A Prospective Randomized Crossover Trial of Systemic Chemotherapy in Patients with Low-Grade Mucinous Appendiceal Adenocarcinoma

ABSTRACT Importance Appendiceal Adenocarcinoma is a rare tumor and given the inherent difficulties in performing prospective trials in such a rare disease currently there is a scant amount of high-quality data upon which to guide treatment decisions, which highlights the unmet need for more pre-clinical and clinical investigation for this orphan disease Objective To objectively evaluate the effectiveness of flouropyrimdine-based systemic chemotherapy in inoperable low-grade mucinous Appendiceal Adenocarcinoma patients. Design This open label randomized crossover trial recruited patients from September 2013 to January 2021. The data collection cutoff was May 2022. Setting Single tertiary care comprehensive cancer center. Participants Enrollment of up to 30 patients was planned. Eligible patients had histological evidence of a metastatic low grade, mucinous Appendiceal Adenocarcinoma, with radiographic images demonstrating the presence of mucinous peritoneal carcinomatosis and were not considered a candidate for complete cytoreductive surgery. Key exclusion criteria were concurrent or recent investigational therapy, evidence of a bowel obstruction, use of total parental nutrition. Interventions Patients were randomized to either 6 months observation followed by 6 months of chemotherapy, or initial chemotherapy followed by observation. The majority of patients were treated with either 5FU or capecitabine as single agent (n = 15, 63%); 3 (13%) received doublet chemotherapy (FOLFOX or FOLFIRI), bevacizumab was added to cytotoxic chemotherapy for 5 (21%) patients. Main Outcomes and Measures The difference in tumor growth and patients reported outcomes between the chemotherapy and observation periods. Also, the objective response rate, the rate of bowel complications, and differences in overall survival. Results A total of 24 patients were enrolled. Fifteen patients were available to evaluate difference in tumor growth between treatment and observation; there was not a significant difference (8.4% (1.5, 15.3%) increase from baseline on treatment vs. 4.0% (−0.1, 8.0%) increase from baseline on observation; p=0.26). Of the 18 patients who received any chemotherapy, zero had an objective response (14 (77.8%) SD, 4 (22.2 %) PD). Median OS was 53.2 months, there was no significant difference in OS between the Observation First arm (76 months) and the Treatment First arm (53 months) (HR, 0.64; 95% CI, 0.16 to 2.6; p = 0.48). Patient reported quality of life metrics identified that fatigue (Mean scores were 18.5 vs 28.9, p=0.02), peripheral neuropathy (6.7 vs 28.9, p=0.014), and financial difficulty (8.9 vs 28.9, p=0.0013) were all significantly worse while on treatment. Conclusions and Relevance These data suggest that patients with low-grade mucinous appendiceal adenocarcinoma do not derive benefit from systemic fluoropyrimidine-based chemotherapy. Trial Registration ClinicalTrials.gov Identifier: NCT01946854 . URL: https://clinicaltrials.gov/ct2/show/NCT01946854 KEY POINTS Question Is fluoropyrimidine-based systemic chemotherapy effective in treating inoperable low-grade mucinous Appendiceal Adenocarcinoma patients? Findings In this randomized clinical trial that included 24 patients, there was no significant difference in tumor growth between treatment and observation (8.4% increase from baseline on treatment vs. 4.0% increase from baseline on observation; p=0.26). Meaning Patients with low-grade mucinous appendiceal adenocarcinoma do not derive benefit from systemic fluoropyrimidine-based chemotherapy.