Don't throw the baby out with the bath water.

Abstract

Dear Editor, We read with interest the recently published article “Survival rates with external beam radiation therapy in newly diagnosed elderly metastatic prostate cancer patients.” The authors conducted a SEER database review and concluded that external beam radiotherapy (EBRT) does not affect survival in an elderly population of patients with metastatic prostate cancer. We agree that it is likely that not all elderly patients with metastatic disease benefit from local radiotherapy to the prostate. However, we are concerned that a significant subcohort that derives substantial benefit from local radiotherapy is lost in this large database study that is severely limited by a lack of granularity and randomization. Our strongest criticism is that the authors do not specify the site, intent nor dose and fractionation schedule of the EBRT delivered to the patients in this study, which renders the results uninterpretable. The survival benefit demonstrated in the STAMPEDE trial was from high‐dose radiotherapy to the prostate. It is quite plausible that many (or even the majority) of the patients in the study by Wenzel et al. received palliative radiotherapy for painful bone metastases, which would not be expected to benefit survival and could conceivably correlate with more advanced or aggressive disease. Furthermore, the patients in this study were not stratified by the burden of metastatic disease. In the STAMPEDE trial, it was only patients with a low burden of metastatic disease (defined as visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis) for whom a survival benefit to high‐dose radiotherapy to the prostate was demonstrated. In the unselected population of the STAMPEDE trial, there was no survival benefit to prostate radiotherapy. Similarly, subgroup analysis of the HORRAD trial also found a trend to benefit in those with lower metastatic burden, statistical significance perhaps obscured by a higher cut‐off of <5 metastases. Redemonstration of the same result in the population unselected by the burden of disease by Wenzel et al. should not be taken as a refutation of the survival benefit seen in the low metastatic burden subgroup of the STAMPEDE trial. Even for patients with a low burden of metastatic disease treated with high‐dose radiotherapy to the prostate, survival is not the only end‐point of interest. Durable local control may prevent subsequent local complications. The NCIC CTC PR.3/MRC UK PR07 trial randomized patients with high risk or locally advanced prostate cancer to androgen deprivation therapy with or without local radiotherapy. One hundred eleven of 602 patients in the androgen deprivation therapy (ADT) alone group (compared to only 14 of 603 patients in the ADT plus radiotherapy group) progressed locally, with just over half of those with local progression receiving radiotherapy for presumably symptomatic disease. Radiotherapy when delivered at the time of castrate resistance is less likely to provide control than in the hormone‐sensitive upfront setting. This scenario is likely to become increasingly prevalent in the era of novel imaging. Hofman and colleagues demonstrated in the pro‐prostate‐specific membrane antigen (PSMA) study that PSMA PET‐CT provides superior accuracy, including markedly improved sensitivity compared to conventional imaging (85% vs. 38%) for the detection of nodal and distant metastatic disease. Use of PSMA PET‐CT for primary staging results in substantial up‐staging including 14.7% to N1% and 6.4% to M1 disease in one study. The current study by Wenzel et al. appropriately behoves radiation oncologists to select elderly patients judiciously for local radiotherapy as per the evidence from the STAMPEDE trial as well as other factors including performance status, comorbidities, depth of response to systemic treatment; and of course, patient expectations. However, a return to the days of fixed (and un‐fixable) pelvic recurrences in castrate‐resistant men who were denied treatment to the primary (while hormone‐sensitive) is unacceptable. So please, let us not throw the baby out with the bath water.