Efficacy of Systemic Chemotherapy in Patients With Low-grade Mucinous Appendiceal Adenocarcinoma

Abstract

ImportanceAppendiceal adenocarcinoma is a rare tumor, and given the inherent difficulties in performing prospective trials in such a rare disease, there are currently minimal high-quality data to guide treatment decisions, highlighting the need for more preclinical and clinical investigation for this disease.ObjectiveTo prospectively evaluate the effectiveness of fluoropyrimidine-based systemic chemotherapy in patients with inoperable low-grade mucinous appendiceal adenocarcinoma.Design, Setting, and ParticipantsThis open-label randomized crossover trial recruited patients at a single tertiary care comprehensive cancer center from September 2013 to January 2021. The data collection cutoff was May 2022. Enrollment of up to 30 patients was planned. Eligible patients had histological evidence of a metastatic low-grade mucinous appendiceal adenocarcinoma, with radiographic imaging demonstrating the presence of mucinous peritoneal carcinomatosis and were not considered candidates for complete cytoreductive surgery. Key exclusion criteria were concurrent or recent investigational therapy, evidence of bowel obstruction, and use of total parenteral nutrition. Data were analyzed from November 2021 to May 2022.InterventionsPatients were randomized to either 6 months observation followed by 6 months of chemotherapy, or initial chemotherapy followed by observation.Main Outcomes and MeasuresThe primary end point was the percentage difference in tumor growth in treatment and observation groups. Key secondary end points included patient-reported outcomes in the chemotherapy and observation periods, objective response rate, rate of bowel complications, and differences in overall survival (OS).ResultsA total of 24 patients were enrolled, with median (range) age of 63 (38 to 82) years, and equal proportion of men and women (eg, 12 men [50%]); all patients had ECOG performance status of 0 or 1. A total of 11 patients were randomized to receive chemotherapy first, and 13 patients were randomized to receive observation first. Most patients (15 patients [63%]) were treated with either fluorouracil or capecitabine as single agent; 3 patients (13%) received doublet chemotherapy (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin or folinic acid, fluorouracil, and irinotecan hydrochloride), and bevacizumab was added to cytotoxic chemotherapy for 5 patients (21%). Fifteen patients were available to evaluate the primary end point of difference in tumor growth during treatment and observation periods. Tumor growth while receiving chemotherapy increased 8.4% (95% CI, 1.5% to 15.3%) from baseline but was not significantly different than tumor growth during observation (4.0%; 95% CI, −0.1% to 8.0%; P = .26). Of 18 patients who received any chemotherapy, none had an objective response (14 patients [77.8%] had stable disease; 4 patients [22.2%] had progressive disease). Median (range) OS was 53.2 (8.1 to 95.5) months, and there was no significant difference in OS between the observation-first group (76.0 [8.6 to 95.5] months) and the treatment-first group (53.2 [8.1 to 64.1] months; hazard ratio, 0.64; 95% CI, 0.16-2.55; P = .48). Patient-reported quality-of-life metrics identified that during treatment, patients experienced significantly worse fatigue (mean [SD] score, 18.5 [18.6] vs 28.9 [21.3]; P = .02), peripheral neuropathy (mean [SD] score, 6.67 [12.28] vs 38.89 [34.88]; P = .01), and financial difficulty (mean [SD] score, 8.9 [15.2] vs 28.9 [33.0]; P = .001) compared with during observation.Conclusions and RelevanceIn this prospective randomized crossover trial of systemic chemotherapy in patients with low-grade mucinous appendiceal adenocarcinoma, patients did not derive clinical benefit from fluorouracil-based chemotherapy, given there were no objective responses, no difference in OS when treatment was delayed 6 months, and no difference in the rate of tumor growth while receiving chemotherapy.Trial RegistrationClinicalTrials.gov Identifier: NCT01946854

Serum Tumor Markers and Outcomes in Patients With Appendiceal Adenocarcinoma

“…There was a significant difference in median OS between the 2 groups; median OS for patients who had 2 ng/mL or less elevation in CEA was 10 vs 49 months for patients who had CEA levels that decreased or remained stable (HR, 3.0; 95% CI, 1.6-5.6; P < .001) (eFigure 12 in Supplement 1). These data suggest a possible role for serial TM measurement while receiving chemotherapy to assess for therapeutic response, important in appendiceal cancer given the difficulty in quantitating response by traditional imaging methods …”

“…This observation could be explained by early diagnosis in these patients when the tumor volume is insufficient to cause elevation of the TMs, which would be associated with an especially favorable outcome. This should be studied prospectively, but there could be a role for treatment deescalation in these patients, particularly considering recent prospective data showing 5-fluorouracil–based chemotherapy is ineffective in this patient population . Conversely, for patients with highly elevated tumor markers, the poor prognoses seen with current treatments, which have historically been chemotherapy designed for CRC, suggests that these patients be prioritized for clinical studies testing appendiceal cancer–specific therapies.…”

Consensus guideline for the management of patients with appendiceal tumors Part 1: Appendiceal tumors without peritoneal involvement

“…At present, available studies indicate no benefit from the use of 5-FU based chemotherapy in this population, so it is not recommended. 24,53,69–71…”

“…Given the rarity of appendiceal tumors, prospective studies are challenging and randomized studies are nearly non-existent, so data to guide their management are low-quality and there are no well-established standards of care. 24,25 To fill this need, the multidisciplinary Chicago Consensus Working Group was formed in 2018 to generate consensus recommendations for peritoneal malignancies including appendix tumors. 26 Herein, these recommendations are updated by expert consensus for the clinical management of patients with localized appendiceal mucinous neoplasms and localized appendiceal adenocarcinoma, supported with recent evidence synthesized through rapid systematic reviews.…”

Dihydromyricetin reverses capecitabine‐induced peripheral myelin dysfunction through modulation of oxidative stress

“…Although capecitabine ameliorates 5‐Fu‐induced adverse effects, recent clinical reports have revealed that capecitabine, both in monotherapy and combined therapy, could induce severe peripheral neuropathy, manifested as numbness, paresthesia, hypoesthesia and even somatization disorders 5 . Based on various clinical trials, the peripheral neuropathy rates caused by capecitabine range from 36% to 73%, 4,6,7 greatly lowering the patients’ quality of life. To date, investigations of capecitabine‐induced peripheral neurotoxicity have only focused on clinical symptoms without further mechanistic studies.…”