Adjuvant chemotherapy not linked to improved outcomes in localized appendiceal adenocarcinoma

1. Adjuvant chemotherapy was not associated with improved relapse-free or overall survival in patients with localized appendiceal adenocarcinoma.

2. Patients with localized appendiceal adenocarcinoma had a low rate of relapse after surgical resection, with risk varying by histologic subtype and tumor stage.

Evidence Rating Level: 2 (Good)

Study Rundown: Appendiceal adenocarcinoma (ApAC) is a rare gastrointestinal cancer, and the role of adjuvant chemotherapy following surgical resection of localized disease remains unclear. This retrospective cohort study evaluated relapse risk and outcomes associated with adjuvant chemotherapy in patients with localized ApAC treated at the University of Texas MD Anderson Cancer Center and was validated in an independent cohort from Memorial Sloan Kettering Cancer Center (MSKCC). Among patients who underwent resection at MD Anderson, less than ten percent experienced relapse. Relapse risk varied substantially by histologic subtype, with goblet cell adenocarcinoma featuring the lowest observed relapse rate and signet ring cell tumors having the highest. Histologic subtype and pT4 stage were independently associated with relapse. However, several established colorectal cancer risk factors, including tumor perforation, lymphovascular invasion, and perineural invasion, were not associated with relapse in ApAC. Adjuvant chemotherapy was not associated with improved relapse-free or overall survival after adjustment for clinical confounders. Among patients with stage II disease at MD Anderson, chemotherapy was associated with lower relapse-free survival in the primary cohort but had no impact on overall survival. Neither outcome differed significantly according to chemotherapy use in the independent MSKCC validation cohort. These findings suggest that relapse risk in localized ApAC may be better characterized by histologic and molecular features than by risk factors commonly used for colorectal cancer. Strengths of this study included its large cohort for a rare malignancy, long follow-up, and detailed histopathologic characterization. Limitations included the retrospective design, potential referral bias from tertiary cancer centers, and lack of adjustment for multiple comparisons. In addition, the observational design limited the ability to determine whether chemotherapy itself affected survival outcomes.

Click to read the study in JAMA

Relevant Reading: Defining a role for systemic chemotherapy in local and advanced appendix adenocarcinoma

In-Depth [retrospective cohort]: This retrospective cohort study included 439 patients with localized appendiceal adenocarcinoma managed at MD Anderson between January 2000 and February 2024, of whom 202 underwent surgical resection. An independent validation cohort of 128 patients with stage II ApAC was also evaluated at Memorial Sloan Kettering. Among the 202 patients in the MD Anderson surgical cohort, 19 (9.4%) experienced relapse over a median follow-up of 62.6 months, with cumulative relapse rates of 2.7% at 1 year, 5.5% at 2 years, and 9.7% at 5 years. Relapse rates differed by histologic subtype, occurring in 3% of patients with goblet cell adenocarcinoma, 14% with mucinous tumors, 17.5% with enteric-type tumors, and 29% with signet ring cell tumors. Multivariate analysis revealed that mucinous (HR 5.60; 95% CI, 2.1-15.4; P < .001) and enteric-type histology (HR 6.60; 95% CI, 2.9-15.1; P < .001) were associated with worse relapse-free survival compared to goblet cell adenocarcinoma. Pathologically confirmed T4 disease was also associated with relapse (HR 3.30; 95% CI, 1.9-5.7; P < .001). In the MD Anderson surgical cohort, 28.2% of patients underwent adjuvant chemotherapy. After adjusting for confounding variables including cancer stage, adjuvant chemotherapy was not found to be associated with improved relapse-free survival (HR 0.98; 95% CI, 0.5-1.8; P = .94) or overall survival (HR 0.71; 95% CI, 0.2-2.1; P = .53). These findings were validated in the independent MSKCC cohort of 128 patients with stage II ApAC, in which adjuvant chemotherapy was similarly not associated with improved relapse-free survival (HR 1.10; 95% CI, 0.6-2.2; P = .70) or overall survival (HR 1.10; 95% CI, 0.5-2.6; P = .80). Finally, among patients with available genomic profiling, TP53 mutations in goblet cell tumors and GNAS mutations in nongoblet tumors were associated with increased relapse risk. Overall, these findings indicate that relapse following resection of localized ApAC was uncommon and that histologic and molecular characteristics may provide important information for risk stratification.

Image: PD

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