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The effect of treatment delay on quality of life and overall survival in head and neck cancer patients

Abstract Objective Head and neck squamous cell carcinomas (HNSCC) are rapidly developing tumours, and substantial delay in treatment initiation is associated with decreased overall survival. The effect of delay on health‐related quality of life (HRQOL) is unknown. The aim of this study was to assess the impact of delay on QOL and overall survival. Methods Patients with mucosal HNSCC were prospectively included. HRQOL and 2‐year overall survival were analysed using linear mixed‐model analyses and cox regression, respectively. Delay was defined as care pathway interval (CPI) of ≥30 days between first consultation and treatment initiation. Results Median CPI was 39 days for the 173 patients included. A trend towards higher HRQOL‐scores (indicating better HRQOL) during 2‐year follow‐up for patients with delay in treatment initiation was visible in the adjusted models (HRQOL summary score—β: 2.62, 95% CI: 0.57–4.67, p = 0.012). Factors associated with decreased overall survival were moderate comorbidities (HR: 5.10, 95% CI: 1.65–15.76, p = 0.005) and stage‐IV tumours (HR: 12.37, 95% CI: 2.81–54.39, p = 0.001). Delay was not associated with worse overall survival. Conclusion Timely treatment initiation is challenging, especially for patients with advanced tumours and initial radiotherapy treatment. Encountering delay in treatment initiation did not result in clinically relevant differences in HRQOL‐scores or decreased overall survival during 2‐year follow‐up.


| INTRODUCTION
Head and neck squamous cell carcinomas (HNSCC) are relatively rare.
HNSCC are potentially fast-growing tumours, in an anatomically and functional complex area (Dejaco et al., 2019;Jensen & Overgaard, 2007). Disease stage at diagnosis is a strong indicator for prognosis (Du et al., 2019). As a result, timely diagnosis and treatment initiation is crucial, and numerous initiatives to reduce delay are described (Schutte et al., 2018;van Huizen et al., 2018). The complexity of the HNSCC population, with a high prevalence of frailty de Vries et al., 2020) and comorbidities (Stordeur et al., 2020), might contribute to prolonged time to treatment initiation.
The quality-indicator norm for timely treatment initiation in the Netherlands is set at 30 days, stating that treatment should be initiated within 30 days after first consultation in a head and neck oncology centre (HNOC) (Dutch Head and Neck Society, 2017).
The effect of prolonged time to treatment has recently been described in a recent systematic review (Schoonbeek, Zwertbroek, et al., 2021), reporting a strong association between delay and decreased overall survival. Although survival rates of HNSCC in general are increasing (Pulte & Brenner, 2010), the treatment of these complex tumours in vital areas can result in severe disabilities and permanent loss of function. Survival as primary outcome measure does not adequately reflect patient perspective. Therefore, long-term patient-reported health-related quality of life (HRQOL) scores are increasingly considered a valuable additional endpoint. Although highly relevant, the effect of delay on HRQOL has not been previously described. The direct effects of prolonged time to treatment initiation (i.e., tumour progression and more extensive treatment) might be indirectly reflected in patient HRQOL perception.
The aim of this prospective study was therefore to investigate the effect of delay on the course of HRQOL and on overall survival, using the quality-indicator cut-off of 30 days. Assessment of these effects might result in further understanding of the impact of delay and subsequent improvement of care pathways.

| Study design and patient selection
Patients were included from the data-biobank registered in the Dutch Trial Register (registration number NL7839). Detailed information on inclusion of patients and data collection were described in a covering paper (Sidorenkov et al., 2019). This prospectively collected databiobank registered all consecutive patients after obtaining written informed consent, treated in either the departments of head and neck surgery, oral and maxillofacial surgery or radiation oncology in this tertiary HNOC. All patients were reviewed in the multidisciplinary tumour board and treated according to (inter)national guidelines. The current study protocol was approved by the scientific board of the databiobank.
Patients seen between 2014 (October) and 2016 (May) were enrolled ( Figure 1). Inclusion criteria yielded a first primary HNSCC located in either the oral cavity, oropharynx, hypopharynx or larynx.
When baseline HRQOL scores were not available, patients were excluded. Patients treated with palliative treatment intention or synchronous second primary tumour were excluded as well.

