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. 2006 Oct 18;2006(4):CD005247.
doi: 10.1002/14651858.CD005247.pub2.

Chemotherapy for hormone-refractory prostate cancer

Mike Shelley  1 , Craig Harrison, Bernadette Coles, John Staffurth, Timothy J Wilt, Malcolm D Mason
Affiliations

Chemotherapy for hormone-refractory prostate cancer

Mike Shelley et al. Cochrane Database Syst Rev. .

Abstract

Background: Prostate cancer mainly affects elderly men, and its incidence has steadily increased over the last decade. The management of this disease is replete with controversy. In men with advanced, metastatic prostate cancer, hormone therapy is almost universally accepted as the initial treatment of choice and produces good responses in most patients. However, many patients will relapse and become resistant to further hormone manipulation; the outlook for these patients is poor. Many have disease extending to the skeleton, which is associated with severe pain. Therapies for these men include chemotherapy, bisphosphonates, palliative radiotherapy, and radioisotopes. Systemic chemotherapy has been evaluated in men with hormone-refractory prostate cancer (HRPC) for many years, with disappointing results. However, more recent studies with newer agents have shown encouraging results. There is therefore a need to explore the value of chemotherapy in this disease.

Objectives: The present review aims to assess the role of chemotherapy in men with metastatic HRPC. The major outcome was overall survival. Secondary objectives include the effect of chemotherapy on pain relief, prostate-specific antigen (PSA) response, quality of life, and treatment-related toxicity.

Search strategy: Trials were identified by searching electronic databases, such as MEDLINE, and handsearching of relevant journals and conference proceedings. There was no restriction of language or location.

Selection criteria: Only published randomised trials of chemotherapy in HRPC patients were eligible for inclusion in this review. Randomised comparisons of different chemotherapeutic regimens, chemotherapy versus best standard of care or placebo, were relevant to this review. Randomised, dose-escalation studies were not included in this review.

Data collection and analysis: Data extraction tables were designed specifically for this review to aid data collection. Data from relevant studies were extracted and included information on trial design, participants, and outcomes. Trial quality was also assessed using a scoring system for randomisation, blinding, and description of patient withdrawal.

Main results: Out of 107 randomised trials of chemotherapy in advanced prostate cancer identified by the search strategy, 47 were included in this review and represented 6929 patients with HRPC. Only two trials compared the same chemotherapeutic interventions and therefore a meta-analysis was considered inappropriate. The quality of some trials was poor because of poor reporting, low-patient recruitment, or poor trial design. For clarity, trials were categorised according to the major drug used, but this was not a definitive grouping, since many trials used several agents and would be eligible for inclusion in a number of categories. Drug categories included estramustine, 5-fluorouracil, cyclophosphamide, doxorubicin, mitoxantrone, and docetaxel. Only studies using docetaxel reported a significant improvement in overall survival compared to best standard of care, although the increase was small (< 2.5 months). The mean percentage of patients achieving at least a 50% reduction in PSA compared to baseline was as follows: estramustine 48%; 5-fluorouracil 20%; doxorubicin 50% (one study only); mitoxantrone 33%; and docetaxel 52%. Pain relief was reported in 35% to 76% of patients receiving either single agents or combination regimens. A three weekly regime of docetaxel significantly improved pain relief compared to mitoxantrone plus prednisone (the latter regimen approved as standard therapy for HRPC in the USA). All chemotherapeutics, either as single agents or in combination, were associated with toxicity; the major ones being myelosuppression, gastrointestinal toxicity, cardiac toxicity, neuropathy, and alopecia. Quality of life was significantly improved with docetaxel compared to mitoxantrone plus prednisone.

Authors' conclusions: Patients with HRPC have not traditionally been offered chemotherapy as a routine treatment because of treatment-related toxicity and poor responses. Recent data from randomised studies, in particular those using docetaxel, have provided encouraging improvements in overall survival, palliation of symptoms, and improvements in quality of life. Chemotherapy should be considered as a treatment option for patients with HRPC. However, patients should make an informed decision based on the risks and benefits of chemotherapy.

