Study Links Early Salvage Radiotherapy at Low PSA After Prostatectomy with Improved Survival

PSA levels found to be a ‘significant predictor’

In the largest study of its kind, researchers have found that prostate cancer patients who undergo early salvage radiotherapy (SRT) after radical prostatectomy, when prostate-specific antigen (PSA) levels are low, have significantly lower mortality than patients who have delayed SRT at higher PSA levels.

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The retrospective analysis of 2,454 node-negative patients with detectable post-prostatectomy PSA levels determined that SRT initiated at PSA levels ≤ 0.2 ng/mL was associated with reduced rates of both prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM), compared with SRT at higher PSA amounts.

“Mortality outcomes from salvage radiotherapy after prostatectomy have been largely unexplored, so this study provides us with important information,” says senior author Rahul D. Tendulkar, MD, Clinical Director of the Department of Radiation Oncology at Cleveland Clinic Cancer Center.

Most studies in similar populations have examined biochemical outcomes following post-prostatectomy SRT, but PCSM and ACM outcomes are less well-studied. In a study published earlier this year in the Journal of Clinical Oncology, a research team led by Dr. Tendulkar found that patients in the same dataset as used in the current research who were treated with early SRT were more likely to remain free from biochemical failure and less likely to develop distant metastases.

The present analysis included patients followed for a median of 5.1 years after SRT with or without neoadjuvant or concurrent androgen-deprivation therapy (ADT). Findings were presented at the 2016 annual meeting of the American Society for Radiation Oncology (ASTRO) in Boston.

Clinical implications: PSA is strong predictor of mortality

“The PSA at time of salvage radiotherapy seems to be an independent predictor of mortality outcomes,” Dr. Tendulkar says. “Historically, in previous studies, most predictors of mortality have been tumor-related. But in our study, PSA was a significant predictor of mortality, while some tumor-related factors such as extraprostatic extension and surgical margins were not significant in mortality outcomes upon multivariate analysis.”

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These findings are supportive of current American Society for Radiation Oncology and American Urological Association consensus guidelines, which recommend that SRT should be offered at the first sign of a PSA rise after prostatectomy. “Those patients who have a detectable PSA after radical prostatectomy appear to have a decreased risk of prostate cancer mortality when SRT is initiated at the lower detectable PSA,” Dr. Tendulkar says.

Prostate cancer-specific mortality and all-cause mortality

According to the analysis, overall PCSM rates at 5 and 10 years were 3 percent and 6 percent, respectively. The 10-year PCSM rate was 5 percent for patients with pre-SRT PSA ≤ 0.20 ng/mL; 6 percent for patients with PSA 0.21-0.5 ng/mL; 8 percent for those with PSA 0.51-1.0 ng/mL; 18 percent for patients with PSA 1.01-2.0 ng/mL; and 22 percent for those with PSA > 2.0 ng/mL.

Other factors besides higher PSA levels that contributed to increased PCSM were higher Gleason score, seminal vesicle invasion and year of SRT (since more recent treatment dates may preclude sufficient follow-up duration to observe prostate cancer-related deaths).  Factors that were not associated with higher PCSM rates were extraprostatic extension, surgical margins, ADT use, SRT dose and age at treatment.

For all-cause mortality, the 10-year mortality rates were 14 percent for patients with pre-SRT PSA ≤ 0.2 ng/mL; 16 percent for patients with PSA 0.21-0.5 ng/mL; 23 percent for those with PSA 0.51-1.0 ng/mL; 30 percent for PSA 1.01-2.0 ng/mL; and 38 percent for those with PSA > 2.0 ng/mL.

Limitations and future research

Dr. Tendulkar credits a “robust database” as one of the study’s greatest strengths. “The study includes the world’s largest series of patients treated with salvage radiotherapy, all of whom were treated by prostate cancer specialists at 10 well-established academic institutions,” he says. The study’s primary limitation is that it does not rely on prospective data but is retrospective in nature, he says.

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Optimal postoperative management of men with prostate cancer remains an area of ongoing research. The present study does not support basing treatment decisions solely on detectable PSA; instead, a combination of factors should be considered, Dr. Tendulkar says.

“There is no magic PSA cut point before which radiation therapy should be initiated,” he says. “It still requires clinical judgment to determine the best course of treatment for each patient. We have to take into account how well the patient has healed after prostatectomy, the rate of rise of PSA, comorbidities, and life expectancy. Personalized care is very important to select the right patient for the right treatment.”

Dr. Tendulkar and colleagues are planning further analyses of the cohort, potentially to investigate the optimal integration of ADT with SRT and an analysis of outcomes for patients who received lymph node radiation.

Dr. Tendulkar also notes that two prospective trials with adjuvant RT (given for an undetectable PSA) versus early SRT are underway: RADICALS (Radiotherapy and Androgen Deprivation in Combination After Local Surgery) and RAVES (Radiotherapy – Adjuvant Versus Early Salvage) trials. The hope is that results from these trials will offer additional guidance on how soon postoperative treatment should begin, he says.