NMA plus antitumor therapy versus antitumor therapy alone in patients with BCLC stage B or C hepatocellular carcinoma and pre-cachexia or cachexia: protocol for a prospective, multicenter, randomized, open-label phase II trial.

Abstract

Background: Cancer anorexia-cachexia syndrome (CACS) is prevalent among patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C hepatocellular carcinoma (HCC) and is strongly associated with poor prognosis, reduced treatment tolerance, and impaired quality of life. Megestrol acetate (MA) has demonstrated efficacy in improving appetite and body weight; however, conventional formulations are limited by variable bioavailability. This trial will evaluate the efficacy and safety of nanocrystalline megestrol acetate (NMA) in patients with BCLC stage B or C HCC and pre-cachexia or cachexia receiving systemic therapy combined with transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC).

Methods: This multicenter, randomized, open-label, parallel-group Phase II trial protocol will enroll 68 adults aged 18-75 years with BCLC stage B or C HCC and pre-cachexia or cachexia. Participants will be stratified according to BCLC stage and weight loss during the previous 6 months and then randomized in a 1:1 ratio to receive either NMA (625 mg/day for 12 weeks) plus antitumor therapy (systemic therapy combined with transarterial chemoembolization [TACE] or hepatic arterial infusion chemotherapy [HAIC]) or antitumor therapy alone. Antitumor therapy will comprise systemic therapy combined with TACE or HAIC. The co-primary endpoints are the proportions of Anorexia/Cachexia Subscale-12 (A/CS-12) responders and body mass index (BMI) responders at Week 12. Secondary endpoints include objective response rate, progression-free survival, changes in the L3 skeletal muscle index (L3 SMI), and the incidence of adverse events. Exploratory endpoints will evaluate inflammatory and nutritional biomarkers as well as quality of life, assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30).

Discussion: This trial will provide preliminary comparative data on NMA plus antitumor therapy versus antitumor therapy alone in patients with BCLC stage B or C HCC and pre-cachexia or cachexia.

Ethics: The study protocol was approved by the Ethics Committee of West China Hospital, Sichuan University (IRB No. 2025-2539). The trial is registered at ClinicalTrials.gov NCT07356037.