Should radiotherapy be offered for metastatic prostate Ca?

 "Journal Article of the Month” is a new Urology Times section in which Badar M. Milan, MD (left), offers perspective on noteworthy research in the peer-reviewed literature. Dr. Milan is associate  professor of  surgery in the division of urology at Albany Medical College, Albany, NY.

The management of primary tumors in the setting of metastases has remained an active area of investigation for several malignancies, including genitourinary cancers. A large randomized controlled trial was conducted at 117 hospitals in Switzerland and the United Kingdom (STAMPEDE Trial) to determine the benefit of radiation therapy (RT) to the prostate, in addition to androgen deprivation therapy (ADT), in men with newly diagnosed metastatic prostate cancer (Lancet Oct. 18, 2018 [Epub ahead of print]). According to Parker et al, there was no improvement in the overall survival for the entire group, but survival improvement was noted in a subset of patients by adding RT to the standard of care ADT.

The investigators randomly assigned 2,061 patients to either receive standard of care ADT (1,029 men; control group) or ADT plus RT (1,032 men; radiotherapy group). Standard of care was lifelong ADT alone, but during the trial, upfront docetaxel (Taxotere) use was permitted (given to 18% of men). RT was delivered either as daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) treatment. The primary outcome was overall survival in the entire study population, seeking a 25% relative reduction in death from any cause. Secondary outcomes included failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival (including urinary tract infection).

The researchers also documented the metastatic burden in 94% of men during the study. High metastatic volume, defined as four or more bony or visceral metastases, was noted in roughly 58% while all remaining 42% were classified as having low-volume metastases. Median PSA before ADT was quite high at 97 ng/mL, and the groups were quite comparable in terms of the usual clinical parameters.

There was no improvement in overall survival from the addition of RT to ADT when compared with controls receiving only ADT. After a median follow-up of 37 months, 391 patients had died in the control group (median survival, 46 months) with 370 deaths in the radiotherapy group (median survival, 48 months; stratified log-rank test p=.451; HR: 0·92, 95% CI: 0.80-1.06; p=.266). The median failure-free survival improved in the RT group compared to the control group (17 months vs. 13 months; HR: 0.76, 95% CI: 0.68-0.84; p<.0001).

When analyzed based on metastatic burden, overall survival was improved in patients with low-volume metastases who received RT and ADT when compared with the controls who received ADT (with or without docetaxel) as their initial treatment (HR: 0.68, 95% CI: 0.52-0.90; p=.007). The 3-year median survival was 73% in control group and 81% in the RT group. Similarly, the failure-free survival was improved in patients with low metastatic burden who received RT (HR: 0.59, 95% CI: 0.49-0.72; p<.0001).

One or more “symptomatic local events” were reported by 432 patients (42%) in the control group and 450 patients (44%) in the RT group. There was no difference in the time to first symptomatic local event. The most common events were urinary catheterization (3%) and UTI (5%-7%), with ≤ 2% of the patients in each group requiring ureteral stents or transurethral resection of the prostate. In patients receiving RT, grade 1-4 bladder toxicity was noted in 68% while grade 1-4 bowel toxicity was noted in 55%. There was somewhat lower toxicity noted with the weekly RT treatment schedule when compared to the daily treatment.

Intriguing results, but caution needed

The authors suggest that radiotherapy in the subgroup of men with low metastatic burden should now be considered standard, but it’s important to remember that the study was not designed to evaluate the radiotherapy treatment benefit in these men. While the analysis yielded intriguing results, the conclusion based on subgroup analysis should be viewed with caution. The total number of deaths in the low-volume metastases cohort was relatively low in both the RT group (90/410, 22%) and the control group (116/409, 28%), with absolute difference of 6%. This would suggest that more events (ie, deaths) and longer follow-up may be needed to assess the benefit of RT in this subgroup of men.

The radiation dose used in this trial is lower than what is used in clinical practice. Could higher dose of RT result in improved survival and better local control? Other local therapy options such as prostatectomy were not included in this trial. There is clinical evidence to suggest that surgery should be as effective as RT in this setting. Another challenge is the numerous definitions used in the literature to define low-volume, or oligometastatic, disease and the most appropriate imaging studies to detect metastases.

Many of these questions regarding the type, duration, and benefits of local therapy in men with metastatic prostate cancer will likely be answered through several ongoing clinical trials such as SWOG 1802 (ClinicalTrials.gov Identifier: NCT03678025). In the meantime, hopefully these data are not viewed as license to indiscriminately offer local therapy, either RT or surgery, to men with metastatic prostate cancer.