James Edward Bates

Background: Cisplatin remains the cornerstone radiosensitizer for definitive and adjuvant chemoradiation in patients with locally advanced squamous cell carcinoma of the head and neck. However, despite decades of clinical use, many practical aspects of cisplatin administration remain unstandardized in clinical practice and trials. Methods: Drawing on the collective experience of the NRG Oncology Head and Neck Working Group, this consensus article provides practical guidance on the administration of cisplatin during radiation therapy. We review and propose recommendations regarding the timing of chemotherapy and radiation initiation, premedication and hydration regimens by dose, monitoring and grading of cisplatin-induced ototoxicity, and management strategies during cisplatin shortages. Our guidance is informed by clinical trial protocols, retrospective and prospective data, and multidisciplinary expert consensus. We emphasize the importance of protocol flexibility to support equitable trial accrual, minimize treatment delays, and improve patient-centered outcomes. Conclusions: This article offers a unified framework to optimize the use of cisplatin in chemoradiation protocols, improve adherence, reduce toxicity, and preserve oncologic efficacy. Our recommendations are particularly timely in the context of evolving clinical practices and recent cisplatin shortages. Insights from the NRG Oncology collaborative group aim to inform future trial designs and clinical practice guidelines, ensuring consistent and equitable care for patients with head and neck cancer.

PURPOSE: Among childhood cancer survivors, we evaluated not previously explored relationships between colorectal subsequent malignant neoplasm (SMN) incidence and colorectum-specific radiation dose metrics currently used in radiation therapy (RT) planning and expanded upon previously reported chemotherapy associations. METHODS: The Childhood Cancer Survivor Study (CCSS) includes 5-year survivors of childhood cancer diagnosed between 1970 and 1999. RT was assessed as mean colorectal dose (MCD) and the percent volume (V _{X Gy} ) receiving ≥5, 10, 20, 30, and 40 Gy. Chemotherapy was assessed as cumulative doses for procarbazine and platinum agents, cyclophosphamide-equivalent doses for alkylating agents, and doxorubicin-equivalent doses for anthracyclines. Piecewise-exponential models and excess rate ratio (ERR) models evaluated dose-response relationships for the incidence of colorectal SMNs. Reference groups were those not receiving the assessed treatment(s). RESULTS: Among 25,723 survivors (median follow-up = 28.5 years; range = 5.0-48.9), 104 colorectal SMNs were identified. A dose-response relationship was observed between MCD and colorectal SMN rates; incidence rate ratios (IRRs) for 10 to 20 Gy IRRs were 3.8 (95% CI, 1.9 to 7.6), 4.9 (95% CI, 2.0 to 12.0), and 8.7 (95% CI, 3.5 to 21.6) for irradiated volumes of 20% to 2 , 3.7 (95% CI, 2.2 to 6.4) for cyclophosphamide-equivalent dose ≥6,000 mg/m ² , and 4.5 (95% CI, 2.0 to 10.1) for platinum dose ≥450 mg/m ² . For procarbazine dose, the IRR was 6.3 (95% CI, 3.0 to 13.2) for 4,200 to 2 and 9.0 (95% CI, 4.3 to 18.9) for ≥7,036 mg/m ² . In the absence of RT, colorectal SMN rates increased with exposure to any platinum-based agent (IRR, 3.8 [95% CI, 1.1 to 12.7]), alkylator (IRR, 4.8 [95% CI, 1.6 to 14.4]), or procarbazine (IRR, 16.9 [95% CI, 5.9 to 48.8]). Colorectal SMN rates increased linearly with procarbazine dose (ERR per 1,000 mg/m ² = 73.0 [95% CI, 26.4% to 119.6%]) and MCD (ERR per 1 Gy = 20.8 [95% CI, 9.0% to 32.5%]). Quadratic ERR models did not improve data fit compared with linear ERR models. CONCLUSION: These RT and chemotherapy dose-response relationships can better inform contemporary RT planning for pediatric patients and surveillance guidelines for high-risk survivors.

