An analysis of parameters related to late effects in patients treated with concomitant boost hyperfractionated radiotherapy for advanced carcinomas of the head and neck

Purpose: Altered fractionation schemes for head and neck cancers have been shown to improve local control rates with the expectation that late effects will not be significantly increased. Little data, however, exists which examines the incidence and severity of late tissue effects from these aggressive treatment schedules. This study will examine a cohort of prospectively irradiated patients followed closely after completing a course of concomitant boost twice-daily hyperfractionated irradiation (CB-BID) for advanced head and neck cancer. Statistical techniques will be used to examine the influence of patient, tumor, and treatment related factors which might influence the development of late normal tissue complications. Materials and Methods: Follow-up records of 55 patients with stage II, III, and IV squamous cell carcinoma of the head and neck managed with CB-BID irradiation were examined. The concomitant boost treatment phase treated to a total tumor dose of 70.2-72 Gy using fractions of 1.8 Gy to the large field and 1.6 Gy to the boost field separated by a 6 hour interfraction interval. Late events recorded in the records were scored using RTOG/EORTC criteria for subcutaneous soft tissue, mandible, larynx, salivary gland, and mucosa. A total of 735 observations were made and the follow-up range was 4.7 to 63.7 months. Analysis was restricted to cases having 12 month minimum follow-up from completion of radiotherapy. Hence, the follow-up range for analyzed cases was 12.03-63.7 months (median 31.2 months and mean 32 months). Of these patients, 19 had oropharyngeal tumors, 6 oral cavity, 3 nasopharynx, 2 hypopharynx, 11 larynx and one a primary of unknown origin. In addition, doses to critical structures (mandible, larynx, mucosa, parotid, soft tissues of the neck) were recorded. The treatment volumes of maximum dose (in cm3) were derived from simulation films and computer treatment plans using a digital integration technique. Cox proportional hazards models were developed to test the risk of late complications in relationship to T-stage, N-stage, maximum dose volume, maximum dose to reference structures, patient age, sex, and primary site. Results: The calculated 36 month local tumor control rate was 82%. For the mucosa, the grade 1, 2, 3 complication incidences were 26%, 53% and 2% respectively. For soft tissue, the incidences were 26%, 36% and 9% respectively. For salivary gland, they were 48%, 19% and 21% respectively. For larynx, they were 50%, 7% and 0% respectively. No grade 4 complications were seen and no mandibular complications occurred. Multivariate techniques failed to identify any correlation of T-stage, maximum dose volume, age, sex, primary site, or maximum dose to reference structures in any of the late effect categories. Subcutaneous soft tissue changes, however, correlated strongly with the nodal status of the neck (p = 0.009) and likewise marginally correlated with AJCC stage group (p = 0.067). For lymph node negative cases, there was a 25% probability of having grade 2 or greater soft tissue late effects. For node positive necks, there was an 80% probability of developing grade 2 or greater soft tissue effects in the neck. This phenomenon was statistically independent of radiation dose to the neck. Conclusion: Our quantitative analysis found that the risk of late neck fibrosis was strongly correlated with the presence of metastatic disease in the neck. Treatment parameters, including high dose treatment volume and total dose, failed to correlate with late tissue changes. The lack of correlation of treatment parameters with late complications may be related to the small boost volumes used to treat the primary tumor. The association of neck fibrosis with nodal status may be related to the larger treatment volumes necessary in these cases. This data demonstrated that severe late tissue complications were uncommon for this treatment schedule and were quite similar to data reported by the RTOG. This study underscores the importance of standardized and detailed follow-up data collection methods