Androgen-Independent Disease: Definition and Guide to Therapy

Sandra Srinivas, MD
Assistant Professor of Medicine
Stanford University School of Medicine
Stanford, California, USA

Introduction

Prostate cancer is exquisitely sensitive to hormonal therapy. In about 80% of patients, therapy aimed at depriving or depleting testosterone results in a fall in serum prostate-specific antigen (PSA) and in objective responses in bone scan and measurable diseases. The median time to progression is approximately 18-24 months and the median survival is about 24-30 months.

Eventually, resistant disease develops in almost all individuals, as manifested by a climb in serum PSA and, ultimately, worsening of symptoms. This resistant disease is defined as hormone-refractory or androgen-independent disease and is associated with a dismal prognosis. Median survival is 6-12 months after relapse. Subsets of patients may continue to respond to secondary hormonal maneuvers, however, leading to confusion in terminologies. New classification schemes have been proposed for hormone-refractory prostate cancer. Scher et al¹ have proposed that tumors be categorized as hormone-naive, androgen-independent but hormone-sensitive, and hormone-independent.

Prostate-Specific Antigen as a Measure of Disease

One of the difficulties in developing new drugs for prostate cancer is the difficulty in evaluating response in this disease. Since more than 75% of patients have no measurable disease, serum PSA has been used as a surrogate endpoint. Decline in serum PSA from pretreatment levels of greater than 50%, 75%, or 80% have been used to define responders. Myers and coworkers² demonstrated that patients who had a greater than 75% fall in serum PSA had a longer survival. Kelly et al³ reported on a combination of trials that patients had a longer median survival if they had a greater than 50% fall in serum PSA by 2 months of treatment. Smith et al⁴ reported that a serum PSA value after 8 weeks of therapy was most predictive of survival and response. With the use of hormones in early stage disease, groups of patients may have serum PSA as the only measure of disease. The prognosis and survival of this group is very different from a patient with stage-D2 hormone-refractory disease. Clearly, serum PSA is being used with increased frequency as a surrogate marker for response in patients with hormone-refractory prostate cancer. However, its utility in evaluating therapies such as suramin remains controversial.

A need exists for consensus in defining response criteria in hormone-refractory prostate cancer. Dawson,⁵ in her report of a survey of 35 investigators found consensus on eligibility criteria, but less consensus in reporting outcomes. Therefore, most clinical trials in hormone-refractory prostate cancer include serum PSA data, as well as standard data, for measurable disease.

Continued Testicular Suppression

In patients with progressive hormone-refractory disease, it is necessary to maintain continued castrate levels of testosterone. Discontinuation of testicular suppression may have adverse effects. Taylor⁶ reported that continuation of androgen suppression was an independent predictor of survival. However, a Southwest Oncology Group (SWOG) study⁷ failed to demonstrate a survival advantage to continuing testicular suppression. Fowler and Whitmore⁸ reported that 87% of the 52 men who were treated with exogenous testosterone had progressive disease and increased morbidity. Thus, it appears that continued testicular suppression is prudent for patients with progressive hormone-refractory disease, despite the cost associated with such treatment.

Secondary Hormonal Therapies

The serendipitous observation that patients with metastatic prostate cancer on combined androgen blockade, when withdrawn from flutamide, experienced subjective and objective improvement and a fall in serum PSA led to the discovery of "the antiandrogen withdrawal syndromes." Withdrawal of flutamide has been shown to result in a greater than 50% fall in serum PSA, and objective responses in about 30% of patients. The duration of this response, however, is short lived, with a median duration of response of about 3-5 months. Initially described with flutamide, this response also has now been reported with bicalutamide, diethylstilbestrol, chlormadinone, and megestrol acetate. The mechanism of this withdrawal syndrome is thought to be due to a mutation in the androgen-receptor–binding domain. Therefore, the first intervention for patients who progress on therapy with an antiandrogen should be withdrawal of that agent with a period of observation appropriate to the half life of the agent, especially prior to enrollment on a clinical trial.

Bicalutamide

Evidence suggests that patients treated initially with surgical castration alone or monotherapy with luteinizing hormone releasing hormone (LHRH) analog may benefit from the addition of an antiandrogen at the time of progression.

High-dose bicalutamide has been studied in patients who have failed first-line therapy. Fenton et al⁹ demonstrated a 40% response rate in 15 patients treated with 150 mg of bicalutamide. However, no objective responses were seen in 52 patients treated on a phase-II SWOG study, though disease stabilized and pain scores decreased.

