Refers to Michalski, J. M. et al. Effect of standard versus dose-escalated radiation therapy for patients with intermediate-risk prostate cancer: the NRG Oncology RTOG 0126 randomized clinical trial. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2018.0039 (2018).

Several randomized trials have reported on dose-escalation of radiotherapy to improve biochemical-recurrence-free survival (bRFS) in patients with localized prostate cancer of all risk groups1. The results of one of these trials also suggested that the rate of distant metastasis was reduced by an increased radiotherapy dose to the prostate in a subgroup of patients with high-risk disease2. Another trial, conducted predominantly in patients with intermediate-risk to high-risk prostate cancer and powered to detect an overall survival (OS) benefit, only reported improved bRFS after increased radiotherapy doses3.

However, trials of dose escalation reported increased acute and late toxic effects after elevated doses1,2,3 with older, non-intensity-modulated radiation therapy (IMRT) radiotherapy techniques, but IMRT was shown to reduce acute and late gastrointestinal and genitourinary toxic effects compared with 3D conformal radiotherapy (3D-CRT) (reactions up to 6 months P < 0.001; late toxicity Pgenitourinary < 0.02, Pgastrointestinal < 0.001)4. Moreover, retrospective data suggested that image-guided radiotherapy (IGRT) improves bRFS in patients with high-risk prostate cancer and reduces late genitourinary toxic effects5. Thus, dose-escalated radiotherapy using IMRT plus IGRT is currently regarded as the standard of care for localized prostate cancer6. Whether androgen deprivation therapy (ADT) should be used in combination with dose-escalated radiotherapy in patients with intermediate-risk disease is unclear, but retrospective data suggest improved cancer-specific survival for the combined approach7.

In their recent article, Michalski et al.8 report results of their large, randomized trial (NRG Oncology/RTOG 0126) of 1,499 eligible patients with localized prostate cancer that had intermediate-risk features. Patients were treated with either 70.2 Gy or 79.2 Gy (all with 1.8 Gy per fraction), using 3D-CRT or IMRT, all without ADT. The median follow-up duration was 8.4 years. Patients were stratified according to clinical risk group (Gleason score 2–6 with a PSA level ≥10 ng/ml but <20 ng/ml, or Gleason score 7 and PSA <15 ng/ml) and treatment modality (3D-CRT or IMRT). The primary trial end point was OS. 3D-CRT was used in 66.2% of patients and IMRT in the remaining patients. Prostate cancer was the cause of death in only 51 men (3.4% of all patients enrolled) of 431 patients who died, with no statistically significant difference between the trial arms. Moreover, no difference was observed in OS between the 751 men in the 79.2 Gy arm and the 748 men in the 70.2 Gy arm. The 8-year overall survival was 76% for those who received 79.2 Gy and 75% for those receiving 70.2 Gy (HR 1.00; 95% CI 0.83–1.20; P = 0.98). The 8-year cumulative rates of distant metastases (including biochemical failure with negative biopsy) were 4% for the 79.2 Gy arm and 6% for the 70.2 Gy arm (HR 0.65; 95% CI 0.42–1.01; P = 0.05). The 8-year rate of biochemical failure (defined as the nadir plus 2 ng/ml) was 20% in the 79.2 Gy arm and 35% in the 70.2 Gy arm (HR 0.54; 95% CI 0.44–0.65; P < 0.001). The proportion of patients with late grade 3 gastrointestinal toxic effects was 3% and 5%, and with late grade 3 genitourinary toxic effects 2% and 3% for the 70.2 Gy and 79.2 Gy arms, respectively. The 5-year rates of late grade 2 or greater gastrointestinal and genitourinary toxic effects were 21% and 12% for 79.2 Gy versus 15% and 7% for 70.2 Gy (P = 0.006 and P = 0.003), respectively. Salvage therapies were less frequently needed after 79.2 Gy dose than after 70.2 Gy with the 8-year cumulative incidence of salvage therapy being 14% for the 79.2 Gy arm and 22% for the 70.2 Gy arm (HR 0.63; 95% CI 0.50–0.80; P < 0.001).

This trial demonstrated, to our best knowledge for the first time, a reduction in distant metastasis owing to the use of dose-escalation in patients with intermediate-risk prostate cancer (Fig. 1); however, OS was not different between the two trial arms. Importantly, at the time of this planned interim analysis, only 431 deaths were recorded, but the statistical considerations of this trial required a minimum of 715 deaths to detect the assumed OS difference. Thus, the final results of this trial with a longer follow-up duration are awaited. Cancer-specific mortality in this trial was 3.4%, which is lower than expected when the trial was designed. Current systemic treatments and salvage approaches apparently prevent cancer-specific mortality in the majority of patients, as has also been observed in other large contemporary trials, such as ProtecT9.

Fig. 1: Dose-escalated intensity-modulated radiotherapy (IMRT) reduces distant metastases in men with intermediate-risk localized prostate cancer.
figure 1

More than 80% of prostate cancer metastases are usually observed in bone. In the RTOG 0126 trial, this type of dissemination was detected by bone scans. However, no data are available from Michalski et al.8 reporting the distribution of metastatic sites exactly. IMRT is now the recommended standard treatment.

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This trial demonstrated … a reduction in distant metastasis owing to the use of dose-escalation

The rates of severe late gastrointestinal and genitourinary toxic effects observed in this trial seem to be relatively high, especially in the dose-escalated arm. Importantly, IMRT was used only in 33.8% of patients and the use of IGRT was not required within the trial protocol; thus, wider use of IMRT plus IGRT could probably serve to further reduce the rate of late gastrointestinal and genitourinary toxic effects4,5.

This trial did not use concurrent short-term ADT; nevertheless, dose-escalated radiotherapy without concurrent ADT was associated with an 8-year cumulative distant metastasis rate of 4% and a cancer-specific mortality of 2% in patients with intermediate-risk disease8. These results compare well with prospective data from the RTOG 9910 trial, in which the 10-year cumulative rate of distant metastasis and cancer-specific mortality were 6% and 5%, respectively, after radiotherapy with 70.2 Gy plus short-term ADT in patients with intermediate-risk disease10.

Thus, it seems that a proportion of patients with intermediate-risk disease could safely be treated with dose-escalated radiotherapy alone (without ADT) without compromising long-term cancer control. The NRG/RTOG 0815 trial (NCT00936390) specifically addresses the question of whether patients with intermediate-risk prostate cancer who undergo dose-intensified radiotherapy benefit from additional short-term ADT in terms of OS, and the results of this trial are awaited to clarify this important issue.