- Email: [email protected]
Systemic treatment for prostate cancer
Annals of Oncology 17 (Supplement 10): x211–x213, 2006 doi:10.1093/annonc/mdl262
Systemic treatment for prostate cancer A. Horwich Institute of Cancer Research & Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
treatment of metastatic prostate cancer
ª 2006 European Society for Medical Oncology
side-effects of androgen ablation Common side-effects of androgen ablation include loss of libido and hot flashes, but a range of others have been reported such as fatigue, weight gain, depression, memory loss and loss of bone mineral density. Osteopenia is a particular problem of long-term therapy, but may be prevented by bisphosphonates [7]. intermittent hormone therapy This is based on the idea that allowing reversal of the castrate state may prolong the period to development of androgenindependence and improve quality of life [8]. Results from phase III trials are needed to evaluate the place of this approach. hormone-refractory prostate cancer There are a number of systemic management approaches for the patient with prostate cancer progressing while on hormone ablation therapy. These include secondary hormone manipulation, cytotoxic chemotherapy, systemic isotope therapies and bisphosphonate therapy. Since the predominant pattern of metastatic prostate cancer includes bone and pelvic lymph node metastases the most prevalent clinical problems are bone pain, urinary obstruction, spinal cord compression, lymph edema of the lower limbs, anemia and cachexia. Management of patients who have failed hormone ablation therapy is more difficult than treating patients who are hormone-naı¨ve since second-line treatments tend to have only transient benefit. Early referral for palliative and supportive care should be considered, including radiotherapy for bone pain, spinal cord compression, lymph edema or hematuria. The sequence of further therapeutic attempts is influenced by factors such as the disease-free interval induced by primary hormone therapy, the grade and growth rate of the cancer and the specific symptoms, general health and performance status of the patient. second-line hormones The first approach to patients who become refractory to hormone ablation is usually with an additional hormone
Downloaded from http://annonc.oxfordjournals.org/ at Kungl Tekniska Hogskolan Biblioteket on July 28, 2015
hormone therapy Patients with symptomatic metastatic prostate cancer should be treated by androgen deprivation. Historically this was accomplished by surgical castration. However, the standard treatment in modern medicine is the use of a luteinizing hormone-releasing hormone (LHRH) agonist such as goserelin acetate (Zoladex) or leuprorelin acetate (Prostap), which have an effect equivalent to castration on testosterone level and on prostate cancer response [1]. They act by downregulation of pituitary receptors and the consequent inhibition of release of follicle stimulation hormone (FSH) and leutinizing hormone (LH) with a decrease in testosterone production from the testis. These agents initially mimic the natural hormone and cause a transient rise in testosterone and their inception should be covered by an anti-androgen at full dose to prevent worsening of symptoms such as bone pain or urinary obstruction. A standard approach is to use anti-androgens for 7 days prior to the first LHRH agonist injection and for 14 days following it. Depot preparations of LHRH agonists lasting at least 3 months are as effective as the 1-month preparations. Direct LHRH antagonists such as abarelix have been developed that avoid the tumor flare phenomenon. Preliminary assessments suggest equivalent response rates to the agonists [2]. In hormone-naive patients with symptomatic metastatic disease, approximately 85% have a symptomatic response for a median of 12–18 months. Duration of response appears to relate to the burden of disease and patients treated with hormone therapy for localized or soft tissue disease tend to have longer responses than those with multiple bone metastases. The non-steroidal anti-androgen, bicalutamide appears to be less effective than castration in patients with metastatic disease [3]. A range of trials investigated the concept of complete androgen blockade in which an anti-androgen was added longterm either to surgical castration or to an LHRH agonist. A report based on more than 8000 patients randomized to either androgen ablation or to androgen ablation plus an antiandrogen showed on meta-analysis that combined androgen blockade is not more effective than simple medical or surgical castration with 5-year survival rates of 25.4% and 23.6%, and 10-year survivals of 6.2% and 5.5%, respectively [4]. Another issue, addressed in a more limited way, is whether asymptomatic patients with metastases should be treated immediately or whether hormone therapy should be deferred until they develop symptoms. A Medical Research Council
(MRC) trial [5] suggested an advantage to early treatment. However, the advantage was seen in patients with locally advanced rather than disseminated disease. There seemed a clear benefit to early treatment in preventing some of the more distressing complications of metastatic prostate cancer. The advantage of early hormone therapy in locally advanced prostate cancer was also seen in a European Organization for Research and Treatment of Cancer (EORTC) trial [6].
