Weekly or Every-Three-Week Cisplatin? Trial Finds Similar Acute Toxicity Burden in p16-Negative Head and Neck Cancer

For decades, the treatment of locally advanced head and neck cancer has rested on a deceptively simple choice. Patients receiving definitive chemoradiation are typically given cisplatin, the most widely used radiosensitizing chemotherapy agent in this disease, according to one of two schedules: a high dose of 100 milligrams per square meter of body surface area administered once every three weeks, or a lower dose of 40 milligrams per square meter delivered weekly. Both approaches have long coexisted in clinical practice, supported by pharmacologic reasoning on each side. The every-three-week schedule delivers higher peak plasma concentrations of the platinum compound, while the weekly schedule spreads exposure across more frequent, smaller increments, a pattern that many oncologists assumed would translate into a gentler acute toxicity profile without sacrificing tumor control. What the field lacked, however, was rigorous randomized evidence comparing the two regimens head to head in a modern, well-stratified patient population.

That evidence gap is precisely what the NRG-HN009 trial was designed to close, and the results presented at the 2026 American Society for Radiation Oncology Annual Meeting in Boston have now delivered a sobering answer for one important subgroup of patients. In the Phase II portion of the trial, which enrolled patients with p16-negative squamous cell carcinoma of the head and neck, weekly cisplatin failed to demonstrate a significantly lower burden of acute treatment-related toxicity compared with the conventional every-three-week schedule. Because the study did not meet its predefined criteria for reduced acute toxicity with the weekly approach, the p16-negative cohort did not advance to the planned Phase III portion of the trial, halting what many had hoped would become a practice-defining shift toward weekly dosing.

The significance of this result is amplified by the specific population under study. Patients with p16-negative disease, meaning tumors that do not overexpress the p16 protein marker associated with human papillomavirus-driven oropharyngeal cancer, tend to have distinct clinical characteristics. These patients are frequently older, more often have extensive smoking histories, and commonly present with multiple comorbidities that can lower their tolerance for intensive combined-modality therapy. For such a population, the theoretical appeal of weekly cisplatin was considerable: if smaller, more frequent doses could reduce the severity of acute side effects while preserving the radiation-sensitizing effect of the drug, patients might complete treatment more comfortably and with fewer interruptions. The NRG-HN009 findings now challenge that assumption directly.

The trial accrued 234 eligible patients with p16-negative squamous cell carcinoma of the head and neck, a sample size chosen to provide adequate statistical power for the Phase II toxicity question. Investigators stratified participants by Zubrod Performance Score, a standardized measure of functional status, as well as by smoking history, tumor stage, and age, before randomly assigning them to one of the two treatment arms. All patients received a total radiation dose of 70 Gy, the standard curative dose for locally advanced disease, delivered concurrently with either 100 mg/m2 of cisplatin every three weeks or 40 mg/m2 weekly. Of the patients treated on the trial, 91 percent completed the six-month follow-up assessment, a retention rate that lends credibility to the toxicity comparisons that formed the heart of the analysis.

The primary endpoint was acute toxicity measured by a metric called the T-score, defined as the number of all treatment-related grade 3-4 adverse events occurring during treatment or within six months of its completion. Grade 3-4 events represent severe toxicity, the kind that requires hospitalization, invasive intervention, or major deviation from the planned treatment course. The results showed a mean T-score ratio of 1.11, with a 90 percent upper confidence bound of 1.33 and a p-value of 0.77, indicating no statistically meaningful difference between the arms. The mean T-score was 2.23 in the every-three-week arm, with a 95 percent confidence interval of 1.81 to 2.65, and 2.48 in the weekly arm, with a 95 percent confidence interval of 1.97 to 2.99. If anything, the numerical trend favored the less frequent, higher-dose schedule.

