Highlight
- In a multicenter retrospective cohort of 564 patients with head and neck squamous cell carcinoma (HNSCC), weekly low‑dose cisplatin was associated with markedly lower rates and severity of hearing loss than standard high‑dose cisplatin given every 3 weeks.
- Absolute reductions were large: any hearing loss by CTCAE criteria fell from 69% to 39% and CTCAE grade ≥2 hearing loss from 50% to 18% with weekly dosing.
- Two‑year overall and disease‑free survival were similar between groups, supporting consideration of weekly cisplatin where hearing preservation is a priority.
Background
Cisplatin remains a cornerstone cytotoxic agent in definitive chemoradiation therapy (CRT) for locally advanced head and neck squamous cell carcinoma (HNSCC). Its radiosensitizing benefits are well established, but cisplatin is also among the most ototoxic systemic agents used in oncology. Ototoxicity is typically irreversible and can profoundly affect communication, quality of life, employment, and social function, particularly for older adults and those relying on hearing for their work.
Clinical practice varies: many centers use a high‑dose regimen (75–100 mg/m2 every 3 weeks), whereas others prefer lower, more frequent dosing (typically 30–40 mg/m2 weekly). While cumulative cisplatin dose correlates with oncologic benefit, pharmacokinetic and mechanistic considerations suggest different toxicity profiles between schedules. Peak plasma concentrations are higher with bolus, every‑3‑week dosing and may increase cochlear exposure to reactive species and direct hair‑cell damage; lower, more frequent dosing may reduce peak exposure while preserving cumulative cytotoxic effect.
Study design and population
The report by Fernandez et al. (JCI Insight, 2025) analyzed the Enhancing Cancer Hearing Outcomes (ECHO) dataset, a pooled, multicenter retrospective cohort from five academic centers. Inclusion criteria were adults (≥18 years) with HNSCC treated with definitive cisplatin‑based CRT who had audiometric testing performed within 120 days before and after treatment. Participants were grouped by cisplatin schedule: every 3 weeks (≥75 mg/m2 per dose) or weekly (<75 mg/m2 per dose). Importantly, cumulative cisplatin doses were similar between groups, isolating schedule as the exposure of interest.
Primary ototoxicity outcomes used two complementary, standardized definitions: the American Speech‑Language‑Hearing Association (ASHA) threshold shift criteria and the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 for hearing threshold shift. Analyses included per‑ear evaluations (1,127 ears among 564 participants), χ2 testing for univariate associations, multivariable regression to control for confounders, and Kaplan‑Meier estimates for overall and disease‑free survival up to two years.
Key findings
The main results show a consistent, clinically meaningful reduction in ototoxicity with weekly low‑dose cisplatin:
- By ASHA criteria (a sensitive audiometric threshold shift definition), hearing loss occurred in 57% of ears in the weekly group versus 82% in the every‑3‑week group.
- By CTCAE v5.0 criteria, any hearing loss occurred in 39% (weekly) versus 69% (every‑3‑week).
- Clinically significant ototoxicity (CTCAE grade ≥2) occurred in 18% of the weekly group versus 50% of the every‑3‑week group — an absolute reduction of ~32 percentage points.
These differences were statistically significant and persisted in multivariable models adjusting for potential confounders. The authors report that cisplatin schedule was an independent predictor of ototoxicity. Importantly, two‑year overall survival and disease‑free survival did not differ between the groups, suggesting that the weekly schedule did not compromise short‑term oncologic efficacy in this cohort.
Magnitude and clinical interpretation
The absolute risk reduction for CTCAE‑defined any hearing loss (69% to 39%) is approximately 30 percentage points, equivalent to a number needed to treat (in this context, number needed to change schedule) of about 3–4 to prevent one case of ototoxicity. For moderate or worse hearing loss (CTCAE grade ≥2), the absolute difference (~32 points) likewise indicates a substantial clinical impact. These are large effect sizes for a toxicity endpoint and support the schedule itself as a major determinant of ototoxic risk when cumulative dose is held similar.
Safety, QoL, and other toxicities
Detailed non‑otologic toxicities were not the principal focus of the report. The study primarily addresses audiometric outcomes; the authors indicate no obvious compensatory increase in other severe toxicities with weekly dosing in their dataset, but complete safety profiles and quality‑of‑life measures were not deeply reported in the primary analysis. The absence of survival differences is reassuring, but the potential tradeoffs in hematologic or gastrointestinal toxicity with schedule modification should be considered and evaluated prospectively.
Mechanistic plausibility
Cisplatin ototoxicity is believed to involve generation of reactive oxygen species (ROS) in cochlear tissues, damage to outer hair cells, and stria vascularis injury leading to permanent hearing threshold shifts. Peak plasma concentration (Cmax) and extent of cochlear exposure are thought to contribute to this toxicity. A weekly low‑dose schedule yields lower peaks and steadier systemic exposure than bolus high‑dose regimens and therefore plausibly reduces cochlear insult while delivering similar cumulative exposure to tumor tissue, consistent with the observed outcomes.
