Postprostatectomy radiation dose and timing affect quality of life

Badar M. Mian, MD

Three different randomized trials comparing adjuvant radiotherapy (RT) with salvage RT (sRT), all including men at high risk of recurrence post radical prostatectomy (post-RP), have demonstrated that adjuvant RT does not improve oncological outcomes.¹ Consequently, early sRT (delivered after some increase in prostate-specific antigen [PSA] level) has emerged as the de facto standard approach to post-RP men with adverse pathology. The oncologic benefits of RT dose escalation for treating primary prostate cancer have been well established over the last 20 years. However, the optimal dose and timing of post-RP RT to treat any residual microscopic prostate cancer have remained controversial. To address these questions, 2 recent studies examined the outcomes of early vs delayed RT, and of RT dose escalation, on health-related quality of life (HRQOL) and functional outcomes.

Is higher-dose salvage RT superior to the standard dose?

Ghadjar et al² conducted a prospective, open-label, multicenter, randomized phase 3 trial with the aim to demonstrate the superiority of dose-escalated sRT over the standard-dose sRT (without hormonal therapy) in terms of biochemical (PSA) progression. Men in the standard-dose sRT (control) group received 64 Gy and those in the dose-escalated group received 70 Gy, with 175 patients in each group. The median PSA at randomization was 0.3 ng/mL (75% with PSA ≤ 0.5 ng/mL). Median follow-up was 6.2 years.

The median PSA progression-free survival was similar in the standard and dose-escalated arms, at 8.2 years and 7.6 years, respectively (log-rank P = .4). Other outcome measures such as clinical progression, time to hormonal treatment, and overall survival also did not differ between the 2 arms. The estimated biochemical progression–free rate at 6 years was 62% in the control arm and 61% in the dose-escalated arm.

Late grade 2 and 3 genitourinary (GU) toxicity was observed in 21% and 7.9% of patients in the control arm and 26% and 4% patients in the dose-escalation arm, respectively, which were statistically similar between the groups. However, late-grade 2 gastrointestinal (GI) toxicity was observed at a higher rate in the dose-escalation group: 7.3% in the control arm vs 20% in the higher-dose arm (odds ratio, 2.20; P = .009). Grade 3 erectile dysfunction did not differ significantly between the 2 arms (27% vs 30%; p: NS). For late GU toxicity, the grade 2 incidence was higher in those men who underwent 3D-conformal RT (35%) than in those who underwent intensity-modulated RT/rotational techniques (26%).

Does early salvage RT affect quality of life?

To assess the effect of timing of post-RP RT, Westhofen et al³ conducted a propensity score-matched retrospective analysis of a large contemporary patient cohort. Men were divided in 2 study group including those men receiving early RT (eRT; within 6 month after RP) vs those receiving deferred RT (dRT). The investigators evaluated the HRQOL using the validated European Organization for Research and Treatment of Cancer (EORTC) QOL C30 (EORTC QLQ-C30) questionnaire, as well as on functional outcomes following RT.

The primary end point was HRQOL, with good general HRQOL defined as global health status (GHS) of higher than 70 (out of 100). Patient-reported outcomes were obtained through mailed-in questionnaires to 1599 eligible patients at 6 weeks (postop), 12 months, 24 months, 36 months, and 48 months after surgery. The inclusion criteria for post-RP RT included stage pT3 or higher, high-risk International Society of Urological Pathology Grading System grade 4 or 5, or positive surgical margins.

Of the 1599 patients, 307 patients received eRT whereas 1292 patients were observed and treated with dRT. After propensity score matching, the two groups were similar in age, body mass index, preoperative PSA, tumor stage, Gleason score, lymph node involvement, nerve sparing status, and surgical approach.

In the eRT subgroup, all 307 patients received RT within 6 months, whereas in the dRT subgroup, 27.0% had received dRT by 12 months after RP, 44.4% at 24 months, 46.2% at 36 months, and 51.4% at 48 months. Median PSA prior to RT was 0.13 ng/mL in the eRT group and 0.18 ng/mL in the dRT group.

International Index of Erectile Function–5 scores were significantly better in the dRT group at 12 and 24 months, but were similar at 36 and 48 months among the eRT and dRT groups. Similarly, the mean International Consultation on Incontinence Questionnaire–short form scores were significantly better for the dRT group at 12 and 24 months. Continence recovery rates were higher in the dRT group than in the RT group at 12, 24, and 36 months.

HRQOL scores were generally higher in the dRT group at 12 and 24 months, with significantly higher mean GHS scores compared to the eRT group. Good general HRQOL was reported by 35.5% (eRT) vs 52.7% (dRT) after 12 months, and 37.3 % (eRT) vs 45.8% (dRT) after 24 months (P > .02). Multivariate regression analysis identified dRT as an independent predictor of good general HRQOL. Further, the longer time interval from RP to RT was an independent predictor of increased postoperative general HRQOL in univariate analysis (OR, 1.09; 95% CI, 1.04-1.14; P < .001).

It is apparent from the results of these 2 studies that neither the higher-dose RT nor early RT after RP provide sufficient oncological benefits to justify the adverse impact on functional outcomes and HRQOL. Dose-intensified sRT was not superior to conventional-dose sRT, but it was associated with higher rates of late grade 2 GI toxicity. A limitation noted in the higher-dose sRT study is the relatively small proportion of patients with Gleason score ≥ 8 and/or pT3b disease.

To improve the outcomes for patients with biochemical progression after RP, selection criteria should be adjusted to identify patients (e.g. those with multiple high-risk features) who are more likely to benefit from more intensified RT dose or schedule. The anticipated wider availability of prostate-specific membrane antigen (PSMA) PET scans will improve risk stratification and patient selection for postoperative RT by rendering visible the disease foci that are currently invisible on conventional imaging. However, the impact of the inevitable stage-shift related to PSMA scans and any potential oncologic and functional benefits will remain unclear for years to come.

At present, however, an initial period of observation and deferred RT, appears to be a safe and effective approach for most post-RP patients with high-risk pathology in order to avoid the adverse effects on HRQOL, without compromising cancer control.

References

1. Vale CL, Fisher D, Kneebone A, et al; ARTISTIC Meta-analysis Group. Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data. Lancet. 2020;396(10620):1422-1431. doi: 10.1016/S0140-6736(20)31952-8

2. Ghadjar P, Hayoz S, Bernhard J, et al; Swiss Group for Clinical Cancer Research (SAKK). Dose-intensified versus conventional-dose salvage radiotherapy for biochemically recurrent prostate cancer after prostatectomy: the SAKK 09/10 randomized phase 3 trial. Eur Urol. Published online June 14, 2021. doi: 10.1016/j.eururo.2021.05.033

3. Westhofen T, Buchner A, Schlenker B, et al. Timing of radiotherapy after radical prostatectomy: effects on health-related quality of life. J Urol. Published online June 29, 2021. doi:10.1097/JU.0000000000001930