Background
Phase III RCT from Dana-Farber Cancer Institute and Massachusetts General Hospital. 206 men with intermediate-to-high-risk localized prostate cancer (PSA >10 ng/mL or T2b–T2c disease or Gleason score ≥7) randomized between 1995 and 2001 to external beam radiotherapy alone vs RT + 6 months of androgen suppression (leuprolide ± bicalutamide). This trial established 6 months of neoadjuvant and concurrent ADT as beneficial for intermediate-to-high-risk localized prostate cancer treated with RT.
Interventions and follow up
Arm A: External beam radiotherapy (70–70.4 Gy to prostate ± seminal vesicles)
Arm B: RT + 6 months ADT (leuprolide 7.5 mg monthly + bicalutamide 50 mg/d, starting 2 months before RT)
Primary endpoint: Overall survival
mFollow up: Median 8 years (per 2008 JAMA report)
Arm B: RT + 6 months ADT (leuprolide 7.5 mg monthly + bicalutamide 50 mg/d, starting 2 months before RT)
Primary endpoint: Overall survival
mFollow up: Median 8 years (per 2008 JAMA report)
Results
8-year OS: 74% RT+ADT vs 61% RT alone, P=.01 (absolute 13% benefit)
8-year disease-specific survival: 83% RT+ADT vs 78% RT alone
Prostate cancer mortality: 4% RT+ADT vs 9% RT alone (P=.01)
OS benefit (patients without severe comorbidity): Significant; patients with severe cardiovascular comorbidities: no benefit (P=.64)
8-year disease-specific survival: 83% RT+ADT vs 78% RT alone
Prostate cancer mortality: 4% RT+ADT vs 9% RT alone (P=.01)
OS benefit (patients without severe comorbidity): Significant; patients with severe cardiovascular comorbidities: no benefit (P=.64)
Adverse events
Main adverse events: Hot flashes, impotence, and fatigue common with ADT. No significant increase in cardiovascular deaths in the overall population. Grade 3+ ADT toxicity: <5%. Late RT toxicity similar between arms.
Conclusions
Six months of androgen-deprivation therapy added to RT significantly improves overall survival and prostate cancer-specific mortality in intermediate-to-high-risk localized prostate cancer. The benefit is concentrated in patients without severe cardiovascular comorbidities. This trial, alongside RTOG 94-08 and EORTC 22863, established the role of ADT as an essential component of curative-intent RT for non-low-risk prostate cancer.
Key Limitations
Key Limitations: Small sample size (n=206); underpowered for subgroup analyses. RT dose (70 Gy) is lower than current standard. Cardiovascular comorbidity finding raises the clinically important question of which patients should receive ADT, and for how long. Benefit was seen with 6 months; RTOG 94-08 also showed benefit with 4 months — suggesting even shorter ADT may be effective. ADT cardiovascular toxicity (MI, sudden cardiac death) was later identified as a concern, particularly in older men with existing cardiovascular disease.
Clinical Context
The D'Amico trial contributed to establishing the concept that ADT duration should be risk-stratified: ~4–6 months for intermediate-risk (D'Amico, RTOG 94-08) vs 18–36 months for high-risk (EORTC 22863, RTOG 9202). The cardiovascular safety concern raised by this analysis has led to careful patient selection for ADT, with cardiologic evaluation recommended before initiation in men with baseline cardiovascular disease. Current guidelines (NCCN, AUA/ASTRO/ASTRO) recommend 4–6 months ADT for intermediate-risk and 1.5–3 years for high-risk.
References