Reprinted from PCRI Insights May 2003 v 6.2
By Glenn Tisman, M.D.,
Dr. Glenn Tisman Medical Corporation
Early use of hormonal ablation in prostate cancer therapy is a controversial issue in the urological community. This controversy catches many newly diagnosed patients by surprise. Patients often think of medicine as black and white. Disease A receives treatment A, disease B gets treatment B, and so on.
However, as patients pursue different medical evaluations, they soon find themselves in a complex universe of opinions and ambiguities, and making decisions can be troubling at best. Some physicians may recommend early hormonal therapy. Others will reject such treatment as nonsense. Which is best for the patient? Which opinion best reflects their needs? Which will extend life? Perhaps extending life is not all that counts.
I generally reassure newly diagnosed prostate cancer patients that chances are greater than 90 percent that their tumor cells will die from the depletion of circulating blood and tissue of testosterone. The suppression of blood and tissue testosterone is the most powerful weapon that a physician has for the treatment of advanced prostate cancer. Because testosterone lowering is so powerful in advanced disease, many study projects in recent years have attempted to use this therapy in patients with early, less advanced prostate cancer.
In this article, I plan to review some important studies that have evaluated the use of testosterone lowering in the early as well as late stages of disease. I will focus on patients with minimal and locally advanced prostate cancer, and we will review testosterone lowering as a definitive therapy exclusive of other therapies, or as an adjuvant therapy to the standard therapies such as radiation and surgery. Adjuvant therapies are those directed to destroy any minimal, residual tumor cells that may have escaped removal or destruction by surgical or radiation therapy. It is hoped that through this review of clinical trials you will become empowered with the knowledge necessary to help you and your physician choose the best therapy for your stage of disease.
Testosterone Lowering: Historical Perspective
Decades ago, Nobel Laureate Charles Huggins demonstrated that normal canine prostate tissue required testosterone (a male hormone, also called “androgen”) for growth and development. Since then, withdrawal of testosterone has provided the best therapy for patients with advanced prostate cancer.
Normally, the hypothalamic–pituitary–testicular axis regulates the synthesis of testosterone. Think of this axis as a network of hormone-producing organs that speak to each other, assuring that proper amounts of testosterone are available for the maintenance of normal cellular function. Many tissues, e.g. bone, depend on the presence of testosterone for peak performance but are capable of reasonable function without it. Other tissues such as the prostate gland and prostate cancer cells cannot live without it.
Figure 1. The pituitary-hypothalamic axis of hormone stimulation (fat white arrows) and feedback inhibition circles with minus signs.
Approximately eighty-five percent of the body’s testosterone comes from the testes, while two small glands that rest atop the kidneys, the adrenal glands, produce the remaining fifteen percent. Testosterone, once synthesized in the testes or from precursor hormones within the adrenal glands, undergoes a conversion within the cells that use the hormone. It becomes dihydrotestosterone (DHT) by the action of two enzymes called 5-alpha reductase I (5-AR-I) and 5-alpha reductase-II (5-AR-II). DHT is four times as potent as testosterone in producing masculinizing effects. Once formed, DHT binds to the cytoplasmic androgen receptor complex of normal prostate cells and of the prostate cancer cell. This union prepares DHT for its journey into the cell nucleus (where chromosomal DNA resides). Once in the nucleus, the complex binds to nuclear DNA, initiating a process that ends with the synthesis of various proteins capable of mediating the biochemical effects of the hormone (Figures 1 and 2).
Figure 2: Prostatic Cell Stimulation. Testosterone is reduced by the 5-alpha reductase enzyme present in prostate cancer cells. The reduced hormone then binds to the testosterone receptor for transportation into the cell nucleus. The bound testosterone-receptor complex next binds to nuclear DNA (this binding may be modulated by several compounds) thus inducing new protein synthesis. The synthesized proteins may have differing androgenic functions.
Androgen ablation, termed “testosterone withdrawal”, may be achieved surgically by removal of both testicles (bilateral orchiectomy) or pharmacologically, with Lupron® and Zoladex®. Lupron and Zoladex are two luteinizing hormone-releasing hormone agonists (LHRH agonists) that initially stimulate a release, or “surge”, of luteinizing hormone from the pituitary gland (a small endocrine gland residing in the base of the skull). The initial LH surge is responsible for the subsequent testosterone surge, which may last a week after initiating the first dose of a LHRH agonist. This initial stimulation gives way to prolonged inhibition of LH secretion and testicular testosterone production, leading to very low blood and tissue levels of the hormone.
