A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003.

Fu KK, Pajak TF, Trotti A, Jones CU, Spencer SA, Phillips TL, Garden AS, Ridge JA, Cooper JS, Ang KK

Patients with locally advanced head and neck cancer were randomly assigned to receive radiotherapy delivered with: 1) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy/35 fractions/7 weeks; 2) hyperfractionation at 1. 2 Gy/fraction, twice daily, 5 days/week to 81.6 Gy/68 fractions/7 weeks; 3) accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 5 days/week, to 67.2 Gy/42 fractions/6 weeks including a 2-week rest after 38.4 Gy; or 4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5 Gy/fraction/day to a boost field as a second daily treatment for the last 12 treatment days to 72 Gy/42 fractions/6 weeks. Of the 1113 patients entered, 1073 patients were analyzable for outcome. The median follow-up was 23 months for all analyzable patients and 41.2 months for patients alive. RESULTS: Patients treated with hyperfractionation and accelerated fractionation with concomitant boost had significantly better local-regional control (p = 0.045 and p = 0.050 respectively) than those treated with standard fractionation. There was also a trend toward improved disease-free survival (p = 0.067 and p = 0.054 respectively) although the difference in overall survival was not significant. Patients treated with accelerated fractionation with split had similar outcome to those treated with standard fractionation. All three altered fractionation groups had significantly greater acute side effects compared to standard fractionation. However, there was no significant increase of late effects. CONCLUSIONS: Hyperfractionation and accelerated fractionation with concomitant boost are more efficacious than standard fractionation for locally advanced head and neck cancer. Acute but not late effects are also increased.

Eligible patients were randomized to receive radiotherapy delivered using: 1) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy/35 fractions/7 weeks; 2) hyperfractionation at 1.2 Gy/fraction, twice daily, 6 hours apart, 5 days/week to 81.6 Gy/68 fractions/7 weeks; 3) accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 6 hours apart, 5 days/week, to 67.2 Gy/42 fractions/6 weeks including a 2-week rest after 38.4 Gy; or 4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/day, 5 days/week to large field + 1.5 Gy/fraction/day to boost field given 6 hours after treatment of the large field for the last 12 treatment days to a total dose of 72 Gy/42 fractions/6 weeks. Additional boost doses not exceeding 5.0 Gy through reduced fields to persistent primary tumor and/or clinically positive nodes were allowed. Neck dissection was allowed for neck nodes >3 cm prior to radiotherapy at the discretion of the responsible head and neck surgeon and radiation oncologist.


A combination of lateral opposing fields, anterior and lateral wedged fields, or other field arrangements was used to treat the primary tumor and the lymph nodes in the upper neck. A single anterior field was used to treat the neck below the fields for the primary tumor. For patients with nodes >6 cm, supraclavicular nodes, or pyriform sinus tumors that were T3 or T4 or with clinically positive nodes, the anterior field could extend 5 cm inferiorly to include the upper mediastinum. All fields were treated on each treatment day.

At least two field reductions were recommended for all four arms. The first field reduction off the spinal cord occurred at 40–44 Gy for arm 1, 45.6 Gy for arm 2, and 38.4 Gy for arm 3. The second field reduction occurred at 50–60 Gy for arm 1, 50.4–60.0 Gy for arm 2, and 51.2–60.8 Gy for arm 3. A third field reduction at 69.4 Gy was recommended for arm 2. A minimum 2-cm margin around the initial tumor volume and positive neck node(s) for the first field reduction, a minimum of 1–1.5 cm margin for the second field reduction, and a minimum 1 cm margin for the third field reduction were required. For arm 4, the concomitant boost field with a minimum 1–1.5 cm margin around the initial tumor volume and positive neck node(s) was begun at 32.4 Gy. The primary treatment fields were reduced off the spinal cord at 45 Gy.