| Definitions and data collection
The number of days between first consultation in this HNOC and treatment initiation (either date of surgery, or first day of radiotherapy or chemoradiation) was defined as Care Pathway Interval (CPI) (Schoonbeek, de Vries, et al., 2021). This interval was dichotomized into two groups: patients starting treatment within 30 days, and patients with start of treatment ≥30 days (the 'delayed' group), based on the quality-indicator norm set by the Dutch Head and Neck Society (Dutch Head and Neck Society, 2017).
Patient, tumour and treatment characteristics were provided by the databiobank and were supplemented with time to treatment and follow-up data. The Union for International Cancer Control (UICC) TNM classification was used to report tumour stage (Sobin et al., 2009), and the Adult Comorbidity Evaluation (ACE-27) was used to grade presence of comorbidities, dividing patients into four categories (none, mild, moderate or severe) (Piccirillo, 2000).
The primary outcome was HRQOL, measured by the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) at baseline (before treatment initiation), and at 3, 6, 12 and 24 months after treatment initiation (Aaronson et al., 1993). The EORTC-QLQ-C30 scoring manuals were used to calculate summary scores, global health status, functional scales and symptom scales (EORTC Study Group, 2013;Fayers et al., 2001). For these scales, scores range from 0 to 100, with a higher score indicating a better level of functioning/global health status or a high level of symptomatology (symptom scores). Within our analyses, a positive β indicates a higher score.

| Statistical analysis
SPSS ® Statistics version 25.0 (Armonk, NY: IBM Corp.) was used to analyse data. Descriptive statistics are presented as means and standard deviations, medians and quartiles, or absolute numbers and percentages, depending on their distribution. Student's t tests, the Mann-Whitney U test or the χ 2 test were used for comparison, depending on the type of variable studied.
To analyse repeated continuous measures such as HRQOL scores, linear mixed-effect models (LMM) were used. These models are validated for accurate analysis, allowing for missing data points without discarding entire cases (Shek & Ma, 2011). As described earlier (Bjordal et al., 2000;de Vries et al., 2020;Roick et al., 2020), HRQOL decreases during the weeks after treatment, to recover over time subsequently. In this study, the 3-to 24-month interval was therefore treated as being linear. Death or tumour recurrence led to exclusion from further HRQOL analyses from that time point onwards.
For the LMM analyses, the compound symmetry covariance type was set after model fit comparing using likelihood ratio testing. Fixed effects included the intercept and the parameters time, delay (CPI, dichotomous), and delay * time. The predicted coefficients (β) represent the difference in HRQOL score of the corresponding domain for patients with (≥30 days) and without (<30 days) delay in treatment initiation at 3 months after treatment (delay) and over time per year (delay * time), also reporting 95% confidence intervals (CI) and pvalues. All models were adjusted for baseline scores, age, sex, comorbidities, tumour site and stage and initial treatment modality. An intercept was included for random effects for between subject differences. Predicted values and standard errors were used for graphical representation (using GraphPad Prism version 8, GraphPad Software, San Diego, CA), and estimation method was set to Maximum Likelihood.
Cox regression analysis was performed to assess the effect of delay (and other parameters) on 2-year overall survival, establishing hazard ratio's (HR, >1 indicating a higher risk of deceasing). To validate the models, cox proportional hazard assumptions were verified.
A two-sided p < 0.05 was considered statistically significant.

| Patient characteristics
A total of 173 patients had complete HRQOL baseline scores and were enrolled in this study ( Figure 1). Mean age was 65.9 years (±10.3), and the majority was male (71.1%). Laryngeal carcinomas were present in 36.4%, and the second most common tumour site was the oral cavity (30.6%). Response rates of the HRQOL questionnaires ranged between 83% and 94% during follow-up. During the 2 years of follow-up, 38 patients (21.9%) died.

| Care pathway interval
Baseline characteristics were compared for patients starting treatment within 30 days, versus patients starting ≥30 days (the 'delayed' group), displayed in Table 1. The proportion of current smokers was greater in the delayed group (56.4% vs. 31.1%, p = 0.006, respectively). Patients with oropharyngeal and hypopharyngeal tumours were more frequently represented in the delayed group (p < 0.001), just like patients treated with initial radiotherapy or chemoradiation (p < 0.001). Stage II and IV tumours were mostly represented in the delayed group (p < 0.001).
F I G U R E 1 Flowchart of study population, including inclusion and exclusion criteria and follow-up characteristics. SCC: squamous cell carcinoma. Response rate based on alive, disease-free patients In total, 61 patients (35.3%) started treatment within 30 days.
Median CPI was 39.0 days and differed for patients with initial surgery treatment (27.0 days) and patients with initial radiotherapy (39.0 days, p < 0.001, Figure 2, left panel). For patients with stage I-II tumours, median CPI was 29.0 days, compared with 39.0 for patients with stage III-IV tumours (p < 0.001, Figure 2, right panel).