Annals of Oncology
treatment such as an anti-androgen or simple use of prednisone to cause adrenal suppression, either of which leads to a further remission in about 15%–20% of patients [9]. The thinking behind these interventions is that low levels of androgen continue to be produced from other organs, especially the adrenal glands, and access of these to the prostate cancer can be blocked by an anti-androgen or, alternatively, production from the adrenal can be stopped by physiological levels of replacement adrenal steroid such as prednisone 7.5 mg/day. A further effective hormonal agent, although probably more toxic, is estrogen such as stilboestrol [10]. The risks are thrombo-embolism, gastro-intestinal upset and, occasionally, fluid retention.
x212 | Horwich
isotope therapy and bisphosphonates Patients with multiple sites of painful bone metastasis have been treated with the bone-seeking isotopes strontium-89, rhenium186 or samarium-153 [22]. These technologies give effective pain relief in approximately 70% of patients and trials have suggested that in comparison with more localized palliation from external beam radiotherapy there is a delay in the time to the next skeletal-related event [23]. Treatment seldom causes any symptomatic toxicity, although myelosuppression may impair subsequent tolerance to cytotoxic chemotherapy. There is also considerable interest in the role of bisphosphonates to inhibit prostate cancer metastases in bone. A placebo controlled phase III trial of pamidronate, a second generation bisphosphonate that had shown benefit in treatment of myeloma, did not demonstrate any reduction in skeletalrelated events in men with metastatic prostate cancer and bone pain [24]. Zoledronic acid, a potent third-generation bisphosphonate was studied in a randomized placebocontrolled trial in patients with HRPC [25]. Athough there was no overall benefit detected by quality of life scores and only minor difference in subsequent need for palliative radiotherapy, a higher proportion of patients on placebo had skeletal-related events than those who received zoledronic acid at 4 mg every 3 weeks (44.2% versus 33.2% P = 0.021). In contrast a placebocontrolled trial of clodronate in patients treated with a combination of mitoxantrone and prednisolone showed no difference in the rate of palliative response or overall quality of life [26].
Volume 17 | Supplement 10 | September 2006
Downloaded from http://annonc.oxfordjournals.org/ at Kungl Tekniska Hogskolan Biblioteket on July 28, 2015
chemotherapy Chemotherapy is being explored increasingly in the management of patients with prostate cancer especially now that sensitive measures of response based on prostate specific antigen (PSA) enable early detection of progression on hormone therapy. The recent demonstration of a survival advantage to inclusion of docetaxel in first-line chemotherapy has encouraged this trend. In the past there has been investigation of estramustine as an anti-cancer agent specific to prostate cancer, based on a conjugate of nitrogen mustard and oestradiol. It has modest activity but it is associated with significant gastrointestinal toxicity. The modern era of prostate cancer chemotherapy was heralded by a seminal trial by Tannock et al. [11] who randomized patients between mitoxantrone at 12 mg/m2 plus prednisone 10 mg versus prednisone alone. There was significant benefit to the use of mitoxantrone in terms of pain scores and analgesic use but no overall difference in PSA response or survival. This result was essentially confirmed in a CALGB trial. Taxanes also have activity in prostate cancer and appeared on phase II and comparative studies to be more effective than mitoxantrone [12]. An industry-sponsored multi-national trial comparing docetaxel to mitoxantrone (both with prednisone) was reported recently. The TAX327 study was a three-armed trial and randomized 1006 patients comparing docetaxel given at 75 mg/m2 intravenously (i.v.) every 21 days or 30 mg/m2 every 7 days for 5 out of 6 weeks to mitoxantrone 12 mg/m2 i.v. every 21 days [13]. All patients received prednisone 5 mg twice a day. The docetaxel arms achieved a more frequent pain response (33% versus 22%), PSA response (47% versus 32%) and slightly longer median survival (18.3 versus 16.5 months). As was expected, more cardiac events were seen in the mitoxantrone group compared with patients receiving docetaxel but a significantly higher incidence of sensory neuropathy, diarrhea, stomatitis, fatigue, peripheral edema, alopecia, nail toxicity and hyperlacrimation was seen in the patients treated with docetaxel. Grade 3 or 4 neutropenia was significantly less with weekly than with 3-weekly docetaxel. The concurrently reported SWOG trial compared docetaxel and estramustine with mitoxantrone and prednisone in 770 randomized patients [14]. Prophylactic anticoagulation with daily warfarin (2 mg) plus aspirin (325 mg) was introduced during the trial for patients receiving estramustine following
