A New Method for Synthesizing Radiation Dose–Response Data From Multiple Trials Applied to Prostate Cancer

Abstract

Purpose-A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. non-randomized) and risk group (low vs. intermediate-high) Methods and materials-Nine published prostate cancer dose escalation studies including 6539 patients were identified in the MEDLINE and CINAHL databases and reviewed to assess the relationship between dose and biochemical control. A novel method of analysis is presented in which the normalized dose-response gradient, γ 50 , is estimated for each study and subsequently synthesized across studies. Our method does not assume that biochemical control rates are directly comparable between studies.Results-Non-randomized studies produced a statistically significantly higher γ 50 than randomized studies for intermediate-high risk patients (γ 50 = 1.63 vs γ 50 = 0.93, p=0.03) and a borderline significantly higher (γ 50 = 1.78 vs γ 50 = 0.56, p=0.08) for low risk patients. No statistically significant difference in γ 50 was found between low and intermediate-high risk patients (p=0.31). From the pooled data of low and intermediate-high risk patients in randomized trials, we obtain the overall best estimate of γ 50 =0.84 with 95% confidence interval 0.54-1.15.Conclusions-Non-randomized studies over-estimate the steepness of the dose-response curve as compared to randomized trials. This is probably the result of stage migration, improved treatment techniques and a shorter follow-up in higher-dose patients that were typically entered more recently. This over-estimation leads to inflated expectations regarding the benefit from doseescalation and could lead to under-powered clinical trials. There is no evidence of a steeper doseresponse for intermediate-high risk compared to low risk patients.

Meta-analysis of the Alpha/Beta Ratio for Prostate Cancer in the Presence of an Overall Time Factor: Bad News, Good News, or No News?

“…Estimates of γ 50 = 0.78 and its standard error 0.16 came from our recently published meta-analysis (7, 9). When modeling the effect of proliferation, we used the synthesized value of 0.31 Gy/d with a standard error of 0.056 Gy/d from the studies of Thames et al (5) and Miralbell et al (10) as detailed below (compare Fig.…”

“…1). Furthermore, we use a modified value of γ 50 = 1.0 (standard error 0.20), which was calculated as in reference 7 but with the synthesized time factor taken into account.…”

“…A key quantity in estimating the clinical gain from target dose escalation is the steepness of the radiation dose-control curve, which was recently derived for prostate cancer from a meta-analysis of a series of randomized dose-escalation studies (7). …”

Clinical development of new drug–radiotherapy combinations

“…A variety of strategies have shown promise in ameliorating ionizing radiation damage to normal tissues, including protection with radical scavengers, stimulating recovery with cytokines, modifying the p53 response, reducing the negative effects of inflammatory cascades and oxidative stress, and the use of stem-cell therapy. Of note, the slopes of clinical dose-response curves (the relationship between the probability of tumour control and the ionizing radiation dose) indicate that increasing the effective ionizing radiation dose by just 10% (a dose enhancement factor of 1.1) will increase tumour control rates by 5-30%, depending on the tumour site and whether control rates are already low or high 121,122 . …”

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“…In a previous meta-analysis, the steepness of the dose-response curve 3,4 was estimated at ␥ 50 ϭ 1.0, which together with the observed bNED rates after SFX and HFX, leads us to a D obs of 71 Gy when a time factor is included in the analysis.…”