1. Phase 1 dose‐finding study of metformin in combination with concurrent cisplatin and radiotherapy in patients with locally advanced head and neck squamous cell cancer
- Author
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Nooshin Hashemi Sadraei, J. Silvio Gutkind, Pankaj B. Desai, Muhammad Kashif Riaz, Roman Jandarov, Zheng Zhu, Janki Desai, Alfredo A. Molinolo, Trisha Wise-Draper, Vinita Takiar, Michelle Mierzwa, Sarah Palackdharry, John C. Morris, and Shuchi Gulati
- Subjects
Diarrhea ,Male ,Mucositis ,Cancer Research ,medicine.medical_specialty ,Maximum Tolerated Dose ,Vomiting ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,030212 general & internal medicine ,Adverse effect ,Aged ,Neoplasm Staging ,Retrospective Studies ,Dose-Response Relationship, Drug ,Squamous Cell Carcinoma of Head and Neck ,business.industry ,Head and neck cancer ,Anemia ,Nausea ,Common Terminology Criteria for Adverse Events ,Retrospective cohort study ,Chemoradiotherapy ,Leukopenia ,Acute Kidney Injury ,Middle Aged ,medicine.disease ,Head and neck squamous-cell carcinoma ,Metformin ,Progression-Free Survival ,Survival Rate ,Oncology ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Female ,Cisplatin ,business ,Follow-Up Studies ,medicine.drug - Abstract
Background The 5-year overall survival (OS) rate remains at 50% for patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC), thereby underscoring the need for improved treatments. An antidiabetic agent, metformin, was found in retrospective studies to improve survival in patients with HNSCC. Therefore, the authors conducted a phase 1 dose escalation study combining metformin with chemoradiotherapy in patients with LAHNSCC. Methods Nondiabetic patients with LAHNSCC were enrolled in the current study to receive escalating doses of metformin and CRT based on the modified toxicity probability interval design. Metformin cohort doses included 2000 mg, 2550 mg, and 3000 mg daily in divided doses in addition to cisplatin (at a dose of 100 mg/m2 on days 1, 22, and 43) and standard radiotherapy (70 grays). Adverse events were categorized as per the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Results Twenty patients were enrolled, 2 of whom withdrew consent. The median age of the patients was 56 years and the majority were male (83%), were white (88%), had p16-positive disease (72%), and were tobacco users (61%). The median length of metformin exposure was 28.5 days. The most common grade ≥3 toxicities were nausea (11%), vomiting (11%), mucositis (6%), acute kidney injury (17%), anemia (6%), and leukopenia (11%). Dose-limiting toxicities included diarrhea and acute kidney injury. After a median follow-up of 19 months, the 2-year overall survival and progression-free survival rates were 90% and 84%, respectively. No hypoglycemia events or lactic acidosis were observed. Cisplatin administration did not appear to affect metformin pharmacokinetics. The maximum tolerated dose for metformin could not be determined given the limited number of patients who tolerated metformin during chemoradiotherapy. Conclusions To the authors' knowledge, the current study is the first phase 1 trial combining metformin with chemoradiotherapy. Rates of overall survival and progression-free survival were encouraging in this limited patient population, and warrant further investigation in a phase 2 trial.
- Published
- 2019