Accelerated repopulation of tumor cells during radiotherapy has been suggested as an important cause of treatment failure in squamous cell carcinoma of the head and neck. Due to tumor heterogeneity, not all tumors may benefit from accelerated radiotherapy at the expense of a lower total dose. This analysis evaluates the impact of histological differentiation on loco-regional control in relation to treatment duration.

A total of 501 patients with advanced supraglottic and pharyngeal squamous cell carcinoma with known histopathological grading were treated with planned split-course (191 patients) or continuous radiotherapy (310 patients) in two consecutive randomized controlled trials. Irradiation was given 2 Gy per fraction, 5 fractions per week to a dose of 66-68 Gy in 9.5 or 6.5 weeks, respectively.

Overall, split-course and continuous treatment resulted in a 5-year loco-regional control of 30% and 41% (P = 0.007), respectively. However, the detrimental effects of split-course were only found in moderately and well-differentiated tumors, where the 5-year tumor controls were 38% and 21% after continuous and split-course treatment, respectively (P = 0.001). In contrast, in poorly differentiated tumors loco-regional control was obtained in 44% of the cases for continuous and 40% for split-course treatment (P = 0.63).

It is suggested that the ability to accelerate repopulation may be lost by dedifferentiation, and that prolongation of the overall treatment time only lead to reduced loco-regional control in well to moderately differentiated tumors.