Other hormones and medications can suppress testosterone levels. The synthetic estrogen, diethylstilbestrol, reduces testosterone to castrate levels in a dose-dependent fashion (1-3 mg daily is required). Because levels greater than 0.5-1 mg daily are associated with increased cardiovascular complications in as high as 20% of treated patients, it is no longer available in the United States unless purchased from compounding pharmacists by prescription.
Other antiandrogen drugs that block androgen receptors from binding to DHT include Casodex®, flutamide and nilutamide. Ketoconazole (Nizoral®) is an anti-fungal drug that as a side effect directly inhibits androgen precursor and testicular testosterone production. Ingestion of large doses of ketoconazole (1200 mg daily) is the fastest way to achieve castrate levels of testosterone (within 24 hours) short of surgical removal of the testicles. When antiandrogens are used in combination with LHRH agonists, the treatment is referred to as combined androgen blockade or combined androgen deprivation therapy. Some physicians have been adding a third drug, a 5-alpha reductase inhibitor, called finasteride, in an attempt to enhance testosterone deprivation. Though most androgen deprivation medications have been available for years, issues relating to the best time to use them and which doses and combinations of drugs to use for best results have not yet been resolved.
Animal models of prostate cancer have been helpful in studying the effects of various drugs and hormone therapies on prostate cancer growth. One such model is the Dunning R-3327 rat model, in which, Isaacs1 and co-workers showed that early removal of the testes was associated with decreased growth of transplanted prostate cancer cells and increased survival.
Although all animals, regardless of when orchiectomy was carried out, succumbed to tumors, this was a landmark study in demonstrating that early withdrawal of testosterone by castration could be more beneficial than delayed withdrawal. This study laid the scientific groundwork for clinical studies of early androgen withdrawal in patients with prostate cancer.
Early Human Adjuvant Trials
Medical Research Council Study
The Medical Research Council (MRC) in the United Kingdom is involved in many large cooperative group medical research projects, and it undertook one of the earliest trials of immediate versus delayed hormonal withdrawal as treatment for advanced prostate cancer.
The MRC study revealed significant differences in favor of immediate androgen withdrawal with respect to disease-free survival (survival without evidence of prostate cancer) and overall survival (survival with or without evidence of prostate cancer). The study group that was given immediate therapy suffered fewer major complications, including reductions in pathologic bone fractures, spinal cord compression from tumor and paralysis, urethral outlet obstruction (inability to pass urine), and development of new distant metastases.
This clinical trial, initiated 17 years ago supported the principle of early hormonal withdrawal for prostate cancer. Interestingly, the benefit in terms of surviving prostate cancer was largely seen in patients with locally advanced disease, but not in those with distant metastases.
This study suggested that adjuvant or early hormonal ablation is better targeted at patients with minimal residual disease, as is often present after definitive surgery or radiation.
Veterans Administration Cooperative Urological Research Group (VACURG) Studies
Three large Veteran Administration Cooperative Urological Research Group (VACURG) studies, conducted throughout the 1960s and mid 70s, established the generally accepted guidelines for treatment with hormonal therapy for the 70s through the late 80s, and gave further insight into the role of early hormone therapy for prostate cancer.2 The results of these clinical studies shaped the direction of further research and standard clinical urological practice for the next four decades. Their historical and current importance demands that we summarize their results.
The researchers at VACURG first took a group of stage I and stage II patients. They were treated with radical prostatectomy followed by either no further therapy, or 5 mg daily of the testosterone suppressing diethylstilbestrol (DES). Surprisingly, stage I patients who received DES had a significantly worse overall rate of survival compared to those who did not receive the hormone. DES-treated patients suffered from heart attacks, strokes, blood clots and pulmonary embolisms (blood clots that spread to the lungs). Stage II patients had no significant differences in disease-specific or overall rates of survival. This study group, in which hormones were used in a truly adjuvant setting, failed to demonstrate the benefit in early testosterone suppressing therapy with DES.
