Recent Advances in Hormonal Therapy for Advanced Prostate Cancer

For many years, prostate cancer has been known to be sensitive to androgens. Indeed, endocrine manipulations aimed at the reduction of serum testosterone to below or around the castrate range have been the mainstay in the management of advanced prostate cancer for the past 60 years. Despite widespread testing, the advances with this treatment modality for prostate cancer over the past several decades have been modest. Unfortunately, the answers to many relevant critical questions still lie in the future. The limiting factor of hormonal therapy is that a significant proportion of tumor cells are not affected by androgen deprivation. Drs. Oottamasathien and Crawford eloquently review several important issues regarding hormonal therapy for prostate cancer. We would like to provide the reader with our views of the data pertinent to these issues. Does Hormonal Therapy Prolong Survival in Patients With Recurrent/Metastatic Disease?
There is still no evidence that androgen deprivation therapy prolongs survival in patients with recurrent or metastatic disease. In the Veterans Affairs Cooperative Urological Research Group study (VACURG I), patients with metastatic disease were randomly assigned to receive treatment with bilateral orchiectomy and placebo, 5 mg of diethylstilbestrol(Drug information on diethylstilbestrol) (DES), orchiectomy and DES, or placebo alone as their initial treatment. Patients were followed carefully and crossed over at the time of progression. Although this study was not designed to evaluate the concept of immediate vs deferred treatment, the investigators noted that after 9 years 100% of patients with metastatic disease in the placebo group received active treatment at the time of progression. This provided an opportunity to evaluate the survival of immediate treatment vs treatment at the time of progression. There was no difference in cancer-specific survival between any of the groups and no difference in overall survival among patients with stage III or IV disease (contrary to the figures cited in the article).[1] More recently, the United Kingdom's Medical Research Council (MRC) conducted a trial to evaluate immediate vs deferred therapy in patients with locally advanced or metastatic disease. The initial report in 1997 suggested a higher death rate from prostate cancer in patients with locally advanced disease randomized to receive delayed hormonal therapy. There was no significant difference in prostate cancer mortality between the two arms in patients with metastatic disease.[2] With longer follow-up, the authors reported that there was no longer a survival benefit for early treatment in patients with locally advanced disease.[3] Importantly, the MRC trial illustrated that initiation of early androgen deprivation, although not affecting survival of patients with metastatic disease, significantly reduced the incidence of serious disease-related morbidity (pain, anemia, renal failure, and epidural cord compression). This finding justifies immediate treatment for all patients with clinically evident metastatic disease. Adjuvant Hormonal Therapy
Current data from prospective randomized trials indicate that neoadjuvant treatment significantly reduces the rate of positive margins in patients with T2 disease. However, this has not translated into an improved outcome that would support routine use of neoadjuvant hormonal therapy prior to prostatectomy.[4] The data for adjuvant hormonal therapy after radical prostatectomy are more encouraging but still not conclusive. The positive study reported by the Eastern Cooperative Oncology Group (ECOG) randomized 98 patients with surgically node-negative disease to immediate hormonal therapy or follow-up until clinical progression. All parameters including overall survival were significantly improved for the adjuvant therapy group. The main concerns about the ECOG study were that this was a relatively small trial that accrued only a fraction of the initially projected sample size and that cancer-specific survival was significantly worse in the observation arm compared with historical data available in the literature.[5] Furthermore, the patients entered in the ECOG trial had node-positive disease, which limits the study observations to about 5% of the patient population initially diagnosed with prostate cancer in the United States. Similarly, the observations on the node-positive patients should not be extrapolated to other high-risk groups (ie, node-negative patients) and those with evidence of biochemical failure alone after definitive local treatment. Additional confirmatory studies are clearly needed before adjuvant hormonal therapy should be routinely recommended in this patient population. Another large international adjuvant trial randomized over 8,000 patients with clinically localized and locally advanced prostate cancer undergoing surgery, radiation, or observation, to bicalutamide(Drug information on bicalutamide) (Casodex), 150 mg/d, or placebo.[6] Unfortunately, the study was stopped early and treatment was unblinded after the investigators found an initial reduction in the risk of disease progression in favor of the treatment groups. As a result, it is unlikely that this large international study will ever provide reliable survival information. As adequately reviewed by the authors, the data regarding the role of neoadjuvant/adjuvant androgen deprivation therapy with radiotherapy is more convincing. Interestingly, the European Organization for Research and Treatment of Cancer (EORTC) experience was not entirely reproduced by the Radiation Therapy Oncology Group (RTOG) trials, which until recently have demonstrated a survival benefit for this combination only in patient subsets. In RTOG 8610, 4 months of androgen deprivation therapy resulted in a survival benefit in low-risk patients only (Gleason score ≤ 6). Similarly, in preliminary reports of RTOG 9202, 2 years of androgen deprivation therapy resulted in a 5-year disease-specific survival benefit, compared to 4 months of such treatment, in the high-risk population (Gleason score ≥ 8) only.[7] More recently, Pilepich et al[8] reported the long-term results of RTOG 8531, wherein androgen deprivation therapy was given indefinitely or until progression in a fairly heterogeneous population of patients, many of whom were accrued prior to the availability of the prostate-specific antigen (PSA) test. In the initial reports, RTOG 8531 indicated a survival advantage only in the group with Gleason score ≥ 8 (no overall survival difference). With longer follow-up, RTOG investigators now report a significant survival benefit in all patients. The data from the RTOG studies and Bolla trial[9] suggest that 2 years or longer androgen deprivation therapy benefits high-risk patients treated with radiotherapy. Current laboratory data indicate that adjuvant/neoadjuvant hormonal therapy may enhance the biologic effects of radiation,[10] suggesting that the clinical benefit seen in the above trials may not reflect evidence to support adjuvant hormonal therapy in patients treated with surgery only. Intermittent Androgen Blockade
In preclinical data, intermittent androgen blockade was shown to delay the development of androgen-independent tumor growth.[11] The investigators' possible explanation was that since androgen independence develops partially from adaptive cell survival mechanisms activated by androgen deprivation, reexposure of tumor cells to androgens may prolong the time to the development of androgen-independence. Other clinical advantages are a better quality of life in periods off treatment (eg, the potential for regaining potency and libido), fewer long-term side effects from prolonged hormonal therapy, and a lower cost. The initial results of two phase III trials were recently published. The first studied the role of intermittent androgen blockade in advanced disease patients (mostly metastatic and some node-positive). Although quality of life seemed better for patients receiving intermittent androgen blockade, their median time to clinical progression/PSA escape was shorter than that in the patients treated continuously.[12] The second study was conducted in patients with evidence of PSA relapse after prostatectomy but no other evidence of disease (M0). The intermittent androgen blockade group experienced a quality-of-life benefit. In addition, more than 90% of patients in this group recovered gonadal function and attained normal testosterone levels. No difference was reported in time to progression.[13] In conclusion, intermittent androgen blockade may be used judiciously in clinical practice but only in patients with M0 disease at high risk for the development of distant metastasis. It should be considered investigational until more definitive data from clinical trials become available.