To drain or not to drain after distal pancreatectomy: reflexions on the PANDORINA trial

We read with great interest the PANDORINA study (1). This international multicenter (mostly from the Netherlands) randomized controlled trial aimed at determining whether omitting drainage after distal pancreatectomy (DP) was equivalent in terms of complications to systematic drainage placement. The primary outcome was the occurrence of severe complications at 90 days defined as Dindo-Clavien grade ≥3. The main secondary outcome was the occurrence of grade B–C postoperative pancreatic fistula (POPF) at 90 days. For both outcomes, the non-inferiority threshold was set at 8%. Randomization was performed intraoperatively, stratified by annual center volume (high volume defined as DP ≥40/year) and the risk of POPF according to the distal fistula risk score (D-FRS) combining pancreas thickness (high risk, >19 mm) and main pancreatic duct diameter (high risk, >3 mm) measured both at the isthmus (2).

Over 30 months, 282 patients were included and randomized in 12 centers into two groups: “without drain” (D−, n=138) and “with drain” (D+, n=144). In intention-to-treat analysis, the PANDORINA trial was positive with no difference in severe complication rates between the two groups (D−, 15% vs. D+, 20%; P_{non-inferiority}=0.0022), thus demonstrating non-inferiority of omitting drainage compared to systematic drainage. Regarding the main secondary outcome measure, the occurrence of grade B–C POPF, the non-inferiority threshold of 8% was exceeded (D−, 12% vs. D+, 27%; P_{non-inferiority}<0.0001). Due to surpassing this non-inferiority threshold, the authors tested the hypothesis of superiority of D− over D+ and confirmed the superiority in terms of POPF occurrence (P_superiority=0.0011). It is noteworthy that in the subgroup of patients who presented with grade B–C POPF, there was no difference in the time to diagnosis of POPF between the D− group (7.5 days) and D+ group (9 days, P=0.89). All these findings were similar in per-protocol analysis. Subgroup analysis based on different variables considered to influence the risk of complications [risk of pancreatic fistula (PF) according to D-FRS, center volume, blood loss, type of DP, American Society of Anesthesiologists (ASA) score, body mass index (BMI)] showed no difference between the two groups.

Comments

Despite previously published data suggesting the safety of omitting drainage after DP, it is worth noting that the most recent data on drainage after DP in France showed a systematic drainage rate exceeding 95% (3,4). This prospective, randomized, controlled, multicenter trial is the second to address the role of drainage during DP. The first was a North American multicenter study, which already showed no difference in terms of severe complications (26% vs. 29%; P=0.48) or grade B–C POPF (12 vs. 18%; P=0.11) between no drainage or systematic drainage (5). Nevertheless, the results of the PANDORINA trial go even beyond, by suggesting that omitting drainage may be associated with a reduction in severe complications and grade B–C POPF! These results warrant some comments.

Firstly, regarding methodology, robust sample size calculations have been based on observed POPF rates in other prospective trials. However, it is worth noting that randomization was stratified based on the D-FRS score combining pancreas thickness and main pancreatic duct diameter measured on preoperative imaging at the presumed site of transection, mostly the isthmus. Nevertheless, since randomization was performed intraoperatively, D-FRS could have been calculated intraoperatively for the sake of precision. Indeed, pancreas thickness and pancreatic duct diameter can be measured intraoperatively using ultrasound at the exact site of future transection for more accurate score calculation and thus more accurate stratification. Additionally, the pancreatic transection technique was standardized, although no surgical technique or equipment have shown superiority. Finally, the type of drainage (passive/active, size) was not standardized among centers, unlike the type of stapling used for parenchymal transection. Therefore, results of this study could be safely extrapolated to daily practice.

Regarding the results, it should be noted that over 70% of DP were performed minimally invasively, with an equal distribution of laparoscopic and robotic approaches. The main results were the non-inferiority of omitting drainage compared to systematic drainage in preventing severe complications (primary outcome measure), but it also suggested superiority of omitting drainage with a reduction in the rate of grade B–C POPF (secondary outcome measure). This difference involved grade B POPF only, with no difference in terms of reintervention such as radiological or endoscopic drainage. As a reminder, according to the International Study Group of Pancreatic Surgery (ISGPS) classification, POPF grades are defined a posteriori, with grade B POPF encompassing PF requiring solely drainage to remain in place for more than 3 weeks after surgery without any other treatment, PF requiring medical treatment only, and PF requiring new radiological or endoscopic drainage. Several teams have even proposed a subclassification of grade B (B1: drainage left in place for more than 3 weeks; B2: medical treatment; B3: interventional treatment) and have shown a notable difference between these B subgrades in terms of clinical impact. In the PANDORINA study, data on POPF B subgrades were not available. Consequently, one can question the clinical relevance of such superiority of omitting drainage in the occurrence of grade B POPF. Nonetheless, regarding drainage, it is important to keep in mind that this was a non-inferiority trial, and this remarkable study once again proved the validity of not placing drainage after DP.

Finally, numerous studies have suggested that spleen preservation is associated with a reduction in the risk of POPF after DP. The authors conducted several subgroup analyses based on different variables considered to influence the risk of complications and notably PF. It would have been interesting to have data on the impact of omitting drainage in subgroups of patients undergoing DP with and without concomitant splenectomy.

In conclusion, this study confirms the non-inferiority of omitting drainage compared to systematic drainage after DP and even suggests superiority of drain omission with a reduced risk of grade B POPF. It will be interesting to observe the extent of dissemination of the results of this study and their impact on drainage practice after DP in real life setting.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-296/coif). The authors have no conflicts of interest to declare.

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