However, the VACURG researchers also studied patients in the more advanced stages of prostate cancer (stage III and stage IV). These patients were treated with placebo, 5 mg DES, orchiectomy plus placebo, or orchiectomy plus 5 mg DES. The three hormonal treatment groups had significantly less disease progression than the placebo group. However, the delayed progression did not translate into an overall survival benefit for these patients. Part of the reason for that was because of the increased cardiovascular deaths in the DES groups. Yet even in groups with no exposure to DES (placebo alone or orchiectomy plus placebo), the results failed to translate into decreased progression and overall survival benefit. This was largely because the orchiectomy group had multiple competing, non-cancer-related deaths.
The fact that the observed delay in progression, including a decrease in prostate cancer death, did not translate into a survival benefit would be noted again in studies to come. Researchers generally accepted that the increased cardiovascular mortality and deaths from other causes in the DES treated group obviated any appreciable survival benefit by DES responders. They also considered that any study group that contained a greater number of patients with cardiovascular disease would be expected to do worse than a healthier study group, regardless of any beneficial effects of treatment on the prostate cancer.
The second VACURG study involved stage III and IV patients. They were given no treatment, 0.2 mg of DES, l mg of DES, or 5 mg of DES daily. The study ended prematurely because of unacceptable numbers of cardiovascular deaths in the 5-mg DES group. However, this study, similar to VACURG #1, demonstrated that l mg and 5 mg of DES significantly delayed the progression of stage III prostate cancer patients into stage IV patients. It showed that those taking l mg of DES had a significantly better overall survival rate than the other groups.
The delayed progression seen in the group with the largest dose, 5 mg of DES, again did not translate into a survival benefit because of the excessive number of cardiovascular deaths. The study suggested that immediate estrogen therapy would be most beneficial for younger patients (younger than 75 years old with higher Gleason’s score tumors, ranging between 7 to 10), and that a low dose of DES was as effective and less toxic than the higher dose.
The third VACURG study gave stage I and II patients without prior surgery or radiation l mg of DES, or no therapy. Strangely, DES produced an excess of cardiovascular deaths in stage I patients, but not stage II patients. The authors were unable to account for such results. DES still decreased progression and increased the 5-year overall survival.
Based on these three studies, some clinicians found that the benefit of delayed disease progression in some patient subgroups provided them with a basis for further development of the early use of hormonal therapy as adjuvant therapy for prostate cancer. Clinicians knew that patient selection and the use of newer less toxic therapy would play a key role in the future success of early hormone withdrawal therapy.
Neoadjuvant Androgen Deprivation Therapy
Neoadjuvant Therapy and Surgical Margins
When treatment is applied before definitive radiation or surgery, it is termed neoadjuvant therapy. This modality has been quite successful in patients with breast cancer and helps define those who will have prolonged survival. Patients responding thoroughly to neoadjuvant treatment have invariably enjoyed prolonged survival when compared to those enjoying only a partial response. It is not unusual to have all traces of breast cancer disappear before surgery in patients treated with neoadjuvant chemotherapy (17-30% of patients). Neoadjuvant therapy is a way one can tell early on in the disease whether a particular patient may need more than usual therapy and whether the drugs used as neoadjuvant treatment are effective.
Table 1 reveals results from five studies of neoadjuvant androgen withdrawal therapy in prostate cancer patients. Treatment efficacy was measured by primary tumor shrinkage and the frequency of positive surgical margins. A positive surgical margin means that the entire tumor could not be surgically removed from the patient. As can be seen in Table 1, neoadjuvant therapy significantly decreased the frequency of positive surgical margins by a factor of 50% or more. These exciting initial observations have given way to critical pessimism by some urologists.
The criticism comes from the inability thus far to demonstrate increased survival for patients undergoing neoadjuvant therapy. However, since neoadjuvant protocols are relatively new and the course of prostate cancer is quite long, some feel that these study results are premature and may later demonstrate prolongation of survival in years to come.
