Correlation Between Early Time-to-Event Outcomes and Overall Survival in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma Receiving Definitive Chemoradiation Therapy: Systematic Review and Meta-Analysis

Abstract

Background: Overall survival (OS) is the most patient-relevant outcome in oncology; however, in early cancers, large sample sizes and extended follow-up durations are needed to detect statistically significant differences in OS between interventions. Use of early time-to-event outcomes as surrogates for OS can help facilitate faster approval of cancer therapies. In locally advanced head and neck squamous cell carcinoma (LA-HNSCC), event-free survival (EFS) was previously evaluated as a surrogate outcome (Michiels 2009) and demonstrated a strong correlation with OS. The current study aimed to further assess the correlation between EFS and OS in LA-HNSCC using an updated systematic literature review (SLR) focusing on patients receiving definitive chemoradiation therapy (CRT).

Methods: An SLR was conducted on May 27, 2021 to identify randomized controlled trials assessing radiotherapy alone or CRT in the target population. Studies assessing CRT and reporting hazard ratios (HRs) or Kaplan-Meier data for OS and EFS were eligible for the analysis. CRT included any systemic treatments administered concurrently or sequentially with radiation therapy. Trial-level EFS/OS correlations were assessed using regression models, and the relationship strength was measured with Pearson correlation coefficient (R). Correlations were assessed across all CRT trials and in trial subsets assessing concurrent CRT, sequential CRT, RT+cisplatin, targeted therapies and intensity-modulated RT. Subgroup analysis was conducted among trials with similar EFS definitions (i.e. EFS including disease progression and/or death as events) and longer length of follow-up (i.e.≥ 5 years).

Results: The SLR identified 149 trials of which 31 were included in the analysis. A strong correlation between EFS and OS was observed in the overall analysis of all CRT trials (R=0.85, 95% confidence interval: 0.72-0.93). Similar results were obtained in the sensitivity analyses of trials assessing concurrent CRT (R=0.88), sequential CRT (R=0.83), RT+cisplatin (R=0.82), targeted therapies (R=0.83) and intensity-modulated RT (R=0.86), as well as in trials with similar EFS definitions (R=0.87), with longer follow-up (R=0.81).

Conclusion: EFS was strongly correlated with OS in this trial-level analysis. Future research using individual patient-level data can further investigate if EFS could be considered a suitable early clinical endpoint for evaluation of CRT regimens in LA-HNSCC patients receiving definitive CRT.

Keywords: chemoradiation therapy; correlation analysis; event-free survival; head and neck squamous cell carcinoma; overall survival; progression-free survival; surrogate endpoints; systematic literature review.

Figure 1

PRISMA flow diagram for the systematic literature review and the meta-analyses. CRT was defined as the combination of RT and any class of systemic therapies, including chemotherapy, targeted therapy or a combination of both. ^aTrials comparing different doses/schedules of the same CRT regimen; to one another. HR, hazard ratio; KM, Kaplan-Meier; OS, overall survival; PRISMA, Preferred Reporting Items for Systematic Reviews; RT, radiotherapy; SLR, systematic literature review; TTE, time-to-event.

Figure 2

Relationship between ln(HRs) of EFS and OS in (A) all CRT trials; (B) Model with interaction term for timing of CRT; (C) Model with interaction term for length of follow-up duration; and (D) subset of trials with matching EFS definitions, only including death and disease progression as endpoints. CRT was defined as the combination of RT and any class of systemic therapies, including chemotherapy, targeted therapy or a combination of both. CI, confidence interval; CRT, chemoradiation therapy; EFS, event-free survival; HR, hazard ratio; OS, overall survival.