Prostate cancer dose-response, fractionation sensitivity and repopulation parameters evaluation from 25 international radiotherapy outcome data sets

Abstract

Objective: This study was undertaken to model the biochemical free survival at 5 years and to evaluate the parameters defining dose-response curve, dose-fractionation radiosensitivity and repopulation.

Methods: It was carried out a literature search on Pubmed to retrieve data sets of patients treated with external beam radiation therapy of 1.8-4.0 Gy per fraction and overall treatment time of 3 to 10 weeks. 10 groups were identified, based on risk class and androgen deprivation therapy (ADT). Dose-response curve D₅₀ (dose at 50% probability of control) and g₅₀ (steepness), α/β (dose-fractionation radiosensitivity), and repopulation parameters, d_prolif and T_prolif , were calculated. Bootstrap-based cross-validation was performed and median and 95% CI (confidence interval) were evaluated.

Results: 25 data sets, including 20,310 patients, were considered. The median (95% CI) D₅₀ and g₅₀ values were 62 (CI 53 - 66) Gy and 1.6 (0.8 - 2.4). ADT patients showed lower values of D₅₀ and g₅₀ (57 ± 5 Gy and 1.1 ± 0.4) compared to no-ADT patients (65 ± 2 Gy and 2.3 ± 0.6), with p < 0.0001 and p = 0.002. If we did not consider any dependence on overall treatment time, the median (95% CI) value of α/β was 1.4 (1.0 - 1.9) Gy with p < 0.0001 for all patients. The median values of d_{proli f} and T_prolif were 0.0 to 0.3 Gy/d and 18-40 days.

Conclusion: Dose-response curve resulted dependent on risk class and ADT, with higher steepness for no-ADT patients. Low values of dose-fractionation radiosensitivity were found, supporting the use of moderate hypofractionated radiotherapy in each risk class. A limited dependence on repopulation was observed.

Advances in knowledge: Prostate cancer response to moderate hypofractionated radiotherapy was reliably quantified considering risk class and androgen deprivation therapy.

Figure 1.

Literature search strategy and selection of clinical data sets. ADT, androgen deprivation therapy; 5y BCFS, biochemical free survival at five years; SABR, stereotactic ablative radiotherapy.

Figure 2.

Bootstrap-based averages and standard deviations of D₅₀ (2.a) and g₅₀ (2.b) derived for each patient group in Table 2. ADT, androgen deprivation therapy.

Figure 3.

The plots of bootstrap-based cross-validated dose–response curve with standard dose scheduling (thick line with experimental points as filled circles) with 95% CI for the groups “L” (low risk—Figure 3.a, “I”) (intermediate risk—Figure 3.b and “H”) (high risk—Figure 3.c) of Table 2. The empty circles are the experimental points with no standard dose scheduling. BCFS, biochemical free survival; CI, confidence interval; EQD, equivalent dose.

Figure 4.

Bootstrap-based averages and standard deviations of α/β derived for each patient group in Table 2. ADT, androgen deprivation therapy.

Figure 5.

The plots of 5 year BCFS obtained from EQD2 against the experimental 5 year BCFS with no standard dose scheduling of the groups “L” (low risk—Figure 5.a, “I”) (intermediate risk—Figure 5.b and “H”) (high risk—Figure 5.c). In the plots there are the bisector, as black continuous line, and the experimental points, as thick filled circles. 5 year BCFS from EQD2 is obtained using the bootstrap-based cross-validated dose–response curve and median value of α/β without any dependence on OTT. The points coming from the bootstrap 95% CI (thin circles) are also shown. BCFS, bio chemical free survival; CI, confidence interval; EQD, equivalent dose.