Duration of Neoadjuvant Therapy
The reported duration of pre-operative or preradiation neoadjuvant androgen withdrawal has varied between 3-8 months. A summary of clinical studies illustrated in Table 2 reveals that prostate volume as well as the frequency of positive surgical margins decreases as a function of duration of neoadjuvant therapy. This should be a lesson to those urologists who recommend a single month or as few as three months of neoadjuvant therapy before radical prostatectomy. In my opinion, one to three months of therapy is inadequate if maximal prostatic tumor shrinkage is the purpose of neoadjuvant therapy. The use of neoadjuvant therapy for women with breast cancer shows that maximum regression of the primary tumor before surgery portends for a better overall survival, and I believe that the same paradigm holds true for patients with prostate cancer.
The return of measurable levels of PSA in the blood to values greater then 0.3 ng/ml after surgical removal of the prostate gland (radical prostatectomy) almost always means that the disease has returned and the treatment has failed. This is termed PSA failure. The frequency of PSA failure after radical prostatectomy preceded by neoadjuvant therapy was compared to PSA failure after radical prostatectomy alone; the results are displayed in Table 3.
As is evident in Table 3, six of seven clinical studies administered some form of preoperative androgen ablation for only three months while Baret et al continued therapy for six months before patients were subjected to radical prostatectomy.
Each study had a control group that was immediately sent to radical prostatectomy. Though neoadjuvant treatment decreased the percentage of patients with a positive surgical margin, there has not yet been a definitive reduction in the rate of PSA failure or overall survival when compared to the control or placebo treated groups. Why?
Figure 3 presents data obtained from patients undergoing adjuvant chemotherapy for breast cancer with the antiestrogen drug, tamoxifen. The data from the Early Breast Cancer Trialists’ Collaborative Group20 suggests that five years of antiestrogen therapy is more effective than two years of therapy in preventing the recurrence of breast cancer. The fact that there was no significant difference in cancer recurrence between the treated and untreated groups until more than two years of therapy is of great importance, and has monumental implications for patients with prostate cancer.
Figure 3: Women with breast cancer treated with adjuvant tamoxifen (an antiestrogen) benefited maximally if therapy was continued for five years.
Since both prostate and breast cancer are responsive to antihormone drugs, we should take the lead from successful studies already completed for breast cancer and deduce that a similar duration (2-5 years) of treatment for prostate cancer patients may be necessary to demonstrate increased survival.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-14, evaluated five years versus 10 years of adjuvant tamoxifen for early stage breast cancer and their data indicated no advantage for continuation of tamoxifen beyond five years.
Adjuvant Therapy Following Prostatectomy
Horst Zincke is a leading urologist at the Mayo clinic in Rochester, MN and he has carefully analyzed pre- and post-PSA era Mayo Clinic studies of prostate cancer patients undergoing radical prostatectomy and lymphadenectomy (removal of lymph nodes).21,22 Studying patients with disease that had progressed to involve lymph nodes, he compared the survival rates of those who were treated with immediate hormonal blockade to those receiving hormonal blockade only after disease progression. He found statistically significantly improved survival for those undergoing immediate androgen withdrawal as shown in Table 4. His initial report demonstrated that patients whose tumors had a normal complement of nuclear DNA (diploid tumors) benefited the most from early androgen withdrawal.
In still another study of early hormonal withdrawal in patients with locally advanced disease, Wirth and coworkers23 found that patients immediately treated with the antiandrogen flutamide (250 mg twice daily) given after they underwent radical prostatectomy had one-third the recurrence rate of those not receiving such therapy. Subsequently, the Eastern Cooperative Oncology Group (ECOG) under the leadership of Edward Messing24 randomized 98 men with prostate cancer that had spread to pelvic lymph nodes at the time of surgery. These men received immediate antiandrogen therapy (with either goserelin, an LHRH agonist, or orchiectomy), or were followed until disease progression. There was a dramatic increase in survival for only those patients treated with early androgen withdrawal, as shown in Figures 4, 5, and 6.
Androgen Deprivation as Adjuvant Therapy for Radiation Treated Patients
Early Orchiectomy Plus Radiation
A second leading definitive treatment for localized prostate cancer is some form of radiation. Thus a Swedish study undertaken by Hans Modig25 compared the combination of orchiectomy and radiotherapy to external beam radiotherapy alone as treatment for prostate cancer confined to the pelvis. The clinical characteristics of the patients in Modig’s study are summarized in Table 5.
