The Role of Systemic Chemotherapy to Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in Patients With Appendiceal Cancers

Abstract

Background: Appendiceal cancer frequently presents with peritoneal metastases. Cytoreductive surgery combined (CRS) with heated intraperitoneal chemotherapy (HIPEC) is currently standard practice for metastatic appendiceal cancer, particularly mucinous subtypes. However, the specific benefit of adding standard postoperative systemic chemotherapy, either alone or in addition to HIPEC, remains unclear. Methods: Using the National Cancer Database (NCDB) from 2018 to 2022, we identified 888 patients with appendiceal cancer (goblet cell/composite, signet-ring/diffuse, or adenocarcinoma) characterized by peritoneal metastases. Mucinous subtypes were excluded. All patients underwent cytoreductive surgery, and many underwent primary tumor resection concurrently. Patients were stratified based on initial systemic treatment received: no chemotherapy (n = 181), standard adjuvant chemotherapy (n = 415), perioperative chemotherapy (n = 62), HIPEC with additional systemic therapy (n = 122) or without additional systemic chemotherapy (n = 124). Survival outcomes were compared using Kaplan–Meier analysis and multivariable Cox regression, adjusting for age, sex, Charlson–Deyo comorbidity index and histologic subtype. Results: With a median follow-up of 41 months, the 3-year overall survival was 20.2% for no chemotherapy, 25.3% for adjuvant chemotherapy, 39.3% for perioperative chemotherapy, and 58.4% for HIPEC without additional systemic therapy and 46.3% for HIPEC with additional systemic therapy. Compared to surgery alone, standard adjuvant chemotherapy reduced mortality risk by approximately 20% (HR 0.80; 95% CI, 0.60-1.07; P = .13), and HIPEC-based therapy reduced mortality risk by approximately 43% (HR 0.57; 95% CI, 0.40-0.81; P = .002), regardless of whether additional systemic therapy was received. Neither age, sex, nor specific histologic subtype independently influenced survival. A higher comorbidity burden (Charlson–Deyo ≥ 2) trended towards worse survival (HR 1.81; P = .05). Conclusions: While prior literature suggests a role of systemic therapy in addition to cytoreductive surgery and HIPEC in treating peritoneal metastases from appendiceal cancers, our findings demonstrate that additional systemic chemotherapy, whether standard adjuvant or perioperative, is not associated with significantly improved survival outcomes compared to surgery and HIPEC alone. These results do not support the routine consideration of postoperative or perioperative systemic therapy for all patients undergoing cytoreductive surgery and HIPEC, irrespective of histologic subtype.