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Conflict of interest statement

None

Update of

  • doi: 10.1002/14651858.CD005247

References

References to studies included in this review

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References to studies excluded from this review

Ahles 2004 {published data only}
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Hervonen 2002 {published data only}
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Janknegt 1997 {published data only}
    1. Janknegt RA, Boon TA, Beek C, Grob P. Combined hormono/chemotherapy as primary treatment for metastatic prostate cancer: a randomized, multicenter study of orchiectomy alone versus orchiectomy plus estramustine phosphate. The Dutch Estracyt Study Group. Urology 1997;49(3):411‐20. - PubMed
    1. Miyake H, Hara I, Fujisawa M, Eto H, Okada H, Arakawa S, Kamidono S. Comparison of hormonal therapy and chemohormonal therapy in patients with newly diagnosed clinical stage D prostatic cancer. International Journal of Urology 1996;3(6):472‐7. - PubMed
Johansson 1987 {published data only}
    1. Johansson JE, Andersson SO, Beckman KW, et al. Clinical evaluation of flutamide and estramustine as initial treatment of metastatic carcinoma of prostate. Urology 1987;29(1):55‐9. - PubMed
Johansson 1988 {published data only}
    1. Johansson JE, Andersson SO, Beckman KW, Zador G. Clinical evaluation with long‐term follow‐up of flutamide and estramustine as initial treatment of metastatic carcinoma of the prostate. American Journal of Clinical Oncology: Cancer Clinical Trials 1988;11(SUPPL. 2):S183‐6. - PubMed
    1. Miyake H, Hara I, Fujisawa M, Eto H, Okada H, Arakawa S, Kamidono S. Comparison of hormonal therapy and chemohormonal therapy in patients with newly diagnosed clinical stage D prostatic cancer. International Journal of Urology 1996;3(6):472‐7. - PubMed
    1. Ruff P, Derman DP, Weaving A, Bezwoda WR. Sequential hormonal therapy and sequential hormonal and chemotherapy for advanced prostatic cancer. Oncology 1989;46(5):288‐92. - PubMed
Johnson 1977 {published data only}
    1. Johnson DE, Scott WW, Gibbons RP, Prout GR, Schmidt JD, Chu TM, Gaeta J, Saroff J, Murphy GP. National randomized study of chemotherapeutic agents in advanced prostatic carcinoma: a progress report. Cancer Treatment Reports 1977;61(2):317‐23. - PubMed
Kitahara 1988 {published data only}
    1. Kitahara S, Fukui I, Higashi Y, Kihara K, Takeuchi S, Oshima H, Negishi T, Hosoda K, Kawai T, Ikegami S, Yamauchi A, Sakai K, Wakui M, Sarada T, Ishiwata D, Tari K, Tohma T, Yokokawa M, Goto S. A randomized trial of chemotherapy for advanced prostatic cancer with ifosfamide alone versus ifosfamide, 5‐fluorouracil and cisplatin (preliminary report). Journal of Japan Society for Cancer Therapy 1988;23(10):2507‐13. - PubMed
Komatus 1996 {published data only}
    1. Komatus H, Maesawa H, Tanabe N, Tago K, Ueno A. Comparison of hormone therapy alone and in combination with chemotherapy of cisplatin and methotrexate in newly diagnosed patients with stage D2 prostatic cancer. [Japanese]. Nippon Hinyokika Gakkai Zasshi Japanese Journal of Urology 1996;87(4):789‐96. - PubMed
Kuriyama 2001 {published data only}
    1. Kuriyama M, Takahashi Y, Sahashi M, Ono Y, Tanaka T, Shimizu H, Ohshima S. Prospective and randomized comparison of combined androgen blockade versus combination with oral UFT as an initial treatment for prostate cancer. Japanese Journal of Clinical Oncology 2001;31(1):18‐24. - PubMed
Kylmala 1997 {published data only}
    1. Kylmala T, Taube T, Tammela TLJ, Risteli L, Risteli J, Elomaa I. Concomitant i.v. and oral clodronate in the relief of bone pain ‐ A double blind placebo‐controlled study in patients with prostate cancer. British Journal of Cancer 1997;76(7):939‐42. - PMC - PubMed
Lundgren 1995 {published data only}
    1. Lundgren R, Nordle O, Josefsson K. Immediate estrogen or estramustine phosphate therapy versus deferred endocrine treatment in nonmetastatic prostate cancer: a randomized multicenter study with 15 years of followup. The South Sweden Prostate Cancer Study Group. Journal of Urology 1995;153(5):1580‐6. - PubMed
Manni 1986a {published data only}
