Influence of Treatment Package Time on Outcomes in High-Risk Oral Cavity Carcinoma in Patients receiving Adjuvant Radiation and Concurrent Systemic Therapy: A Multi-Institutional Collaborative Study

Abstract

In patients with head and neck squamous cell carcinoma, the overall treatment package time (TPT) impacts outcomes in patients receiving adjuvant radiotherapy alone. We investigated the role of TPT on survival endpoints for high risk oral cavity squamous cell carcinoma (OCSCC) receiving adjuvant radiation with concurrent chemotherapy (CRT). We queried our collaborative database of patients with primary OCSCC with 1282 cases among 6 academic medical centers diagnosed between 2005 and 2015 to identify cases that received adjuvant CRT after surgery. All cases had at least one high risk feature [extracapsular nodal extension (ECE) and/or positive margin (PM)] and were treated with adequate RT doses within 180 days. TPT was calculated for each case in days between surgery and the last RT fraction and was categorized in 10 day increments (10D-INC). After reporting demographic data, pathological features and treatment details we performed univariate (UVM), multivariate (MVA) analyses as well as Log-rank p-values for overall (OS), locoregional failure (LRFS) and distant metastases free survival (DMFS) in relation to TPT. We identified 187 high risk cases who met our inclusion criteria. whites were 81% of cohort, males 66%, smokers 69% and most frequent locations were in oral tongue (49%) and floor of mouth (18%). Median age was 58 years (range: 24-87) and median smoking pack years was 30. Per AJCC 8th edition stages IVA & IVB prevailed (24% & 71%); PM and ECE were detected in 32% & 85% respectively and median lymph nodes (LN) dissected were 37 with median positive (+ve) LN of 2. Median RT dose was 66Gy, cisplatin was utilized in 76% with median total dose of 200mg/m2 and 24% received other systemic treatment. Median TPT was 98 days for the entire cohort (range: 63-162) with 51 and 45 days for median time to start RT and total RT duration respectively. TPT was >90 days in 72%, and was >100 and >110 days in 43% and 21% respectively. Two and 5 years OS and LRFS were (66%, 50% and 73%, 62% respectively) and DMFS was 78% and 73% for all cases. On UVA, 10D-INC of TPT and TPT> 90 days were associated with significantly worse OS (p=0.05 & p=0.003 for both respectively); whereas TPT was not significant for LRFS (p=0.38) and DMFS (p=0.59). On MVA, TPT in 10D-INC was independent prognostic factor for OS (p=0.043, HR: 1.14 (1-1.28)); in addition to +ve LN, perineural invasion and age (p<0.05 for all). In one of the largest cohorts to date for OCSCC treated with modern modalities with adequate follow up, TPT did not predict LRFS or DMFS for high risk cases managed with adjuvant CRT. Longer TPT was associated only with poorer overall survival. A longer TPT likely reflects the poorer outcome of patients with perioperative complications, poor support, or performance status rather than a direct effect of time on oncologic outcomes.