Split High-Dose Cisplatin: An Alternate High-Dose Cisplatin Administration Schedule for Definitive Chemoradiation in Oropharyngeal Cancer

Abstract

Despite its toxicity, high-dose cisplatin remains the standard of care with definitive chemoradiation (CRT) in locally advanced oropharyngeal cancer (OPC). Prospective studies typically administer cisplatin as a bolus high-dose (BHD, 100 mg/m2 x 1 day, every 3 weeks) as per historical trials, and often mandate early in the week administration by convention to optimize radiosensitization. This retrospective analysis reports our institutional experience with an alternate high-dose cisplatin dosing schedule, split high-dose cisplatin (SHD, 50mg/m2 x2 days, every 3 weeks), and evaluates the impact of day of week (DOW) administration on outcomes. We reviewed 435 AJCC7 Stage III/IV OPC patients treated with definitive CRT at our institution from 7/31/2001-2/7/2014. Patients treated with induction chemotherapy, non-cisplatin regimens (i.e. carboplatin/paclitaxel or cetuximab), or low-dose cisplatin (20-40 mg/m2 weekly) were excluded. Data collected included dosing schedule (BHD vs. SHD), DOW (Monday/Tuesday vs. Wednesday/Thursday/Friday), total cumulative cisplatin dose (TCD, < 200mg/m2 vs. >200mg/m2), T stage, N stage, p16/HPV status when available, and smoking history. Renal toxicity was assessed by collecting creatinine values (baseline, peak during CRT, and post-treatment baseline > 3 months after last chemotherapy). Outcomes including local control (LC), regional control (RC), distant metastasis free survival (DMFS), and overall survival (OS) were calculated from RT start. The Cochran-Armitage test for trend was used to compare TCD between dosing groups. The Kaplan-Meier method was used to estimate time-to-event outcomes. The Wilcoxon rank sum test was used to compared creatinine values between groups. Median follow up was 7.9 years (1.8 months – 18.9 years). The vast majority of patients received TCD >200mg/m2 (96% BHD vs. 98% SHD, p = 0.51). There was no difference in 5-yr LC (98% vs. 97%, p = 0.44), RC (92% vs. 94%, p = 0.38), DMFS (92% vs. 88%, p = 0.22), or OS (89% vs. 87%, p = 0.66) with BHD vs. SHD administration. There was no difference in 5-yr LC (98% vs. 97%, p = 0.31), RC (93% vs. 94%, p = 0.85), DMFS (84% vs. 90%, p = 0.80), or OS (87% vs. 90%, p = 0.58) with Monday/Tuesday vs. Wednesday/Thursday/Friday DOW administration. TCD < 200mg/m2 was associated with inferior DMFS. There was no difference in median peak creatinine (1.35 vs. 1.30, p = 0.13) or new baseline creatinine levels (1.10 vs. 1.10, p = 0.92) with BHD versus SHD administration. SHD cisplatin is a viable alternate dosing schedule to BHD administration of concurrent high-dose cisplatin, with no differences in TCD, outcomes, or renal toxicity. The absence of an association between DOW and outcomes in OPC suggests that cisplatin could be administered at any time during the week without compromising outcomes in these patients.