Ketoconazole

Ketoconazole, a cytochrome p450 inhibitor, has shown to be very effective when given in high doses in prostate cancer. It blocks the synthesis of both testicular and adrenal androgens and may have a direct antitumor effect on prostate cancer cells. Ketoconazole use in metastatic prostate cancer has a clinical response of 10% and stabilizes disease in 35%. Small et al¹⁰ have reported on 50 patients treated with ketoconazole and hydrocortisone. They observed that 62.5% of patients had a greater than 50% fall in serum PSA. The toxicity profile was mild with gastrointestinal symptoms occurring in 15% of patients treated.

Liarazole

Liarazole, another potent p450-dependent inhibitor has been studied in a phase I/II study. A 30% response was noted in hormone-refractory prostate cancer patients.

Megestrol Acetate

Megestrol acetate has been used as an antiandrogen in patients with progressive metastatic prostate cancer. Cancer and Leukemia Group B (CALGB)¹¹ compared high dose of 640 mg/day to standard dose of 160 mg/day in 149 patients. No difference was seen in the response rates to the different dosing. The objective response rate was 3%, with 12% having a greater than 50% fall in serum PSA.

Glucocorticoids

Glucocorticoids, by suppressing pituitary adrenocorticotrophic hormone, reduce adrenal androgen production. Glucocorticoid therapy has been used as a palliative measure in prostate cancer. At a low dose, prednisone has improved quality of life in 40% of patients. In a randomized trial comparing mitoxantrone and prednisone with prednisone alone, Tannock et al¹² demonstrated that 21% of patients on the prednisone arm had improvement in quality of life, with a decrease in pain intensity. Other steroid preparations such as hydrocortisone and dexamethasone also have shown subjective responses with minimal toxicity.

PC-SPES

PC-SPES, a Chinese herbal preparation containing chrysanthemum, isatis (dyers woad), licorice, saw palmetto, Ganoderma lucidum (reishi), Panax pseudoginseng, Rabdosia rubescens, and scutellaria, has activity in prostate cancer. A drop in PSA and decline in testosterone to castrate levels are seen in all hormone-naive patients. Interestingly, PSA drops with some objective responses in patients with androgen-independent disease as well. PC-SPES is associated with an increased risk of vascular thrombosis. Therefore, second-line hormones are reasonable alternates to chemotherapy. They are less toxic and have predictable response rates.

Chemotherapy in Hormone-Refractory Prostate Cancer

Responses to single-agent chemotherapy in prostate cancer occur in about 5% to 30% of patients. The difficulty in evaluating response, the toxicity associated with chemotherapy, and the lack of survival benefit have resulted in significant skepticism regarding the routine use of chemotherapy. However, newer agents and newer combinations have triggered a renewed enthusiasm and resurgence of chemotherapy in this disease. The active single agents have included estramustine, anthracyclines, vinblastine, etoposide, and taxanes.

Estramustine

Estramustine phosphate is a conjugate of nitrogen mustard and estradiol. As a single agent, it has an activity of about 20% in prostate cancer. On the basis of preclinical data (Table 1) showing synergy between estramustine and vinca alkaloids, Hudes et al¹³ used oral estramustine at 600 mg/m² daily in combination with vinblastine at 4 mg/m² intravenously once a week for 6 weeks. In 36 patients, they observed a 61.1% response rate of a greater than 50% fall in serum PSA and a 14% partial response in measurable soft tissue disease. Seidman,¹⁴ using estramustine at a dose of 10 mg/kg daily and intravenous vinblastine at 4 mg/m² weekly for 6 weeks, reported a 54% response rate with a greater than 50% fall in serum PSA.

Estramustine, in combination with etoposide, a topoisomerase-II inhibitor, has been studied. A regimen employing estramustine at a dose of 15 mg/kg /day and oral etoposide at 50 mg/m² daily for 21 days was repeated every 28 days. Fifty percent of patients had a greater than 50% fall in serum PSA and a 50% overall response rate in patients with measurable disease.

Paclitaxel, as a single agent given as a continuous infusion, results in a 3% partial response. In a phase-II study by Hudes,¹⁶ paclitaxel given as a 96-hour continuous infusion every 3 weeks, along with estramustine at 600 mg/m², resulted in a 44% response rate in bidimensional measurable tumors and a 50% response rate in serum PSA in 14 of 25 patients. Paclitaxel, when combined with estramustine and etoposide in a phase-II study by Pienta et al,¹⁷ resulted in 57% of patients demonstrating a greater than 50% fall in serum PSA.

Cyclophosphamide

Cyclophosphamide, as a single agent and in combination, has minimal activity in hormone-refractory prostate cancer. Saxman et al¹⁸ reported very minimal response in a randomized study with cyclophosphamide alone versus a combination of cyclophosphamide with doxorubicin and methotrexate. In a phase-II trial with 30 patients treated with oral cyclophosphamide at a dose of 100 mg/m²/day for 14 days, Raghavan et al¹⁹ reported a 20% partial response. A significant proportion of patients (60%) achieved a reduction in pain. A French study reported the results on 20 patients treated with a combination of oral cyclophosphamide with oral etoposide. An objective response was seen in 35% of patients, and the regimen was well tolerated.

