Is progress by selection, really progress?

As I reflect on 30 years of managing patients with pancreatic adenocarcinoma, I wonder what I can feel good about. My generation, including those recently retired, have certainly brought pancreatic resection from a high risk, high mortality procedure to a low risk, low mortality technical exercise, while morbidity remains high. Progress in selection and in diagnosis has allowed many patients with histopathologies other than adenocarcinoma of the pancreas to benefit from the improvements in technical skill learned by many as they confront this lethal disease. When one looks at survival outside of operative mortality for resected pancreatic adenocarcinoma, few can be encouraged. Actual disease specific survival at five years is approximately 10% and half of those patients will go on to die of recurrent pancreatic adenocarcinoma in the subsequent five years.1 We have made progress in defining statistically significant factors such as nodal positivity and margin status but that is of little help when all it does is add or detract a percentage point or two from 10%. Attempts at more extensive resection intended to improve local margin and gather more lymph nodes have had at best “marginal success.”2 In the present issue of the journal, Dr. Menon and his colleagues provide a paper that addresses the issue of soft tissue margin following pancreaticoduodenectomy.3 We would all envy the surgeons at Leeds who are fortunate to have such dedicated pathologists. They have previously demonstrated an R1 resection rate of 85% when resected specimens are subjected to a standardized and extensive pathological staging system (the LEEP protocol). The LEEP protocol involves extensive multicolor inking of the specimen with serial slices in an axial plane. An R1 resection was then defined as tumor within 1 mm of a resected margin. The present manuscript examines 83 consecutive patients with adenocarcinoma of the pancreatic head region. As the margin in pancreatic carcinoma is usually limited by the surrounding vascular structures, particularly the vena cava, the aorta and the left renal vein, have the authors improved negative margin rate by dissection in that plane? Without the information as to the extent of the operation then it is hard to comment on the significance of this carefully examined margin status. Of the 81 adenocarcinomas, 27 were primary pancreatic, 24 were ampullary and 32 of distal bile duct origin, an unusual predominance of distal bile duct cancers. The key issue of the present manuscript addresses the high rate of margin involvement, 82% in pancreatic and 72% in distal bile duct cancer. Not surprisingly, this is far greater than what is seen in ampullary carcinoma, 25%. Again, not surprisingly, margin positivity was greater in more advanced T stage in all tumors. The manuscript emphasizes that in advanced cancers, T3 or N1, a high proportion will have positive margins if searched for diligently. The study is further confabulated by the fact that the pancreatic and distal bile duct cancers were T3 while a significant number of the ampullary cancers were T1 or T2. The ampullary cancers were smaller and 23 of 27 were node positive. In the pancreatic cancers, 16 of 24 were node positive and 24 of 32 were node positive for the distal bile duct cancers. The authors show that the number of positive nodes was not correlated with margin status. Only when they apply a ‘positive lymph node rate,’ which varies between histologies, do these numbers become significant. Figure 2 leaps from the manuscript where patients with pancreatic adenocarcinoma and negative margin status are suggested to have an 80% 50 months actuarial survival. This contrasts five R0 patients with 22 R1 patients and gains statistical significance at 0.046; surely, an example of torturing the data until it confesses! As three different histopathologies and all stages are included, it is not surprising that R0 and R1 resections vary in outcome, particularly given the association with more advanced T and N stage. Only resection margin status in pancreatic adenocarcinoma was significant in a univariate analysis. The table should be read by all young faculty. We have three different pathologies, eight different variables providing 24 comparisons, so we would expect one of 24 to be significant by random chance. This they have shown! The authors’ focus on margin can therefore be misleading. It is no surprise that margin is defined by the extent of the procedure (and that information is not available) and the diligence of the pathologist, for which they have admirable expertise. That patients with small tumors who are more likely to have negative margins do better, is not a new concept! Our surgical heritage is replete with unproven claims that larger and more morbid procedures to gain negative margins translates into improved survival for diseases that kill by systemic disease. What do we take of this observation? It is clear that diligence and pathological examination can increase the positive marginrate in pancreatic adenocarcinoma, but unless this can be improved by more extended operation, it has little meaning. It is correct that margin status is reflected in outcome as it is in so many other diseases, but margin status alone is unlikely to influence the outcome in pancreatic adenocarcinoma, which is so poor regardless of the underlying pathological variables. So, what have I learned? Twenty-five years of examining the deck chairs on the Titanic and regardless of how I rearrange them, paint them, reappoint them or even sit in them, the outcome remains the same.