Long Term Results in Prostate Cancer Patients after Short Term Androgen Suppression and Radiation Dose Escalation

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 248,530 new cases of prostate cancer will be diagnosed in 2021 and 34,130 men will die of the disease.

The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Treatment options for patients with intermediate and high risk prostate cancer include Radical Prostatectomy and External Beam Radiation Therapy (EBRT), and long term outcomes are similar with both treatment approaches. For those receiving EBRT, based on several clinical trials, a minimum radiation dose of 74 Gy is recommended for both intermediate and high risk prostate cancer patients. Numerous studies have demonstrated the benefit of combining Androgen Suppression (AS) with EBRT as initial treatment of localized prostate cancer. However, the optimal Androgen Suppression treatment duration has remained unclear. For patients with intermediate risk disease, 4-6 months of neoadjuvant/adjuvant Androgen Suppression is considered sufficient, whereas 2-3 years of Androgen Suppression is recommended for localized high risk disease.

EORTC 22991 was launched in 2001 to assess the benefit of 6 months of concomitant and adjuvant Androgen Suppression added to EBRT in men with intermediate and limited high risk localized prostate cancer. Eligible patients had histologically confirmed prostate adenocarcinoma (T1b-T2b), with PSA 10-20 ng/mL and/or Gleason sum equals 7, or patients with PSA less than 10 ng/mL, Gleason sum less than 7 and cT2b disease. Patients had no involvement of pelvic lymph nodes (N0) as assessed by CT or MRI or laparoscopic surgery, no clinical evidence of metastatic spread (M0), no previous pelvic irradiation or radical prostatectomy and no previous hormonal therapy. Either, a PSA of more than 20 ng/mL, a Gleason sum more than 7, or a disease stage more than cT2c, was classified high-risk disease, and these patients were ineligible. Patients (N=819) were randomly assigned to receive EBRT or EBRT plus Androgen Suppression, started on day 1 of EBRT. The treating Radiation Therapy (RT) facilities centers selected the EBRT dose (70Gy, 74Gy, or 78 Gy) as well as RT technique (3D-Conformal Radiation Therapy or IMRT). Androgen Suppression consisted of two subcutaneous injections of 3-monthly depot LHRH analog (Goserelin) given the first day of RT and then 3 months later. To avoid Flare phenomenon, patients received antiandrogen agent, Bicalutamide 50 mg orally daily for one month, starting 1 week before the first LHRH injection. Of the 481 patients with intermediate-risk disease, 342 patients had EBRT planned at 74 Gy and 139 patients had EBRT planned at 78 Gy. Of the 481 patients, 245 were randomly assigned to EBRT plus Androgen Suppression (173 patients at 74 Gy, 72 patients at 78 Gy) and 236 patients to EBRT only (169 patients at 74 Gy, 67 patients at 78 Gy). The Primary endpoint was Event Free Survival (EFS). Secondary end points included clinical Disease Free Survival (DFS), Overall Survival (OS) and Distant Metastasis Free Survival (DMFS).

The authors in 2016 reported that after a median follow up of 7.2 years, 6-month concomitant and adjuvant AS combined with EBRT improved 5-year EFS and clinical DFS of intermediate and limited high risk prostate cancer patients, compared with those treated with EBRT alone. The researchers in this publication reported the updated results. Limited high risk patients, and all patients treated with EBRT at 70 Gy were excluded from this present analysis, because this is considered suboptimal according to the current practice standards.

At a median follow up of 12.2 years, it was confirmed that the addition of 6 months of concomitant and adjuvant Androgen Suppression significantly improved EFS (HR=0.53; P<0.001), clinical DFS (HR=0.67; P=0.008) and locoregional control (HR=0.44; P=0.013), compared to EBRT alone. These benefits were seen across age groups (less than 70 yrs versus 70 yrs or more), and were independent of radiation dose (74Gy versus 78 Gy). The observed improvements in DMFS and OS however did not reach statistical significance and this was expected, as the trial was not powered to detect difference in these endpoints.

It was concluded that External Beam Radiation Therapy at 74 or 78 Gy, along with 6 months of concomitant and adjuvant Androgen Suppression, significantly improves Event Free Survival and Disease Free Survival in intermediate risk prostate carcinoma. The authors added that these are the most robust data yet, from a randomized trial with long term follow up, addressing this important question.

Short Androgen Suppression and Radiation Dose Escalation in Prostate Cancer: 12-Year Results of EORTC Trial 22991 in Patients With Localized Intermediate-Risk Disease. Bolla M, Neven A, Maingon P, et al. DOI: 10.1200/JCO.21.00855 Journal of Clinical Oncology. Published online July 26, 2021.