Anthracyclines

Doxorubicin has been used extensively in prostate cancer. As a single agent, both a fall in PSA as well as objective responses have been noted. Doxorubicin has also been used in combination with a variety of agents. When combined with 5-fluorouracil and mitomycin C, responses ranged from 14% to 42%. Significant myelosuppression was associated with this combination. Weekly doxorubicin combined with ketoconazole had an impressive 58% soft-tissue response rate, and a greater than 50% fall in serum PSA was observed in 55%. However, the toxicities were preclusive of routine use of this regimen. The same regimen has also been combined with estramustine and vinblastine on an alternating weekly schedule. A serum PSA response was seen in 67% of patients. Significant thrombotic events occurred, including myocardial infarctions and venous thrombosis. Doxorubicin also has been combined with dose-escalating cyclophosphamide, with a 33% partial response and a 46% serum PSA response. Myelosuppression was significant, with patients requiring growth factor support.

Mitoxantrone has structural similarity to doxorubicin, but has a more favorable toxicity profile. Moore et al²⁰ demonstrated that the combination of mitoxantrone and prednisone yielded a significant palliation in patients with hormone-refractory prostate cancer. A phase-III trial comparing mitoxantrone with prednisone versus prednisone alone demonstrated significant palliation with chemotherapy and prolonged duration of palliation with chemotherapy. The PSA response was only 39% with mitoxantrone.

Suramin

Suramin is a polysulfonated napthylurea. It binds to proteins, inhibits growth factors, causes induction of differentiation, and inhibits protein kinase, topoisomerase II, G proteins, etc. Suramin has a very long half life related to its protein binding. It has been in use as an antiparasitic agent for decades, but more recently has been used as an antineoplastic agent. The initial trials in prostate cancer were very promising, but subsequent studies have demonstrated a lower response rate and an association with significant toxicity (Table 2). Suramin use in prostate cancer produces many unresolved issues: dosing of the drug, the duration of therapy, and its toxicity profile, including the development of skin cancers.

In conclusion, many effective chemotherapy regimens are available. The response proportion as measured by serum PSA is reasonable. Some trials have demonstrated a decrease in pain and improvement in quality of life. It currently is unclear if asymptomatic patients benefit from chemotherapy. The stage is well set for a randomized trial with chemotherapy or the best supportive care to answer that question. In the interim, patients are encouraged to participate in clinical trials.

Bisphosphonates

Randomized trials in breast cancer and multiple myeloma have shown that monthly use of bisphosphonates in patients with metastases decreases adverse skeletal events. Use of bisphosphonates also has decreased the requirement for narcotics and bone pain. Men with prostate cancer treated with hormones are at increased risk of osteoporosis, and it appears that bisphosphonates may play a role in routine management of patients with metastatic prostate cancer in the future. Trials are underway in evaluating this question in a randomized fashion.

Radioisotopes

Since bone is the predominant site of metastases in prostate cancer, and a significant proportion of patients have pain and morbidity from bone metastases, a systemic form of therapy has been very attractive. Three radioisotopes have been available for systemic use. They include phosphorus 32 (32P), strontium chloride 89 (89Sr) and samarium 153 (153Sm). These agents get incorporated into bone and emit low energy electrons that get incorporated preferentially into bony lesions rather than normal bone.

89Sr has been used the most in prostate cancer. It is a beta emitter and has a long half life. Following treatment with 89Sr, 80% of patients have had a decrease in pain. 89Sr also has been used as an adjuvant following local radiation to a painful metastatic spot. A randomized placebo-controlled trial demonstrated that patients who had 89Sr were less likely to require further radiation than those who did not receive 89Sr. The most significant toxicity of 89Sr is myelosuppression, especially which typically occurs 6-12 weeks after the injection.

153Sm is another beta-emitting radioisotope that is approved by the Food and Drug Administration for treatment of painful metastases. 153Sm has been compared to placebo in 141 patients with metastatic prostate cancer and found to decrease pain and reduce analgesic use compared to placebo.

Future strategies include the combination of radioisotopes with chemotherapy. The timing on the use of these radionuclides is still unclear. These agents will certainly play a role in the treatment or palliation of bone metastases from prostate cancer.

Conclusion

In conclusion, androgen-independent disease is on the rise and related to the early use of hormones. Many agents and combinations are effective in palliating pain and improving quality of life. Several novel agents, such as phenylbutyrate, vitamin D, genistein, and polyphenols, are being tested in this group of patients. However, questions remain, especially regarding the timing of therapy. Until a survival advantage is demonstrated, routine use of such therapy in asymptomatic patients cannot be recommended for patients outside of a clinical trial.