ADVERTISEMENT
Outcomes of randomized crossover trial of systemic chemotherapy in patients with low-grade mucinous appendiceal adenocarcinoma
Background
Appendiceal adenocarcinoma is both a rare and heterogenous tumor, with marked contrast in the natural history of low-grade and high-grade tumors (5-year OS 68% for low-grade vs. 7% for high-grade). The rarity of appendiceal adenocarcinoma has made it difficult to study with traditional prospective, randomized controlled trials. As a result, current national guidelines still suggest that appendiceal cancer be treated similarly to colorectal cancer (CRC) despite clear differences between the two in terms of both clinical and molecular features. While low-grade appendiceal adenocarcinoma is primarily treated with surgical resection sometimes followed by hyperthermic intraperitoneal chemotherapy (HIPEC), many inoperable candidates are treated with systemic chemotherapy although there is no prospective data supporting this practice. The purpose of our study was to objectively evaluate the effectiveness of systemic chemotherapy in low-grade mucinous appendiceal adenocarcinoma.
Methods
A randomized crossover trial of surgically unresectable low-grade (well differentiated) mucinous appendiceal adenocarcinoma was performed with patients randomized to either 6 months observation followed by 6 months of chemotherapy (physician’s choice), or initial chemotherapy followed by observation. In this way each patient would serve as their own control. Up to 30 patients were planned to have complete 6- and 12-month tumor measurements for 24 patients, providing 80% power at 0.05 significance level to detect a 5.0% difference in change in tumor size in observation vs. treatment periods. Patients were monitored for rate of bowel complications as a secondary endpoint for the study.
Results
The trial closed early due to slow accrual. A total of 24 patients were enrolled. The majority of patients were treated with either 5FU or capecitabine (n = 15, 63%), bevacizumab was added for 3 (13%), one patient was treated with FOLFOX, 2 (8%) were treated with FOLFIRI. Four patients did not get any chemotherapy (17%). There were 15 patients available for the primary analysis of change in tumor volume as measured by modified peritoneal RECIST. The mean difference in tumor size was -4.5 (95% CI: -12.6, 3.7), indicating a trend towards faster growth on treatment than observation, however there was no significant difference in growth of tumor during observation vs. treatment time periods (8.4% growth treatment vs. 4.0% observation, p=0.26). Separately we combined all patients with available 6- or 12-month information regardless of treatment order accounting for repeated measures again finding no significant difference (13.1% vs. 4.4%, p=0.14, n=18). There was no significant difference in overall survival between treatment first or observation first arms (76 vs. 42 months, p = 0.37). There was not a significant difference in rate of bowel obstruction between the treatment first vs. observation first arms (12.5%, (n=3) vs 8.3%, (n=2)), and no bowel perforations occurred on study.
Conclusions
These data from a prospective, randomized crossover design trial suggest that patients with low-grade mucinous appendiceal adenocarcinoma do not appear to derive benefit from 5FU based chemotherapy. These data further highlight the unique biology of low-grade mucinous appendiceal adenocarcinomas and demonstrates the need to identify effective systemic therapies for this patient population.
Legal entity responsible for the study
The authors.
Funding
This work was supported by the National Cancer Institute (L30 CA171000 and K22 CA234406 to J.P.S., and the Cancer Center Support Grant (P30 CA016672), the Cancer Prevention & Research Institute of Texas (RR180035 to J.P.S., J.P.S. is a CPRIT Scholar in Cancer Research), and the Col. Daniel Connelly Memorial Fund.
Disclosures
M. Overman: Advisory / Consultancy: AbbVie and Takeda Pharamceuticals (Japan), AgilVax and Merck Sharp & Dohme Corp, Acrotech Biopharma and Novartis Pharmaceuticals corp. All other authors have declared no conflicts of interest.
