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. nonrandomized) and risk group (low vs. intermediate-high).

Methods and materials: Nine published prostate cancer dose escalation studies including 6,539 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, gamma(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: Nonrandomized studies produced a statistically significantly higher gamma(50) than randomized studies for intermediate- to high-risk patients (gamma(50) = 1.63 vs. gamma(50) = 0.93, p = 0.03) and a borderline significantly higher (gamma(50) = 1.78 vs. gamma(50) = 0.56, p = 0.08) for low-risk patients. No statistically significant difference in gamma(50) was found between low- and intermediate- to high-risk patients (p = 0.31). From the pooled data of low and intermediate- to high-risk patients in randomized trials, we obtain the overall best estimate of gamma(50) = 0.84 with 95% confidence interval 0.54-1.15.

Conclusions: Nonrandomized studies overestimate the steepness of the dose-response curve as compared with 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 overestimation leads to inflated expectations regarding the benefit from dose-escalation and could lead to underpowered clinical trials. There is no evidence of a steeper dose response for intermediate- to high-risk compared with low-risk patients.

Figure 1

Pooled analysis of studies reporting the steepness of the dose response curve for low risk patients. Non-randomized and randomized studies are analyzed separately using inverse variance weighting. Horizontal lines in the forest plot indicate the range of the 95% CI of individual studies, while the left and right corner of the diamond shapes depict the 95% CI of the combined estimate.

Figure 2

Pooled analysis of studies reporting the steepness of the dose response curve for intermediate to high risk patients. Non-randomized and randomized studies are analyzed separately and a significant difference between the pooled estimates is seen (p=0.03). The meaning of the symbols is explained in Figure 1

Figure 3

Pooled analysis of the steepness of the radiation dose response curve in randomized trials compared between the low risk group and the intermediate-high risk group. No evidence of difference is seen (p=0.31).