For patients with prostate cancer who have persistent or rising prostate-specific antigen (PSA) levels after radical prostatectomy, the addition of short-term androgen-deprivation therapy and radiotherapy to the pelvic lymph nodes demonstrated increased rates of freedom from disease progression, according to data presented at the 2018 Annual Meeting of the American Society for Radiation Oncology (ASTRO).¹

The addition of pelvic lymph node radiotherapy resulted in early, meaningful reductions in failure, and this is the first trial to document that effect in the salvage setting.

— Alan Pollack, MD, PhD

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Interim analysis of the phase III randomized SPPORT trial demonstrated significant improvements in freedom-from-progression rates at 5 years with the addition of 4 to 6 months of androgen-deprivation therapy to prostate bed salvage radiotherapy (82.7%) vs prostate bed radiotherapy alone (71.7%). Moreover, when radiotherapy of the pelvic lymph nodes was added to hormone therapy and prostate bed salvage radiotherapy, 89.1% of patients remained free of prostate cancer progression at 5 years. There wasalso a trend toward reduction in distant metastases in those treated with the combination.

“The addition of pelvic lymph node radiotherapy resulted in early, meaningful reductions in failure, and this is the first trial to document that effect in the salvage setting,” said Alan Pollack, MD, PhD, Professor and Chair of the Department of Radiation Oncology at the University of Miami Sylvester Comprehensive Cancer Center. “This is the strongest level 1 evidence supporting pelvic lymph node radiotherapy that we have available, whether it’s for primary treatment or salvage.”

Study Background

As Dr. Pollack reported, biochemical failure rates after salvage prostate bed radiotherapy at 5 to 10 years are typically between 30% and 40%. Although neoadjuvant and concurrent short-term androgen-deprivation therapy had been used frequently in the setting of primary radiotherapy when the trial was designed in 2005, it had not yet been tested with salvage radiotherapy. Pelvic lymph node radiotherapy has shown promise as well, said Dr. Pollack, but has never been conclusively proven to be effective in a phase III randomized trial.

For this study, Dr. Pollack and colleagues randomly assigned patients to three arms: arm 1, salvage prostate bed radiotherapy alone (64.8–70.2 Gy); arm 2, salvage prostate bed radiotherapy plus 4 to 6 months of androgen-deprivation therapy; and arm 3, salvage prostate bed radiotherapy, short-term androgen-deprivation therapy, plus radiotherapy to the pelvic lymph nodes (45 Gy). The researchers stratified patients by seminal vesicle involvement, prostatectomy Gleason score, pre-radiotherapy PSA, and pathology stage.

The study’s primary endpoint was freedom from disease progression, defined as an increase in PSA of 2.0 ng/mL above the nadir, clinical disease progression, or death due to any cause. Patients who received “secondary salvage” therapy initiated before reaching any of the above events were censored.

Combined Regimen Yielded Nearly 90% Progression-Free Rate

At the ASTRO Annual Meeting, Dr. Pollack reported results from the third planned interim analysis, which included the first 1,191 eligible patients with at least 5 years of follow-up (median of 6.4 years). The 5-year freedom-from-progression rates were 71% for prostate bed radiotherapy alone (arm 1), 83% with the addition of short-term androgen-deprivation therapy (arm 2), and 89% with the addition of short-term androgen-deprivation therapy plus pelvic lymph node treatment (arm 3). When freedom-from-progression rates were compared between arms, the differences between arm 3 and arm 1 (P < .0001), arm 2 and arm 1 (P = .001), and arm 3 and arm 2 (P = .0063) all achieved statistical significance. Similar results were seen for the entire cohort of 1,736 eligible men.

The data also showed an improvement in freedom from metastasis with the combined treatment. Among patients followed for up to 8 years, the rate of distant metastases was lowest for those in the three-treatment regimen, reaching significance when compared with prostate bed salvage radiotherapy alone (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.32–0.85; P = .014) but not when compared withprostate bed salvage radiotherapy plus androgen-deprivation therapy (HR = 0.64, 95% CI = 0.39–1.06; P = .28).

Finally, acute side effects were relatively low but were significantly higher with the addition of pelvic lymph node treatment for grade 2+ GI (6.9% in arm 3 vs 3.9% in arm 2 vs 2.0% in arm 1), grade 2+ blood/bone marrow (5.1% in arm 3 vs 1.8% in arm 2 vs 2.3% in arm 1) and grade 3+ blood/bone marrow (2.6% in arm 3 vs 0.2% in arm 2 vs 0.5% in arm 1). In terms of late effects, only a significant difference in grade2+ blood/bone marrow (4.1% in arm 3 vs 1.6% in arm 2 vs 3.1% in arm 1) was seen.

Favorable Population

In terms of patient characteristics, said Dr. -Pollack, this was a relatively favorable salvage radiotherapy population, with 85% of patients having no seminal vesicle involvement, 54% having organ-confined disease (pT2), and 50% having positive prostatectomy margins. In addition, approximately 68% of these patients had Gleason 7 disease, whereas very few had Gleason 8 or 9 disease. Finally, the median PSA level was low (0.34 ng/mL), and 25% of patients had PSA levels of 0.2 ng/mL or less.

Although investigators looked at the median PSA cutpoint in terms of freedom from disease progression and found that pelvic radiotherapy had less of an effect in men with PSA levels below that, Dr. Pollack reported that more data are required, and other factors might be considered, such as the role of positron-emission tomography imaging.

“Pelvic lymph node treatment plus short-term androgen-deprivation therapy resulted in a robust signal that, as compared to the standard of prostate bed salvage radiotherapy alone, with the number needed to treat to prevent 1 progression within 5 years being only 6 (95% CI = 4.6–8.6). The use of pelvic lymph node radiotherapy should be strongly considered in men with a rising PSA level. Follow-up of patients is continuing to further elucidate the magnitude of the differences between arms 2 and 3,” Dr. Pollack concluded. ■

DISCLOSURE: Dr. Pollack disclosed relationships with RTOG/NRG Oncology and Varian Medical Systems.

REFERENCE

1. Pollack A, et al: Short term androgen deprivation therapy without or with pelvic lymph node treatment added to prostate bed only salvage radiotherapy. 2018 ASTRO Annual Meeting. Abstract LBA5. Presented October 22, 2018.