    1. Manni A, Santen RJ, Boucher AE, et al. Hormone stimulation and chemotherapy in advanced prostate cancer: Interim analysis of an ongoing randomized trial. Anticancer Research 1986;6(2):309‐14. - PubMed
Manni 1986b {published data only}
    1. Manni A, Santen RJ, Boucher AE, Lipton A, Harvey H, Simmonds M, White‐Hershey D, Gordon RA, Rohner TJ, Drago J. Androgen priming and response to chemotherapy in advanced prostatic cancer. Journal of Urology 1986;136(6):1242‐6. - PubMed
Matsuda 1995 {published data only}
    1. Matsuda H, Nonomura K, Nagamori S, Shinohara N, Koyanagi T, Maru A, Matsuno T, Fujieda J, Minami S, Morita H, Abe N, Kawakura K, Sakakibara N, Nojima T, Nakazono N. Clinicopathological evaluation of etoposide or estramustine phosphate in castrated patients with advanced prostatic cancer. Japanese Journal of Urology 1995;86(10):1530‐37. - PubMed
Miyake 1996 {published data only}
    1. Miyake H, Hara I, Fujisawa M, Eto H, Okada H, Arakawa S, Kamidono S. Comparison of hormonal therapy and chemohormonal therapy in patients with newly diagnosed clinical stage D prostatic cancer. International Journal of Urology 1996;3(6):472‐7. - PubMed
Murphy 1986 {published data only}
    1. Murphy GP, Huben RP, Priore R. Results of another trial of chemotherapy with and without hormones in patients with newly diagnosed metastatic prostate cancer. Urology 1986;28(1):36‐40. - PubMed
Newling 1990 {published data only}
    1. Newling DW, Fossa S, Tunn U, Kurth KH, Pauw M, Sylvester R. Comparison of the effects of high dose Estramustine phosphate and mitomycin C on the time to progression and length of survival of patients with progressive, advanced endocrine‐independent prostatic cancer: an interim analysis of EORTC‐GU Group study no. 30865. Journal of Steroid Biochemistry & Molecular Biology 1990;37(6):971‐5. - PubMed
Noguchi 2004 {published data only}
    1. Noguchi M, Noda S, Yoshida M, Ueda S, Shiraishi T, Itoh K. Chemohormonal therapy as primary treatment for metastatic prostate cancer: A randomized study of estramustine phosphate plus luteinizing hormone‐releasing hormone agonist versus flutamide plus luteinizing hormone‐releasing hormone agonist. International Journal of Urology 2004;11(2):103‐9. - PubMed
Osborne 1990 {published data only}
    1. Osborne CK, Blumenstein B, Crawford ED, Coltman CA, Jr, Smith AY, Lambuth BW, Chapman RA. Combined versus sequential chemo‐endocrine therapy in advanced prostate cancer: final results of a randomized Southwest Oncology Group study. Journal of Clinical Oncology 1990;8(10):1675‐82. - PubMed
Patel 1990 {published data only}
    1. Patel SR, Kvols LK, Hahn RG, Windschitl H, Levitt R, Therneau T. A phase II randomized trial of megestrol acetate or dexamethasone in the treatment of hormonally refractory advanced carcinoma of the prostate. Cancer 1990;66(4):655‐8. - PubMed
Pienta 2003 {published data only}
    1. Pienta KJ, Radiation Therapy Oncology Group P. Radiation Therapy Oncology Group P‐0014: a phase 3 randomized study of patients with high‐risk hormone‐naive prostate cancer: androgen blockade with 4 cycles of immediate chemotherapy versus androgen blockade with delayed chemotherapy. Urology 2003;1:95‐101. - PubMed
Pummer 1991 {published data only}
    1. Pummer K. Epirubicin plus flutamide and orchidectomy in previously untreated advanced prostatic cancer. Seminars in Oncology 1991;18(5 SUPPL. 6):26‐8. - PubMed
Ruff 1989 {published data only}
    1. Ruff P, Derman DP, Weaving A, Bezwoda WR. Sequential hormonal therapy and sequential hormonal and chemotherapy for advanced prostatic cancer. Oncology 1989;46(5):288‐92. - PubMed
Sakai 1999 {published data only}
    1. Sakai H, Shono T, Minami Y, Kanetake H, Saito Y, Kusaba Y, Hara T, Shindo K, Kubota Y, Nakada T. Randomized trial of chemo‐endocrine therapy versus endocrine therapy alone in newly diagnosed patients with advanced prostate cancer. Nishinihon Journal of Urology 1999;61(5):401‐4.
Schmidt 1976 {published data only}
    1. Schmidt JD, Gibbons RP, Johnson DE, Prout GR, Scott WW, Murphy GP. Chemotherapy of advanced prostatic cancer. Evaluation of response parameters. Urology 1976;7(6):602‐10. - PubMed
Schmidt 1979 {published data only}
