Abstract
In recent years several clinical studies have investigated deintensified treatments in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma. Two large phase III trials, RTOG 1016 and De-ESCALaTE, which attempted to reduce toxicity by replacing radiotherapy in combination with cisplatin with the use of cetuximab in combination with radiotherapy, recently suggested that radiotherapy + cetuximab leads to inferior survival compared with standard therapy (observed HRs of 1.45 and 5 in RTOG 1016 and De-ESCALaTE), as well as increased rates of locoregional failure. These unexpected results should prompt a careful examination of deintensification trials, both in HPV-associated oropharyngeal cancer and in other contexts. Statistical designs for deintensification studies should be consistent with the study aims of reducing toxicities while maintaining survival nearly identical to the standard of care. We suggest criteria to design future deintensification trials and discuss important operating characteristics, including tradeoffs between power and stringent early stopping rules to reduce the number of patients exposed to inferior treatments. Using retrospective analyses of previous clinical studies, we compared designs with different operating characteristics. As an example, using outcomes data from RTOG 1016 and De-ESCALaTE, we conducted analyses to determine advantages of (i) stringent futility early-stopping rules and of (ii) study designs that leverage both toxicity and efficacy endpoints for interim analyses. We show that increasing the frequency of interim-futility analyses has little impact on power, but the average study duration and number of subjects enrolled before the trial is closed for inferiority can decrease substantially (from 57.8 to 18 months, and from 764 to 645 subjects). Moreover, the number of observed deaths during the study can be reduced by up to 68%.
Highlights
The incidence of human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is increasing rapidly in many high-income countries [1,2,3,4]
We suggest criteria to design future deintensification trials and discuss important operating characteristics, including tradeoffs between power and stringent early stopping rules to reduce the number of patients exposed to inferior treatments
We considered the original design of RTOG 1016, including the null and alternative hypotheses specified using HRs for OS (HROS) equal to 1.45 and 1.00, early stopping rules, observed accrual rate, and the size of 800 randomized patients
Summary
The incidence of human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is increasing rapidly in many high-income countries [1,2,3,4]. Using retrospective analyses of two large phase III clinical studies in HPV-associated HNSCC, we evaluate designs for future deescalation studies under realistic scenarios, including enrollment rates, and survival distributions for the standard of care and the deintensified treatment. We used a Bayesian model (see Supplementary Materials and Methods) to estimate the average number of adverse events (grade 3–5 events) per patient, EE and EC; on the experimental and control arm, and we computed the posterior probability of a reduction in toxicities If this probability falls below a predefined threshold, the trial is stopped for futility. This determines a reduction of up to 54% in the average number of enrollments compared with a Bayesian design without toxicity monitoring (Fig. 1B)
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