reports of vascular effects. The median survival was 17.5 months among the patients assigned to docetaxel and estramustine and 15.6 months among the patients assigned to mitoxantrone and prednisone (P = 0.02). Comparing the two trials in the light of similar survival but worse toxicity with estramustine, the combination of docetaxel every 3 weeks with prednisolone is currently the preferred chemotherapeutic option for hormone refractory prostate cancer (HRPC). A number of drugs are being investigated for patients who have progressed after docetaxel. These include combinations of paclitaxel with estramustine [15] or with capecitabine. Platinum-containing regimens such as epirubicin, carboplatin and 5-fluorouracil have shown modest activity in HRPC but their use is limited by toxicity and methods of administration [16]. Satraplatin (JM-216) is a third-generation oral platinum compound that has demonstrated in vitro activity against taxane-resistant cell lines. A small phase III trial showed evidence of biochemical response with minimal toxicity [17] and a larger international trial (SPARC) comparing satraplatin plus prednisone against placebo plus prednisone as second-line chemotherapy has completed recruitment. As discussed further below, there is considerable interest in combining such cytotoxic chemotherapy with growth factor receptor inhibition or other targeted agents such as calcitriol [18]. Biologically targeted approaches are still in early trial [19], including investigations of anti-angiogenic drugs such as thalidomide [20], endothelin receptor antagonists [21] or vaccine immunotherapies.
Annals of Oncology
Bisphosphonates have the risk of a number of side-effects including fatigue, anemia, myalgia, edema, jaw necrosis and weight loss. Thus the role of bisphosphonates in patients with advanced metastatic prostate cancer requires further study.
developments in drug therapy
references 1. Denis L. European Organization for Research and Treatment of Cancer (EORTC) prostate cancer trials, 1976–1996. Urology 1998; 51 (Suppl 5A): 50–57. 2. Koch M, Steidle C, Brosman S et al. An open-label study of abarelix in men with symptomatic prostate cancer at risk of treatment with LHRH agonists. Urology 2003; 62: 877–882. 3. Tyrrell CJ, Kaisary AV, Iversen P et al. A randomised comparison of ‘Casodex’ (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol 1998; 33: 447–456. 4. Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. The Lancet 1995; 346: 265–269. 5. Medical Research Council Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council trial. Br J Urol 1997; 79: 235–246. 6. Bolla M, Gonzalez D, Warde P et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin (see comments). N Engl J Med 1997; 337: 295–300. 7. Smith MR, McGovern FJ, Zietman AL et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001; 345: 948–955. 8. Wolff JM, Tunn UW. Intermittent androgen blockade in prostate cancer: rationale and clinical experience. Eur Urol 2000; 38: 365–371. 9. Fossa SD, Slee PH, Brausi M et al. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol 2001; 19: 62–71. 10. Smith DC, Redman BG, Flaherty LE et al. A phase II trial of oral diethylstilbesterol as a second-line hormonal agent in advanced prostate cancer. Urology 1998; 52: 257–260.
Volume 17 | Supplement 10 | September 2006
doi:10.1093/annonc/mdl262 | x213
Downloaded from http://annonc.oxfordjournals.org/ at Kungl Tekniska Hogskolan Biblioteket on July 28, 2015
Increases in antitumor activity, which may be possible with combinations of currently available cytotoxic agents, are likely to be limited by unacceptable toxicities, especially in patients heavily pretreated with docetaxel or systemic isotopes. However, there is potential for combining chemotherapy with signal transduction inhibitors or other targeted agents. For example, calcitriol [27], which binds the vitamin D receptor and has differentiation, anti-proliferative, proapoptotic and anti-angiogenic properties, has been assessed as a high-dose oral formulation (DN-101) in a small randomized trial (ASCENT) with weekly docetaxel and appeared to lead to a lower risk of skeletal events (hazard ratio 0.78) and a longer median overall survival (23.5 versus 16.4 months) [28]. The vascular targeting agent, bevacuzimab is also now in a phase II trial being studied with docetaxel, and there are early and encouraging studies of endothelin receptor antagonists [21] and of thalidomide [29]. Immunotherapeutic approaches include vaccines [30] and dendritic cells presenting a prostatic acid phosphatase antigen (Provenge) [31]. The systemic treatment of castration-independent prostate cancer has become a major focus of biological and therapeutic research.
