Influence of overall treatment time and radiobiological parameters on biologically effective doses in cervical cancer patients treated with radiation therapy alone.

The aim of the study was to examine the influence of overall treatment time (OTT) on the value of calculated biological effective doses (BEDs) for different biological variables. These variables were: tumour proliferation rate, different cell radiosensitivity (alpha=0.2, 0.3, and 0.4 /Gy), and different start time for repopulation (Tk=21, 28, and 35 days). Also the influence of age (</= 50 years >), Hb level (</= 116 g/l>), tumor proliferation rate (bromodeoxyuridine labelling index; BrdUrdLI), and DNA ploidy on survival after shorter (</= 60 days) or longer (>60 days) OTT was investigated. The study included 229 patients with cervix carcinoma treated entirely by standard radiotherapy (RT) (external beam RT plus low-medium dose-rate (LDR/MDR) brachytherapy (BT) at the Center of Oncology in Krakow. The linear quadratic equation was used to calculate BED, which is proportional to log cell kill. BEDs 10 (for tumours) were calculated with consideration of OTT for each patient and tumour proliferation rate (standardized potential doubling time; standardized Tpot) based on BrdUrdLI assessed on biopsy material before RT. Median OTT was 90 days (range 30-210). The mean calculated total BED for point A for tumour and 'early reactions' was equal to 103.0 Gy10. The longest median survival time--52 months--was seen for patients treated with OTT </= 60 days. If OTT exceeded 90 days to more than 120 days, loss in BED10 for relatively radiosensitive tumours (alpha=0.3-0.4/Gy and Tk=28 days) was equal to 0.37-0.26 Gy/day. However, for radioresistant tumours (alpha=0.2/Gy) it was 0.6 Gy/day. For fast proliferating tumours (BrdUrdLI >8.8%) BED loss was 1.4 Gy/day and for slowly proliferating tumours (BrdUrdLI </= 8.8%) it was 0.2 Gy/day. Assuming shorter (21 days) or longer (35 days) periods for Tk and relatively radiosensitive tumours similar BED loss of 0.38 Gy/day was observed. Kaplan-Meier analysis revealed that OTT </= 60 days was a significant prognostic factor for overall survival (OS) (p=0.019), disease-free survival (DFS) (p=0.0173), and local control (LC) (p=0.011). BED10 had significant influence on survival (p=0.047). Cox multivariate analysis revealed that for OTT shorter than 60 days the only favourable significant parameters were: age >50 years (p=0.003) and high Hb level (>116 g/l) (p=0.041). For longer treatments (OTT >60 days) the unfavourable parameters were: age </= 50 years (p=0.037), BrdUrdLI </= 8.8% (p=0.003), tumour aneuploidy (p=0.043), and BED10 </= 103 Gy (p=0.017). The examined tumour biological parameters should be taken into account for RT and provide a basis for adjuvant RT.