Impact of increased cell loss on the repopulation rate during fractionated irradiation in human FaDu squamous cell carcinoma growing in nude mice

Abstract

Purpose: To determine the impact of increased necrotic cell loss on the repopulation rate of clonogenic cells during fractionated irradiation in human FaDu squamous cell carcinoma in nude mice.

Materials and methods: FaDu tumours were transplanted into pre‐irradiated subcutaneous tissues. This manoeuvre has previously been shown to result in a clear‐cut tumour bed effect, i.e. tumours grow at a slower rate compared with control tumours. This tumour bed effect was caused by an increased necrotic cell loss with a constant cell production rate. After increasing numbers of 3‐Gy fractions (time intervals 24 or 48 h), graded top‐up doses were given to determine the dose required to control 50% of the tumours (TCD₅₀). All irradiations were given under clamp hypoxia.

Results: With increasing numbers of daily fractions, the top‐up TCD₅₀ decreased from 37.9 Gy (95% CI: 31; 45) after single dose irradiation to 14.1 Gy (8; 20) after irradiation with 15 fractions in 15 days. Irradiation with 18 daily 3‐Gy fractions controlled more than 50% of the tumours without a top‐up dose. After irradiation with six fractions every second day, the top‐up TCD₅₀ decreased to 26.9 Gy (22; 32). No further decrease of the TCD₅₀ was observed after 12 and 18 irradiations every second day. Assuming a constant increase of TCD₅₀ with time, the calculated doubling time of the clonogenic tumour cells (T_clon) was 7.8 days (4.4; 11.3). The T_clon calculated for FaDu tumours growing in pre‐irradiated tissues was significantly longer (p=0.0004) than the T_clon of 5.1 days (3.7; 6.5) determined under the same assumptions in a previous study for FaDu tumours growing in normal subcutaneous tissues.

Conclusions: Increased necrotic cell loss by pre‐irradiation of the tumour bed resulted in longer clonogen doubling times during fractionated radiotherapy of human FaDu squamous cell carcinoma. This implies that a decreased necrotic cell loss might be the link between reoxygenation and repopulation demonstrated previously in the same tumour model.