Men with lymph node–positive prostate cancer fare better if they receive up-front adjuvant radiotherapy (RT) after prostatectomy instead of waiting for salvage RT, conclude researchers who conducted a review of 1614 such cases.
After adjusting for the use and duration of androgen deprivation therapy (ADT), the review investigators found decreased all-cause mortality at a median follow-up of 7 years among men with four or more positive pelvic nodes on pathology.
The all-cause mortality was 23.4% among 115 early salvage RT patients compared to 7.7% in 86 men who received adjuvant RT.
For each additional positive node, there was an 8% drop in all-cause mortality risk with adjuvant RT.
The findings were not statistically significant for the 1323 men with one to three positive nodes, but it may be that a larger cohort is needed for the results to reach significance, the authors comment.
The study was led by Derya Tilk, MD, a urology professor at the University Hospital–Hamburg-Eppendorf, Germany, where the patients were treated from 1995 to 2017.
It was published July 10 in the Journal of Clinical Oncology.
The findings suggest that in this particular patient population, salvage RT "may not be early enough" comment radiation oncologists in a related editorial.
"In an era where early salvage radiotherapy (sRT) is being broadly embraced over aRT [adjuvant radiotherapy] despite a continuous lack of randomized data for certain high-risk groups, such as pN1 patients," the findings from this study are "provocative," comment radiation oncologist Curtiland Deville Jr, MD, and resident Yilin Cao, MD, both of Johns Hopkins University, Baltimore, in the editorial.
Plugging an Evidence Gap
Past trials into RT timing after radical prostatectomy support salvage RT at prostate-specific antigen (PSA) progression, but they included very few men who were found to have positive nodes on post-surgery pathology (pN1), and in some cases the studies did not adjust for ADT use, the editorialist comment.
Even so, "in an overwhelming desire to avoid overtreatment, some clinicians ― whether consciously or subconsciously ― may inappropriately extrapolate" the conclusions of those trials to pN1 patients, they continue.
"Assuming that the preference for early salvage RT over adjuvant RT similarly applies to pN1 patients with an undetectable postprostatectomy PSA may lead to misguided clinical decision making and risk undertreatment of this decidedly higher-risk group," Deville and Cao say.
"By broadly abandoning aRT in favor of early sRT," there's "a distinct possibility" that "we are...harming pN1 patients," they say.
The editorialists conclude that "all patients with pN1 prostate cancer ― and particularly those with increasing node positivity ― should be counselled on the potential survival benefits of upfront adjuvant RT demonstrated in this study and the risk that early salvage RT may not be early enough," they add.
As for the investigators, they counsel that "the magnitude of the possible modest reduction in men with one to three positive" lymph nodes "should be personalized by considering life expectancy...and weighed against the potential toxicities of pelvic RT."
Men with four or more positive nodes "would likely benefit, and this should be considered when deciding on whether to recommend adjuvant RT," they say.
The median number of lymph nodes sampled in the study was 12. In both the adjuvant and salvage RT groups, 45 Gy was delivered to pelvic nodes, and a median dose of 68.4 Gy was delivered to the prostatic bed.
Adjuvant RT was administered at a median of 3.42 months after prostatectomy, and salvage RT was delivered at a median of 21.36 months.
Men who received adjuvant RT were more likely to have worse disease, with PSA levels >20 ng/mL; tumors of stage pT3b or higher; positive surgical margins; and adjuvant ADT use. The investigators used propensity scoring and other methods to adjust for differences in patient and disease characteristics and treatment selection.
The editorialist note that among the possible confounders in the study, PSA at the start of salvage RT was a median 0.3 ng/mL, not the typical trigger of 0.1 – 0.2 ng/mL, so it's possible salvage therapy came later than it would in general practice.
Treatment at progression to castrate-resistant or metastatic prostate cancer followed European guidelines and was comparable whether men received adjuvant or salvage RT. The investigators say that even as standards of care evolved over the study period, "it is very unlikely" that differences in subsequent treatment between the groups accounted for the study findings.
No funding was reported. Tilki is an advisor, researcher, and/or reported honoraria from many companies, including Janssen, AstraZeneca, and Advanced Accelerator Applications. A second investigator reported similar ties, and another is an employee of Boehringer Ingelheim. Edororialists Deville and Cao have disclosed no relevant financial relationships.
M. Alexander Otto is a physician assistant with a master's degree in medical science. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape and is an MIT Knight Science Journalism fellow. Email: firstname.lastname@example.org.
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