Survival benefit of dose escalation for higher risk patients

As discussed in a previous article, there is a seeming discrepancy between the findings of Kalbasi et al. and RTOG 0126, at least for intermediate-risk patients. Kalbasi et al. found that higher dose radiation is associated with higher overall survival rates for intermediate and high-risk patients (but not low-risk patients), while RTOG 0126 found no such association. Kalbasi et al. was a retrospective database analysis, while RTOG 0126 was a randomized clinical trial. Which is right?

I’ve had a chance to review the full text of the Kalbasi et al. study, but the RTOG 0126 trial has not yet been published. This article provides some additional observations based on what is currently available.

One shortcoming common to both is that they were attempting to find differences in overall survival after just 10 years. Because prostate cancer is often detected very early, has a long natural history, and there are many medicines now that extend survival, 10 years may not be enough to observe a difference. They also both used overall survival rather than cause-specific survival as endpoints, so we don’t know how many of the deaths were incidental to rather than because of prostate cancer. The database analysis did not include data on prostate cancer–related deaths, while in RTOG 0126, the prostate cancer-specific mortality was only 3%. RTOG 0126 did find differences in biochemical failure, distant metastases, and local progression related to higher doses of radiation. It is likely that differences in survival may emerge with longer follow up.

RTOG 0126 excluded the least favorable intermediate risk patients from their study. Those with Gleason score of 7 and stage T2c, and those with a PSA of 15-20 were excluded, and may be the group most likely to benefit from dose escalation.

Kalbasi et al. point out that RTOG 0126 may have been underpowered to detect the dose response. They also conjecture that the highly selected clinical trial patient sample of RTOG 0126 may not reflect the wider patient population – over 300,000 patients - in their data analysis. On the other hand, the retrospective nature of their study allows for confounding. Those patients who received lower doses of radiation may be the ones who had serious co-morbidities that precluded a higher dose. We can never establish a cause/effect relationship based on a retrospective study.

As often happens with long-term radiation studies, the findings become irrelevant by the time we get them. The finding that low-risk patients don’t need the higher dose is becoming increasingly irrelevant as those patients are more safely managed with active surveillance. The finding that intermediate risk (at least unfavorable intermediate risk) and high-risk patients do better with higher doses is irrelevant because IMRT doses of at least 80 Gy have become the standard of care already.

Kalbasi et al. suggest that even higher doses of radiation may improve survival. The problem with their suggestion is a limitation of IMRT – doses beyond 80 Gy become increasingly toxic. The solution is not to push the envelope on IMRT, but to use other methods. In a recent article, we saw that the combination of low dose rate brachytherapy and external beam radiation was able to push the effective radiation dose higher than IMRT alone, and resulted in increased oncological control. Toxicity, however, was higher than with monotherapy. As discussed there, adding a high dose rate brachytherapy boost has proven to be an equally effective technique for escalating dose. While SBRT has been used to increase the effective dose in intermediate-risk patients, and does so with extremely low toxicity, it has not yet been widely used in high-risk patients. In a recent article, we discussed the clinical trials that may prove to be a game changer in the management of such patients.