11. Tannock IF, Osoba D, Stockler MR et al. Chemotherapy with mitroxantrone plus prednisone or prednisone along for symptomatic hormone-resistant prostate cancer: A Canadian randomised trial with palliative end points. J Clin Oncol 1996; 14: 1756–1764. 12. Petrylak DP. Docetaxel (Taxotere) in hormone-refractory prostate cancer. Semin Oncol 2000; 27 (2 Suppl 3): 24–29. 13. Tannock IF, de Wit R, Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502–1512. 14. Petrylak DP, Tangen CM, Hussain MH et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: 1513–1520. 15. Vaishampayan U, Fontana J, Du W, Hussain M. An active regimen of weekly paclitaxel and estramustine in metastatic androgen-independent prostate cancer. Urology 2002; 60: 1050–1054. 16. Birtle AJ, Newby JC, Harland SJ. Epirubicin carboplatin and 5-fluorouracil (ECarboF) chemotherapy in metastatic hormone refractory prostate cancer. Br J Cancer 2004; 91: 1472–1476. 17. Sternberg CN, Whelan P, Hetherington J et al. Phase III trial of satraplatin, an oral platinum plus prednisone vs. prednisone alone in patients with hormonerefractory prostate cancer. Oncology 2005; 68: 2–9. 18. Beer TM, Eilers KM, Garzotto M et al. Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer. J Clin Oncol 2003; 21: 123–128. 19. Gulley J, Dahut W. Novel clinical trials in androgen-independent prostate cancer. Clin Prostate Cancer 2002; 1: 51–57. 20. Figg WD, Kruger EA, Price DK et al. Inhibition of angiogenesis: treatment options for patients with metastatic prostate cancer. Invest New Drugs 2002; 20: 183–194. 21. Carducci MA, Padley RJ, Breul J et al. Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial. J Clin Oncol 2003; 21: 679–689. 22. Finlay IG, Mason MD, Shelley M. Radioisotopes for the palliation of metastatic bone cancer: a systematic review. Lancet Oncol 2005; 6: 392–400. 23. Porter AT, McEwan AJ. Strontium-89 as an adjuvant to external beam radiation improves pain relief and delays disease progression in advanced prostate cance: results of a randomised controlled trial. Semin Oncol 1993; 20 (3 Suppl 2): 38–43. 24. Lipton A, Small E, Saad F et al. The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate. Cancer Invest 2002; 20 (Suppl 2): 45–54. 25. Saad F, Gleason DM, Murray R et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94: 1458–1468. 26. Ernst DS, Tannock IF, Winquist EW et al. Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol 2003; 21: 3335–3342. 27. Beer TM. Development of weekly high-dose calcitriol based therapy for prostate cancer. Urol Oncol 2003; 21: 399–405. 28. Beer T, Ryan C, Venner P et al. Interim results from ASCENT: A double-blinded randomized study of DN-101 (high-dose calcitriol) plus docetaxel vs. placebo plus docetaxel in androgen-independent prostate cancer (AIPC). 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, Florida, 13–17 May 2005. 29. Figg WD. The 2005 Leon I. Goldberg Young Investigator Award Lecture: Development of thalidomide as an angiogenesis inhibitor for the treatment of androgen-independent prostate cancer. Clin Pharmacol Ther 2006; 79: 1–8. 30. Gulley J, Chen AP, Dahut W et al. Phase I study of a vaccine using recombinant vaccinia virus expressing PSA (rV-PSA) in patients with metastatic androgenindependent prostate cancer. Prostate 2002; 53: 109–117. 31. Small EJ, Fratesi P, Reese DM et al. Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J Clin Oncol 2000; 18: 3894–3903.
