A network meta-analysis published in November/December 2024 in Practical Radiation Oncology compared weekly versus bolus cisplatin regimens given concurrently with definitive radiation therapy for squamous cell carcinoma of the head and neck. The study, which received no specific funding, aimed to indirectly compare these two common cisplatin schedules by analyzing data from randomized controlled trials that had compared each regimen to cetuximab.
The researchers conducted a systematic review to identify eligible trials comparing cisplatin to cetuximab for non-metastatic, locoregionally advanced head and neck squamous cell carcinoma treated with definitive radiation therapy. They excluded trials involving primary surgery or induction therapy. Using a novel "mixed" meta-analysis approach, the investigators extracted individual patient survival data from published survival curves and validated it against reported outcomes.
Five randomized trials met the inclusion criteria, encompassing a total of 1,678 patients. Of these, 835 patients were randomized to cetuximab and 843 to cisplatin (572 to bolus cisplatin and 271 to weekly cisplatin). The included studies were RTOG 1016, De-ESCALaTE, ARTSCANIII, TROG 12.01, and a phase II trial by Maddalo et al. These trials recruited patients with locoregionally advanced disease, with some variations in specific eligibility criteria related to tumor stage, HPV status, and smoking history.
The primary analysis utilized a mixed-effects multivariable Cox regression model, adjusting for smoking status, HPV status, baseline variance, and between-trial effect heterogeneity. The results showed no statistically significant difference in overall survival between weekly and bolus cisplatin regimens, with a hazard ratio of 0.90 (95% CI, 0.53-1.52, p=0.34). The model predicted that for the average patient in the cohort, the difference in 5-year overall survival was only 1.2% higher for weekly cisplatin compared to bolus cisplatin (95% CI, -6.1% to +5.9%).
Secondary endpoints and toxicity profiles were analyzed qualitatively due to differences in reporting across trials. The trends in alternative endpoints appeared similar in magnitude and direction between trials using weekly versus bolus cisplatin. Toxicity, as measured by the average T score, was comparable between the two regimens (3.5 for bolus studies vs 3.3 for weekly studies).
The study had several limitations. The "mixed" meta-analysis approach, while allowing for more nuanced analysis of the primary endpoint, precluded subset analyses and testing of interactions due to the lack of individual patient-level covariate data. Additionally, there were subtle differences in treatment regimens between studies, such as variations in radiation dose and fractionation, which the authors deemed unlikely to significantly affect the overall conclusion but could introduce some heterogeneity.
The authors concluded that the differences between cisplatin schedules are likely subtle and unlikely to substantially alter survival outcomes. They suggested that clinicians may have flexibility in deciding the optimal schedule of platinum-based chemotherapy when combined with definitive radiation therapy for head and neck cancer.
This study has potential clinical implications for the management of head and neck cancer patients. The finding that weekly and bolus cisplatin regimens appear to have similar efficacy in terms of overall survival may allow oncologists to tailor the chemotherapy schedule based on individual patient factors, institutional practices, or preferences for managing acute toxicities. However, the authors noted that while their analysis suggests similar outcomes in aggregate, it's possible that certain subsets of patients might benefit more from one schedule over the other, a question that could not be addressed by this study design.
The network meta-analysis approach used in this study represents an innovative method for comparing treatment regimens in the absence of direct head-to-head trials. By leveraging data from multiple randomized controlled trials with a common comparator (cetuximab), the researchers were able to provide valuable insights into a clinically relevant question. However, they also emphasized the need for ongoing prospective studies, such as the NRG Oncology phase III trial comparing high-dose and low-dose cisplatin schedules, to further elucidate potential differences in efficacy, toxicity, and patient-reported outcomes.
In conclusion, this comprehensive network meta-analysis provides reassurance that both weekly and bolus cisplatin regimens, when given concurrently with definitive radiation therapy, appear to offer similar survival benefits for patients with locally advanced head and neck squamous cell carcinoma. The findings support a flexible approach to cisplatin scheduling in clinical practice, while also highlighting the need for continued research to optimize treatment strategies for this challenging disease.
References
Ward MC, Prabhu RS, Atlas JL, et al. Weekly Versus Bolus Cisplatin Concurrent With Definitive Radiation Therapy for Squamous Carcinoma of the Head and Neck: A Systematic Review and Network Meta-Analysis. Pract Radiat Oncol. 2024;14(6):e458-e466. doi:10.1016/j.prro.2024.03.007
