This population-based, case-matched analysis demonstrates no significant survival benefit for adjuvant chemotherapy after curative resection of DA and PVA. Although patients treated with adjuvant therapy more often demonstrated poor prognostic factors such as lymph node involvement, no benefit for adjuvant therapy was found after case-matching. The OS did not differ significantly between patients receiving adjuvant chemotherapy and patients not receiving adjuvant chemotherapy.
This is the first study to explore the role of adjuvant chemotherapy in a nation-wide analysis of all patients with only DA and PVA presenting over a period of 15 years. PVA was included due to its resemblance with DA on its intestinal histopathological phenotype and reported survival rates. Our study focusses only on DA and PVA and excluded patients with pancreaticobiliary type papilla of Vater carcinoma since OS is more favorable in patients with intestinal type tumors compared to pancreaticobiliary type tumors[6, 21]. This is reflected in a median survival of 60 months vs 17 months respectively (P = 0.002). DA and PVA are presumed to be comparable to small bowel adenocarcinomas (SBAs) and CRC by many authors[2, 17]. In patients suffering from CRC, administration of adjuvant therapy is mostly based on disease stage and poor prognostic factors. In patients with CRC administration of adjuvant chemotherapy is standard of care in case of positive lymph nodes after resection of the primary tumor (i.e. stage III disease) or high risk stage II disease.
The putative benefit of adjuvant therapy after curative resection has been a topic for debate in DA. In line with the current results, another population-based retrospective analysis found no benefit for the use of adjuvant chemotherapy. Adjuvant chemotherapy after curative resection also demonstrated no survival benefit in patients with SBA, including DA. However, combining all patients with SBA together and heterogeneity of the reported adjuvant treatment regimens could bias these results[17, 23]. In contrast, there are also studies that show a possible benefit of adjuvant therapy in patients with SBA. Ecker et al. found a significant survival benefit in patients who received adjuvant chemotherapy in SBA (HR 1.36 CI 1.24–1.50, P < 0.001) and also a significant difference in OS in stage III duodenal adenocarcinoma (median OS 34.1 vs 24.3 months, P = 0.002). Legué et al. showed a significant survival benefit in patients who received adjuvant chemotherapy in SBA with a median survival of 66 months compared to 48 months (P = 0.034). No subgroup analysis for patients with DA was performed and information on the chemotherapy treatment schedules that were used lacked in both studies[2, 16]. Thus, adjuvant therapy for DA remains at least doubtful.
The open label BALLAD trial (NCT02502370) is currently open for patient accrual  and aims to determine the potential benefit of two different adjuvant chemotherapy schedules in patients with resected SBA (including DA) stage I, II and III. In the future, the results of this trial could potentially aid to also determine the benefit of adjuvant therapy for patients with DA if a subgroup analysis for patients with DA will be performed. This is relevant as a worse 5-year survival was reported in DA compared to adenocarcinomas located in jejunum or ileum (28.1%, 50.9% and 42.8% respectively).
Legué et al. reported different 5-year crude survival rates for patients with tumors on different locations of the primary tumor in the small bowel for duodenum, jejunum and ileum.
Besides adjuvant chemotherapy, the combination of chemotherapy and radiotherapy was not found to improve survival in the analysis performed by Ecker et al. However, the addition of radiotherapy was often based on poor prognostic factors compromising interpretation[12, 25].
Multiple chemotherapeutic regimens are currently in use for (metastatic) SBA. Mostly, fluorouracil-based regimens are used, either alone or combined with a platinum analog. A significant survival benefit was reported for fluorouracil-based regimens combined with a platinum analog compared to other types of chemotherapy. And in addition, the combination of capecitabine and oxaliplatin (CAPOX) improved response rates and overall survival in SBA and advanced and metastatic ampullary adenocarcinoma.
Several limitations of this study warrant emphasis, especially regarding the retrospective study design of this nation-wide registration. The data collection could be influenced by data omission and miscoding during the data collection process. Case matching was performed to ensure equal groups for survival analysis, but this case matching could not control for variables which are not registered in the NCR. In our registry, several important prognostic factors were not reported, including resection margins, tumor perforation, performance status, surgical complications, the specific type of chemotherapy used and data on disease free survival. Positive margins have been associated with poorer survival outcomes and could e.g. have affected the use of adjuvant chemotherapy but also the lack of information on the other parameters may have resulted in bias because of unbalanced matching
In conclusion, this case–matched cohort study demonstrated no statistically significant survival benefit for the use of adjuvant chemotherapy in patients with DA and PVA after curative-intent surgical resection of the primary tumor. The lack of specified treatment regimens withholds a final conclusion on the potential benefit specified per treatment regimen. Differences in the 1-, and 3 year OS rates were notable and in favor of the use of adjuvant chemotherapy, but did not reach statistical significance.
Future studies with specified treatment regimens as well as thorough stratification for prognostic factors could help to unravel the true role of adjuvant therapy in patients with DA and PVA.