Systemic treatment for prostate cancer A. Horwich Institute of Cancer Research & Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
treatment of metastatic prostate cancer
ª 2006 European Society for Medical Oncology
side-effects of androgen ablation Common side-effects of androgen ablation include loss of libido and hot flashes, but a range of others have been reported such as fatigue, weight gain, depression, memory loss and loss of bone mineral density. Osteopenia is a particular problem of long-term therapy, but may be prevented by bisphosphonates [7]. intermittent hormone therapy This is based on the idea that allowing reversal of the castrate state may prolong the period to development of androgenindependence and improve quality of life [8]. Results from phase III trials are needed to evaluate the place of this approach. hormone-refractory prostate cancer There are a number of systemic management approaches for the patient with prostate cancer progressing while on hormone ablation therapy. These include secondary hormone manipulation, cytotoxic chemotherapy, systemic isotope therapies and bisphosphonate therapy. Since the predominant pattern of metastatic prostate cancer includes bone and pelvic lymph node metastases the most prevalent clinical problems are bone pain, urinary obstruction, spinal cord compression, lymph edema of the lower limbs, anemia and cachexia. Management of patients who have failed hormone ablation therapy is more difficult than treating patients who are hormone-naı¨ve since second-line treatments tend to have only transient benefit. Early referral for palliative and supportive care should be considered, including radiotherapy for bone pain, spinal cord compression, lymph edema or hematuria. The sequence of further therapeutic attempts is influenced by factors such as the disease-free interval induced by primary hormone therapy, the grade and growth rate of the cancer and the specific symptoms, general health and performance status of the patient. second-line hormones The first approach to patients who become refractory to hormone ablation is usually with an additional hormone
Downloaded from http://annonc.oxfordjournals.org/ at Kungl Tekniska Hogskolan Biblioteket on July 28, 2015
hormone therapy Patients with symptomatic metastatic prostate cancer should be treated by androgen deprivation. Historically this was accomplished by surgical castration. However, the standard treatment in modern medicine is the use of a luteinizing hormone-releasing hormone (LHRH) agonist such as goserelin acetate (Zoladex) or leuprorelin acetate (Prostap), which have an effect equivalent to castration on testosterone level and on prostate cancer response [1]. They act by downregulation of pituitary receptors and the consequent inhibition of release of follicle stimulation hormone (FSH) and leutinizing hormone (LH) with a decrease in testosterone production from the testis. These agents initially mimic the natural hormone and cause a transient rise in testosterone and their inception should be covered by an anti-androgen at full dose to prevent worsening of symptoms such as bone pain or urinary obstruction. A standard approach is to use anti-androgens for 7 days prior to the first LHRH agonist injection and for 14 days following it. Depot preparations of LHRH agonists lasting at least 3 months are as effective as the 1-month preparations. Direct LHRH antagonists such as abarelix have been developed that avoid the tumor flare phenomenon. Preliminary assessments suggest equivalent response rates to the agonists [2]. In hormone-naive patients with symptomatic metastatic disease, approximately 85% have a symptomatic response for a median of 12–18 months. Duration of response appears to relate to the burden of disease and patients treated with hormone therapy for localized or soft tissue disease tend to have longer responses than those with multiple bone metastases. The non-steroidal anti-androgen, bicalutamide appears to be less effective than castration in patients with metastatic disease [3]. A range of trials investigated the concept of complete androgen blockade in which an anti-androgen was added longterm either to surgical castration or to an LHRH agonist. A report based on more than 8000 patients randomized to either androgen ablation or to androgen ablation plus an antiandrogen showed on meta-analysis that combined androgen blockade is not more effective than simple medical or surgical castration with 5-year survival rates of 25.4% and 23.6%, and 10-year survivals of 6.2% and 5.5%, respectively [4]. Another issue, addressed in a more limited way, is whether asymptomatic patients with metastases should be treated immediately or whether hormone therapy should be deferred until they develop symptoms. A Medical Research Council
(MRC) trial [5] suggested an advantage to early treatment. However, the advantage was seen in patients with locally advanced rather than disseminated disease. There seemed a clear benefit to early treatment in preventing some of the more distressing complications of metastatic prostate cancer. The advantage of early hormone therapy in locally advanced prostate cancer was also seen in a European Organization for Research and Treatment of Cancer (EORTC) trial [6].
