Stage II Prostate Cancer Treatment
External-beam radiation therapy (EBRT) with or without hormonal therapy
EBRT is another treatment option often used with curative intent.[17,18,19,20,21] Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce the incidence of stricture. Adjuvant hormonal therapy should be considered for patients with bulky T2b to T2c tumors.
The role of adjuvant hormonal therapy in patients with locally advanced disease has been analyzed by the Agency for Health Care Policy and Research (now the Agency for Healthcare Research and Quality). Most patients had more advanced disease, but patients with bulky T2b to T2c tumors were included in the studies that were re-evaluating the role of adjuvant hormonal therapy in patients with locally advanced disease.
Evidence (EBRT with or without adjuvant hormonal therapy):
- The Radiation Therapy Oncology Group's (RTOG) trial 7706 (RTOG-7706).[Level of evidence: 1iiA]
- Prophylactic radiation therapy to clinically or pathologically uninvolved pelvic lymph nodes does not appear to improve OS or prostate cancer-specific survival.
- RTOG-9413 (RTOG-9413) trial.[25,26][Level of evidence: 1iiDiii]
- Although RTOG-9413 showed increased progression-free survival at 4 years for patients who had a 15% estimated risk of lymph node involvement and received whole-pelvic radiation therapy compared with prostate-only radiation therapy, OS and PSA failure rates were not significantly different.
- In a randomized trial, 875 men with locally advanced nonmetastatic prostate cancer (T1b–T2 moderately or poorly differentiated tumors; T3 tumors of any grade) were randomly assigned to receive 3 months of a luteinizing hormone-releasing hormone (LH-RH) agonist plus long-term flutamide (250 mg orally 3 times a day) with or without EBRT.[Level of evidence 1iiA]
- Nineteen percent of the men had tumor stage T2, and 78% of the men had tumor stage T3. At 10 years, both overall mortality (29.6% vs. 39.4%; 95% CI for the difference, 0.8%–18.8%) and prostate cancer-specific mortality (11.9% vs. 23.9%; 95% CI for the difference, 4.9%–19.1%) favored combined hormonal and radiation therapy.
- Although flutamide might not be considered a standard hormonal monotherapy in the setting of T2 or T3 tumors, it is interesting to see that radiation therapy provided a disease-free survival or tumor-specific survival advantage even though this monotherapy was applied. This analysis rests on the assumption that flutamide does not shorten life expectancy and cancer-specific survival. Radiation therapy was not delivered by current standards of dose and technique.
- Another trial compared androgen deprivation therapy (ADT: an LH-RH agonist or orchiectomy) to ADT plus radiation therapy (65–69 Gy to the prostate by 4-field box technique, including 45 Gy to the whole pelvis, seminal vesicles, and external/internal iliac nodes unless the lymph nodes were known to be histologically negative). This trial, NCIC CGT PR.3/MRC UKPRO7 [NCT00002633], from the National Cancer Institute of Canada randomly assigned 1,205 patients with high-risk (PSA >40 ng/ml or PSA >20 ng/ml and Gleason score ≥8), T2 (12%–13% of the patients), T3 (83% of the patients), and T4 (4%–5% of the patients) with clinical or pathologically staged N0, M0 disease.[Level of evidence; 1iiA]
- At a median follow-up of 6 years (maximum = 13 years), OS was superior in the ADT plus radiation therapy group (HR death of 0.77; 95% CI, 0.61–0.98, P = .03). OS at 7 years was 74% for the ADT plus radiation therapy group versus 66% for the ADT alone group.
- Although radiation therapy had the expected bowel and urinary side effects, quality of life was the same in each study group by 24 months and beyond.
- A meta-analysis of randomized clinical trial evidence comparing radiation therapy with radiation therapy plus prolonged androgen suppression has been published. The meta-analysis found a difference in 5-year OS in favor of radiation therapy plus continued androgen suppression (LH-RH agonist or orchiectomy) as compared with radiation therapy alone (HR, 0.631; 95% CI, 0.479–0.831).[Level of evidence: 1iiA]
- A meta-analysis of seven randomized controlled trials comparing early hormonal treatment (adjuvant or neoadjuvant) to deferred hormonal treatment (LH-RH agonists and/or antiandrogens) in patients with locally advanced prostate cancer, whether treated with prostatectomy, radiation therapy, or watchful waiting or active surveillance, showed improved overall mortality for patients receiving early treatment (RR, 0.86; 95% CI, 0.82–0.91).[Level of evidence: 1iiA]
- Short-term neoadjuvant-androgen therapy administered before and during radiation therapy has shown benefit in at least some patients with clinically localized prostate cancer. In an open-label, randomized trial (RTOG-9408 [NCT00002597]), 1,979 men with nonmetastatic stage T1b–c, T2a, or T2b tumors and a PSA level of 20 ng/ml or less were randomly assigned to receive radiation therapy (66.6 Gy prostate dose in 1.8 Gy daily fractions) with or without 4 months of ADT (flutamide 250 mg by mouth 3 times per day plus either monthly goserelin 3.6 mg subcutaneously or leuprolide 7.5 mg intramuscularly), beginning 2 months prior to radiation therapy. Median follow-up was about 9 years.[Level of evidence: 1iiA]
- The 10-year OS rate was 57% in the radiation only group versus 62% in the combined therapy group (HRdeath of 1.17; 95% CI, 1.01–1.35; P = .03).
- In a post-hoc analysis, there was no statistically significant interaction between the treatment effect and baseline-risk category of the patients. However, there appeared to be little, if any, benefit associated with combined therapy in the lowest-risk category of patients (Gleason score ≤6; PSA ≤10 ng/ml; and clinical stage ≤T2a).
- The OS benefit was most apparent in men with intermediate-risk tumors (Gleason score 7; or Gleason score ≤6 and PSA >10 ng/ml; or clinical stage T2b).
- The duration of neoadjuvant hormonal therapy has been tested in a randomized trial (TROG 96.01 [ACTRN12607000237482]) involving 818 men with locally advanced (T2b, T2c, T3, and T4) nonmetastatic cancer treated with radiation therapy (i.e., 66 Gy in 2 Gy daily fractions to the prostate and seminal vesicles but not including regional lymph nodes). In an open-label design, patients were randomly assigned to radiation therapy alone, 3 months of neoadjuvant androgen deprivation therapy (NADT) (goserelin 3.6 mg subcutaneously each month plus flutamide 250 mg by mouth 3 times per day) for 2 months prior to and during radiation, or 6 months of NADT for 5 months prior to and during radiation.[Level of evidence: 1iiA]
- After a median follow-up of 10.6 years, there were no statistically significant differences between the radiation alone group and the radiation plus 3 months of NADT group.
- However, the 6-month NADT arm showed better prostate cancer-specific mortality and overall mortality than radiation alone; 10-year all-cause mortality 29.2% versus 42.5% (HR, 0.63; 95% CI, 0.48–0.83, P = .0008).
- Addition of androgen suppression therapy to EBRT may benefit men who are at an elevated risk of disease recurrence and death from prostate cancer (RTOG-9202).