Controversies Surrounding Androgen Deprivation for Prostate Cancer

Stephen G. Patterson, MD, Lodovico Balducci, MD, Julio M. Pow-Sang, MD

Disclosures

Cancer Control. 2002;9(4) 

In This Article

Immediate vs Delayed Hormonal Therapy

Hormonal therapy involves medical complications, effects on quality of life, and cost. It is reasonable to ask whether this form of treatment should be instituted as soon as the diagnosis of metastatic disease is established or if it should be delayed until symptoms develop. Reports from the Veterans Administration Cooperative Urological Group (VACURG) studies suggested hormonal treatment with DES could be delayed until the development of symptoms.[29] Re-examination of those studies, however, may temper these conclusions. In VACURG I, patients with metastatic disease were randomized to 5 mg of DES, 5 mg of DES plus orchiectomy, orchiectomy alone, or placebo.[50] Patients progressing on observation were eligible for crossover to DES, but their assigned study arm was not changed. No differences in survival were seen between treatment arms. Patients randomized to treatment with DES had a higher incidence of cardiovascular death and lower incidence of prostate cancer death. Lower DES doses were studied in VACURG II. Patients were randomized to 3 different dosages of DES (0.2 mg, 1 mg, and 5 mg) vs placebo.[31] There was a crossover design. Institutional investigators were concerned about toxicity from high-dose DES treatment as well as the conclusions of VACURG I, and they often withheld crossover therapy too long, particularly in patients in the 0.2 mg DES arm and in the placebo arm.[50] Therefore, VACURG II actually studied hormonal treatment vs no treatment.[51] The second study results showed some survival benefit for hormonal treatment.

Five recent randomized, controlled studies have investigated treatment timing. In 1997, the Medical Research Council (MRC) Prostate Cancer Working Party Investigators Group[52] reported the results of 938 patients with locally advanced or asymptomatic metastatic prostate cancer. Patients were randomized to immediate or delayed treatment with orchiectomy or LHRH analog. The results consistently favored immediate treatment. Progression from M0 to M1 disease (P<.001) and development of metastatic pain occurred more rapidly in the deferred-treatment patients. In addition, pathological fracture, spinal cord compression, ureteric obstruction, and development of extra-skeletal metastases were more common in this group. A significant decrement in the death rate from prostate cancer and an improvement in survival was observed. The authors commented that for approximately 10% of patients, treatment does not become necessary during their lifetime. It is unlikely a younger patient will fall into this 10% population who never require treatment. For the elderly man with nonmetastatic disease, deferred treatment probably still remains an option. Because 3% of patients experienced pathologic fracture or spinal cord compression, a major concern with the MRC study was whether patients in the deferred-therapy arm were allowed to progress too far before initiation of hormonal therapy. If patients were allowed to progress too far, it creates the potential for bias that would inflate differences in outcomes between immediate and deferred therapy.

Bolla et al[53] reported results of 415 patients with locally advanced prostate cancer. Patients were randomized to receive radiation therapy alone or radiotherapy plus immediate treatment with goserelin for 3 years. The median follow-up was 45 months. Kaplan-Meier estimates of overall survival at 5 years were 79% in the combined-treatment group and 62% in the radiotherapy group (P=.001). The proportion of surviving patients who were free of disease at 5 years was 85% in the combined-treatment group and 48% in the radiotherapy-alone group (P<.001). The authors concluded adjuvant treatment with goserelin when started simultaneously with external-beam radiation improved local control and survival in patients who had locally advanced prostate cancer.

In 1997, the Radiation Therapy Oncology Group (RTOG) Protocol 85-31[54] published the results of 977 patients enrolled in a randomized phase III study investigating the benefit of adjuvant goserelin in definitively radiated patients with locally advanced prostate cancer. The actuarial projections showed at 5 years, 84% of patients on the adjuvant goserelin arm and 71% on the observation arm had no evidence of local recurrence (P<.0001). The corresponding figures for freedom from distant metastases and disease-free survival were 83% vs 70% (P<.001) and 60% vs 44% (P<.0001). If a PSA level greater than 1.5 ng/mL is included as a failure (after >1 year), the 5-year disease-free survival rate on the adjuvant goserelin arm was 53% vs 20% on the observation arm (P<.0001). The 5-year survival rate (for the entire population) was 75% on the adjuvant arm vs 71% on the observation arm (P=.52). However, in patients who had tumors with a Gleason score of 8 to 10, the difference in actuarial 5-year survival (66% on the adjuvant goserelin arm vs 55% on the observation arm) reached statistical significance (P=.03). The authors concluded that application of androgen suppression as an adjuvant to definitive radiotherapy has been associated with a significant improvement in local control and freedom from disease progression. With a median follow-up of 4.5 years, a significant improvement in survival was observed only in patients with centrally reviewed tumors with a Gleason score of 8 to 10.

