Can you give a brief summary of the Radiation Therapy Oncology Group (RTOG) 1216 trial?

RTOG 1216: Phase III Trial in High-Risk Resected Head and Neck Cancer

RTOG 1216 (NCT01810913) is an ongoing phase III randomized trial comparing four treatment arms—standard chemoradiotherapy (CRT), docetaxel plus IMRT, cetuximab plus docetaxel and IMRT, and CRT plus atezolizumab—in patients with resected high-risk squamous cell carcinoma of the head and neck, with primary data expected in 2027. 1

Trial Design and Patient Population

Eligibility Criteria:

• Patients with resected squamous cell carcinoma of the head and neck with high-risk pathologic features 1
• High-risk features defined as involved (positive) surgical margins and/or extracapsular nodal extension (ENE) 1
• The trial does not restrict enrollment based on cisplatin eligibility 1

Treatment Arms: The trial is testing four distinct approaches 1:

1. Standard platinum-based chemoradiotherapy
2. Docetaxel plus intensity-modulated radiotherapy (IMRT)
3. Cetuximab plus docetaxel and IMRT
4. Chemoradiotherapy plus atezolizumab (immunotherapy)

Clinical Context and Rationale

Historical Standard of Care: The pathologic factors triggering adjuvant treatment recommendations have remained relatively unchanged for decades 1. These are best demonstrated by inclusion criteria for intermediate-risk (RTOG 0920) and high-risk (RTOG 1216) protocols 1. The standard approach for high-risk disease—positive margins and/or ENE—has been cisplatin-based CRT at 100 mg/m² every 3 weeks for 3 cycles concurrent with radiotherapy, based on RTOG 9501 and EORTC 22931 trials 1.

Unmet Clinical Need: Cisplatin-ineligible patients with resected high-risk locally advanced squamous cell carcinoma represent a population with high unmet need 1. The 5-year disease-free survival rates for high-risk patients treated with standard CRT remain suboptimal at approximately 57.1%, with overall survival at 5 years around 57-69% 1.

Trial Endpoints and Timeline

Primary Endpoints:

• Disease-free survival (DFS) 1
• Overall survival (OS) 1

Expected Data Release: Primary data are anticipated in 2027 1. This represents one of the few active phase III studies enrolling patients regardless of cisplatin eligibility in the adjuvant setting 1.

Significance in Treatment Landscape

Novel Approaches Being Tested: RTOG 1216 is unique in simultaneously evaluating multiple strategies 1:

• Alternative cytotoxic chemotherapy (docetaxel) as a cisplatin substitute
• Targeted therapy (cetuximab) combined with chemotherapy
• Immunotherapy (atezolizumab) added to standard CRT

Comparison to Other Trials: While RTOG 0920 focuses on intermediate-risk patients (perineural invasion, lymphovascular invasion, single lymph node >3 cm or two lymph nodes, close margins <5 mm, pT3-T4a) 1, RTOG 1216 specifically addresses the highest-risk population with positive margins and/or ENE 1. This distinction is critical because the combined analysis of RTOG 9501 and EORTC 22931 demonstrated that patients with ENE and/or positive margins derive the greatest benefit from adding chemotherapy to radiotherapy 1.

Clinical Implications Pending Results

Current Practice: Until RTOG 1216 results are available, cisplatin-based CRT remains the standard of care for eligible patients with high-risk features 1. For cisplatin-ineligible patients, no established standard exists, though cetuximab plus radiotherapy or platinum/5-FU combinations are options 1.

HPV Status Considerations: The trial does not appear to stratify by HPV status, though this has become increasingly important in oropharyngeal cancers 1. HPV-positive patients generally have superior outcomes, but current guidelines do not recommend treatment de-intensification outside clinical trials 1.