Impact of positive resection margins on recurrence and survival following resection and adjuvant chemotherapy in pancreatic cancer: Results of the PRODIGE 24-CCTG PA-6 trial.
Authors: Lambert Aurélien , Salleron Julia , Harle Alexandre , Biagi James Joseph , Leroux Agnès , Thomas Jacques , Monard Laure , Cros Jerome , Marchal Frédéric , Ayav Ahmet , Conroy Thierry 
Published: June 2023

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Background: Pancreatic adenocarcinoma (PDAC) has a poor prognosis. Only 10-15% of patients present with resectable tumors upfront, and most patients develop recurrence and die prematurely. The data are incongruous when considering R1 status, direct invasion is not consistently a significant prognostic factor. It is recommended that 7 margins be identified for surgery: the bile duct, pancreatic neck, proximal and distal duodenum, superior mesenteric vein (SMV), superior mesenteric artery (SMA), and posterior pancreas. By analyzing data from the PRODIGE 24-CCTG PA-6 trial that validated the mFOLFIRINOX regimen in adjuvant setting, our main objective was to analyze the prognostic value of margin involvement on disease-free survival (DFS). Methods: The protocol recommended that the surgeon inked the resection margins. R1 was defined as direct tumor margin infiltration within 1 mm of one or more resection margins. All patient data were re-evaluated centrally by an external review committee including pathologists, surgeons, and medical oncologists to verify key prognostic factors, including inking and filling of resection margins. Results: Among the 400 patients included in the study, the median number of documented margins was 6, IQR (5-7). In 214 patients (53.5%), fewer than 7 margins were reported. The most common margin involvement was on the SMV groove (28.3%), posterior margin (21%), SMA (14.5%), and pancreatic neck transection (5.3%). Margin inking was performed in 64.9% of cases. Misclassification of the R1 status concerned 24.1% of the files after centralized review. When positive, only 3 margins (SMV groove, median and posterior) were significant prognostic factors in unifactorial analysis (all p < 0.01). When combined, one R1 margin among these three had independent prognostic value in multivariable analysis. In multivariate analysis, DFS was significantly different by quality of resection margins in the gemcitabine arm (HR 95% CI 1.97 [1.23;3.16]; p = .005) but not in the mFOLFIRINOX arm (HR 95% CI 1.46 [0.91;2.35]; p = .114). Conclusions: Few studies have examined the prognostic implications of each margin. We consider that every effort should be made to evaluate the 3 best prognostic margins. One finding of this work is the likely effect of mFOLFIRINOX on local invasion in operated patients. It seems that this chemotherapy regimen (unlike gemcitabine) corrects the alteration related to margin involvement, probably explaining all or part of the improved survival. Therefore, the value of additional therapies, such as cloture radiotherapy, should be evaluated in patients with unknown marginal status or in those who did not benefit from mFOLFIRINOX chemotherapy. A patient who received mFOLFIRINOX as adjuvant therapy is more likely to recur with distant metastasis (80%) and with a better survival of 28 months. Clinical trial information: NCT01526135 .