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Chemotherapy for Prostate Cancer
Clinical Oncology (2001)13:453–454 # The Royal College of Radiologists
Clinical Oncology
Editorial Chemotherapy for Prostate Cancer J. Wang and J. Waxman Imperial College School of Medicine, London, UK Hormonal treatments for prostate cancer have a limited duration of effect. Prostate specific antigen (PSA) levels start to increase to a median of 12–16 months from the start of treatment [1]. Subsequently, prostate cancer becomes refractory to treatment, due to the selection of androgen-independent tumour cells [2]. Second line hormonal treatments have a transient effect, with progression inevitable and the overall survival of patients with metastases is only 3 years [1]. There is clearly a need to improve on the outlook for patients with prostate cancer. Is there a role for chemotherapy? In the 1970s, when cytotoxic chemotherapy agents became available for different cancers, their use in prostate cancer was studied mostly in the context of second line treatment. These studies, most of which involved small numbers of patients, suggested subjective response rates of up to 31% [3]. In the 1980s, many of these earlier studies were reviewed [3] and, using more stringent response criteria, the objective response rate was described as 5%. It was clear that responses were not sustained and there was no significant survival benefit to chemotherapy. Aggressive therapy was also often poorly tolerated because these patients were usually elderly, with concomitant illnesses, and with poor marrow reserve and performance status. In the 1990s, new, less toxic cytotoxic agents became available and the role of chemotherapy in prostate cancer was revisited. It became recognized that chemotherapy in hormone-resistant cancer, although not improving survival significantly, results in good palliation, and it emerged that the most effective of the newer agents was mitozantrone. Tannock et al. compared mitozantrone and prednisone with prednisone alone in 161 patients and showed a symptom response rate of 29% versus 12%, with no significant toxicity and an improved quality of life [4]. This study pointed the way to the importance of Correspondence and offprint requests to: Prof. J. Waxman, Department of Cancer Medicine, Division of Medicine, Imperial College School of Medicine, Hammersmith Campus, Du Cane Road, London W12 ONN, UK. Tel: 0208 383 4651.
quality of life as endpoints for chemotherapy treatments. The lack of a survival advantage with conventional chemotherapy agents [3] and increasing numbers of deaths from prostate cancer have prompted the development of new chemotherapy agents for this condition. Drug development has concentrated on the delicate balance between efficacy and toxicity. Novel approaches have been applied over the years, such as the use of estramustine, which was designed to have both oestrogenic and alkylating properties, with the steroid moiety active as a delivery system. Unfortunately this agent is relatively ineffective and has all the disadvantages of oestrogen therapy. Suramin, an antihelminth drug, was also shown to be effective in prostate cancer, probably owing to growth factor inhibitory effects. PSA levels are suppressed irrespective of treatment response, and newer trials have not shown definite improvement in symptoms [5]. Hormone-resistant cancers overexpress the bcl group of anti-apoptosis oncoproteins. Certain agents, such as vinca alkaloids and taxanes, in addition to their cytotoxic effect, act to inhibit microtubule function and induce bcl-2 phosphorylation, thereby facilitating apoptosis. These drugs seem to offer some promise; docetaxel, in particular, was shown in an early study to improve patient survival [6]. There have also been several early studies on the value of chemotherapy as an adjuvant therapy, in both localized and metastatic prostate cancer. The biological rationale for this strategy is that at presentation prostate cancers contain heterogeneous populations of hormone-sensitive and hormone-resistant cells [2]. Treatment with hormonal therapy is eventually accompanied by the selective growth of hormoneresistant clones but treatment with chemotherapy in addition to hormonal therapy could potentially target both populations, leading to a synergistic effect. It would be reasonable to investigate this approach on the basis of the benefits of adjuvant chemotherapy in breast and colorectal cancer. Adjuvant chemotherapy trials have been carried out in several groups of patients. These include those patients with localized disease who have been treated
by prostatectomy or radical radiotherapy and patients who have received hormonal therapy for advanced tumours. Adjuvant therapy trials for patients with localized cancer after surgery or radiotherapy have been largely carried out on patients with a high risk of relapse, such as those with high-grade carcinoma, incomplete excision margins or pelvic node involvement. Two large trials conducted by the National Prostate Cancer Project and published in 1993, in which estramustine or cyclophosphamide were administered after surgery or radiotherapy, seemed to indicate a beneficial effect of adjuvant chemotherapy in terms of disease-free survival [7]. Currently, trials are underway using newer chemotherapy agents, and on combinations of hormonal therapy and chemotherapy. The use of chemotherapy in conjunction with hormone treatment in advanced or metastatic cancer has been limited. There has been no consensus emerging from the trials. Some trials showed a minor improvement in response rates but no survival benefit, while others failed to show any advantage [8]. These studies were conducted in the 1980s and early 1990s with agents that are relatively ineffective treatments of prostate cancer. We have recently completed a Phase III study of adjuvant therapy using what is arguably the most effective cytotoxic agent. Ninety-six patients with locally advanced (T3 or T4) or metastic (M1) prostate cancer were treated by total androgen blockade, with or without four courses of mitozantrone. After a follow-up period of up to 10 years, subset analysis showed a more than twofold increase in the duration of survival in patients with locally advanced disease [9]. There are clear limitations to the validity of any conclusion that we can draw from this study because of the small patient numbers involved. However, given the increasing number of people that have prostate cancer and the transcience of response, further investigation of this approach is warranted.
