Supplemental Digital Content Table S2, available at http://links.lww.com/SLA/A779, shows the technical varieties used for PG and PJ at the trial centers. According to the ISGPS classification for pancreatic anastomoses,16 the most commonly performed techniques were nonstented duct-mucosa anastomosis (ISGPS type I-A-S0) with 2 interrupted monofilament resorbable suture rows for PJ and nonstented dunking PG (ISGPS type II-B-S0) anastomosis with purse-string plus interrupted monofilament resorbable suture.
Primary Endpoint Analysis
The rate of clinically relevant POPF was 20% after PG and 22% after PJ in the control group (P = 0.62, 2-sided χ2 test, Table 2). In a multivariate logistic regression model (Table 2), including anastomotic technique (PG vs PJ), age, center (north vs south), pancreatic texture (soft vs hard) and surgeon volume (pancreatic resections per year), and soft pancreatic texture was the only significant factor affecting POPF B/C, with an odds ratio estimate of 2.1 (P = 0.016) (Table 2).
As there were 12 patients allocated to PG receiving PJ instead and 15 patients with PG instead of PJ, we also performed an as-treated analysis of the primary endpoint (see Supplemental Digital Content Table S3, available at http://links.lww.com/SLA/A780). The results did not differ from those of the intention-to-treat analysis.
Assessment of Learning Effects
The odds ratio estimate for fistula rate in surgeons with less than 10 pancreatoduodenectomies was 1.2 to 6.8 (95% confidence interval) but did not reach the significance level (P = 0.064 in multivariate analysis, see Table 2). Surgeons with less than 10 pancreatoduodenectomies per year had a higher fistula rate with PJ (46%) than with PG (27%), and this effect was gradually lost with increasing individual case load (see Supplemental Digital Content Table S4, available at http://links.lww.com/SLA/A781); however, these differences did not reach statistical significance. There was also no significant center effect as to the preferred type of anastomosis in the participating centers (see Supplemental Digital Content Table S4, available at http://links.lww.com/SLA/A781).
Perioperative Secondary Endpoint Analysis
Operation time did not differ between PG and PJ. There were no significant differences between PG and PJ with regard to the frequency of surgical complications such as delayed gastric emptying, intra-abdominal abscesses, relaparotomy, completion pancreatectomy, anastomotic leaks, and surgical site infection. There was also no difference in the incidence of systemic complications such as septic shock, respiratory failure, deep vein thrombosis, lung embolism, and myocardial infarction. There were more (n = 5) stroke events in the PG group but none in the PJ group (P = 0.035) and significantly more postpancreatectomy hemorrhage events in the PG group (P = 0.023), the latter due to more grade A (5% vs 1%) and B (9% vs 4%) hemorrhages. Stroke and grade A/B bleeding were not associated, however (P = 0.998). Perioperative in-house mortality in the treatment groups (PG vs PJ, 6% vs 5%, P = 0.963) and 90-day mortality (PG vs PJ, 10% vs 5%, P = 0.167) were not statistically different. Postoperative hospital stay was equal with a median of 16 days (Table 3).
Survival During Follow-up
Overall survival curves are given in Supplemental Digital Content Fig. S2, available at http://links.lww.com/SLA/A777. One-year (365 days) Kaplan-Meier survival estimates (±standard error) were 77% ± 3% in PG and 76% ± 4% in PJ and thus comparable (P = 0.675 in 2-sided log-rank test) (see Supplemental Digital Content Fig. S2, available at http://links.lww.com/SLA/A777).
Pancreatic Function and Long-term Follow-up
The percentage of patients receiving oral enzyme replacement rose from 8% preoperatively to around 80% during 6- and 12-month follow-up. Exploratory analysis also suggested a significantly reduced rate of oral enzyme replacement therapy in patients with PG at 6 months after the operation (PG vs PJ, 72% vs 89%, P < 0.001). This difference did not persist at 12-month follow-up because of a slightly decreasing percentage of PJ patients using oral enzyme supplementation (PG vs PJ, 72% vs 81%, P = 0.11). However, simultaneously the rate of patients reporting steatorrhea in the PJ group increased (from 17% at 6 months to 22% at 12 months), suggesting now insufficient enzyme supplementation in some patients. This was not the case with PG, where reported steatorrhea decreased from 20% to 13%. The amount of enzyme units taken per day was comparable in both treatment groups.
