Outcomes and Treatment Options for Duodenal Adenocarcinoma: A Systematic Review and Meta-Analysis

This systematic review was conducted and reported in accordance with the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines.25 A systematic literature search was performed in the PubMed, EMBASE, and Wiley/Cochrane Library electronic databases from inception to 25 April 2017. The following terms were used (including synonyms and closely related words) as index terms or free-text words: ‘adenocarcinoma’, ‘duodenum’, ‘ampulla of Vater’, and ‘therapeutics’. All studies reporting on survival for histologically confirmed DA or intestinal-type ampullary adenocarcinoma (IAA) were eligible for inclusion. The reported survival rates had to be specified either per intervention group or per disease stage.26 Statistical analyses included pooling of the studies to compare the number of events after 5 years by the odds ratios (ORs) for death with their associated 95% confidence interval (CI). The Mantel–Haenszel method was used to calculate the weighted pooled OR and their associated 95% CIs for dichotomous data under the random effects model.27^,28 Statistical heterogeneity was estimated using the Cochrane’s Q and I² statistics,29 and the Newcastle–Ottawa quality assessment was implemented to assess the quality and risk of bias of the included studies.30 The full search strategies for all databases, eligibility criteria, inclusion and exclusion criteria, data collection process and analysis, and assessment of methodological quality can be found in the electronic supplementary material. Two investigators (LM and AA) independently reviewed the literature and conducted study selection. Data extraction and analysis were conducted by three investigators (LM, AA and JB). Discordant judgment was resolved by discussion and consensus.

This systematic review of the literature and meta-analysis shows a clear survival benefit for patients with DA after curative surgical resection, compared with palliative-treated patients. Both segmental duodenal resection and pancreaticoduodenectomy allow for adequate removal of lymph nodes and result in similar OS when negative resection margins can be achieved. Involvement of lymph nodes is a negative prognostic factor for survival and results in a significantly lower 5-year OS rate than node-negative disease. The included studies show no associated survival benefit for the use of any type of adjuvant therapy for DA, although this remains debatable due to the inequality of regimes used and insufficient patient stratification. No consensus regarding palliative treatment was found. Rarity of the tumor precluded a reliable assessment of the outcome of DA for each disease stage as the number of patients included per study was often low and staging was poorly specified.

To adequately attribute the relevance of lymph node metastases to prognosis, the number of involved lymph nodes and the pattern of regional lymph node spread is important.14^,26^,46 Lymphatic spread pattern is different among locations of DA, with lymphatic drainage of the distal portions of the duodenum ending mostly in the small bowel mesentery. These lymphatic basins are not removed with lymphadenectomy performed during pancreaticoduodenectomy, suggesting no additive effect of extended lymph node resection on survival for distal tumors.31 Although some still advocate pancreaticoduodenectomy for all DA tumors,14 our results emphasize that segmental resection is the resection of choice for distal DA whenever radical resection margins can be accomplished.10‐12^,22^,32^,34^,39^,43

Both DA and IAA display an intestinal histopathological phenotype and reported survival rates appear to be comparable.51 Notably, periampullary tumors with an intestinal histopathological phenotype with no lymph node metastasis showed an exceptionally good prognosis compared with pancreaticobiliary tumors.52 This provides rationale for similar treatment strategies for DA and IAA since therapies may be more adequately addressed based on histopathological classifications.53 Remarkably, no studies reporting treatment of IAA met the predefined inclusion criteria due to low numbers and thus these could not be incorporated for critical appraisal.54 Besides a histopathological approach, a targeted approach might be even more suitable to optimize treatment allocation for patients with DA and IAA. Recent comprehensive studies gained insight into the biology of periampullary cancers. Using genomic analysis, including driver gene mutations, they underlined the resemblance of IAA to intestinal tumors, such as CRC, while distinct alterations were also found.55^,56 Periampullary tumors and DA showed overlapping alterations in pathway genes, irrespective of tumor origin.56 These new insights support the clinical treatment of these tumor types as a unique entity and endeavor personalized treatment guided by genomic analysis.

Since local treatment of colorectal liver metastases prolongs survival, it has been suggested that patients with solitary or oligocentric hepatic metastases from DA and IAA should be considered for resection of metastases.32^,57 In contrast to resection of liver metastases of pancreaticobiliary lesions, intestinal-type tumors show an impressively better survival.57 Although too little experience exists to compare survival after resection of metastases to local or systemic treatment, first results regarding hepatic or (retro)peritoneal metastatic resection in DA show an encouraging improvement in OS.32

In this study, adjuvant chemo(radiation) therapy did not result in a proven survival benefit,22^,24^,31^,34^,36^,41^,48^,50 even after correction for nodal metastases.42^,45 In the latter two studies, adjuvant therapy resulted in similar survival rates compared with no adjuvant therapy, despite a higher prevalence of lymph node involvement in the adjuvant therapy group.45 Although further subgroup assessment is needed, these results could indicate a selection bias of patients for adjuvant therapy and might suggest a benefit for administration of adjuvant therapy in patients with worse prognosis. Adequate data on disease stage are essential to make definite conclusions as to whether adjuvant chemotherapy can be beneficial and to tailor treatment strategies accordingly. In comparison, adjuvant chemotherapy prolongs survival in node-positive disease (stage III), but not in node-negative disease (stage II) CRC.58 Since this stratification has not yet been thoroughly investigated for DA, the true value of adjuvant therapy based on the current literature remains unknown. The ongoing open-label randomized controlled BALLAD trial (NCT02502370) aims to answer this challenging clinical question by evaluating the potential benefit of two different adjuvant chemotherapy schedules for patients with resected stage I, II, and III SBA.

Growing evidence indicates favorable outcomes for combined modality therapies in CRC.59^,60 Subgroup analyses in CRC emphasize the importance of location and molecular subtypes to further stratify patients for optimal therapy outcomes.61^,62 These experiences gained in the CRC field in the past 20 years may also be explored in DA.17^,56 However, in DA, monotherapy with fluorouracil-based regimens is still commonly offered in the clinic, with no clear evidence of benefit.10^,22^,31^,32^,36^,38^,42^,45^,48^,49 In the last years, some studies have shown that multimodality treatment can be beneficial for SBAs. Prolonged survival for patients with SBA and IAA has been demonstrated for treatment with capecitabine and oxaliplatin, and fluorouracil, leucovorin and oxaliplatin combination chemotherapy.15^,21^,63 In addition, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy was reported to enhance survival in SBA with peritoneal metastases.64

The major limitation of this review is the retrospective design of the included studies, with a lack of patient stratification for confounding factors and a lack of specification of treatment modalities in most studies, resulting in clinical heterogeneity of the included studies and risk of bias. Most studies described small patient groups with single-center experience, and provided limited information, in particular on adjusted survival per disease stage and administration of chemo- and/or radiation therapy. Due to variety in the treatment regimens and poor specification of confounding and prognostic factors, bias of these factors could not be investigated in this study.

Evidence to guide optimal therapeutic outcome is limited due to the rarity of DA. Resection remains the only curative therapeutic option for DA, with equal outcomes after segmental resection and pancreaticoduodenectomy. Based on the included studies, the current use of monotherapy regimens shows no survival benefit, while the optimal approaches for (neo)adjuvant therapy with combined modality therapies are not yet well established. This systematic review and meta-analysis underlines the necessity of improving stratification for high-risk disease, including tumor biology-related factors, subgroup analysis, and targeted approaches, and warrants further research for survival benefit of (neo)adjuvant chemotherapy and metastasectomy in DA.