Quantitative survival impact of composite treatment delays in head and neck cancer

Abstract

Background: Multidisciplinary management of head and neck cancer (HNC) must reconcile increasingly sophisticated subspecialty care with timeliness of care. Prior studies examined the individual effects of delays in diagnosis-to-treatment interval, postoperative interval, and radiation interval but did not consider them collectively. The objective of the current study was to investigate the combined impact of these interwoven intervals on patients with HNC.

Methods: Patients with HNC who underwent curative-intent surgery with radiation were identified in the National Cancer Database between 2004 and 2013. Multivariable models were constructed using restricted cubic splines to determine nonlinear relations with overall survival.

Results: Overall, 15,064 patients were evaluated. After adjustment for covariates, only prolonged postoperative interval (P < .001) and radiation interval (P < .001) independently predicted for worse outcomes, whereas the association of diagnosis-to-treatment interval with survival disappeared. By using multivariable restricted cubic spline functions, increasing postoperative interval did not affect mortality until 40 days after surgery, and each day of delay beyond this increased the risk of mortality until 70 days after surgery (hazard ratio, 1.14; 95% confidence interval, 1.01-1.28; P = .029). For radiation interval, mortality escalated continuously with each additional day of delay, plateauing at 55 days (hazard ratio, 1.25; 95% confidence interval, 1.11-1.41; P < .001). Delays beyond these change points were not associated with further survival decrements.

Conclusions: Increasing delays in postoperative and radiation intervals are associated independently with an escalating risk of mortality that plateaus beyond certain thresholds. Delays in initiating therapy, conversely, are eclipsed in importance when appraised in conjunction with the entire treatment course. Such findings may redirect focus to streamlining those intervals that are most sensitive to delays when considering survival burden. Cancer 2018. © 2018 American Cancer Society.

Keywords: diagnosis-to-treatment interval; head and neck cancer; postoperative interval; radiation treatment breaks; radiation treatment time; time to treatment initiation; treatment delay; treatment package time.

Figure 1

Treatment intervals in study patient cohort.

Figure 2

(A) Unadjusted and (B) adjusted Kaplan-Meier estimates of overall survival, stratified by diagnosis to treatment interval. (C) Unadjusted and (D) adjusted Kaplan-Meier estimates of overall survival, stratified by postoperative interval. (E) Unadjusted and (F) adjusted Kaplan-Meier estimates of overall survival, stratified by radiation interval.

Figure 2

(A) Unadjusted and (B) adjusted Kaplan-Meier estimates of overall survival, stratified by diagnosis to treatment interval. (C) Unadjusted and (D) adjusted Kaplan-Meier estimates of overall survival, stratified by postoperative interval. (E) Unadjusted and (F) adjusted Kaplan-Meier estimates of overall survival, stratified by radiation interval.

Figure 2

(A) Unadjusted and (B) adjusted Kaplan-Meier estimates of overall survival, stratified by diagnosis to treatment interval. (C) Unadjusted and (D) adjusted Kaplan-Meier estimates of overall survival, stratified by postoperative interval. (E) Unadjusted and (F) adjusted Kaplan-Meier estimates of overall survival, stratified by radiation interval.

Figure 2

(A) Unadjusted and (B) adjusted Kaplan-Meier estimates of overall survival, stratified by diagnosis to treatment interval. (C) Unadjusted and (D) adjusted Kaplan-Meier estimates of overall survival, stratified by postoperative interval. (E) Unadjusted and (F) adjusted Kaplan-Meier estimates of overall survival, stratified by radiation interval.

Figure 2

(A) Unadjusted and (B) adjusted Kaplan-Meier estimates of overall survival, stratified by diagnosis to treatment interval. (C) Unadjusted and (D) adjusted Kaplan-Meier estimates of overall survival, stratified by postoperative interval. (E) Unadjusted and (F) adjusted Kaplan-Meier estimates of overall survival, stratified by radiation interval.

Figure 2

(A) Unadjusted and (B) adjusted Kaplan-Meier estimates of overall survival, stratified by diagnosis to treatment interval. (C) Unadjusted and (D) adjusted Kaplan-Meier estimates of overall survival, stratified by postoperative interval. (E) Unadjusted and (F) adjusted Kaplan-Meier estimates of overall survival, stratified by radiation interval.

Figure 3

Natural logarithm of adjusted hazard ratio (HR) with increasing postoperative interval and radiation treatment interval. (A) Black solid line represents smoothed restricted cubic spline plot of the natural logarithm of predicted adjusted HR versus postoperative interval (days), with reference value of 14. Blue vertical lines represent the estimated change points at 40 and 70 days. (B) Black solid line represents smoothed restricted cubic spline plot of the natural logarithm of predicted adjusted HR versus radiation treatment interval (days), with reference value of 40. Blue vertical line represents the estimated change point at 55 days. Gray dashed lines represent estimated 95% CIs of the predicted HRs.

Figure 3

Natural logarithm of adjusted hazard ratio (HR) with increasing postoperative interval and radiation treatment interval. (A) Black solid line represents smoothed restricted cubic spline plot of the natural logarithm of predicted adjusted HR versus postoperative interval (days), with reference value of 14. Blue vertical lines represent the estimated change points at 40 and 70 days. (B) Black solid line represents smoothed restricted cubic spline plot of the natural logarithm of predicted adjusted HR versus radiation treatment interval (days), with reference value of 40. Blue vertical line represents the estimated change point at 55 days. Gray dashed lines represent estimated 95% CIs of the predicted HRs.