The prevalence of diabetes mellitus rose only slightly after pancreatoduodenectomy (from 25% at operation to 31% at 12-month follow-up) and was comparable after PG and PJ. Among diabetic patients, there was an increase of insulin dependence from around 50% to around 70% after pancreatoduodenectomy, whereas the percentage of patients with dietary therapy dropped only from 23% preoperatively to 13% and 9% at 6 and 12 months, respectively. There was no significant difference between both treatment arms (Table 4).
Quality of Life and Long-term Follow-up
At the time of operation, EORTC QLQ-C30 and PAN26 scores were balanced between the treatment groups except for the physical functioning scale scores, which were higher in the PG group (P = 0.002). The patients assigned the lowest scores to role functioning and body image. Other major reported problems were fatigue, insomnia, pain, and digestive symptoms such as altered bowel habit. At 6 and 12 months after the operation, the most severe impairments were observed in role functioning, altered bowel habit, and fatigue. On the contrary, appetite, nausea, and hepatic symptoms improved. At 6 months, a reduced score on the financial problems scale could be observed (P = 0.044) in PG compared with PJ, which persisted at 12-month follow-up. Furthermore, emotional and social functioning scale scores were significantly better after PG than after PJ (P = 0.039 and 0.019) (see Supplemental Digital Content Table S5, available at http://links.lww.com/SLA/A782).
We report the currently largest RCT to compare PG and PJ in terms of POPF and perioperative complications and long-term outcome including quality of life. Of note, this multicenter trial was independently monitored. In contrast to previous RCTs, PG or PJ was not restricted to a specific subtype. The results of this trial have several implications for clinical practice. First, although it was designed to confirm the hypothesis of a reduction of clinically relevant POPF in patients with PG, the results show similar rates of grade B/C POPF regardless of the reconstruction method with an overall rate of 21%. This is higher than the reported range of 4% to 18% from large retrospective benchmark series (see Supplemental Digital Content Table S1, available at http://links.lww.com/SLA/A778). The previous RCTs report fistula rates between 12% and 24% (see Supplemental Digital Content Table S1, available at http://links.lww.com/SLA/A778). In comparison with the other RCTs, RECOPANC included the oldest patients (average 68 years vs 56–67 years in other RCTs) with the highest body mass index (average 25 vs 21–25 in other RCTs). Of note, RECOPANC is also the first RCT to report independent monitoring. Taken together, the observed POPF rate must be considered valid in view of an ageing general population with increased operative risk.
Also, overall in-hospital mortality of 6% and the 90-day mortality of 7% in this trial do not meet the usually cited 5% benchmark for pancreatoduodenectomy. It is above the reported range of 0.7% to 3.7% from current large-scale retrospective series (see Supplemental Digital Content Table S1, available at http://links.lww.com/SLA/A778), whereas some RCTs report comparable perioperative mortality rates of 0% to 11% (see Supplemental Digital Content Table S1, available at http://links.lww.com/SLA/A778). In agreement with a current study,41 our data highlight the relevance of 90-day mortality figures in pancreatic surgery. It seems appropriate to accept that clinically relevant fistula rates of 20% and perioperative mortality of more than 5% mirror clinical reality even in high-volume pancreatic surgery. A similar effect was observed in the distal pancreatectomy trial, which reported a pancreatic fistula rate after distal pancreatic resection more than twice as high as previously reported in several retrospective series.42,43
Meta-analysis of the available RCTs19–26 incorporating data from this trial suggests no significant reduction in POPF rates (odds ratio: 0.66; 95% confidence interval: 0.43–1.01; P = 0.056) (see Supplemental Digital Content Table S6, available at http://links.lww.com/SLA/A783 for details). This stands in contrast to current meta-analysis.44
In a multivariate analysis, the single most important factor influencing POPF rates was the quality and texture of the organ. Soft pancreatic texture, as judged intraoperatively by the surgeon, has been demonstrated to bear a higher risk for secondary complications, erosion bleeding, and mortality in previous studies.6,9,11,24,37,38,40 It has been shown that subjective evaluation of the pancreatic hardness and texture strongly correlates with the histopathological degree of fibrosis.40 On the one hand, pancreatic cancer and chronic pancreatitis are usually associated with hardening of the whole organ including the pancreatic remnant; on the other hand, prophylactic surgery for benign lesions such as cystic neoplasms or small tumors such as ampullary cancer is usually associated with soft pancreatic tissue.9,19,40
As outlined, all participating clinics were high-volume academic centers for pancreatic surgery, and there was no statistically significant center effect regarding POPF rate. Nevertheless, a high odds ratio for POPF in the low-volume surgeons indicates that besides center volume, individual surgeon volume is a relevant factor influencing complication rates in pancreatoduodenectomy.
