Optimal Total Dose of Cisplatin for High-Risk Oral Cavity Squamous Cell Carcinoma

In oral cavity squamous cell carcinoma (OCSCC), the standard of care is resection. In high-risk cases — those identified by positive surgical margins and extranodal extension — resection is followed by radiation therapy and intravenous cisplatin.

However, high-dose cisplatin is extremely toxic and difficult for patients to tolerate. It is highly emetogenic, nephrotoxic and ototoxic, and patients often experience additional side effects common with chemotherapy, including myelosuppression and peripheral neuropathy.

These adverse effects are compounded by those caused by radiation therapy to the head and neck. For example, mucositis often causes dysphagia and odynophagia, which can lead to malnutrition, necessitating alternative means of obtaining enteral nutrition.

“Regarding toxicities and side effects, I explain to my patients that adding chemotherapy to radiation can be a ‘1 + 1 = 10’ situation,” says Cleveland Clinic oncologist Jessica Geiger, MD.

High dose vs weekly cisplatin dosing

Identifying therapies and administration schedules with the best effectiveness and least toxicity is always the goal, she notes.

To this end, Dr. Geiger and a multi-institutional team established a large database of patients treated for OCSCC. Patients were treated at one of six academic institutions:

• Cleveland Clinic’s Taussig Cancer Institute.
• Lee Moffitt Cancer Center & Research Institute.
• Henry Ford Health System.
• Memorial Sloan Kettering Cancer Center.
• Princess Alexandra Hospital (Australia).
• University of Louisville Hospital.

With nearly 1,300 patients, the IRB-approved multi-institutional database is one of the largest cohorts for OCSCC in the modern era, says Dr. Geiger. Many studies have mined the extensive, long-term data for survival and toxicity statistics.

Most recently, Dr. Geiger led a retrospective study evaluating alternative cisplatin dosing schedules.

“We weren’t able to discern if administering cisplatin in a high-dose bolus or in weekly cumulative doses affected survival end points,” says Dr. Geiger. “But we did reaffirm an optimal total dose that had been suggested previously in the literature.”

Dr. Geiger presented results of the study at the 2019 American Society of Clinical Oncology Annual Meeting.

Optimal total dose: at least 200 mg/m2

For this study, a subset of 196 patients met inclusion criteria:

• Treated for OCSCC between 2005 and 2015.
• Had either positive surgical margins (35.7%) and/or extranodal extension (82.7%) following resection.
• Treated concurrently with radiation therapy and chemotherapy.

Of these patients:

• Median age was 56 years old.
• 3% were men.
• 1% were Caucasian.
• 9% had significant tobacco history.

“Looking retrospectively at this cohort, we learned that patients who received 200 mg/m2 or more of cisplatin had nearly double the median disease-free survival of patients who received less,” says Dr. Geiger.

Median disease-free survival was:

• 5 months in patients who received less than 200 mg/m2 of cisplatin.
• 8 months in patients who received 200 mg/m2 or more of cisplatin.

There was no significant difference in disease-free survival among patients who received cisplatin as a bolus and those who received weekly dosing.

Univariate analysis also showed associations between higher doses of cisplatin and improved locoregional control (P = 0.131), metastatic disease (P = 0.084) and overall survival (P = 0.187). However, none of these associations were statistically significant, notes Dr. Geiger.

Administration options

“This study reaffirms that patients with high-risk resected OCSCC require systemic therapy with cisplatin and need to receive as much of it as possible during the course of radiation therapy,” says Dr. Geiger. “There is a distinct benefit when patients get at least 200 mg/m2, whether in a bolus or weekly dosing.”

Prospective study is needed to evaluate different cisplatin dosing schedules and determine the optimal administration for high-risk OCSCC patients.

Image credit: National Cancer Institute