Evaluation of Systemic Treatments of Small Intestinal Adenocarcinomas: A Systematic Review and Meta-analysis

IMPORTANCE: Although small intestinal adenocarcinomas (SIAs) are rare, they have a poor prognosis, and the optimal treatment strategies are largely unknown. Because of the lack of high-quality evidence, guidelines for colorectal cancer are often followed in the treatment of SIAs. OBJECTIVE: To review the current evidence regarding survival benefit of systemic therapies, including chemotherapy, targeted agents, and immunotherapy, for patients with SIAs. DATA SOURCES: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses, MEDLINE and Embase were searched for articles published from January 1, 2005, until June 1, 2022. STUDY SELECTION: Retrospective cohort studies and prospective phase 2 or 3 trials describing survival after systemic therapies for patients with SIAs were eligible for inclusion. Assessment of study eligibility was blinded and performed by 3 reviewers. DATA EXTRACTION AND SYNTHESIS: The reviewers independently extracted data. Random effects, inverse variance, pairwise meta-analyses were performed. MAIN OUTCOMES AND MEASURES: Primary outcomes were overall survival (OS) and progression-free survival (PFS) of patients with SIAs after systemic therapies. Measures of interest included hazard ratios for survival and median survival times. RESULTS: Overall, 57 retrospective cohort and phase 2 studies of 35 176 patients were included. Adjuvant chemotherapy, generally fluoropyrimidine-based, was associated with increased OS in stage I to III SIAs (hazard ratio [HR], 0.60; 95% CI, 0.53-0.68), especially in stage III tumors (HR, 0.55; 95% CI, 0.48-0.64), irrespective of tumor localization. Palliative chemotherapy was also associated with an OS benefit (HR, 0.48; 95% CI, 0.40-0.58). Fluoropyrimidine-oxaliplatin combinations were superior to other regimens (OS: HR, 0.54; 95% CI, 0.30-0.99; PFS: HR, 0.46; 95% CI, 0.30-0.71). Furthermore, bevacizumab added to chemotherapy compared with chemotherapy alone was associated with significantly prolonged PFS (HR, 0.62; 95% CI, 0.43-0.89). Immunotherapy showed a 50% overall response rate in previously treated defective mismatch repair tumors. CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, adjuvant and palliative chemotherapy were both associated with improved survival of patients with SIAs, especially fluoropyrimidine-based regimens and fluoropyrimidine-oxaliplatin combinations. Adding bevacizumab to chemotherapy appears to prolong PFS and deserves further investigation. Immunotherapy seems beneficial and should be considered for patients with defective mismatch repair tumors. International collaborations should be undertaken to confirm and improve efficacy of systemic therapies for patients with SIAs.