Annals of Oncology
treatment such as an anti-androgen or simple use of prednisone to cause adrenal suppression, either of which leads to a further remission in about 15%–20% of patients [9]. The thinking behind these interventions is that low levels of androgen continue to be produced from other organs, especially the adrenal glands, and access of these to the prostate cancer can be blocked by an anti-androgen or, alternatively, production from the adrenal can be stopped by physiological levels of replacement adrenal steroid such as prednisone 7.5 mg/day. A further effective hormonal agent, although probably more toxic, is estrogen such as stilboestrol [10]. The risks are thrombo-embolism, gastro-intestinal upset and, occasionally, fluid retention.
x212 | Horwich
isotope therapy and bisphosphonates Patients with multiple sites of painful bone metastasis have been treated with the bone-seeking isotopes strontium-89, rhenium186 or samarium-153 [22]. These technologies give effective pain relief in approximately 70% of patients and trials have suggested that in comparison with more localized palliation from external beam radiotherapy there is a delay in the time to the next skeletal-related event [23]. Treatment seldom causes any symptomatic toxicity, although myelosuppression may impair subsequent tolerance to cytotoxic chemotherapy. There is also considerable interest in the role of bisphosphonates to inhibit prostate cancer metastases in bone. A placebo controlled phase III trial of pamidronate, a second generation bisphosphonate that had shown benefit in treatment of myeloma, did not demonstrate any reduction in skeletalrelated events in men with metastatic prostate cancer and bone pain [24]. Zoledronic acid, a potent third-generation bisphosphonate was studied in a randomized placebocontrolled trial in patients with HRPC [25]. Athough there was no overall benefit detected by quality of life scores and only minor difference in subsequent need for palliative radiotherapy, a higher proportion of patients on placebo had skeletal-related events than those who received zoledronic acid at 4 mg every 3 weeks (44.2% versus 33.2% P = 0.021). In contrast a placebocontrolled trial of clodronate in patients treated with a combination of mitoxantrone and prednisolone showed no difference in the rate of palliative response or overall quality of life [26].
Volume 17 | Supplement 10 | September 2006
Downloaded from http://annonc.oxfordjournals.org/ at Kungl Tekniska Hogskolan Biblioteket on July 28, 2015
chemotherapy Chemotherapy is being explored increasingly in the management of patients with prostate cancer especially now that sensitive measures of response based on prostate specific antigen (PSA) enable early detection of progression on hormone therapy. The recent demonstration of a survival advantage to inclusion of docetaxel in first-line chemotherapy has encouraged this trend. In the past there has been investigation of estramustine as an anti-cancer agent specific to prostate cancer, based on a conjugate of nitrogen mustard and oestradiol. It has modest activity but it is associated with significant gastrointestinal toxicity. The modern era of prostate cancer chemotherapy was heralded by a seminal trial by Tannock et al. [11] who randomized patients between mitoxantrone at 12 mg/m2 plus prednisone 10 mg versus prednisone alone. There was significant benefit to the use of mitoxantrone in terms of pain scores and analgesic use but no overall difference in PSA response or survival. This result was essentially confirmed in a CALGB trial. Taxanes also have activity in prostate cancer and appeared on phase II and comparative studies to be more effective than mitoxantrone [12]. An industry-sponsored multi-national trial comparing docetaxel to mitoxantrone (both with prednisone) was reported recently. The TAX327 study was a three-armed trial and randomized 1006 patients comparing docetaxel given at 75 mg/m2 intravenously (i.v.) every 21 days or 30 mg/m2 every 7 days for 5 out of 6 weeks to mitoxantrone 12 mg/m2 i.v. every 21 days [13]. All patients received prednisone 5 mg twice a day. The docetaxel arms achieved a more frequent pain response (33% versus 22%), PSA response (47% versus 32%) and slightly longer median survival (18.3 versus 16.5 months). As was expected, more cardiac events were seen in the mitoxantrone group compared with patients receiving docetaxel but a significantly higher incidence of sensory neuropathy, diarrhea, stomatitis, fatigue, peripheral edema, alopecia, nail toxicity and hyperlacrimation was seen in the patients treated with docetaxel. Grade 3 or 4 neutropenia was significantly less with weekly than with 3-weekly docetaxel. The concurrently reported SWOG trial compared docetaxel and estramustine with mitoxantrone and prednisone in 770 randomized patients [14]. Prophylactic anticoagulation with daily warfarin (2 mg) plus aspirin (325 mg) was introduced during the trial for patients receiving estramustine following