In his study, Modig concluded that 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 (Figure 7). His results strongly suggested that early androgen deprivation is better than deferred treatment for patients with positive lymph nodes. These findings are similar to those reported by Horst Zincke and Edward Messing for their surgically treated patients.
Early LHRH Agonist Plus Radiation
A landmark study of the use of adjuvant androgen withdrawal in patients treated with radiation was undertaken by the European Organization for the Research and Treatment of Cancer (EORTC) by Professor Bolla.26,27 Bolla’s study compared both (1) external radiation alone and (2) external radiation combined with the LHRH agonist, goserelin, to investigate the added value of long-term androgen suppression in locally advanced prostate cancer.
The five-year clinical disease-free survival was dramatically different for both groups: 40% in the radiotherapy-alone group, and 74% in the combined treatment group as shown in Figure 9 (above). The five-year overall survival was 62% and 78% respectively as shown in Figure 8 (above), and the five-year disease-specific survival was 79% and 94% (no Figure provided). This study demonstrated that for patients with locally advanced disease, prolonged (three years) combined androgen withdrawal and radiation is superior to radiation alone.
RTOG Studies (see Table 6)
Other clinical studies have addressed the role of androgen suppression as adjuvant therapy to external beam irradiation. The Radiation Therapy Oncology Group reported on three such randomized studies.28
The first, Protocol 86-10, compared androgen deprivation plus radiotherapy with radiotherapy alone; androgen deprivation was found to significantly increase the five year rate of local control and to decrease the frequency of tumor spread to distant sites.
Protocol 85-31, the second study, investigated adding adjuvant androgen suppression with goserelin (1) in patients classified as clinical stage T1–2 (tumor confined to the prostate gland) but with regional lymph-node involvement, and (2) in patients with disease that had penetrated the prostate capsule as noted after prostatectomy. There was a statistically significant increase in the rates of local control and freedom from distant metastases, as well as disease-free survival, in patients with centrally reviewed tumors with a Gleason score of 8–10. There was also a difference in predicted five year survival in favor of the adjuvant-goserelin group.29
In the third study, Protocol 92-02, spearheaded by Gerald Hanks’ patients assigned long-term androgen suppression (28 months; starting two months before XRT) with goserelin. When compared to placebo-treated patients, this protocol resulted in significantly better disease-free survival and local control, time to distant metastasis, and time to biochemical failure. Disease-specific survival was slightly, but not significantly, higher.30
All of the RTOG studies demonstrate some form of benefit from the early addition of androgen blockade to external beam radiation. Gleason score, extent of disease and duration of therapy are parameters that impact on the extent patients benefited from combined therapy(Table 6).
Adjuvant Hormonal Therapy for Brachytherapy (Seeds)
Nelson Stone31,32 from Mt. Sinai Hospital in Manhattan, NY studied 296 patients with localized and locally advanced prostate cancer who were candidates for prostate brachytherapy (seed implant). As shown in Figure 10, his group treated 181 patients with brachytherapy alone, while 115 received complete androgen blockade for three months prior to, and three months after implantation. He found that at the end of two years, repeat prostate biopsies were one fourth as likely to be positive in the hormone treated group.
Figure 10: Hormone withdrawal in conjunction with prostate brachytherapy was studied by Stone and colleagues.
Thus far, studies of radiation or surgery in combination with androgen deprivation in patients with locally or regionally advanced prostate cancer have been criticized because all trials failed to include a control group treated with hormone treatment alone. A current National Cancer Institute of Canada trial is addressing the role of hormone treatment alone, comparing maximum androgen blockade with maximum androgen blockade plus pelvic irradiation in stages T3–4 (disease through the capsule or involving surrounding structures) node negative patients. A prospective randomized study by RTOG is also addressing this issue in a trial of adjuvant therapy for high-risk prostate cancer patients. In my opinion, based on the literature reviewed above, this study will show that patients benefit from early testosterone withdrawal if it is continued for at least two years.
