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

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/m 2 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. Cancer 2020;126:354-362.

A Ferroptosis-Related Gene Signature for Predicting the Prognosis and Drug Sensitivity of Head and Neck Squamous Cell Carcinoma

“…According to National Comprehensive Cancer Network (NCCN) guidelines Version 2.2021, Cisplatin, Paclitaxel, Docetaxel, Doxorubicin, Etoposide, Gemcitabine, Methotrexate, and Cytarabine were main chemotherapeutic agents for head and neck cancers. Besides, on the basis of previous studies ( Tang et al, 2019 ; Gulati et al, 2020 ), IC50 of Gefitinib and Metformin was also explored in different risk groups. Then, we analyzed the correlations between the expression of prognostic risk genes and the resistance/sensitivity of pan-cancer cells to chemotherapeutic drugs based on the CellMiner database ( https://discover.nci.nih.gov/cellminer ), which is an open-access Web interface containing molecular and pharmacological data for the NCI-60 cancerous cell lines (a panel of 60 diverse human cancer cell lines) ( Reinhold et al, 2012 ).…”

Caspase-Independent Regulated Necrosis Pathways as Potential Targets in Cancer Management

“…Further studies have revealed that metformin can trigger pyroptosis via targeting miR497/Proline-, glutamic acid- and leucine-rich protein-1 axis, which indicates a new therapeutic target for treating esophageal squamous cell carcinoma ( 248 ). In addition, a phase 1 dose-finding study of metformin has demonstrated that metformin can promote the efficiency of chemoradiotherapy and elevate the rates of overall survival and progression-free survival in patients with locally advanced head and neck squamous cell carcinoma ( 262 ). Similarly, metformin plays an active anti-cancer effect in breast cancer patients ( 263 ).…”

Combining novel agents with radiotherapy for gynecologic malignancies: beyond the era of cisplatin

“…In retrospective studies, metformin has been associated with improved outcomes in metformin users compared with diabetic non-metformin users including improved overall survival in patients with laryngeal cancer (OR 3, 95% CI 1.04 to 8.4; p=0.04), improved distant metastases-free survival in those with oropharyngeal cancer (adjusted hazard ratio (HR) 0.54, 95% CI 0.32 to 0.93; p=0.03), and improved cancer-specific survival in HPV-associated head-and-neck malignancies (HR 2.33, 95% CI 1.49 to 6.16; p<0.01), as seen in a Surveillance Epidemiology and End Results‒Medicare dataset study 84. A phase I dose-escalation study of metformin with chemo-radiation therapy for locally advanced head-and-neck cancers resulted in encouraging 2 year overall and progression-free survival rates (90% and 84%, respectively) 85…”