Expert commentary and limitations
Strengths of this study include multicenter data, objective audiometric endpoints, and control for cumulative dose. The large absolute differences in hearing outcomes are compelling and immediately relevant to clinical decision‑making.
However, limitations warrant caution in generalizing the findings:
- Retrospective design: unmeasured confounding or selection bias could influence regimen choice (for example, frailer patients or those with baseline hearing deficits may preferentially receive weekly dosing).
- Audiometry timing: evaluations were limited to tests performed ≤120 days before and after treatment. Some cisplatin‑related hearing loss evolves or progresses beyond this window; late audiometric changes and long‑term quality‑of‑life impacts were not captured.
- Heterogeneity in supportive care: differences in hydration, antiemetics, and other supportive measures across centers may modulate toxicity risk.
- Other toxicities and adherence: the report focused on hearing; a comprehensive toxicity profile and treatment adherence metrics would clarify overall tolerability of schedules.
- Oncologic non‑inferiority: while two‑year survival was similar, longer follow‑up and randomized data are required to establish oncologic equivalence definitively.
These limitations highlight the need for prospective randomized trials comparing weekly and every‑3‑week cisplatin with prespecified ototoxicity, oncologic, and patient‑reported outcomes, including long‑term follow‑up.
Clinical implications and practical guidance
For clinicians treating HNSCC with definitive CRT, this study supports consideration of weekly low‑dose cisplatin in patients where hearing preservation is a major concern — for example, patients with preexisting hearing impairment, those in vocations dependent on hearing, older adults at higher risk of social isolation from hearing loss, or patients who place a high value on hearing‑related quality of life.
Key practical points:
- Baseline and serial audiometry should be routine for any patient receiving cisplatin-based CRT. Early detection allows counseling, potential schedule modification, and rehabilitative planning (hearing aids, cochlear implant evaluation where appropriate).
- Discuss the tradeoffs: weekly dosing appears to reduce ototoxicity substantially without short‑term compromise of survival in this cohort, but detailed discussions should include the limits of retrospective evidence and the need for individualized decisions.
- Consider trial enrollment when available. Randomized trials that include ototoxicity and long‑term functional endpoints would provide higher‑quality evidence to inform standard‑of‑care recommendations.
- Otoprotective agents (for example, amifostine or sodium thiosulfate) have shown benefit in some contexts but are not routinely used in head and neck CRT due to concerns about tumor protection and timing; current evidence does not supplant schedule modification as a practical risk‑mitigation strategy.
Research directions
Future studies should prospectively compare weekly versus every‑3‑week cisplatin in randomized designs with the following elements:
- Preplanned audiometric endpoints with long‑term follow‑up (beyond 1–2 years), including patient‑reported hearing‑related quality of life.
- Comprehensive toxicity and functional outcomes to detect tradeoffs in other organ systems or treatment adherence.
- Pharmacokinetic studies correlating cisplatin Cmax and cochlear biomarkers with audiometric change to strengthen causal inference.
- Subgroup analyses by age, baseline hearing, comorbidities (e.g., diabetes), and cumulative dose ranges to identify patients most likely to benefit from schedule modification.
Conclusion
The multicenter retrospective analysis by Fernandez et al. provides strong, clinically actionable evidence that weekly low‑dose cisplatin substantially reduces both the incidence and severity of cisplatin‑related hearing loss compared with standard high‑dose every‑3‑week regimens, without compromising two‑year oncologic outcomes in their cohort. While randomized, long‑term data are still needed to establish oncologic non‑inferiority definitively, the magnitude of reduction in ototoxicity observed argues that weekly cisplatin should be considered a viable strategy for patients in whom hearing preservation is a priority. Routine baseline and follow‑up audiometry, shared decision‑making, and further prospective investigation remain priorities.
Funding and trial registration
Funding and trial registration details are reported in the original publication: Fernandez KA et al., JCI Insight (2025). Readers should consult the primary paper for center‑specific funding sources and any prospective trial identifiers.
References
Fernandez KA, Chowdhury AS, Bonczkowski A, et al. Lower, more frequent cisplatin dosing minimizes hearing loss in head and neck cancer. JCI Insight. 2025 Oct 22;10(20):e196230. doi:10.1172/jci.insight.196230. PMID: 41122972; PMCID: PMC12581672.
Common Terminology Criteria for Adverse Events (CTCAE) v5.0. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute.
American Speech‑Language‑Hearing Association (ASHA). Guidelines for the audiologic management of individuals receiving cochleotoxic drug therapy.
Article provenance and author note
This article was prepared by a medical science writer to summarize and interpret the findings of the cited JCI Insight publication for clinicians and researchers. It aims to synthesize key results, practical implications, and research considerations without replacing individualized clinical judgment.