reports of vascular effects. The median survival was 17.5 months among the patients assigned to docetaxel and estramustine and 15.6 months among the patients assigned to mitoxantrone and prednisone (P = 0.02). Comparing the two trials in the light of similar survival but worse toxicity with estramustine, the combination of docetaxel every 3 weeks with prednisolone is currently the preferred chemotherapeutic option for hormone refractory prostate cancer (HRPC). A number of drugs are being investigated for patients who have progressed after docetaxel. These include combinations of paclitaxel with estramustine [15] or with capecitabine. Platinum-containing regimens such as epirubicin, carboplatin and 5-fluorouracil have shown modest activity in HRPC but their use is limited by toxicity and methods of administration [16]. Satraplatin (JM-216) is a third-generation oral platinum compound that has demonstrated in vitro activity against taxane-resistant cell lines. A small phase III trial showed evidence of biochemical response with minimal toxicity [17] and a larger international trial (SPARC) comparing satraplatin plus prednisone against placebo plus prednisone as second-line chemotherapy has completed recruitment. As discussed further below, there is considerable interest in combining such cytotoxic chemotherapy with growth factor receptor inhibition or other targeted agents such as calcitriol [18]. Biologically targeted approaches are still in early trial [19], including investigations of anti-angiogenic drugs such as thalidomide [20], endothelin receptor antagonists [21] or vaccine immunotherapies.
Annals of Oncology
Bisphosphonates have the risk of a number of side-effects including fatigue, anemia, myalgia, edema, jaw necrosis and weight loss. Thus the role of bisphosphonates in patients with advanced metastatic prostate cancer requires further study.
developments in drug therapy
references 1. Denis L. European Organization for Research and Treatment of Cancer (EORTC) prostate cancer trials, 1976–1996. Urology 1998; 51 (Suppl 5A): 50–57. 2. Koch M, Steidle C, Brosman S et al. An open-label study of abarelix in men with symptomatic prostate cancer at risk of treatment with LHRH agonists. Urology 2003; 62: 877–882. 3. Tyrrell CJ, Kaisary AV, Iversen P et al. A randomised comparison of ‘Casodex’ (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol 1998; 33: 447–456. 4. Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. The Lancet 1995; 346: 265–269. 5. Medical Research Council Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council trial. Br J Urol 1997; 79: 235–246. 6. Bolla M, Gonzalez D, Warde P et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin (see comments). N Engl J Med 1997; 337: 295–300. 7. Smith MR, McGovern FJ, Zietman AL et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001; 345: 948–955. 8. Wolff JM, Tunn UW. Intermittent androgen blockade in prostate cancer: rationale and clinical experience. Eur Urol 2000; 38: 365–371. 9. Fossa SD, Slee PH, Brausi M et al. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol 2001; 19: 62–71. 10. Smith DC, Redman BG, Flaherty LE et al. A phase II trial of oral diethylstilbesterol as a second-line hormonal agent in advanced prostate cancer. Urology 1998; 52: 257–260.
Volume 17 | Supplement 10 | September 2006
doi:10.1093/annonc/mdl262 | x213
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Increases in antitumor activity, which may be possible with combinations of currently available cytotoxic agents, are likely to be limited by unacceptable toxicities, especially in patients heavily pretreated with docetaxel or systemic isotopes. However, there is potential for combining chemotherapy with signal transduction inhibitors or other targeted agents. For example, calcitriol [27], which binds the vitamin D receptor and has differentiation, anti-proliferative, proapoptotic and anti-angiogenic properties, has been assessed as a high-dose oral formulation (DN-101) in a small randomized trial (ASCENT) with weekly docetaxel and appeared to lead to a lower risk of skeletal events (hazard ratio 0.78) and a longer median overall survival (23.5 versus 16.4 months) [28]. The vascular targeting agent, bevacuzimab is also now in a phase II trial being studied with docetaxel, and there are early and encouraging studies of endothelin receptor antagonists [21] and of thalidomide [29]. Immunotherapeutic approaches include vaccines [30] and dendritic cells presenting a prostatic acid phosphatase antigen (Provenge) [31]. The systemic treatment of castration-independent prostate cancer has become a major focus of biological and therapeutic research.
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