Background: Voxel-based analysis (VBA) is an analytic approach to evaluate correlations between local dose and the development of different toxicities. DVHs are used for toxicity prediction as well. Compared with DVH, no contours are required for VBA technique and results tell specific voxels that may be related to the toxicity instead of the whole contoured area. The VBA has been used on different cancer sites and for different toxicities. Most of these studies included patients treated with photon, all published studies were based on planned dose and VBA tools used were developed in house. In our study, patient cohort were treated with proton, our VBA tool was developed based on RayStation and doses fed to the VBA tool were delivered doses with constant and two variable RBE models.

Purpose:Tolinapant is an inhibitor of apoptosis protein antagonist that enhances apoptotic pathways. In preclinical studies, tolinapant + radiotherapy (RT) enhances antitumor immunity. We conducted an open-label, single-arm trial to evaluate the safety and feasibility of concurrent tolinapant and RT in cisplatin-ineligible patients with head and neck squamous cell carcinoma.Patients and Methods:Eligible patients had locally/locoregionally advanced head and neck squamous cell carcinoma, were human papillomavirus positive or negative, and were cisplatin ineligible. RT was delivered via intensity-modulated RT or proton therapy to a total of 70 Gy (35 fractions). Tolinapant was given every other week during RT at 180 mg/day with option to de-escalate to 90 mg for toxicity. Blood samples for research were collected at baseline and during RT.Results:Ten patients were enrolled. Treatment was well tolerated, with the most common adverse events similar to standard chemoRT (radiodermatitis, fatigue, dysphagia, pain, dysgeusia, and dry mouth). All patients completed treatment, and tolinapant dose de-escalation was not required. One patient experienced brief treatment interruptions due to severe dysphagia. Two patients developed distant metastases after treatment. Another patient developed second and third tumors outside the radiation field after treatment and was treated surgically. At a median follow-up of 13.8 months, the remaining 7 (70%) patients remained free of disease. Blood samples showed a burst of activated (CD38+HLA-DR+) CD8+ T lymphocytes in 40% of patients.Conclusions:Tolinapant + RT is well tolerated and induced proliferation of activated T cells in a subset of patients. Larger prospective studies are needed to better assess efficacy.

Supplementary Table 1. Representativeness of Study Participants

Purpose: Tolinapant is an inhibitor of apoptosis protein antagonist that enhances apoptotic pathways. In preclinical studies, tolinapant + radiotherapy (RT) enhances antitumor immunity. We conducted an open-label, single-arm trial to evaluate the safety and feasibility of concurrent tolinapant and RT in cisplatin-ineligible patients with head and neck squamous cell carcinoma. Patients and Methods: Eligible patients had locally/locoregionally advanced head and neck squamous cell carcinoma, were human papillomavirus positive or negative, and were cisplatin ineligible. RT was delivered via intensity-modulated RT or proton therapy to a total of 70 Gy (35 fractions). Tolinapant was given every other week during RT at 180 mg/day with option to de-escalate to 90 mg for toxicity. Blood samples for research were collected at baseline and during RT. Results: Ten patients were enrolled. Treatment was well tolerated, with the most common adverse events similar to standard chemoRT (radiodermatitis, fatigue, dysphagia, pain, dysgeusia, and dry mouth). All patients completed treatment, and tolinapant dose de-escalation was not required. One patient experienced brief treatment interruptions due to severe dysphagia. Two patients developed distant metastases after treatment. Another patient developed second and third tumors outside the radiation field after treatment and was treated surgically. At a median follow-up of 13.8 months, the remaining 7 (70%) patients remained free of disease. Blood samples showed a burst of activated (CD38+HLA-DR+) CD8+ T lymphocytes in 40% of patients. Conclusions: Tolinapant + RT is well tolerated and induced proliferation of activated T cells in a subset of patients. Larger prospective studies are needed to better assess efficacy.