Survival Impact of Increasing Time to Treatment Initiation for Patients With Head and Neck Cancer in the United States

Abstract

Purpose: To estimate the overall survival (OS) impact from increasing time to treatment initiation (TTI) for patients with head and neck squamous cell carcinoma (HNSCC).

Methods: Using the National Cancer Data Base (NCDB), we examined patients who received curative therapy for the following sites: oral tongue, oropharynx, larynx, and hypopharynx. TTI was the number of days from diagnosis to initiation of curative treatment. The effect of TTI on OS was determined by using Cox regression models (MVA). Recursive partitioning analysis (RPA) identified TTI thresholds via conditional inference trees to estimate the greatest differences in OS on the basis of randomly selected training and validation sets, and repeated this 1,000 times to ensure robustness of TTI thresholds.

Results: A total of 51,655 patients were included. On MVA, TTI of 61 to 90 days versus less than 30 days (hazard ratio [HR], 1.13; 95% CI, 1.08 to 1.19) independently increased mortality risk. TTI of 67 days appeared as the optimal threshold on the training RPA, statistical significance was confirmed in the validation set (P < .001), and the 67-day TTI was the optimal threshold in 54% of repeated simulations. Overall, 96% of simulations validated two optimal TTI thresholds, with ranges of 46 to 52 days and 62 to 67 days. The median OS for TTI of 46 to 52 days or fewer versus 53 to 67 days versus greater than 67 days was 71.9 months (95% CI, 70.3 to 73.5 months) versus 61 months (95% CI, 57 to 66.1 months) versus 46.6 months (95% CI, 42.8 to 50.7 months), respectively (P < .001). In the most recent year with available data (2011), 25% of patients had TTI of greater than 46 days.

Conclusion: TTI independently affects survival. One in four patients experienced treatment delay. TTI of greater than 46 to 52 days introduced an increased risk of death that was most consistently detrimental beyond 60 days. Prolonged TTI is currently affecting survival.

Fig 1.

Diagram of analytic cohort for survival analysis. NCDB, National Cancer Data Base; TTI, time to treatment initiation.

Fig 2.

Adjusted hazard ratio (HR) of overall mortality according to time to treatment initiation (TTI) as a continuous variable by using restricted cubic splines with seven knots. The reference equals 1 at a TTI of 0 days. The restricted cubic spline allows for a nonlinear relationship of TTI with the log HR of mortality, estimated from the full Cox regression model adjusted for all covariates. The knots define change points where the cubic function can change. We found that the HR of death with respect to a TTI of zero decreased to a HR of less than 1 and then crossed the HR equivalent to 1 close to day 67, which was the cut point found in the recursive partitioning analysis . With a TTI greater than 67, the HR increased substantially.

Fig 3.

Kaplan-Meier estimates of overall survival (OS) according to time to treatment initiation (TTI); P value is shown for the comparison by using the log-rank test.

Fig 4.

Subgroup effects derived from interaction testing between covariates and time to treatment initiation (TTI). Each hazard ratio (HR) represents the combined effect of a covariate and TTI compared with a TTI of 30 days or fewer within each subgroup (reference, TTI ≤ 30 days; HR, 1). Only covariates identified with significant interactions were added separately to full models; significant interactions included stage (I to II and III to IV), primary tumor site (oral tongue, larynx/hypopharynx, and oropharynx), and treatment modality (surgery alone, radiation therapy [RT], or chemoradiation [CRT]). HR for overall mortality according to TTI varied by (A) stage, (B) primary site, and (C) treatment modality.

Fig A1.

Overall survival by facility type. Comm, community; Comp comm, comprehensive community.