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Simple Summary  Radiotherapy (RT) is an effective treatment for head and neck squamous cell carcinoma (HNSCC). Concurrent RT with high dose cisplatin (100 mg/m 2 , days 1, 22, and 42) is the standard of care (SOC) for non-operative HNSCC in curative settings, however, it is associated with both significant toxicities. In this review, we discussed the evidence of combination of anti-epidermal growth factor receptor, cetuximab, or immune checkpoint inhibitors (ICIs) with RT to compare with SOC. Cetuximab has been shown to be a less effective agent than cisplatin multiple recent trials, but it remains a reasonable alternative for those who are not fit for cisplatin. ICIs are active agents in recurrent and metastatic HNSCC. The role of ICIs with RT in the curative setting is yet to be defined. Multiple clinical trials are currently recruiting. Combining ICIs with stereotactic body radiotherapy (SBRT) is an attractive treatment in patients with oligometastatic or oligoprogressive HNSCC to boost the anti-tumor immune response.    Abstract  Radiotherapy plays an important role of managing head and neck squamous cell carcinoma (HNSCC). Concurrent radiotherapy with radiosensitizing cisplastin chemotherapy is the standard of care (SOC) for non-operable locally advanced HNSCC. Cetuximab, a monoclonal antibody of epidermal growth factor receptor, was the most extensively studied targeted therapy as a chemo-sparing agent that was used concurrently with radiotherapy. Immunotherapy is used in the treatment of metastatic HNSCC. There is evidence to support the synergistic effect when combining radiotherapy with immunotherapy to potentiate anti-tumor immune response. There has been increasing interest to incorporate immune checkpoint inhibitor (ICI) with radiotherapy in the curative setting for HNSCC. In this review, we discuss the latest evidence that supports concurrent radiotherapy with cisplatin which remains the SOC for locally advanced HNSCC (LA-HNSCC). Cetuximab is suitable for patients who are not fit for cisplatin. We then summarize the clinical trials that incorporate ICI with radiotherapy for LA-HNSCC in concurrent, neoadjuvant, and adjuvant settings. We also discuss the potential of combining immunotherapy with radiotherapy as a treatment de-escalating strategy in HPV-associated oropharyngeal carcinoma. Finally, the pre-clinical and clinical evidence of the abscopal effect when combining stereotactic body radiotherapy with ICIs is presented.

cancers

Recent Research on Combination of Radiotherapy with Targeted Therapy or Immunotherapy in Head and Neck Squamous Cell Carcinoma: A Review for Radiation Oncologists