AUTHOR=Abu Taha Shatha , Abu Hejleh Taher , ElHaddad Mostafa , Al-Ibraheem Akram , Abbasi Ahmed , Sumaida Abdulrahman , Bushehri Ahmad , Mostafa Ahmad , Youssef Bassem , Alotain Ibrahim , Abu-Gheida Ibrahim , Aldehaim Mohammed , Alghamdi Majed , Shelan Mohamed , Al Dohan Mohammed , Al-Hussaini Maysa , Pervez Nadeem , Temraz Shoukri , Alrashidi Saad , El-Sheshtawy Wael , Al-Mandhari Zahid , Ghatasheh Hamza , Hosni Ali , Mohamad Issa 

TITLE=Chemotherapy-free innovations in locally advanced head and neck cancer: a comprehensive review

JOURNAL=Frontiers in Oncology

VOLUME=Volume 15 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1552337

DOI=10.3389/fonc.2025.1552337

ISSN=2234-943X

ABSTRACT=The treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC) has traditionally relied on a multimodal approach, combining surgery, radiation therapy (RT), and chemotherapy. While chemotherapy plays a critical role in improving cure rates and functional outcomes, its substantial toxicity remains a major concern, particularly in older patients. These challenges are especially relevant for those who are unfit for chemotherapy or decline conventional concurrent chemoradiotherapy (CCRT), highlighting the need for alternative therapeutic options. Many patients are at high risk for severe side effects, often preventing them from completing the full chemotherapy regimen. This review explores alternative strategies to definitive CCRT of carcinomas of the larynx, hypopharynx and oropharynx, aiming to optimize treatment outcomes while minimizing toxicity. We discuss altered fractionation strategies as a promising alternative to conventional RT, offering a balance between treatment efficacy and quality of life. Additionally, we examine emerging approaches, including the combining of targeted therapies, immunotherapy, hyperthermia, photodynamic therapy and nanoparticle-based treatments with RT, which provide alternative or complementary options to traditional therapies in the management of LA-HNSCC.