficult. The SMA margin is most frequently involved (up to 85% of all positive margins). Increased blood loss and large tumor size are predictive of positive margins.26 Outcomes of these historical series indicate that any positive margin will have a survival equivalent to patients with palliative procedures alone.46 However, the most contemporary series (in the setting of regular multimodality therapy, and no R2 resections) shows R1 resection median survival as high as 22 months. This differed significantly from 28 months for R0 resections, but R status did not predict survival on multivariate analysis.26 Surgical Technique The effect of surgical technique on margin positivity has not been rigorously studied. Meticulous dissection of the pancreatic parenchyma off the adventitia of the SMA is advocated, but is not always practically possible.26,44 Procedures have been proposed to minimize positive margins in body and tail tumors (RAMPS), and en bloc resection of adjacent organs to achieve positive margins is also appropriate.49,50 Numerous devices are available to help the surgeon with transection of the pancreas, but none have been rigorously evaluated and none show superiority over the conventional clamp-and-ligate technique. Many surgeons perform frozen section analysis intraoperatively routinely; however, the utility of this practice is undefined in the literature, except in the specific circumstance of intraductal papillary mucinous neoplasm (IPMN).51,52 Obtaining such analysis at the neck and bile duct transection points would seem appropriate in that further tissue may be resected to achieve a clean margin, if positive. However, this is practically not possible on the SMA margin where the artery provides the absolute boundary. Cases with concomitant vein resection may have higher rates of positive margins, especially at the SMA margin, if the patients are not carefully selected. Venous wall invasion occurs up to two-thirds of the time when a decision is made to resect vein. However, despite these findings, on multivariate analysis survival is driven not by the positive margin, but rather by the larger tumor size encountered in these cases.25 It is quite possible that vein resection may, in fact, decrease margin positivity, by facilitating a more controlled tumor resection off of the veins. Pylorus-preserving resection has been shown to have equivalent rates of margin positivity when compared to classical Whipple’s resections, and extended lymphadenectomy procedures, likewise, are not superior in achieving clean margins.17,53 On the other hand, a surgeon’s experience appears to improve performance in this metric, with a threshold of >60 cases executed showing superior outcomes.54 Effect of Multimodality Oncologic Therapy It is possible that combined multimodality (chemo/radiation) therapy may have a positive biologic effect on a positive margin.26,55 The use of preoperative “neoadjuvant” chemoradiation therapy has been studied in this regard and appears to provide lower rates of positive margins, although this does not necessarily equate to improved survival.47 Similarly, focal “boosts” of adjuvant radiation to the positive resection margin may be beneficial. Consensus Statement 1. Nomenclature regarding margins in pancreaticoduodenectomy should be should be standardized. Currently it is vague, confusing, and imprecise. The margin of the pancreas with the SMA should be termed “the SMA margin.” 2. Pathologic assessment of margins is poorly standardized and inconsistently reported. 3. Whipple specimens should be inked, examined, and reported by techniques in conformity with CAP or AJCC guidelines. Manuscripts that assess vascular (usually venous) resection as a prognostic factor for survival must include a system for the assessment of R status. This would include a clear description by the surgeon (in the operative report) of the presence or absence of gross residual disease, and a pathology report that conforms to CAP or AJCC guidelines. 4. The utility of routine intraoperative frozen-section analysis should be determined by carefully planned studies. 5. Safe achievement of an R0 margin is the main surgical objectives of pancreaticoduodenectomy as it is great importance for extended survival. The SMA margin is the most important driver of this outcome. 6. The impact of a microscopically positive (R1) resection on ultimate clinical outcome is uncertain. Multimodality therapy may “recover” a R1 margin and improve survival to that similar to R0 resections.