There are differences between the Bolla study and the RTOG 85-31 study. In the Bolla study, which reported a survival advantage for patients who received early hormonal therapy, the LHRH analog was started on the first day of radiation, while in the RTOG 85-31 study, which reported no overall survival advantage for early hormonal therapy, the LHRH analog was started during the last week of radiation. A possibility exists, therefore, that either by downsizing the prostate or through some other unidentified beneficial or synergistic effect of hormonal therapy, the radiation was more effective on the localized or regional tumor in the study by Bolla and colleagues than it was in the RTOG 85-31 study where radiation was initiated without any influence of hormonal therapy.

Granfors et al[55] reported the results of 91 patients with clinically localized prostate cancer who were treated for pelvic-confined prostate cancer. Patients had surgical lymph node staging and were then randomized to receive definitive external-beam radiotherapy or combined orchiectomy and radiotherapy. Patients who received radiation alone without hormonal treatment were treated with androgen ablation at clinical evidence of disease progression. Results were reported at a median follow-up of 9.3 years. Clinical progression was observed in 61% of patients treated with radiotherapy alone and in 31% of patients who received combined treatment (P=.005). Mortality was 61% and 38%, respectively, and cause-specific mortality was 44% and 27%, respectively (P=.06), in groups 1 and 2. Differences in favor of combined treatment were mainly seen in lymph node positive tumors. Node-negative tumors showed no significant difference in survival rates. The authors concluded the progression-free, disease-specific, and overall survival rates for patients with prostate cancer and pelvic lymph node involvement are significantly better after combined androgen ablation and radiotherapy than after radiotherapy alone. These results strongly suggest that early androgen deprivation is better than deferred endocrine treatment for these patients.[55]

In 1999, Messing et al[56] published the results on 98 men with prostate cancer who underwent radical prostatectomy and pelvic lymphadenectomy and were found to have nodal metastases. These men were randomized to receive immediate antiandrogen therapy with goserelin or bilateral orchiectomy or to be followed without further therapy until disease progression. After a median of 7.1 years of follow-up, 7 (15%) of the 47 men who received immediate antiandrogen treatment died compared with 18 (35%) of 51 men in the observation group (P<.02). The authors concluded that immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improved survival and reduced the risk of recurrence in patients with node-positive prostate cancer.

Granfors et al[55] and Messing et al[56] have published the only randomized data with pelvic lymph node dissections and definitive treatment to the prostate in which early hormonal therapy was compared with late hormonal therapy. Survival advantages were documented in both studies with the early administration of hormonal therapy in patients who had nodal metastases. Based on these data, immediate hormonal therapy could be justified in patients who have pathologically positive lymph nodes and undergo definitive treatment to the prostate.

Patients who have undergone primary treatment (prostatectomy, radiation therapy, or brachytherapy) and experience a PSA recurrence (D1.5 disease) present a difficult management issue. A recent structured debate recommended delayed androgen deprivation over immediate treatment for men with nonmetastatic disease and biochemical relapse.[51] A review from the Cochrane Foundation noted a small increase in overall survival at 10 years for men treated in this fashion.[57] The natural history of disease in this patient population is unknown, and reasonable concerns about complications and cost of hormonal treatment have been raised. A series of 1,997 men who underwent radical prostatectomy for clinically localized prostate cancer at the Johns Hopkins Hospital between April 1982 and April 1997 was reported.[58] The actuarial metastasis-free survival rate of all 1,997 men was 82% at 15 years after surgery. Of these men, 315 (15%) developed biochemical PSA elevation. One third of the patients with PSA elevation developed detectable metastatic disease, and the remaining two third had no other evidence of disease. The median actuarial time to metastases was 8 years from the time of PSA elevation. In survival analysis, the time to biochemical progression (P<.001), Gleason score (P<.001), and PSA doubling time (P<.001) were predictive of the probability and time to the development of metastatic disease. An algorithm combining these parameters was constructed to stratify men into risk groups. Once men developed metastatic disease, the median actuarial time to death was 5 years.[58] The issue of how early and what to do with the D1.5 patient has not been resolved, and further clinical trials need to be performed.

It appears that starting hormonal therapy at first evidence of PSA elevation after prostatectomy, radiation therapy, or brachytherapy delays the development of overt metastatic disease. A survival advantage with early therapy may be seen only in those patients who at diagnosis had a Gleason score of 8 to 10. One conclusion that could be drawn is for patients at high risk of recurrent disease, it is reasonable to consider initiating hormone treatment early. For the remaining majority of men with standard risk of recurrent disease, early therapy should be done in the setting of a randomized clinical trial.

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