Phase-1 Study of Metformin in Combination with Concurrent Cisplatin and Radiotherapy in Patients with Locally Advanced Head and Neck Cancer
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| Title: | Phase-1 Study of Metformin in Combination with Concurrent Cisplatin and Radiotherapy in Patients with Locally Advanced Head and Neck Cancer |
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| Authors: | Gulati, Shuchi |
| Committee Members: | Chen, Aimin |
| Summary: | BACKGROUND: Head and neck cancer is associated with a significant burden to the society. Recent data from Surveillance, Epidemiology, and End Results (SEER), suggests that approximately 65,000 new cases of head and neck cancer were diagnosed in the United States in 2019, of which nearly 16,500 patients died that year. More than half of the patients of the newly diagnosed head and neck squamous cell carcinoma (HNSCC) have locally advanced disease. Surgical salvage is the preferred modality to treat these patients, however for those unfit for surgery or for those that prefer organ preservation, chemoradiation (CRT) is used instead. 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. In some retrospective and epidemiologic studies, the antidiabetic agent, metformin, has been reported to delay the onset of HNSCC as well as to improve survival in patients who get the cancer. We hypothesized that the drug metformin when combined with chemoradiotherapy in patients with locally advanced head and neck cancer will be safe and will lead to improved outcomes.METHODS: We designed a phase-1 dose escalation study where we enrolled non-diabetic patients with locally advanced HNSCC who were going to be treated with chemotherapy (cisplatin 100 mg/m2 on days 1, 22, and 43) and radiation (70 Gray dose); which were the standard doses used in this patient population. Metformin was started at a low dose of 1500 mg orally daily in divided doses to ensure tolerance and then advanced to the cohort doses of 2000 mg, 2550 mg, and 3000 mg daily in divided doses. Patients were given assigned doses based on the modified toxicity probability interval (mTPI) design and were followed closely for development of adverse events (ranked using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 4.03) to determine the maximum tolerated dose for metformin.RESULTS: 20 patients with locally advanced HNSCC were enrolled. Majority of the patients were male (83%), median age was 56 years. 61% of the enrolled patients were smokers. 72% had a p16 positive disease. The median length of metformin usage was 28.5 days. Adverse events which were high grade (>=grade 3) recorded per CTCAE criteria included nausea (11%), vomiting (11%), mucositis (6%), acute kidney injury (17%), anemia (6%), and leukopenia (11%). Important dose-limiting toxicities included diarrhea and acute kidney injury. Patients were followed for a total of ~19 months at which point, their 2-year overall survival and progression-free survival rates were 90% and 84%, respectively. No adverse events related to metformin alone were reported (hypoglycemia or lactic acidosis) and chemotherapy administration did not seem to affect the pharmacokinetics of metformin.CONCLUSION: Due to a limited number of patients who could tolerate metformin on this trial, we are unable to report the maximum tolerated dose for metformin in combination with CRT. That said, the drug seems to have promise in that it led to an improved survival and hence warrants further investigation. |
| URL: | http://rave.ohiolink.edu/etdc/view?acc_num=ucin1593171585877322 |
| Database: | OpenDissertations |
| Abstract: | BACKGROUND: Head and neck cancer is associated with a significant burden to the society. Recent data from Surveillance, Epidemiology, and End Results (SEER), suggests that approximately 65,000 new cases of head and neck cancer were diagnosed in the United States in 2019, of which nearly 16,500 patients died that year. More than half of the patients of the newly diagnosed head and neck squamous cell carcinoma (HNSCC) have locally advanced disease. Surgical salvage is the preferred modality to treat these patients, however for those unfit for surgery or for those that prefer organ preservation, chemoradiation (CRT) is used instead. 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. In some retrospective and epidemiologic studies, the antidiabetic agent, metformin, has been reported to delay the onset of HNSCC as well as to improve survival in patients who get the cancer. We hypothesized that the drug metformin when combined with chemoradiotherapy in patients with locally advanced head and neck cancer will be safe and will lead to improved outcomes.METHODS: We designed a phase-1 dose escalation study where we enrolled non-diabetic patients with locally advanced HNSCC who were going to be treated with chemotherapy (cisplatin 100 mg/m2 on days 1, 22, and 43) and radiation (70 Gray dose); which were the standard doses used in this patient population. Metformin was started at a low dose of 1500 mg orally daily in divided doses to ensure tolerance and then advanced to the cohort doses of 2000 mg, 2550 mg, and 3000 mg daily in divided doses. Patients were given assigned doses based on the modified toxicity probability interval (mTPI) design and were followed closely for development of adverse events (ranked using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 4.03) to determine the maximum tolerated dose for metformin.RESULTS: 20 patients with locally advanced HNSCC were enrolled. Majority of the patients were male (83%), median age was 56 years. 61% of the enrolled patients were smokers. 72% had a p16 positive disease. The median length of metformin usage was 28.5 days. Adverse events which were high grade (>=grade 3) recorded per CTCAE criteria included nausea (11%), vomiting (11%), mucositis (6%), acute kidney injury (17%), anemia (6%), and leukopenia (11%). Important dose-limiting toxicities included diarrhea and acute kidney injury. Patients were followed for a total of ~19 months at which point, their 2-year overall survival and progression-free survival rates were 90% and 84%, respectively. No adverse events related to metformin alone were reported (hypoglycemia or lactic acidosis) and chemotherapy administration did not seem to affect the pharmacokinetics of metformin.CONCLUSION: Due to a limited number of patients who could tolerate metformin on this trial, we are unable to report the maximum tolerated dose for metformin in combination with CRT. That said, the drug seems to have promise in that it led to an improved survival and hence warrants further investigation. |
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