Markedly Improved Toxicity Rates With Proton-Beam Reirradiation for Recurrent Head and Neck Cancer

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I think these are some encouraging preliminary results. Longer follow-up is needed, and this will hopefully launch a prospective study looking at outcomes and also cost/benefit analysis.

John Han-Chih Chang, MD

Proton-beam radiation therapy may be an attractive option for reirradiation of recurrent head and neck cancer, with encouraging disease control and survival rates and improved toxicity rates compared to photon reirradiation, according to John Han-Chih Chang, MD.

Most head and neck cancers present with locally advanced disease, with radiation as a treatment component. Head and neck cancer recurrence rates after definitive chemotherapy and radiation can range from 20% to 35% (or higher in T3-T4, N2b-N3 and HPV-positive disease), and for recurrent disease, surgery and reirradiation are the only two curative options.

“However, in unresectable cases, reirradiation is possibly the only potentially curative treatment that can yield long-term survival,” said Dr. Chang, a radiation oncologist at the Northwestern Medicine Chicago Proton Center in Warrenville, Illinois. “And most patients with locoregional failure die as a direct consequence of tumor growth at the primary site.”

According to Dr. Chang, photon reirradiation can offer improved disease-free survival and locoregional control when compared to chemotherapy alone, but severe acute and late toxicities often complicate treatment. The physical properties of proton-beam radiation therapy, however, produce an insignificant exit dose, which can lead to reduced toxicity in a reirradiation setting when compared to photons, he explained.

At the 2016 Multidisciplinary Head and Neck Cancer Symposium in Scottsdale, Arizona, Dr. Chang presented the results of a multi-institutional study of proton-beam reirradiation for recurrent head and neck cancer.1

Methods and Study Population

A retrospective analysis of ongoing prospective data registries from two hybrid community-academic proton centers was conducted. Patients with recurrent head and neck cancer who had at least one prior course of definitive-intent external-beam radiation therapy and underwent reirradiation from 2011 to 2014 were included. Acute toxicity was assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0), and late toxicity was measured by the Radiation Therapy Oncology Group late radiation morbidity scoring system.

Among the 92 patients enrolled, median age was 63 years, 71% were male, and 38% were smokers. The most common initial tumor site was the oropharynx, and the most common recurrent histology was squamous cell carcinoma. Twelve patients were treated for metachronous second primary tumors.

Prior Therapies

The median time between prior radiation therapy and the start of proton-beam reirradiation was 34.4 months. Overall, 76 patients (83%) had one prior course of external-beam radiation therapy, and 16 (17%) had two or more courses; the median dose per course of therapy was 61.4 Gy. About half (49%) of the subjects received prior chemotherapy as well.

Reirradiation in Head and Neck Cancer

  • For recurrence of head and neck cancer after definitive chemotherapy and radiation, surgery and reirradiation are the only two curative options.
  • Proton-beam reirradiation in this setting has produced encouraging preliminary outcomes with less toxicity than photon reirradiation.

Thirty-six patients had salvage surgery prior to proton-beam reirradiation therapy. After surgery, 15% of those patients had positive margins, 17% had close margins, and 14% had negative margins. Median time from surgery to proton-beam reirradiation was 2.5 months.

Forty-four patients (48%) had concurrent systemic therapy and 12 (13%) had neoadjuvant therapy and/or concurrent systemic therapy. “The most common agent used concurrently was cetuximab (Erbitux), but cisplatin and carboplatin were also used,” said Dr. Chang.

Encouraging Overall Survival

Ninety patients received reirradiation with proton-beam radiation therapy at a median prescribed dose of 60.6 CGE [cobalt gray equivalent], and median follow-up was 7 months. Actuarial 12-month locoregional failure and freedom from distant metastasis rates were 25.1% and 84%, ­respectively.

Forty patients died after treatment was completed, and median time of death was 7.3 months from the start of proton-beam reirradiation; one patient died of progressive disease while on proton-beam reirradiation.

“Overall survival at 12 months was an encouraging 65%,” said Dr. Chang. Of the 41 patients alive at 1 year, 20 were without evidence of disease, 14 had locoregionally recurrent–only disease, 3 had metastatic-only disease, and 4 had both locoregionally recurrent and metastatic disease.

Acute and Late Toxicities

Eighty-seven patients (95%) finished the prescribed dose of treatment. “Of acute toxicities, about 10% involved mucosal and swallowing function, as you would typically expect as far as grade 3 toxicities,” he stated. “Skin toxicities came in the form of two cutaneous fistulas, which were both healed with conservative management, and one dehiscence of a thigh flap reconstruction that required revision surgery.”

There were five grade 4 late toxicities: a chronic neck wound requiring hyperbaric oxygen treatments, a small neck wound/open ulcer (with plans for future closure), a nonhealing left temporal skin defect requiring a skin flap, a mucocutaneous fistula, and a sinocutaneous fistula with pneumocephalus in the setting of recurrent/progressive disease. Two patients had fatal vascular injury (carotid hemorrhage in the pharyngeal mucosa).

“There were no brainstem or spinal cord injuries and no visual pathway toxicities or neurologic damage either,” said Dr. Chang.

Toxicity Rates

Due to the finite range of protons and subsequent reduced dose to normal tissue, the investigators reported markedly improved toxicity rates compared to photon reirradiation.

Rates of acute grade 3 dermatitis (3%), mucositis (10%), and dysphagia (9%) compared favorably to head and neck cancer cohorts treated with photon reirradiation, and limited long-term follow-up data suggested a favorable late toxicity profile compared to historic controls.

“I think these are some encouraging preliminary results,” Dr. Chang stated. “Longer follow-up is needed, and this will hopefully launch a prospective study looking at outcomes and also cost/benefit analysis.” ■

Disclosure: Dr. Chang in the Director of Clinical Education at the Northwestern Medicine Chicago Proton Center.


1. Chang JHC, Romesser PB, Scher ED, et al: Proton beam reirradiation for recurrent head and neck cancer. 2016 Multidisciplinary Head and Neck Cancer Symposium. Abstract 4. Presented February 18, 2016.

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