Efficacy of adjuvant radiation therapy
The evidence supporting this protocol is provided by four randomised control trials comparing post-operative radiation therapy to a wait and see approach after radical prostatectomy, and one meta-analysis with long-term data from three of the randomised control trials.rrrrr
Between 1988 and 1997, the SWOG 8794 trial randomised 425 men with adverse pathological factors post radical prostatectomy to adjuvant radiation therapy using 60-64 Gy (n = 214) or wait and see (n = 211).r The primary endpoint was metastasis-free survival. At a median follow up of 12.6 years, adjuvant radiation therapy significantly improved both metastasis-free survival (HR = 0.71, 95% CI:0.54-0.94, p = 0.016) and overall survival (HR = 0.72, 95% CI:0.55-0.96, p = 0.023). To prevent one case of metastatic disease at 12.6 years, the number needed to treat is 12.2. Additionally, adjuvant radiation therapy was associated with improved freedom from biochemical and local tumour recurrence, and reduced use of salvage hormonal therapy.
Figure 1 - Biochemical progression-free survival
© J Urol 2009r
In the EORTC trial 22911 between 1992 and 2001, Bolla et al randomly assigned men to post-operative radiation therapy (n = 502) or observation/wait and see approach (n = 503).r After a median follow up of 10.6 years, post-operative radiation significantly improved biochemical progression-free survival where 39.4% in the radiation therapy group showed biochemical or clinical progression, or died; compared with 61.8% in the wait and see group (HR = 0.49, 95% CI:0.41-0.59). Locoregional control was significantly better in the radiation therapy group than the wait and see group (HR = 0.45, 95% CI:0.32-0.68) and the 10-year cumulative rate of locoregional relapse was 16.6% vs 7.3% in the radiation therapy versus wait and see groups, respectively.
Figure 2 - Biochemical progression-free survival
© Lancet 2012r
The ARO 96-02 multi-centre, phase III trial between 1997 and 2004 randomised patients to adjuvant RT of 60 Gy/30 fractions (n = 148) compared with a wait and see approach (n = 159).r At 10-year follow up, superior progression-free survival outcomes (events including biochemical or clinical recurrence, or death) were demonstrated for adjuvant radiation therapy, 56%, versus a wait and see approach, 35%, (HR = 0.51, 95% CI:0.37–0.70, p <0.0001). In EORTC 22911 and ARO 96-02, overall survival and metastases-free survival were not significantly improved by adjuvant radiation therapy, however these trials were not powered for these end points.
Shaikh et al. performed a meta-analysis of the three phase III trials outlined above, with their subsequent long-term outcomes reported.r A total of 1737 patients with pT3 disease or positive surgical margins were included. Of these, 864 men received adjuvant radiation therapy, and 873 had a wait and see approach. Median follow-up ranged from 9.3-12.7 years. Pooled analysis showed a 10-year metastasis-free survival benefit (OR = 0.77, 95% CI:0.62-0.96, p = 0.02). Biochemical progression-free survival was improved with radiation therapy (HR = 0.48, 95% CI:0.42-0.55), with the greatest benefit in subgroups with positive surgical margins and seminal vesicle invasion. It also demonstrated that with adjuvant radiation therapy, there was a hormone-free survival benefit (HR = 0.64, 95% CI:0.51-0.80, p <0.00001), local recurrence-free survival benefit (HR = 0.41, 95% CI:0.30-0.56, p <0.00001), and clinical progression-free survival (HR = 0.73, 95% CI:0.62-0.87, p = 0.0003), compared to wait and see. Prostate cancer-specific survival and overall survival showed no significant difference between radiation therapy and wait and see.
Note, the above trials included in the meta-analysis used outdated radiation therapy techniques and were implemented prior to highly sensitive assays to detect PSA recurrence; none compared adjuvant to early salvage radiation therapy.
Subsequent to the above, Hackman et al. published more contemporary results.r A multicentre, phase III trial between April 2004 and October 2012 was carried out randomising 250 post-prostatectomy men with pT2 and positive margins, or pT3a histopathology to receive either adjuvant radiation therapy (n = 126) to a dose of 66.6 Gy, or observation (n = 124). The primary outcome was biochemical recurrence-free survival. At a median follow up of 9.3 years, the 10-year biochemical recurrence-free survival was improved in the adjuvant radiation group (HR = 0.26, 95% CI:0.14-0.48, p <0.001). There was no significant difference in overall survival, but the trial was not powered for this endpoint. Salvage radiation therapy was used in 86% of patients at a median PSA of 0.7 ng/ml, and 75% of these patients had no evidence of disease at time of last follow-up. In comparison, 30% of patients in the SWOG and EORTC trials had salvage radiation at a median PSA of 1.0 and 1.7 ng/ml, respectively.
Figure 3 - Biochemical recurrence-free survival and overall survival
© Eur Urol 2019r
The previously outlined adjuvant radiation therapy trials do not directly address the role of immediate adjuvant radiation therapy versus early salvage radiation therapy, which is a reasonable alternative in patients with pT3, N0 disease, with an undetectable PSA post-prostatectomy. This approach may avoid over-treatment of some men who would never need radiation therapy and reduce radiation-related adverse effects.
Three recently published trials - RADICALS-RT, RAVES and ARTISTIC - compare adjuvant and early salvage radiation therapy and have published the following results.rrr
RADICALS-RT is a multicentre phase III trial randomising 1396 patients with post-operative PSA <0.2 ng/ml and at least one high risk pathological feature (pT3/4, Gleason 7-10, positive margins or pre-operative PSA ≥10 ng/ml) to immediate adjuvant radiation therapy (ART) (n = 697) versus early salvage radiation therapy (n = 699).r Primary outcome is freedom from distant metastases. After median follow up of 5 years, they reported the secondary outcome of biochemical progression free survival was not significantly improved with immediate adjuvant radiation therapy, 85%, compared to salvage radiation therapy, 88% (HR = 1.1, 95% CI:0.81-1.59).
The RAVES trial is a multicentre, phase III trial randomising 333 post prostatectomy patients with either extraprostatic extension, seminal vesicle invasion or positive surgical margins and a PSA <0.1 ng/ml to either immediate adjuvant radiation therapy (n = 166) or salvage radiation therapy (n = 167).r The primary aim was to exclude a 10% inferiority in freedom from biochemical failure in the salvage radiation arm. The trial closed early due to an unexpectedly low event rate. Similar freedom from biochemical failure rates were shown between groups - adjuvant 86%, and salvage 88% (HR = 1.03, 95% CI:0.65-1.63, p = 0.91).
The GETUG-17 has completed accrual (n = 718) and data is included in the ARTISTIC meta-analysis.rr ARTISTIC is a prospectively planned meta-analysis performed with preliminary data of the three trials listed directly above. Across the trials, 1075 men were randomised to adjuvant radiation therapy and 1078 to salvage radiation therapy. At the time of presentation 39.1% had commenced salvage radiation therapy. Most patients had Gleason sum score of 7 (77.6%). After 270 events (PSA-driven event-free survival) the meta-analysis shows no evidence that event-free survival is improved with adjuvant radiation compared to salvage radiation (HR = 0.95, 95% CI:0.75-1.21, p = 0.70).
It is important to note in the reporting of biochemical progression-free survival, distant metastases-free survival and overall survival outcomes, a median follow-up of at least ten years is needed prior to making definitive conclusions. In the interim, however, this data suggests that in an appropriately consented population early salvage radiation therapy may be an appropriate alternative to adjuvant radiation therapy, with the benefit of delaying, or possibly completely avoiding radiation therapy and associated toxicities.