454
J. Wang and J. Waxman
There is now mounting evidence that chemotherapy is useful and should be offered to patients with hormone-resistant prostate cancer. This is reflected in the USA, where mitozantrone and estramustine have been approved for this use. The role of adjuvant chemotherapy in this condition has yet to be resolved. This area has been neglected since the early 1990s and further large-scale studies are a priority. This issue is especially important as the cure of prostate cancer emerges as a priority for the western world.
References 1. Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989;321:419–24. 2. Issacs, JT, Heston WDW, Weissman RM, et al. Animal models of the hormone-sensitive and insensitive prostatic adenocarcinomas, Dunning R-3327-H, R-3327-H1 and R3327-AT. Cancer Res 1978;38:4353–9. 3. Eisenberger MA, Simon R, O’Dwyer PJ, et al. A Reevaluation of nonhormonal cytotoxic chemotherapy in the treatment of prostatic carcinoma. J Clin Oncol 1985;3:827– 41. 4. Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitozantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996;14:1756–64. 5. Small EJ, Meyer M, Marshall ME, et al. Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: results of a randomized Phase III trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone. J Clin Oncol 2000;18:1440–50. 6. Petrylak DP, Macarthur RB, O’Connor J, et al. Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 1999;17:958–67. 7. Schmidt JD, Gibbons RP, Murphy GP, et al. Adjuvant therapy for localized prostate cancer. Cancer 1993; 71:1005–13. 8. Wang J, Waxman J. Chemotherapy for prostate cancer. Urol Oncol 2000;5:93–6. 9. Wang J, Halford S, Rigg A, et al. Adjuvant mitozntrone chemotherapy in advanced prostate cancer. BJU Int 2000;86:675–80.
Clinical Oncology
Editorial Chemotherapy for Prostate Cancer J. Wang and J. Waxman Imperial College School of Medicine, London, UK Hormonal treatments for prostate cancer have a limited duration of effect. Prostate specific antigen (PSA) levels start to increase to a median of 12–16 months from the start of treatment [1]. Subsequently, prostate cancer becomes refractory to treatment, due to the selection of androgen-independent tumour cells [2]. Second line hormonal treatments have a transient effect, with progression inevitable and the overall survival of patients with metastases is only 3 years [1]. There is clearly a need to improve on the outlook for patients with prostate cancer. Is there a role for chemotherapy? In the 1970s, when cytotoxic chemotherapy agents became available for different cancers, their use in prostate cancer was studied mostly in the context of second line treatment. These studies, most of which involved small numbers of patients, suggested subjective response rates of up to 31% [3]. In the 1980s, many of these earlier studies were reviewed [3] and, using more stringent response criteria, the objective response rate was described as 5%. It was clear that responses were not sustained and there was no significant survival benefit to chemotherapy. Aggressive therapy was also often poorly tolerated because these patients were usually elderly, with concomitant illnesses, and with poor marrow reserve and performance status. In the 1990s, new, less toxic cytotoxic agents became available and the role of chemotherapy in prostate cancer was revisited. It became recognized that chemotherapy in hormone-resistant cancer, although not improving survival significantly, results in good palliation, and it emerged that the most effective of the newer agents was mitozantrone. Tannock et al. compared mitozantrone and prednisone with prednisone alone in 161 patients and showed a symptom response rate of 29% versus 12%, with no significant toxicity and an improved quality of life [4]. This study pointed the way to the importance of Correspondence and offprint requests to: Prof. J. Waxman, Department of Cancer Medicine, Division of Medicine, Imperial College School of Medicine, Hammersmith Campus, Du Cane Road, London W12 ONN, UK. Tel: 0208 383 4651.
