CompARE: study protocol for a phase III randomised controlled platform trial comparing alternative regimens for escalating treatment of intermediate and high-risk oropharyngeal cancer.

BACKGROUND: Patients with intermediate and high-risk oropharyngeal cancer (OPC) have poorer response to standard treatment and poorer overall survival compared to low-risk OPC. CompARE is designed to test alternative approaches to intensified treatment for these patients to improve survival. METHODS: CompARE is a pragmatic phase III, open-label, multicenter randomised controlled trial with an adaptive multi-arm, multi-stage design and an integrated QuinteT Recruitment Intervention. Eligible OPC patients include those with human papillomavirus (HPV) negative, T1-T4, N1-N3 or T3-4, N0, or HPV positive N3, T4, or current smokers (or ≥ 10 pack years previous smoking history) with T1-T4, N2b-N3. CompARE was originally designed with four arms (one control [arm 1] and three experimental: arm 2-induction chemotherapy followed by arm 1; arm 3-dose-escalated radiotherapy plus concomitant cisplatin; and arm 4-resection of primary followed by arm 1). The three original experimental arms have been closed to recruitment and a further experimental arm opened (arm 5-induction durvalumab followed by arm 1 and then adjuvant durvalumab). Currently recruiting are arm 1 (control): standard treatment of 3-weekly cisplatin 100 mg/m2 or weekly 40 mg/m2 with intensity-modulated radiotherapy using 70 Gy in 35 fractions ± neck dissection determined by clinical and radiological assessment 3 months post-treatment, and arm 5 (intervention): one cycle of induction durvalumab 1500 mg followed by standard treatment then durvalumab 1500 mg every 4 weeks for a total of 6 months. The definitive and interim primary outcome measures are overall survival time and event-free survival (EFS) time, respectively. Secondary outcome measures include quality of life, toxicity, swallowing outcomes, feeding tube incidence, surgical complication rates, and cost-effectiveness. The design anticipates that after approximately 7 years, 84 required events will have occurred to enable analysis of the definitive primary outcome measure for this comparison. Planned interim futility analyses using EFS will also be performed. DISCUSSION: CompARE is designed to be efficient and cost-effective in response to new data, emerging new treatments or difficulties, with the aim of bringing new treatment options for these patients. TRIAL REGISTRATION: ISRCTN ISRCTN41478539 . Registered on 29 April 2015.

Safety and Treatment Outcomes of Nivolumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Retrospective Multicenter Cohort Study.

Nivolumab is an anti-PD-1 monoclonal antibody currently used as immunotherapy for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with evidence of disease progression after platinum-based chemotherapy. This study evaluates real-world safety and treatment outcomes of non-trial nivolumab use. A retrospective multicenter cohort study of patients with recurrent/metastatic HNSCC treated with nivolumab between January 2017 and March 2020 was performed. Overall, 123 patients were included. The median age was 64 years, the majority of patients were male (80.5%) and had a smoking history (69.9%). Primary outcomes included overall response rate (ORR) of 19.3%, median progression-free survival (PFS) of 3.9 months, 1-year PFS rate of 16.8%, a median overall survival (OS) of 6.5 months and 1-year OS rate of 28.6%. These results are comparable to the CHECKMATE-141 study. Of 27 patients who had PD-L1 status tested, positive PD-L1 status did not significantly affect PFS (p = 0.86) or OS (p = 0.84). Nivolumab was well tolerated with only 15.1% experiencing immune-related toxicities (IRT) and only 6.7% of patients stopping due to toxicity. The occurrence of IRT appeared to significantly affect PFS (p = 0.01) but not OS (p = 0.07). Nivolumab in recurrent/metastatic HNSCC is well tolerated and may be more efficacious in patients who develop IRT.

Hypofractionated chemoradiation for head and cancer: Data from the PET NECK trial.

