Proton Therapy to Reduce Side Effects in Head and Neck Cancer

Brian C. Baumann, MD; Kelly M. MacArthur, MD

Head and neck cancer patients require specialist care from surgeons, radiation oncologists, and medical oncologists. Patients with larger or more advanced disease who are treated with surgery will frequently receive post-operative radiation therapy with or without chemotherapy. For patients not treated with surgery, radiation therapy, sometimes used in combination with chemotherapy, is a common treatment for more advanced disease. Cure rates have improved, but the side effects of treatment, both during therapy and in the years after therapy is completed, can be significant. In addition, an increasing proportion of head and neck cancer patients are younger and healthier and present with human papilloma virus (HPV)-associated cancers, which generally have a better prognosis. Reducing side effects during treatments and in the months to years after treatment is of critical importance for patients. There have been a number of recent strategies to reduce side effects for head and neck cancer patients in the realm of surgery, systemic therapy, and radiation therapy. We will discuss several recent strategies to reduce radiation therapy side effects and focus on one particular development in radiation oncology: the use of proton therapy to reduce side effects in head and neck cancer patients. 

 Improvements in radiation therapy strategies

Efforts to reduce the toxicity of radiation for head and neck cancer patients have included the development and refinement of intensity-modulated radiation therapy (IMRT) to limit dose to the surrounding normal tissues. There are also ongoing clinical studies in patients with HPV-positive head and neck cancer to assess the feasibility of delivering a lower dose of radiation and/or shrinking the size of the target, all in an effort to reduce collateral damage without sacrificing cancer-control outcomes. For example, there is promising preliminary data that for HPV-positive patients, the radiation dose can be reduced for selected patients without reducing effectiveness. Although current guidelines say that these patients should be treated with the standard, higher doses of radiation, those guidelines may change in the near future as more data becomes available. For other patients, there is growing awareness that it may be possible to avoid radiation to the lymph node regions of the neck on the side opposite the tumor, based on recently published research from Washington University in Saint Louis. Other studies have shown that patients may be able to avoid receiving radiation to the site of the primary tumor if the tumor was small and fully resected. It is important to review with healthcare providers to see if any of these toxicity-reducing strategies are appropriate for an individual patient. While they may be appropriate for some, they are not appropriate for all patients. 

Proton Therapy as a technique to reduce radiation side effects

One particularly exciting development in the treatment of head and neck cancer patients is the expanding role of proton therapy as an alternative radiation treatment modality. Conventional x-ray radiation is used to treat >99% of patients with head and neck cancer in the U.S. and Europe, with most head and neck cancer patients receiving the most sophisticated form of photon radiation: IMRT. IMRT is an excellent treatment modality that allows doctors to safely escalate the radiation dose to the target while greatly minimizing radiation dose to the surrounding normal tissues, including the jaw, salivary glands, and spinal cord, among others. As good as IMRT has become, IMRT still relies on x-ray irradiation, which deposits radiation as the beams enter the body, as it hits the target, and as it exits the body. Proton therapy, by contrast, allows the radiation beams to treat the tumor target without exit dose extending beyond the target and into the healthy tissues. There has been great enthusiasm recently over the potential role of proton therapy to reduce side effects in head and neck cancer, because as many would say, head and neck cancers are located in “prime real estate” in the body. By reducing radiation dose to normal structures, proton therapy may allow doctors to deliver a higher dose of radiation more safely, which may in turn improve cancer outcomes and quality of life.

Proton therapy: The problem of cost and access

One of the challenges of proton therapy is that the upfront costs associated with establishing a proton center are much higher than those for traditional radiation centers. Additionally, maintenance costs for proton therapy are higher and more technical expertise is required. Not surprisingly, the cost of proton therapy passed on to the insurance company can be significantly higher. In addition, most head and neck cancer patients require treatment plans that are so complex that only next-generation proton therapy techniques, called pencil beam scanning, are robust enough to create feasible radiation treatment plans for these patients. Lastly, access to proton therapy remains an issue. While proton centers have proliferated over the last few years, there are still limited facilities in the country, with many larger cities not serviced with a proton machine. The limited availability and higher cost remain important barriers limiting access to proton therapy. 