Furthermore, from our data, it might be speculated that PG offers an easier-to-learn technique suited for less experienced surgeons, but this effect did not reach statistical significance. This opinion has also been expressed by other authors of previous RCTs19,20,24,26 on the basis of the assumption that it is technically easier to achieve secure invagination of the pancreatic remnant with PG, especially in case of a bulky soft pancreas. Reasons given for conversion to PG instead of PJ (soft pancreas in 11 of 12 cases) in the current trial may reflect this assumption. However, operation time was not reduced with PG in the current trial, and only 2 previous RCTs23,26 found a shorter operation time with PG.
The incidence of grade A and B postpancreatectomy hemorrhages was increased after PG. By ISGPS definition, grade A bleeding has no therapeutic consequence, but grade B events require conservative or even invasive therapy and may be sentinels of later grade C hemorrhage. The feared life-threatening (grade C) bleeding events were not increased with PG. These findings confirm previous retrospective and prospective observations, which showed increased bleeding events from PGs.23,45,46 Meticulous hemostatic measures at the pancreatic cut surface are, therefore, advised. There was a higher rate of perioperative stroke events in patients with PGs that were not associated with the bleeding events, however. For lack of a rational explanation, this might be interpreted as an artifact of exploratory data analysis.
Our reported length of hospital stay (median, 16 days) is about twice as long as that usually reported from high-volume North American centers (see Supplemental Digital Content Table S1, available at http://links.lww.com/SLA/A778). Our explanations are that due to law-enforced universal health care insurance in Germany, patients usually do not experience financial pressure to be discharged early, and the common practice is to discharge patients home after full recovery. Even in a fast-track surgery program applied to major pancreatic resections in a German center,47 patients were discharged at median on day 10, with a 30-day readmission rate of only 3.5%, whereas readmission rates of 15% to 20% after pancreatoduodenectomy are currently reported from the United States.48,49 In consequence, readmission has been highlighted as a significant problem by American scientific studies and is financially penalized in the United States but not in Germany.47–51
The results of long-term pancreatic function follow-up in the current trial may be interpreted as suggestive of better exocrine function in patients with PG. However, pancreatic function was not measured directly but by means of the surrogate parameters oral enzyme supplementation and steatorrhea, and the drawback of exploratory data analysis must be kept in mind. Previous RCTs with smaller case numbers have reported inconsistent outcomes.25,26 The current study represents the largest prospective evaluation of this issue and will be followed by a prospective long-term observation of the included patients. Regarding the usually encountered opinion that pancreatic function is worse after PG compared with PJ, our results suggest that this is not the case.
Only one previous retrospective study compared quality of life after pancreatoduodenectomy with PG and PJ and found no difference, but it was unbalanced with regard to the preoperative patient status.52 Follow-up in the present trial did not reveal differences between the treatment groups in most aspects covered by the EORTC QLQ-C30/PAN26 questionnaires. On the contrary, the few detected that differences are not large enough to be considered clinically relevant. We also interpret these as an artifact of explorative analysis of the many quality-of-life aspects. Our results, however, provide valuable data to identify major problems that impair the quality of life of patients before and after pancreatoduodenectomy: role functioning, altered bowel habit, and fatigue.
In summary, this trial demonstrated several salient findings. Reconstruction by PG, when not restricted to a specific subtype and evaluated in a multicenter setting, did not reduce perioperative complications. Soft pancreatic tissue quality remains the most influential factor for POPF rate. PG may offer a technically less demanding but safe anastomotic technique. However, a higher rate of postoperative grade A/B hemorrhage was observed, advocating increased awareness toward hemostatic measures with PG. The rate of POPF remains substantial and is currently underestimated. Perioperative mortality can surpass the 5% margin even in the high-volume academic pancreatic surgery setting. Both may be attributed to extended indications for pancreatoduodenectomy in an ageing population. Quality of life in pancreatoduodenectomy patients is most severely impaired regarding role functioning and body image. The operation seems to ameliorate gastrointestinal and hepatic symptoms but does not improve fatigue and role functioning. Long-term exocrine pancreatic function after PG does not seem to be inferior to PJ.
T. Keck and U. F. Wellner equally contributed to the manuscript and share primary authorship.
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