quality of life as endpoints for chemotherapy treatments. The lack of a survival advantage with conventional chemotherapy agents [3] and increasing numbers of deaths from prostate cancer have prompted the development of new chemotherapy agents for this condition. Drug development has concentrated on the delicate balance between efficacy and toxicity. Novel approaches have been applied over the years, such as the use of estramustine, which was designed to have both oestrogenic and alkylating properties, with the steroid moiety active as a delivery system. Unfortunately this agent is relatively ineffective and has all the disadvantages of oestrogen therapy. Suramin, an antihelminth drug, was also shown to be effective in prostate cancer, probably owing to growth factor inhibitory effects. PSA levels are suppressed irrespective of treatment response, and newer trials have not shown definite improvement in symptoms [5]. Hormone-resistant cancers overexpress the bcl group of anti-apoptosis oncoproteins. Certain agents, such as vinca alkaloids and taxanes, in addition to their cytotoxic effect, act to inhibit microtubule function and induce bcl-2 phosphorylation, thereby facilitating apoptosis. These drugs seem to offer some promise; docetaxel, in particular, was shown in an early study to improve patient survival [6]. There have also been several early studies on the value of chemotherapy as an adjuvant therapy, in both localized and metastatic prostate cancer. The biological rationale for this strategy is that at presentation prostate cancers contain heterogeneous populations of hormone-sensitive and hormone-resistant cells [2]. Treatment with hormonal therapy is eventually accompanied by the selective growth of hormoneresistant clones but treatment with chemotherapy in addition to hormonal therapy could potentially target both populations, leading to a synergistic effect. It would be reasonable to investigate this approach on the basis of the benefits of adjuvant chemotherapy in breast and colorectal cancer. Adjuvant chemotherapy trials have been carried out in several groups of patients. These include those patients with localized disease who have been treated
by prostatectomy or radical radiotherapy and patients who have received hormonal therapy for advanced tumours. Adjuvant therapy trials for patients with localized cancer after surgery or radiotherapy have been largely carried out on patients with a high risk of relapse, such as those with high-grade carcinoma, incomplete excision margins or pelvic node involvement. Two large trials conducted by the National Prostate Cancer Project and published in 1993, in which estramustine or cyclophosphamide were administered after surgery or radiotherapy, seemed to indicate a beneficial effect of adjuvant chemotherapy in terms of disease-free survival [7]. Currently, trials are underway using newer chemotherapy agents, and on combinations of hormonal therapy and chemotherapy. The use of chemotherapy in conjunction with hormone treatment in advanced or metastatic cancer has been limited. There has been no consensus emerging from the trials. Some trials showed a minor improvement in response rates but no survival benefit, while others failed to show any advantage [8]. These studies were conducted in the 1980s and early 1990s with agents that are relatively ineffective treatments of prostate cancer. We have recently completed a Phase III study of adjuvant therapy using what is arguably the most effective cytotoxic agent. Ninety-six patients with locally advanced (T3 or T4) or metastic (M1) prostate cancer were treated by total androgen blockade, with or without four courses of mitozantrone. After a follow-up period of up to 10 years, subset analysis showed a more than twofold increase in the duration of survival in patients with locally advanced disease [9]. There are clear limitations to the validity of any conclusion that we can draw from this study because of the small patient numbers involved. However, given the increasing number of people that have prostate cancer and the transcience of response, further investigation of this approach is warranted.
454
J. Wang and J. Waxman
There is now mounting evidence that chemotherapy is useful and should be offered to patients with hormone-resistant prostate cancer. This is reflected in the USA, where mitozantrone and estramustine have been approved for this use. The role of adjuvant chemotherapy in this condition has yet to be resolved. This area has been neglected since the early 1990s and further large-scale studies are a priority. This issue is especially important as the cure of prostate cancer emerges as a priority for the western world.
References 1. Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989;321:419–24. 2. Issacs, JT, Heston WDW, Weissman RM, et al. Animal models of the hormone-sensitive and insensitive prostatic adenocarcinomas, Dunning R-3327-H, R-3327-H1 and R3327-AT. Cancer Res 1978;38:4353–9. 3. Eisenberger MA, Simon R, O’Dwyer PJ, et al. A Reevaluation of nonhormonal cytotoxic chemotherapy in the treatment of prostatic carcinoma. J Clin Oncol 1985;3:827– 41. 4. Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitozantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996;14:1756–64. 5. Small EJ, Meyer M, Marshall ME, et al. Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: results of a randomized Phase III trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone. J Clin Oncol 2000;18:1440–50. 6. Petrylak DP, Macarthur RB, O’Connor J, et al. Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 1999;17:958–67. 7. Schmidt JD, Gibbons RP, Murphy GP, et al. Adjuvant therapy for localized prostate cancer. Cancer 1993; 71:1005–13. 8. Wang J, Waxman J. Chemotherapy for prostate cancer. Urol Oncol 2000;5:93–6. 9. Wang J, Halford S, Rigg A, et al. Adjuvant mitozntrone chemotherapy in advanced prostate cancer. BJU Int 2000;86:675–80.