What is the available data for proton therapy for head and neck cancer? 

Proton therapy has a long track record for the treatment of rare base-of-skull tumors called chordomas. These tumors require very high doses of radiation to cure and are situated in very sensitive areas close to the brainstem and critical cranial nerves. Proton therapy has allowed for improvements in the treatment of chordomas by allowing an increased dose to be delivered to these tumors, improving outcomes for patients. 

What about proton therapy for patients with more run-of-the-mill head and neck cancers? Several retrospective studies have been performed showing comparable cancer control outcomes for head and neck patients treated with protons, with most showing significant reductions in radiation dose to normal tissues and decreased probability of side effects associated with proton therapy. Proton therapy has been shown to reduce the risk of dry mouth, pain/difficulty with swallowing, mouth sores, and taste changes, among other side effects. Proton therapy may also help patients to avoid the need for a feeding tube during their treatments. 

A recent study published in JAMA Oncology in December 2019 found that for all patients treated with combination chemotherapy and radiation therapy for any cancer at the University of Pennsylvania, proton chemo-radiotherapy was associated with a significant, two-thirds reduction in the rate of severe side effects that lead to unplanned hospitalizations compared to photon chemo-radiotherapy. 

This study included 1483 patients who were followed prospectively for toxicity outcomes. Of the 1483, 437 patients (29%) had head and neck cancer. While the cohort of head and neck patients receiving proton therapy was relatively small, these results demonstrated a similar benefit in the head and neck cohort to what was seen in the overall study group. 

Clinical trials are ongoing to compare proton vs. photon therapy for head and neck cancer, with perhaps the most prominent trial taking place at MD Anderson (Principal investigator: Dr. Steven Frank). Preliminary results from this clinical trial have demonstrated an important reduction in toxicity with proton therapy. Additional data from this and other clinical studies are eagerly awaited.

Is proton therapy right for you?

In our opinion, proton therapy is a very exciting treatment with tremendous promise for patients with head and neck cancer because the target can be treated with the same dose of radiation, but spare the surrounding structures more effectively, reducing the risk of serious side effects both during treatment and in the months to years after treatment. More research is needed to compare proton versus photon therapy for head and neck cancer and to better identify the patients who are most likely to benefit from proton therapy. There are certainly patients with head and neck cancer where proton therapy may not be possible, due to extensive metal artifact near the target that would interfere with the proton particles (e.g. extensive dental work or spinal fusion surgery), or because of challenges in the size/dimensions of the target volume. Insurance coverage also remains a challenge, since many private insurers do not cover proton therapy for head and neck cancer. 

While proton therapy may be worth exploring for some patients, it is important to emphasize that IMRT is an excellent treatment with a long track record in head and neck cancer and is currently considered the standard-of-care. In our opinion, the future looks bright for proton therapy for head and neck cancer as a way to reduce side effects and improve patient quality-of-life. 

Editors Note: Dr. Brian Baumann is an assistant professor of radiation oncology at Washington University in Saint Louis and an adjunct assistant professor of radiation oncology at the University of Pennsylvania. He is an expert on the comparative effectiveness of proton vs. photon therapy, and his research has been reported on extensively in the medical and national lay press. He specializes in the treatment of rare head and neck cancers (Merkel cell carcinoma and sarcoma) and genitourinary cancers. 

Dr. Kelly MacArthur is a Mohs-college fellowship-trained Mohs surgeon and assistant professor of dermatologic surgery at Washington University in Saint Louis. She is an expert on cutaneous skin cancers of the head and neck and has served on the board of the American Society for Dermatologic Surgery. 

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