There has been increased interest in hypofractionated accelerated chemoradiation for head and neck cancer during the recent first peak of the COVID-19 pandemic. Prospective data regarding this approach from randomised trials is lacking. In the PET NECK study, 564 patients with squamous cell carcinoma of the head and neck receiving definitive chemoradiation were randomised to either planned neck dissection or PET CT scan guided surveillance. In this surgical trial, three radiotherapy fractionation schedules delivered over 7, 6 or 4 weeks were permitted with synchronous chemotherapy. The purpose of this study was to determine efficacy and quality of life outcomes associated with the use of these schedules. Primary local control and overall survival in addition to quality of life measures at immediately post treatment and 6, 12 and 24 months post-treatment were compared between the three fractionation cohorts. In the 525 patients where fractionation data was available, 181 (34%), 288 (55%) and 56 (11%) patients received 68-70 Gy in 34-35 fractions (#), 60-66 Gy in 30# and 55 Gy in 20# respectively. At a minimum follow up of two years following treatment there was no significant difference between the three fractionation schemes in local control, overall survival or any quality of life measure. Despite the obvious limitations of this study, some data is provided to support the use of hypofractionated accelerated chemoradiation to avoid delays in cancer treatment and reduce hospital visits during the peak of a pandemic. Data from on-going randomised trials examining hypofractionated chemoradiation may be useful for selecting fractionation schedules during future pandemics.

Assessing Novel Drugs and Radiation Technology in the Chemoradiation of Oropharyngeal Cancer.

Integrating immunotherapy, proton therapy and biological dose escalation into the definitive chemoradiation of oropharyngeal cancer poses several challenges. Reliable and reproducible data must be obtained in a timely fashion. However, despite recent international radiotherapy contouring guidelines, controversy persists as to the applicability of such guidelines to all cases. Similarly, a lack of consensus exists concerning both the definition of the organ at risk for oral mucositis and the most appropriate endpoint to measure for this critical toxicity. Finally, the correlation between early markers of efficacy such as complete response on PET CT following treatment and subsequent survival needs elucidation for biological subsets of oropharyngeal cancer.

Revised Modelling of the Addition of Synchronous Chemotherapy to Radiotherapy in Squamous Cell Carcinoma of the Head and Neck-A Low α/ß?

Background: The effect of synchronous chemotherapy in squamous cell carcinoma of the head and neck (SCCHN) has been modelled as additional Biologically Effective Dose (BED) or as a prolonged tumour cell turnover time during accelerated repopulation. Such models may not accurately predict the local control seen when hypofractionated accelerated radiotherapy is used with synchronous chemotherapy. Methods: For the purposes of this study three isoeffect relationships were assumed: Firstly, from the RTOG 0129 trial, synchronous cisplatin chemotherapy with 70 Gy in 35 fractions over 46 days results in equivalent local control to synchronous cisplatin chemotherapy with 36 Gy in 18# followed by 36 Gy in 24# (2# per day) over a total of 39 days. Secondly, in line with primary local control outcomes from the PET-Neck study, synchronous cisplatin chemotherapy with 70 Gy in 35# over 46 days results in equivalent local control to synchronous cisplatin chemotherapy delivered with 65 Gy in 30# over 39 days. Thirdly, from meta-analysis data, 70 Gy in 35# over 46 days with synchronous cisplatin results in equivalent local control to 84 Gy in 70# over 46 days delivered without synchronous chemotherapy. Using the linear quadratic equation the above isoeffect relationships were expressed algebraically to determine values of α, α/β, and k for SCCHN when treated with synchronous cisplatin using standard parameters for the radiotherapy alone schedule (α = 0.3 Gy−1, α/β = 10 Gy, and k = 0.42 Gy10day−1). Results: The values derived for α/β, α and k were 2 Gy, 0.20 and 0.21 Gy−1, and 0.65 and 0.71 Gy2day−1. Conclusions: Within the limitations of the assumptions made, this model suggests that accelerated repopulation may remain a significant factor when synchronous chemotherapy is delivered with radiotherapy in SCCHN. The finding of a low α/β for SCCHN treated with cisplatin suggests a greater tumour susceptibility to increasing dose per fraction and underlines the importance of the completion of randomized trials examining the role of hypofractionated acceleration in SCCHN.