Carboplatin-Based Chemoradiation Improves Outcomes Compared to Cetuximab Bioradiation in Cisplatin Ineligible Locally Advanced p16 Negative Head and Neck cancer

Many patients cannot tolerate standard of care cisplatin (CP) concurrent with radiation therapy (RT) for the definitive treatment of locally advanced (LA) head and neck cancer (HNSCC). In such cases, cetuximab (CTX) bioradiation (bioRT) is an increasingly popular substitute therapy. Yet, mounting evidence suggests that the addition of cytotoxic chemotherapy to RT is needed to optimize clinical outcomes in HNSCC, especially in p16(-) disease. In this regard, concurrent carboplatin-based (CB) chemoradiation (CRT) is another alternative to CP-CRT; however, there are no large trials comparing the efficacy of CTX-bioRT or CB-CRT to CP-CRT in this population. We hypothesized that CB-CRT would result in superior clinical outcomes compared to CTX-bioRT in p16(-) LA-HNSCC. We identified cases of treatment-naïve p16(-) LA-HNSCC (stage III-IVB) of the oropharynx (31%), larynx (55%), and hypopharynx (13%) who received definitive (≥70 Gy) CTX-bioRT (n = 35), CB-CRT (n = 43), or CP-CRT (n = 67) at our institution from 2009 to 2015. Variables with P < .05 on log-rank/Kaplan-Meier analysis were included as covariates in Cox proportional hazards modeling to adjust for potential confounders; variables included: concurrent systemic agent, sex, age, smoking history, T stage, N stage, performance status, and primary tumor site. We identified 145 cases: 107 men (73.7%), median age 60 years (range, 41-87), ≥T3 (63.4%), and ≥N2b (56.6%). There were no statistical differences in sex, age, smoking history, T stage, N stage, performance status, or frequency of primary site among the groups. The most common reasons for CP ineligibility were hearing loss (41.0%), medical comorbidities (35.9%), and renal disease (9%). Median follow up was 3 years. Locoregional control (LRC), distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS) at 3 years were not statistically different between those treated with CB or CP-CRT. When compared to CTX-bioRT, CB-CRT improved 3-year LRC (81.5 vs 40.0%; P = .001), RFS (76.9 vs 38.3%; P = .009), and OS (60.0 vs 55.2%; P = .05), with a trend toward improved distant metastasis free survival (89.5% vs 65.8%; P = .06). On MVA CB-CRT remained associated with improved LRC (HR 0.25, 95% CI 0.10-0.67; P = .006), RFS (HR 0.30, 95% CI 0.12-0.76; P = 0.01), and OS (HR 0.44, 95% CI 0.20-0.96; P = .04) compared to CTX-bioRT. On subset analysis of non-oropharynx primary tumors, concurrent platinum agents (CP or CB) were associated with improved 3-year larynx preservation compared to CTX-bioRT (83.6 vs 47.1%; P = .02). When patients cannot receive CP, CB-CRT is an effective alternative in p16(-) LA-HNSCC. Furthermore, CB-CRT markedly improved LRC, RFS, and OS compared to CTX-bioRT and should be a preferred substitute for CP in this population. Prospective validation of these results is needed.