Non-cisplatin concurrent agents plus definitive radiotherapy for locally advanced head and neck cancer: A network meta-analysis of randomized studies

Introduction: Head and neck squamous cell carcinoma (HNSCC) poses a significant clinical challenge, particularly in its locally advanced stages. Cisplatin-based, definitive, chemoradiotherapy (CRT) is recognized as the preferred treatment strategy, providing substantial survival benefits and currently achieving the best locoregional control (LRC). However, the toxicity profile of cisplatin, which includes nephrotoxicity, neurotoxicity, and ototoxicity, restricts its application in patients with comorbidities or those of advanced age. Emerging alternatives such as carboplatin, taxanes, cetuximab, and immune checkpoint inhibitors (ICIs) are gaining attention. This study undertakes a network meta-analysis (NMA) to assess the effectiveness and safety of these agents in conjunction with definitive RT. Methods: The inclusion criteria targeted definitive RT in conjunction with non-cisplatin systemic therapies, compared to RT with or without cisplatin in adult HNSCC patients. The outcomes evaluated included overall survival (OS), progression-free survival (PFS), and locoregional control (LRC). Statistical methodologies, including the Surface Under the Cumulative Ranking Curve (SUCRA), were employed to rank the treatment protocols. Results: The analysis incorporated 29 randomized controlled trials assessing 18 treatment modalities. Three cisplatin-based regimens combined with RT consistently demonstrated superior efficacy in OS, ranking as the 3 most effective option for OS, followed by weekly docetaxel combined with RT. Non-cisplatin alternatives such as mitomycin C-based regimens + RT, and methotrexate + RT, demonstrated promising efficacy. For PFS, they ranked first and second, with SUCRA scores of 83 % and 79 %, respectively. Regarding LRC, mitomycin C-based regimens + RT and weekly docetaxel + RT emerged as the top two options, achieving SUCRA scores of 97 % and 93 %, respectively. Cetuximab and ICIs combined with RT ranked lowest across all assessed outcomes. Conclusion: While cisplatin remains the standard of care, carboplatin, mitomycin C-based, and weekly docetaxel + RT regimens present viable alternatives as concurrent agents during RT for patients with stage III-IV HNSCC who are not eligible for cisplatin. It is imperative to develop tailored treatment strategies to enhance clinical outcomes.