Benefit of Short-term Androgen-deprivation Therapy Added to Radiotherapy of Localized Prostate Cancer for Long-term Survival
Androgen-deprivation therapy is associated with several adverse effects that also affect quality of life or increase the risks of serious age-related health problems. An extensive study focused on the benefits of short-term administration of androgen-deprivation therapy as an adjunct to radiotherapy in patients with prostate cancer and monitored its long-term impact on survival and the rate of late treatment toxicity.
Introduction
Phase III clinical trials have demonstrated the benefit of reversible androgen-deprivation therapy (ADT) lasting longer than 2 years in combination with radiotherapy in men with locally advanced prostate cancer. Although this long-term hormonal treatment prolongs survival, it is associated with undesirable side effects, such as an increased risk of myocardial infarction or erectile dysfunction. Therefore, the large randomized study RTOG 9408 aimed to evaluate the benefits of short-term ADT.
Study Methodology
From 1994 to 2001, 2028 men with prostate adenocarcinoma classified as T1b−T2b and prostate-specific antigen (PSA) levels ≤ 20 ng/ml were randomized to either radiotherapy (RT) alone or RT combined with short-term ADT. Patients were stratified according to PSA, tumor grade, and nodal involvement. Patients in the combined treatment arm started with flutamide and goserelin or leuprorelin treatment, which lasted a total of 4 months. RT began 2 months after the start of ADT (total dose 66.6 Gy). In the arm without hormonal treatment, RT was initiated within 21 days of randomization.
Results
The median follow-up time was 14.8 years (range 0.16−21.98 years). 10-year survival was achieved by 56% of participants in the RT-only arm and 63% in the combined treatment arm, and 18-year survival was 23% in both groups. Overall, the difference between the arms was not statistically significant (hazard ratio [HR] 0.94; 95% confidence interval [CI] 0.85−1.05; p = 0.94).
The average survival time over the 18-year follow-up (restricted mean survival time) was 11.3 years for RT alone (95% CI 10.9−11.6) and 11.8 years for the combined treatment, and this difference was borderline statistically significant (p = 0.05).
Disease-specific mortality (DSM) at 10 and 18 years was significantly higher in the RT-only arm (7% and 14% compared to 3% and 8% in the combined therapy arm; HR 0.56; 95% CI 0.41−0.75; p < 0.01). Combined therapy also significantly improved outcomes in terms of biochemical failure and the absence of distant metastases.
The incidence of late hepatic, gastrointestinal, and genitourinary toxicity grade ≥ 3 was low and comparable between arms.
Conclusion
Long-term follow-up results indicate that the addition of short-term androgen-deprivation therapy is beneficial for patients with localized prostate cancer – it prolongs overall survival, reduces disease-specific mortality, biochemical failure, local progression, and promotes the absence of distant metastases. A 4-month hormonal treatment in these patients provided a benefit of approximately 6 additional months of overall survival.
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Sources:
1. Jones C. U., Pugh S. L., Sandler H. M. et al. Adding short-term androgen deprivation therapy to radiation therapy in men with localized prostate cancer: long-term update of the NRG/RTOG 9408 randomized clinical trial. Int J Radiat Oncol Biol Phys 2022; 112 (2): 294−303, doi: 10.1016/j.ijrobp.2021.08.031.
2. Higano C. Side effects of androgen deprivation therapy: monitoring and minimizing toxicity. Urology 2003; 61 (2 Suppl. 1): 32−38, doi: 10.1016/s0090-4295(02)02397-x.
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