Adjuvant radiation therapy may result in a significant reduction in all-cause mortality in high-risk prostate cancer compared to salvage

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“We found that in men with undesirable pathology during radical prostatectomy, including pN1 or prostatectomy Gleason score 8-10 and pT3a or higher PC, adjuvant over early salvage radiotherapy was associated with a significant reduction in the risk of MCA, “wrote the study authors. . “This association of reduced risk of ACD with adjuvant compared to early life-saving radiation therapy is reinforced since men who underwent adjuvant life-saving radiation therapy compared to early life-saving radiation therapy had prognostic factor distributions. less favorable prostate cancer, which should have put them at a higher risk of needing lifesaving androgen deprivation and dying. “

Patients with prostate cancer who present with unwanted pathology following radical prostatectomy continue to be at high risk of recurrence.2 This includes patients with pelvic lymph node involvement, Gleason prostatectomy scores of 8 to 10, and extra-prostatic extension or invasion of seminal vesicles or invasion of nearby organs. When this patient population recurs, their PSA is seen to rise rapidly from the PSA trigger level of 0.1 ng / mL or 0.2 ng / mL to 0.4 ng / mL, which means a progression; this can occur during the planning and administration of lifesaving radiation therapy and before the response of the PSA to lifesaving radiation therapy can be assessed.3

As a result, men experience earlier progression during salvage radiation therapy compared to adjuvant radiation therapy. For this reason, the researchers set out to determine whether people with unwanted pathology during radical prostatectomy could benefit from adjuvant therapy over rescue.4

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

The study took place at several institutions, including the Hamburg-Eppendorf University Hospital; CHU de la Charité; Ulm University Hospital; University of California, San Francisco; and the Johns Hopkins Medical Institution. The patients included in the study were stratified according to the presence or absence of undesirable pathology.

Of the patients included in the study, 3.14% (n = 819) received adjuvant radiation therapy usually within 6 months of radical prostatectomy and 17.72% (n = 4601) received salvage radiation therapy. The 2 groups had PSA levels below 0.1 ng / mL and a median of 0.30 ng / mL, respectively. Of those in the salvage radiation therapy group, 14.24% (n = 655) had persistent PSA levels, defined as postoperative PSA of 0.1 ng / mL or greater, and were classified in the radiation therapy group of early rescue. In addition, adjuvant androgen deprivation and rescue therapy were administered to 1.35% and 9.69% of patients, respectively.

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

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

Those with undesirable pathology who underwent adjuvant versus salvage radiotherapy had a significantly higher proportion of pT3a or greater (97.90% and 94.48%, respectively; P = 0.002) and positive margin 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 and>PP = .06) vs early salvage radiotherapy with undesirable pathology excluding pN1.

After a median follow-up of 8.16 years (range 6.00-12.10), investigators reported that 8.06% (n = 2,104) of the study population had died, of which 25.62% (n = 539) had died of prostate cancer. Other study results indicated that there was a significant association identified in which adjuvant therapy decreased the risk of all-cause mortality in men with positive margins (HR, 0.55; 95% CI : 0.34-0.90; P = 0.02) compared to salvage radiation therapy, although significance was lost by excluding men with persistent PSA (RR: 0.67; 95% CI: 0.37-1.001; P = .0504). No significant association was observed in men without adverse pathology following radical prostatectomy (P .28).

Among patients with adverse pathology, including pN1 who received adjuvant radiotherapy, no radiotherapy, and salvage radiotherapy, the investigators reported a 10-year adjusted point estimate for all-cause morbidity of 13.78% (CI 95%, 8.43% to 22.12%), 27.32% (95% CI, 22.54% to 32.88%) and 21.98% (95% CI, 18.30% at 26.27%), respectively. 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. In addition, 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 one meta-analysis found no difference in progression-free survival for adjuvant compared to early use of salvage radiation therapy. However, a benefit may have been missed in men with undesirable pathology during radical prostatectomy due to insufficient potency and the presence of an immortal time bias, ”the authors concluded.

The references

  1. Tilki D, Chen Ming-Hui, Wu J, et al. Adjuvant radiotherapy versus early salvage radiotherapy in men at high risk of recurrence after radical prostatectomy for prostate cancer and 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 randomized, controlled phase 3 trial. Lancet. 2020; 396 (10260): 14131421. doi: 10.1016 / S0140-6736 (20) 31553-1

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