Radiobiologically derived biphasic fractionation schemes to overcome the effects of tumour hypoxia

Abstract

Objective: As a fractionated course of radiotherapy proceeds tumour shrinkage leads to resolution of hypoxia and the initiation of accelerated proliferation of radioresistant cancer cells with better repair capacity. We hypothesise that, in tumours with significant hypoxia, improved tumour control could be achieved with biphasic fractionation schedules that either use acceleration after 3–4 weeks of conventional radiotherapy or deliver a higher proportional dose towards the end of a course of treatment. We conducted a modelling study based on the concept of biological effective dose (BED) comparing such novel regimens with conventional fractionation. Methods: The comparator conventional fractionation schedule 70 Gy in 35 fractions delivered over 7 weeks was tested against the following novel regimens, both of which were designed to be isoeffective in terms of late normal tissue toxicity. 40 Gy in 20 fractions over 4 weeks followed by 22.32 Gy in 6 consecutive daily fractions (delayed acceleration) 30.4 Gy in 27 fractions over 4 weeks followed by 40 Gy in 15 fractions over 3 weeks (temporal dose redistribution) The delayed acceleration regimen is exactly identical to that of the comparator schedule over the first 28 days and the BED gains with the novel schedule are achieved during the second phase of treatment when reoxygenation is complete. For the temporal redistribution regimen, it was assumed that the reoxygenation fraction progressively increases during the first 4 weeks of treatment and an iterative approach was used to calculate the final tumour BED for varying hypoxic fractions. Results: Novel fractionation with delayed acceleration or temporal fractionation results in tumour BED gains equivalent to 3.5–8 Gy when delivered in 2 Gy fractions. Conclusion: In hypoxic tumours, novel fractionation strategies result in significantly higher tumour BED in comparison to conventional fractionation. Advances in knowledge: We demonstrate that novel biphasic fractionation regimens could overcome the effects of tumour hypoxia resulting in biological dose escalation.

A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial

“…With the close relationship between hypoxia and fractionation in mind, 35 , 36 , 37 we hypothesised that either a delayed acceleration fractionation or temporal fractionation schedule could account for hypoxia in tumours and take advantage of progressive reoxygenation in the first few weeks of treatment. 33 There is little clinical evidence for this effect as data sets for hypoxic tumours with different fractionation schedules are rare.…”

A Retrospective Study of GTV Additive Accelerated Hyperfractionation Radiotherapy Combined with Concurrent Chemotherapy in Stage II-IIIa Non-Small Cell Lung Cancer

“…Numerous studies have con rmed that tumor cells can accelerate re-proliferation after irradiation, which is manifested by prolonged treatment time and adecreased local control rate of tumor [7,8]. Koukourarkis and Hlouverakis et al [9] found a 25-40% decrease in tumor-free survival with a 14-day extension of the tumor treatment course.…”