Adjuvant Radiation Therapy May Yield a Significant Reduction in All-Cause Mortality in High-Risk Prostate Cancer Vs Salvage

Recent findings indicate that men with positive pelvic lymph nodes or a prostatectomy Gleason score of 8 to 10 with disease extending beyond the prostate should be considered for treatment with adjuvant radiation therapy, according to a study published in the Journal of Clinical Oncology.¹

After investigators excluded patients with adverse pathology who had persistent prostate-specific antigen (PSA) expression, the reduced risk of all-cause mortality (ACM) associated with adjuvant radiotherapy remained significant vs early salvage radiation therapy. The association was maintained regardless of whether patients had pelvic nodal involvement (HR, 0.33; 95% CI, 0.13-0.85; P = .02) or not (HR, 0.66; 95% CI, 0.44-0.99; P = .04).

“We found that among men with adverse pathology at radical prostatectomy including pN1 or prostatectomy Gleason score 8-10 and pT3a or higher PC, adjuvant compared with early salvage radiotherapy was associated with a significant reduction in ACM risk,” the authors of the study wrote. “This association of reduced ACM risk with adjuvant compared with early salvage radiotherapy is strengthened given that men who underwent adjuvant compared with early salvage radiotherapy had less favorable prostate cancer prognostic factor distributions, which should have placed them at higher risk for needing salvage androgen deprivation and dying.”

Patients with prostate cancer who have adverse pathology at radical prostatectomy continue to be at a high risk for recurrence.² This includes patients with pelvic node–positive disease, prostatectomy Gleason scores of 8 through 10, and extra-prostatic extension or seminal vesicle invasion or invasion into neighboring organs. When this patient population experiences recurrence, their PSA is found to rapidly increase, rising from the trigger PSA level of 0.1 ng/mL or 0.2 ng/mL to 0.4 ng/mL, signifying progression; this can happen while salvage radiotherapy is being planned and delivered, and before PSA response to salvage radiation therapy can be evaluated.³

This results in men experiencing progression earlier while on salvage radiotherapy vs adjuvant radiotherapy. Due to this, investigators set out to determine whether those with adverse pathology at radical prostatectomy could derive benefit from adjuvant treatment vs salvage.⁴

The study had a cohort of 26,118 men who had a median age of 62 years (range, 57-67) with pT2-4N0 or N1M0 prostate cancer that had been consecutively treated between June 23, 1989 and July 26, 2016. This treatment needed to include radical prostatectomy and pelvic lymph node assessment, after which patients were followed for possible treatment with adjuvant or early salvage radiotherapy.

The study took place at several institutions, including University Hospital Hamburg-Eppendorf; Charité University Hospital; University Hospital Ulm; University of California, San Francisco; and Johns Hopkins Medical Institution. Patients included in the study were stratified based on the presence or absence of adverse pathology.

Of the patients who were included in the study, 3.14% (n = 819) received adjuvant radiotherapy generally within 6 months of radical prostatectomy and 17.72% (n = 4601) received salvage radiotherapy. The 2 groups had PSA levels of less than 0.1 ng/mL and a median of 0.30 ng/mL, respectively. Among those in the salvage radiotherapy group, 14.24% (n = 655) had persistent PSA levels, defined as a postoperative PSA of 0.1 ng/mL or greater, and were categorized into the early salvage radiotherapy group. Additionally, adjuvant and salvage androgen deprivation therapy were administered in 1.35% and 9.69% of patients, respectively.

After receiving radical prostatectomy to the prostatic bed at a median dose of 68.4 Gy and pelvic lymph nodes (45.0 Gy), adjuvant radiotherapy was delivered a median of 3.55 months. Moreover, adjuvant androgen deprivation therapy was administered for a median of 9.17 months. In total, 5.71% (n = 1491) of the study population had pelvic lymph node–positive disease, of which 21.4% were treated with adjuvant radiotherapy and 16.16% received adjuvant androgen deprivation therapy. Notably, salvage androgen deprivation therapy was administered following PSA failure and clinical or radiographic evidence of progression following adjuvant or salvage radiotherapy.

“Men who received neither adjuvant radiotherapy nor early salvage radiotherapy never experienced PSA failure during the conduct of the study or were treated with salvage androgen deprivation therapy alone at progression,” wrote the authors of the study.

Those with adverse pathology who underwent adjuvant radiotherapy over salvage radiotherapy had a notably higher proportion of pT3a or higher (97.90% and 94.48%, respectively; P = .002) and margin-positive disease (82.71% and 45.68%, respectively; P< .001). Additionally, those who received adjuvant therapy had a significantly higher proportion of patients with margin-positive disease (88.07% and 45.17%; P< .001) and less use of salvage androgen deprivation therapy (35.78% and 45.84%; P = .06) vs early salvage radiotherapy with adverse pathology excluding pN1.

After a median follow-up of 8.16 years (range, 6.00-12.10), investigators reported that 8.06% (n = 2104) of the study population had died, 25.62% (n = 539) of whom passed from prostate cancer. Other findings from the study indicated that there was a significant association identified wherein adjuvant treatment decreased risk of all-cause mortality in men with positive margins (HR, 0.55; 95% CI, 0.34-0.90; P = .02) over salvage radiotherapy, although the significance was lost when excluding men with persistent PSA (HR, 0.67; 95% CI, 0.37-1.001; P = .0504). No significant association was observed in men without adverse pathology at radical prostatectomy (P ≥ .28).

Among those with adverse pathology including pN1 who received adjuvant radiotherapy, no radiotherapy, and salvage radiotherapy, investigators reported a 10-year adjusted point estimate for all cause morbidity of 13.78% (95% CI, 8.43%-22.12%), 27.32% (95% CI, 22.54%-32.88%), and 21.98% (95% CI, 18.30%-26.27%), respectively. When excluding pN1, the estimates were 5.13% (95% CI, 2.00%-12.82%), 25.32% (95% CI, 18.95%-33.34%), and 22.15% (95% CI, 17.55%-27.74%), respectively. Moreover, when excluding patients with adverse pathology, the estimates were 7.82% (95% CI, 4.55%-13.28%), 8.81 (95% CI, 7.35%-10.54%), and 7.95% (95% CI, 6.82%-9.24%).

“In conclusion, three randomized trials and a meta-analysis found no difference in progression-free survival for adjuvant compared with early salvage radiotherapy use. However, a benefit might have been missed in men with adverse pathology at radical prostatectomy because of inadequate power and the presence of immortal time bias,” the authors concluded.

References

1. Tilki D, Chen Ming-Hui, Wu J, et al. Adjuvant versus early salvage radiation therapy for men at high risk for recurrence following radical prostatectomy for prostate cancer and the risk of death. J Clin Oncol. Published online June 4, 2021. doi:10.1200/JCO.20.03714
2. Markowski MC, Chen Y, Feng Z, et al. PSA doubling time and absolute PSA predict metastasis-free survival in men with biochemically recurrent prostate cancer after radical prostatectomy. Clinical Genitourinary Cancer. 2019;17(6):P470-475. doi:10.1016/j.clgc.2019.08.002
3. Suissa S. Immortal time bias in pharmacoepidemiology. American Journal of Epidemiology. 2007;167(4):492-499. doi:10.1093/aje/kwm324
4. Parker CC, Clarke NW, Cook AD, et al. Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial. Lancet. 2020;396(10260):14131421. doi:10.1016/S0140-6736(20)31553-1