| Health-related quality of life
The effect of delay in treatment initiation on HRQOL, using a linear mixed model analysis for different domains of the EORTC-QLQ-C30, is presented in Table 2 and plotted over time in Figure 3  Unadjusted HRQOL scores are reported and plotted over time in Table S1 and Figure S1.

| Overall survival
The presence of comorbidities, tumour site and tumour stage were significantly associated with a higher hazard of dying in the univariable cox regression model (

| Delay in the care pathway and effect on overall survival
The results in this study confirm the structural problem in aiming for We found no association between CPI of 30 days or more and inferior overall survival, in contrast to other studies (DeGraaff et al., 2019;Ho et al., 2018;Liao et al., 2019;Murphy et al., 2016;Naghavi et al., 2016;Polesel et al., 2017;Xiao et al., 2018). However, in these studies, this association was only significant starting from a delay of more than 45 days (up to the longest delay of 90 days) (Murphy et al., 2016;Naghavi et al., 2016;Polesel et al., 2017 et al., 2018). Based on the described literature, it seems that the longer the delay, the higher the risk of impact on survival. In the present cohort, the cut-off of 30 days was examined firstly because of the nationally implemented quality-indicator norm and secondly because it is often used in recent studies; however, future studies on larger cohorts may investigate different cut-offs, that is, 45 days or 60 days.
However, due to the sample size of this cohort, and because delays of more than 60 days were rare in this study population, assessment of these cut-offs was not viable. Furthermore, analysing time as a continuous variable might be helpful, although in this study this showed similar results (as reported in the Supporting Information).
Notably, a few studies did not find decreased survival rates in patients who encountered delay, similar to this study (Caudell et al., 2011;Ho et al., 2018;Tham et al., 2019). Consensus and scientific evidence on an optimal cut-off is not yet existing, and might be preferred to be site-specific recommendations, instead of choosing one cut-off for all head and neck tumour sites, as these tumours are quite diverse. For such a study, a larger and more homogeneous study population is needed. Furthermore, tumour progression due to delay might not only result in decreased survival, but also in more extensive treatment, higher costs and treatment-related mortality.

| The effect of delay on health related QOL
Assessment of HRQOL has been increasingly recognised as important treatment outcome and is used for clinical decision-making (Rogers et al., 2016). Summary HRQOL score was higher for patients with delay in treatment initiation, the predicted cumulative difference in score after twenty-four months is 4.6 points (Delay partially explains these surprising findings. Literature describing the association between delay and HRQOL is very scarce, and even non-existing for HNSCC. For patients with ovarian and endometrial cancer, increased total delay (from the start of symptoms to start of treatment) was associated with worse HRQOL (Global Health Status, EORTC-QLQ-C30), although the timing and actual scores of the HRQOL measurements are unclear (Robinson et al., 2012).
To exclude the effect of patients treated with trans-oral laser surgery (TOLS), who are represented for the majority in the group treated within 30 days, a subanalysis was performed (data not shown).
The adjusted models were similar to the models presented in this study, displaying a similar trend for higher scores in delayed patients, although the difference is not expected to result in a clinically significant difference. Variations in confounders, used in the linear mixedmodels were tested (such as addition of adjuvant treatment and smoking status as variables); however, this did not alter findings and the strongest statistical model was chosen to report.

| Strengths and limitations
The

| CONCLUSION
Timely treatment initiation is challenging, and this study adds to the understanding of the impact of delay on HRQOL and survival in HNC patients. Encountering delay before the start of treatment did result in a statistically better course of HRQOL for HNC patients with delay in treatment initiation during two-year follow-up, although this difference was not clinically relevant. A clear benefit in terms of higher HRQOL scores for patient starting treatment within 30 days was absent. Moreover, a CPI ≥ 30 days did not lead to increased risk of dying in this study.
These findings cautiously raise the question whether the advised 30-day cut-off would eventually result in better HRQOL and increased survival and further studies with larger cohorts are needed.

ACKNOWLEDGEMENT
No specific grant from any funding agency was received for this research.

CONFLICT OF INTEREST
All authors have no conflict of interest to declare.

DATA AVAILABILITY STATEMENT
The data supporting the findings of this study are available upon reasonable request directed to the corresponding author. The data are not publicly available due to privacy or ethical restrictions.