Synergistic Relationship Between Radiotherapy and Immunotherapy for Squamous Cell Carcinoma of the Head and Neck

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Recent technologic improvements in radiotherapy now offer an unprecedented opportunity to enhance immune response, and going forward, may play a role in the definitive treatment of head and neck cancer, according to William Stokes, MD, Assistant Professor in the Department of Radiation Oncology at Emory University School of Medicine in Atlanta.

William Stokes, MD

William Stokes, MD

Immunotherapy has proven benefit in metastatic head and neck cancer, and ongoing research is exploring its integration into a number of settings throughout a conventional treatment course, including neoadjuvant, concurrent, and adjuvant settings, as well as in the salvage setting in cases of locoregional recurrence. Dr. Stokes shared these thoughts at the 2019 Winship Cancer Institute of Emory University Updates in the Management of Head and Neck Cancer Symposium.1

Current Clinical Trials Update

A phase I trial, currently recruiting at the Winship Cancer Institute, is exploring a variety of immunotherapeutic approaches in advance of surgery ( identifier NCT03690986). Another phase I/Ib trial, out of the University of Colorado, is combining durvalumab immunotherapy with radiation prior to surgery (NCT03635164). The Radiation Therapy Oncology Group (RTOG) 3504 trial is exploring the addition of nivolumab to concurrent chemoradiotherapy (NCT02764593), whereas another active phase I study is looking at the addition of pembrolizumab to chemoradiotherapy (NCT02775812). Yet another randomized phase II/III trial will compare cetuximab plus radiation with durvalumab plus radiation in cisplatin-ineligible patients (NCT03258554), Dr. Stokes reported.

“We know the adjuvant/consolidation immunotherapy approach worked remarkably well in advanced non–small cell lung cancer (NSCLC), so it’s a reasonable next step to look at it in head and neck cancer,” he added. Patients in a currently recruiting phase III trial will undergo a definitive locoregional treatment course before being randomly assigned to either atezolizumab or placebo (NCT03452137). Additionally, in the salvage setting, patients who have locoregional failure following an upfront radiation-based treatment course are being enrolled on a multi-institutional trial of reirradiation with concurrent and consolidative nivolumab (NCT03521570).

Radiation can enhance the effect of immunotherapy, and vice versa. “One of the reasons I’m excited about all these studies is because of the synergy that takes place between radiation and immunotherapy,” noted Dr. Stokes.

“We know the adjuvant/consolidation immunotherapy approach worked remarkably well in advanced non–small cell cancer, so it’s a reasonable next step to look at it in head and neck cancer.”
— William Stokes, MD

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This synergistic relationship was notably demonstrated in a secondary analysis of the KEYNOTE-001 trial in metastatic NSCLC: patients in the trial who had previously received radiation had better outcomes with pembrolizumab than those who received the drug without radiation.2 Also, in the PACIFIC trial, adding immunotherapy enhanced the effect of chemoradiation enough to improve overall and progression-free survival in patients with NSCLC.3

Challenges of Adding Radiotherapy to Immunotherapy

Lymphopenia appears to predict worse outcomes during and after radiation treatment. A recently published study from the University of Pennsylvania showed that patients with head and neck cancer who had lower lymphocyte counts had worse outcomes, at multiple time points and across multiple endpoints.4 However, research has also suggested that the treatment for these patients—chemoradiation—actually causes the lymphopenia, so according to Dr. Stokes, striking the right balance is crucial.

“On the one hand, we know that radiation can be immunogenic; this is a good thing. Radiation synergizes with immunotherapy and with the immune system and leads to better outcomes,” he added. “On the other hand, we know that chemotherapy and radiation lead to lymphopenia. So how do we appropriately prime the immune system with radiation without causing lymphopenia?”

The current state of radiotherapy involves giving many fractions of radiation over an extended period, targeting not only areas of gross disease, but also areas at risk of harboring active cancer; as a result, there can be a significant amount of collateral damage to healthy tissue, including those involved in the immune response to cancer. But, according to Dr. Stokes, making the shift from standard to immunogenic radiotherapy will consist of shortening the course of treatment: giving fewer fractions with a higher dose of radiation per fraction. This approach would also involve targeting only sites of gross disease, sparing more healthy tissue.

Dr. Stokes maintains that a number of approaches could facilitate such a paradigm shift. Proton therapy can spare the amount of healthy tissue that receives radiation, thereby sparing T lymphocytes. Hypofractionation might translate to more favorable immune responses, as could de-intensifying therapy by reducing the dose of radiation and the volume of tissue irradiated or by decreasing the dose of systemic therapy (or changing agents) to something less toxic for T cells, while still preserving outcomes, he proposed. 

DISCLOSURE: Dr. Stokes reported no conflicts of interest.


1. Stokes W: Integrating immunotherapy in the definitive treatment of SCCHN. 2019 Winship Cancer Institute of Emory University Updates in the Management of Head and Neck Cancer Symposium. Presented April 27, 2019.

2. Shaverdian N, Lisberg AE, Bornazyan K, et al: Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: A secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol 18:895-903, 2017.

3. Antonia SJ, Villegas A, Daniel D, et al: Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 379:2342-2350, 2018.

4. Lin AJ, Gang M, Rao YJ, et al: Association of posttreatment lymphopenia and elevated neutrophil-to-lymphocyte ratio with poor clinical outcomes in patients with human papillomavirus-negative oropharyngeal cancers. JAMA Otolaryngol Head Neck Surg. March 28, 2019 (early release online).