Hyperfractionated Radiation Therapy Improves Local-Regional Control Without Increasing Late Toxicity in Locally Advanced Head and Neck Cancer
Patients with locally advanced squamous cell carcinoma of the head and neck treated with hyperfractionated radiation therapy experienced improved local-regional control and, with patients censored at 5 years, improved overall survival with no increase in late toxicity, according to a study published by Beitler et al in the International Journal of Radiation Oncology • Biology • Physics.
Study Methods
RTOG 9003,a multi-institutional, randomized phase III trial, evaluated patients who received standard fractionation compared to those that received hyperfractionation, accelerated fractionation with a split or accelerated fractionation–continuous. Patients enrolled in RTOG 9003 were age 18 or older and had previously untreated, locally advanced squamous cell cancers of the oral cavity, oropharynx, or supraglottic larynx in stage III or IV or stage II to IV carcinoma of the base of the tongue or hypopharynx. Patients with a prior (within 5 years) or synchronous malignancy other than nonmelanoma skin cancer were excluded. The trial accrued 1,076 eligible patients from September 30, 1991, to August 1, 1997.
Patients were randomly assigned to four different treatment arms: standard fractionation (2 Gy/fraction/d to 70 Gy in 35 fractions over 7 weeks), hyperfractionation (1.2 Gy/fraction, twice daily, to 81.6 Gy over 7 weeks), accelerated fractionation with a split (1.6 Gy/fraction, twice daily, to 67.2 Gy over 6 weeks, with a 2-week break after 38.4 Gy) and accelerated fractionation–continuous (total dose of 72 Gy delivered over 6 weeks in 1.8 Gy daily fractions and additional 1.5 Gy boost field in the afternoon during the last 12 days of treatment). All treatments were delivered 5 days a week, and twice-daily treatments had a minimum interfraction interval of 6 hours.
Local-regional failure was analyzed at 2 years, 5 years, and at last follow-up. As of October 1, 2012, the median follow-up was 14.1 years. At the time of this report’s analysis in October 2012, 52.7% of patients had experienced local-regional failure, with 97.4% occurring within the first 5 years.
Results
Secondary primary cancers were reported for 18.6% of patients, with 50% reported within the first 3 years, and 75% reported within the first 5.5 years. After 5.5 years post-treatment, the rates of secondary malignancies decreased to < 1% per year. There were no significant differences in the rates of second malignancies among all four study arms.
At 5 years, the prevalence of grade 3, 4 or 5 toxicity, any feeding tube use after 180 days or feeding tube use at 1 year did not differ significantly when the standard fractionation arm was compared to the three experimental arms. Grade 3, 4, or 5 toxicity tended to be decreased for patients treated over 7 weeks compared to those treated over 6 weeks (9.0% vs 16.7%, respectively), and 4.8% of disease-free patients treated with hyperfractionation had feeding tubes compared to 13.0% of patients treated with accelerated fractionation–continuous.
At 5-years post-treatment, patients in the hyperfractionation arm had the highest overall survival rates at 37.1% (hazard ratio = 0.81) compared to 33.7% for the accelerated fractionation–continuous arm, 29.3% for the standard fractionation arm, and 29.0%for the accelerated fractionation with a split arm.
New Insight on Long-Term Disease Patterns
“This study, one of only a few large studies to have follow-up beyond 5 years, demonstrates that patients who have head and neck cancers and who are being treated with radiation therapy alone have improved local-regional control and no increase in late toxicity when radiation therapy is delivered twice a day in two smaller doses which we call hyperfractionation,” said Jonathan J. Beitler, MD, MBA, FASTRO, lead author of the study and Professor of Radiation Oncology, Otolaryngology and Hematology/Medical Oncology at the Winship Cancer Institute of Emory University School of Medicine in Atlanta.
“The decrease in the rate of new cancers was unexpected; however, the large database and the long follow-up provided us with a window into information that had not previously been available about the long-term patterns of head and neck tumors and is particularly heartening. The results suggest that twice-daily radiation may improve cure and limit late side effects for patients. Twice-daily radiation might be worth considering in place of concurrent chemoradiotherapy for those patients who are at low risk for distant metastases and those patients who cannot tolerate systemic therapy,” he said.
Dr. Beitler is the corresponding author for the International Journal of Radiation Oncology • Biology • Physics article.
The study was supported by grants from the National Cancer Institute. Each academic institution received financial support from the Radiation Therapy Oncology Group. Dr. Beitler receives support as a Georgia Research Alliance Cancer Scientist.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