Androgen Deprivation as Sole Therapy
So there you have it. It looks to me as though early hormonal blockade as adjuvant to other definitive therapies (surgery or radiation) slows disease progression and may extend life for many years. The laboratory rodent studies of Isaacs, the large World Health Organization clinical study and the Veterans Administration studies, and the Bolla, Messing, Zincke, and Hanks studies were the first to suggest that early hormonal ablation could be of value. I believe, based on the earlier breast cancer work with tamoxifen and the Hanks and Bolla studies, that the duration of androgen withdrawal is very important. Based on current knowledge, I would recommend when using testosterone withdrawal as an adjuvant that a minimum of two and a maximum of five years of therapy be used for maximum benefit. Use for longer periods may be necessary for patients with advanced metastatic disease.
So what’s the big deal? Why the controversy? Some in the urological community will go to their graves believing early hormonal blockade is of no value. They have written books and editorials in journals condemning the practice. They ignore results from newer studies and try to find fault. There is no hope for them.
Others objectively face the other side of the coin with their patients, which is the tradeoff of androgen withdrawal toxicity and the effects of such on quality of life versus true benefit. Testosterone lowering comes at a cost to the patient; the price is higher for some than others.
Younger patients pay more. They miss testosterone much more than older patients who frequently start out with lower blood levels and have been losing testosterone since their thirties and forties. Is the potential increase in survival worth the toll?
For some, yes, and for some, no. In my practice, some patients who would clearly benefit from early androgen withdrawal decline the treatment. Androgen withdrawal issues of loss of libido, decreased muscle strength, depression, and weight gain, osteoporosis, breast enlargement, hot flashes and decreased energy must be weighed against the potential of increased survival. New drugs and treatment protocols are addressing these toxicity issues. For instance, high-dose Casodex® (150 mg/d) may preserve libido for many; bisphosphonate drugs (Fosamax®, Actonel®, Aredia®, Zometa®) with calcium and vitamin D protect against bone loss; vigorous exercise may preserve muscle strength and prevent weight gain; and small doses of progesterone minimize hot flashes. New drugs such as aromatase inhibitors and tamoxifen may prevent breast enlargement.
If you have read this far I congratulate you for enduring a complex and possibly boring literature review. However, now you have been exposed to the same clinical studies as your urologist and you can talk the talk and walk the walk with him. I hope you are now armed with enough information to sit down with your physicians and choose what is best for you.
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2. The Veterans’ Administration Cooperative Urological Research Group studies of carcinoma of the prostate: a review. Cancer Chemotherapy Rep Jan-Feb, 1975, 59 (1) pp 225–7.
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20. Early Breast Cancer Trialists’ Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 339: pp 71- 85 1992
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22. Zincke, Horst, Lau,Weber, Bergstralh Erik et al: Role of early adjuvant hormonal therapy after radical prostatectomy for early prostate cancer. The Journal of Urology® Vol. 166, pp 2208–2215, 2001
23. Wirth M, Frohmuller H, Marz F, et al. Randomized multi-center trial on adjuvant flutamide therapy in locally advanced prostate cancer after radical surgery: Interim analysis of treatment effect and prognostic factors [abstract]. Br J Urol; 80:263, 1997
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25. Granfors; Torvald, Modig; Hans, Damber; Jan-Erik et al: A prospective randomized study. The Journal of Urology; 159:2030-2034, 1998.
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28. Pilepich MV, Winter K, Roach M, et al. Phase III Radiation Therapy Oncology Group (RTOG) trial 86-10 of androgen deprivation before and during radiotherapy in locally advanced carcinoma of the prostate. Proc Am Soc Clin Oncol; 17: 308a, 1998.
29. Pilepich MV, Caplan R, Byhardt RW, et al: Phase III trial of androgen suppression using goserilin in unfavorable prognosis carcinoma of the prostate treated with definitive radiotherapy: Report of Radiation Therapy Oncology Group Protocol 85-31. J Clin Oncol; 15: 1013–21, 1997.
30. Hanks GE, Lu J, Matchay M, et al. RTOG protocol 92-02:. A phase III trial of the use of long term androgen suppression following neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate. Proc Am Soc Clin Oncol; 19: 327a (abstr 1284), 2000.
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33. Fowler, Jackson E. Jr., Bigler, Steven A, Kolski, John M et al: Early results of a prospective study of hormone therapy for patients with locally advanced prostate carcinoma. Cancer Volume 82 pp 1112-1117, March 15, 1998.