Dose–response characteristics of low- and intermediate-risk prostate cancer treated with external beam radiotherapy

Purpose

In this era of dose escalation, the benefit of higher radiation doses for low-risk prostate cancer remains controversial. For intermediate-risk patients, the data suggest a benefit from higher doses. However, the quantitative characterization of the benefit for these patients is scarce. We investigated the radiation dose–response relation of tumor control probability in low-risk and intermediate-risk prostate cancer patients treated with radiotherapy alone. We also investigated the differences in the dose–response characteristics using the American Society for Therapeutic Radiology and Oncology (ASTRO) definition vs. an alternative biochemical failure definition.

Methods and materials

This study included 235 low-risk and 387 intermediate-risk prostate cancer patients treated with external beam radiotherapy without hormonal treatment between 1987 and 1998. The low-risk patients had 1992 American Joint Committee on Cancer Stage T2a or less disease as determined by digital rectal examination, prostate-specific antigen (PSA) levels of ≤10 ng/mL, and biopsy Gleason scores of ≤6. The intermediate-risk patients had one or more of the following: Stage T2b-c, PSA level of ≤20 ng/mL but >10 ng/mL, and/or Gleason score of 7, without any of the following high-risk features: Stage T3 or greater, PSA >20 ng/mL, or Gleason score ≥8. The logistic models were fitted to the data at varying points after treatment, and the dose–response parameters were estimated. We used two biochemical failure definitions. The ASTRO PSA failure was defined as three consecutive PSA rises, with the time to failure backdated to the mid-point between the nadir and the first rise. The second biochemical failure definition used was a PSA rise of ≥2 ng/mL above the current PSA nadir (CN + 2). The failure date was defined as the time at which the event occurred. Local, nodal, and distant relapses and the use of salvage hormonal therapy were also failures.

Results

On the basis of the ASTRO definition, at 5 years after radiotherapy, the dose required for 50% tumor control (TCD₅₀) for low-risk patients was 57.3 Gy (95% confidence interval [CI], 47.6–67.0). The γ50 was 1.4 (95% CI, −0.1 to 2.9) around 57 Gy. A statistically significant dose–response relation was found using the ASTRO definition. However, no dose–response relation was noted using the CN + 2 definition for these low-risk patients. For the intermediate-risk patients, using the ASTRO definition, the TCD₅₀ was 67.5 Gy (95% CI, 65.5–69.5) Gy and the γ50 was 2.2 (95% CI, 1.1–3.2) around TCD₅₀. Using the CN + 2 definition, the TCD₅₀ was 57.8 Gy (95% CI, 49.8–65.9) and the γ50 was 1.4 (95% CI, 0.2–2.5). Recursive partitioning analysis identified two subgroups within the low-risk group, as well as the intermediate-risk group: PSA level <7.5 vs. ≥7.5 ng/mL. Most of the benefit from the higher doses for the low- and intermediate-risk group was derived from the patients with the higher PSA values. For the low-risk group, the dose–response curves essentially plateaued at 78 Gy.

Conclusion

A dose–response relation was found using the ASTRO definition for low-risk prostate cancer. However, we found only marginal or no dose–response relation when the CN + 2 definition was used. Most of the benefit from the higher doses derived from low-risk patients with higher PSA levels. In all cases, little projected gain appears to exist at doses >78 Gy for these patients. A dose–response relation was noted for the intermediate-risk patients using either the CN + 2 or ASTRO definition. Most of the benefit from the higher doses also derived from the intermediate-risk patients with higher PSA levels. Some room for improvement appears to exist with additional dose increases in this group.

Keywords:  Low-risk , Intermediate-risk , Prostate cancer , Radiotherapy , Tumor control probability , Prostate-specific antigen