A long-term follow-up analysis of a phase 3 randomized clinical trial comparing once-weekly versus once-every-3-weeks cisplatin chemotherapy given concurrently with radiation therapy for locally advanced head and neck squamous cell carcinoma (LAHNSCC) has been published in the International Journal of Radiation Oncology, Biology, Physics. The study, conducted at Tata Memorial Hospital in Mumbai, India, provides important insights into the optimal dosing schedule for cisplatin in this patient population.
The original trial, which enrolled patients between 2013 and 2017, randomized 300 patients with LAHNSCC to receive either cisplatin 30 mg/m2 once weekly or cisplatin 100 mg/m2 once every 3 weeks, both given concurrently with radical radiation therapy. The primary endpoint was locoregional control. This updated analysis reports outcomes after a median follow-up of 6.91 years.
The study included adult patients (age ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0-2 and LAHNSCC requiring either definitive or adjuvant chemoradiation. The majority of patients (87.3%) had oral cavity primaries and most (93%) received chemoradiation in the postoperative setting. Patients were stratified by T stage, N stage, and intent of therapy.
The results showed that the once-every-3-weeks cisplatin regimen led to superior locoregional control compared to weekly dosing, both at 2 years (73.95% vs 58.75%) and 5 years (56.76% vs 48.09%). The hazard ratio for locoregional failure was 1.44 (95% CI 1.03-2.03, p=0.034) favoring the once-every-3-weeks arm. This benefit in locoregional control was maintained even after adjusting for age and primary tumor site.
Interestingly, despite the improvement in locoregional control, there were no statistically significant differences in progression-free survival or overall survival between the two arms. The 5-year overall survival was 50.55% in the once-every-3-weeks arm compared to 43.60% in the weekly arm (HR 1.21, 95% CI 0.90-1.62, p=0.19).
Regarding toxicity, both regimens were associated with significant late adverse events. The most common grade 3 or higher late toxicities included hearing dysfunction (10.6%), dysphagia (4.1%), and odynophagia (3.7%). Notably, hearing dysfunction of any grade was significantly more common in the once-every-3-weeks arm (40.3% vs 18.9%, p<0.001).
The authors concluded that cisplatin 100 mg/m2 administered once every 3 weeks concurrently with radical radiation for LAHNSCC leads to superior locoregional control compared to weekly dosing at 30 mg/m2 and should remain a standard of care option. However, they acknowledge the concern of long-term adverse events associated with concurrent cisplatin, regardless of the dosing schedule.
This study has several strengths, including its long-term follow-up and prospective data capture for adverse events. However, there are some limitations to consider. The trial was conducted at a single center and predominantly included patients with oral cavity cancers treated in the postoperative setting, which may limit generalizability to other head and neck cancer subsites or patients receiving definitive chemoradiation. Additionally, the weekly cisplatin dose of 30 mg/m2 used in this study is lower than the 40 mg/m2 dose used in some other trials, which could have impacted the efficacy results.
The findings of this study have important clinical implications for the management of LAHNSCC. They provide strong evidence supporting the use of high-dose cisplatin every 3 weeks as a standard approach when concurrent chemoradiation is indicated. However, the lack of overall survival benefit and the increased risk of hearing dysfunction with this regimen highlight the need for careful patient selection and counseling.
Furthermore, these results underscore the importance of achieving an adequate cumulative cisplatin dose for optimal outcomes. The median cumulative dose in the once-every-3-weeks arm was 300 mg/m2 compared to 210 mg/m2 in the weekly arm, which may have contributed to the difference in locoregional control. This aligns with previous research suggesting that a cumulative cisplatin dose of at least 200-300 mg/m2 is needed for maximal benefit.
Looking ahead, these findings raise several questions for future research. There is a need to explore strategies to mitigate the long-term toxicities associated with high-dose cisplatin while maintaining its efficacy. Additionally, studies comparing cisplatin to newer radiosensitizing agents or immunotherapy combinations in this setting would be of great interest. Finally, further investigation into biomarkers that could help predict which patients are most likely to benefit from intensified chemotherapy regimens could help optimize treatment selection.
In conclusion, this long-term follow-up analysis provides valuable data supporting the use of high-dose cisplatin every 3 weeks as a standard concurrent chemotherapy regimen with radiation for LAHNSCC. However, it also highlights the ongoing challenges of balancing efficacy and toxicity in this patient population. As the field of head and neck oncology continues to evolve, these results will help inform treatment decisions and guide future research efforts aimed at improving outcomes for patients with locally advanced disease.
References
Noronha V, Patil V, Menon N, et al. Long-Term Update of a Phase 3 Randomized Study Comparing Once-a-Week Versus Once-Every-3-Weeks Cisplatin Along With Radiation in Head and Neck Cancer. Int J Radiat Oncol Biol Phys. 2025;121(1):128-136. doi:10.1016/j.ijrobp.2024.07.2315