Yet the aggregate T-score tells only part of the story. Beneath the headline equivalence, the two schedules produced distinctly different toxicity profiles, with several individual grade 3-4 adverse event rates differing between the arms by five percent or more. Patients receiving cisplatin every three weeks experienced higher rates of nausea, dehydration, and acute kidney injury, a pattern consistent with the physiologic stress imposed by large single doses of a nephrotoxic platinum agent. Conversely, patients on the weekly schedule showed higher rates of white blood cell count decreases and magnesium depletion, reflecting the cumulative marrow suppression and electrolyte wasting that can accompany more frequent dosing. In other words, neither schedule spared patients serious toxicity; each simply shifted the burden toward different organ systems.

Adding further complexity to the interpretation is an early efficacy signal that favored the every-three-week arm. At six months, the locoregional failure rate was 4.6 percent among patients treated every three weeks compared with 9.6 percent among those treated weekly, an absolute difference of 5.0 percent with a 95 percent confidence interval of 1.0 to 8.9 percent. Because the Phase II portion of NRG-HN009 was designed and powered around acute toxicity rather than disease control, this difference should be interpreted with appropriate statistical caution, and the cohort did not proceed to the larger Phase III comparison that might have clarified its significance. Nevertheless, the observation that the weekly arm showed both numerically higher acute toxicity and numerically higher early locoregional failure will give clinicians pause when considering weekly cisplatin for p16-negative patients outside a clinical trial.

Paul Harari, MD, of the University of Wisconsin and lead author of the NRG-HN009 manuscript, framed the findings as evidence that weekly cisplatin induces a similar overall burden of serious acute treatment-related toxicity compared with the standard every-three-week schedule in this patient population, while emphasizing that the two approaches resulted in different profiles of side effects. He underscored the need for future research to identify more individualized treatment strategies that can reduce toxicity while maintaining effective cancer control for patients with advanced head and neck cancer. That call reflects a growing recognition in the field that a one-size-fits-all chemoradiation schedule may be an imperfect solution for a patient population marked by substantial heterogeneity in age, functional status, and comorbid disease.

The trial’s design also carries methodological lessons for the broader oncology community. By requiring weekly cisplatin to demonstrate significantly lower acute toxicity as a gate for Phase III advancement, NRG-HN009 embedded a pragmatic decision point into its structure, ensuring that a large Phase III investment would only proceed if the experimental schedule offered a genuine toxicity advantage. This staged approach, common in modern National Cancer Institute-funded trials, conserves resources and protects patients from prolonged exposure to regimens that fail to deliver their promised benefits. The negative Phase II result for the p16-negative cohort is therefore informative in itself: it establishes with randomized data that the presumed toxicity advantage of weekly dosing does not materialize in this population.

The work was supported by grants from the National Cancer Institute, part of the National Institutes of Health, including U10CA180868 for NRG Oncology Operations, U10CA180822 for the NRG Oncology Statistics and Data Management Center, UG1CA189867 for NRG NCORP, U24CA180803 for IROC, and additional awards through CTEP and multiple NCORP sites, with the content remaining the sole responsibility of the authors. NRG Oncology, founded in 2012 and headquartered in Pennsylvania, integrates the legacy research programs of the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group, and operates through more than 1,300 research sites worldwide. For the many patients with p16-negative locally advanced head and neck cancer who face chemoradiation each year, the message of NRG-HN009 is clear and consequential: the every-three-week cisplatin schedule remains the standard against which alternatives must be judged, and weekly dosing offers no reliable reduction in the acute toxicity burden that makes this treatment so demanding.

Subject of Research: Comparison of weekly versus every-three-week cisplatin chemoradiation schedules for acute toxicity in p16-negative locally advanced head and neck cancer

Article Title: Weekly cisplatin shows similar burden of acute treatment side effects as every 3-week schedule for patients with p16-negative head and neck cancer on NRG oncology trial

Article References: Weekly cisplatin shows similar burden of acute treatment side effects as every 3-week schedule for patients with p16-negative head and neck cancer on NRG oncology trial. (n.d.). Original publication

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DOI: Not provided

Keywords: cisplatin, head and neck cancer, chemoradiation, NRG-HN009, p16-negative, acute toxicity, radiation therapy, clinical trial, squamous cell carcinoma, ASTRO, NRG Oncology, treatment side effects