    1. Schmidt JD, Scott WW, Gibbons RP, Johnson DE, Prout GR, Jr, Loening SA, Soloway MS, Chu TM, Gaeta JF, Slack NH, Saroff J, Murphy GP. Comparison of procarbazine, imidazole‐carboxamide and cyclophosphamide in relapsing patients with advanced carcinoma of the prostate. Journal of Urology 1979;121(2):185‐9. - PubMed
Scott 1975a {published data only}
    1. Scott WW, Gibbons RP, Johnson DE, Prout GR, Schmidt JD, Chu TM, Gaeta J, Joiner J, Saroff J, Murphy GP. Comparison of 5‐Fluoururacil (NSC‐19893) and cyclophosphamide (NSC‐26271) in patients with advanced carcinoma of the prostate. Cancer Chemotherapy Reports 1975;59(1):195‐7.
Scott 1975b {published data only}
    1. Scott WW, Johnson DE, Schmidt JE, Gibbons RP, Prout GR, Joiner JR, Saroff J, Murphy GP. Chemotherapy of advanced prostatic carcinoma with cyclophosphamide or 5‐fluorouracil: results of first national randomized study. Journal of Urology 1975;114(6):909‐11. - PubMed
Small 2000 {published data only}
    1. Small EJ, Meyer M, Marshall ME, Reyno LM, Meyers FJ, Natale RB, Lenehan PF, Chen L, Slichenmyer WJ, Eisenberger M. 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. Journal of Clinical Oncology 2000;18(7):1440‐50. - PubMed
Small 2002 {published data only}
    1. Small EJ, Halabi S, Ratain MJ, Rosner G, Stadler W, Palchak D, Marshall E, Rago R, Hars V, Wilding G, Petrylak D, Vogelzang NJ. Randomized study of three different doses of suramin administered with a fixed dosing schedule in patients with advanced prostate cancer: Results of intergroup 0159, cancer and leukemia group B 9480. Journal of Clinical Oncology 2002;20(16):3369‐75. - PubMed
Smith 1986 {published data only}
    1. Smith PH, Suciu S, Robinson MR, Richards B, Bastable JR, Glashan RW, Bouffioux C, Lardennois B, Williams RE, Pauw M. A comparison of the effect of diethylstilbestrol with low dose estramustine phosphate in the treatment of advanced prostatic cancer: final analysis of a phase III trial of the European Organization for Research on Treatment of Cancer. Journal of Urology 1986;136(3):619‐23. - PubMed
Stephens 1984 {published data only}
    1. Stephens RL, Vaughn C, Lane M, et al. Adriamycin and cyclophosphamide versus hydroxyurea in advanced prostatic cancer. A randomized Southwest Oncology Group study. Cancer 1984;53(3):406‐10. - PubMed
Sumiyoshi 1999 {published data only}
    1. Sumiyoshi Y, Hashine K, Kuwahara M, Aki M, Yamamoto A, Akazawa S, Takenaka A. Primary treatment for stage D2 prostate cancer: a randomized study of combined androgen blockade alone versus combined with UFT. [Japanese]. Gan to Kagaku Ryoho [Japanese Journal of Cancer & Chemotherapy] 1999;26(8):1153‐8. - PubMed
Takenaka 2001 {published data only}
    1. Takenaka I, Soramoto S, Kagawa S, Kanayama HO, Yokoyama M, Shuin T, Morioka M, Sumiyoshi Y. Multicenter randomized clinical trial comparing Estracyt mono‐therapy with combined androgen blockade therapy (CAB) in the treatment of advanced prostate cancer. [Japanese]. Nishinihon Journal of Urology 2001;63(1):1‐9.
Vahlensieck 1985 {published data only}
    1. Vahlensieck W, Wegner G, Lehmann HD, Franzen G, Steffens L, Wahlby S. Comparison between continuous and intermittent administration of Estracyt in the treatment of carcinoma of the prostate. Urological Research 1985;13(5):209‐12. - PubMed
Van Poppel 1993 {published data only}
    1. Poppel H, Broucke F, Derluyn J, Popelier G, Casselman J, Billiet I, Uytsel L, Paridaens R, Baert L. Mitomycin C in combination with orchiectomy for newly diagnosed metastatic prostate cancer: Preliminary results on a randomized trial. Journal of Urology 1993;149(6):1485‐7. - PubMed
Walczak 2003 {published data only}
    1. Walczak JR, Carducci MA, Eastern Cooperative Oncology Group E. Phase 3 randomized trial evaluating second‐line hormonal therapy versus docetaxel‐estramustine combination chemotherapy on progression‐free survival in asymptomatic patients with a rising prostate‐specific antigen level after hormonal therapy for prostate cancer: an Eastern Cooperative Oncology Group (E1899), Intergroup/Clinical Trials Support Unit study. Urology 2003;1:141‐6. - PubMed
Wang 2000 {published data only}
    1. Wang J, Halford S, Rigg A, Roylance R, Lynch M, Waxman J. Adjuvant mitozantrone chemotherapy in advanced prostate cancer. BJU International 2000;86(6):675‐80. - PubMed

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