Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. Epirubicin and medroxyprogesterone acetate versus estramustine phosphate in hormone-resistant prostatic cancer: a prospective randomized study. A comparison of estramustine phosphate versus cis-platinum alone versus estramustine phosphate plus cis-platinum in patients with advanced hormone refractory prostate cancer who had had extensive irradiation to the pelvis or lumbosacral area. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. Cisobitan in treatment of prostatic cancer. A prospective controlled multicentre study. 5-Fluorouracil versus folinic acid and 5-fluorouracil in advanced, hormone-resistant prostate cancer: a prospective randomized pilot trial. A comparison of estramustine phosphate and streptozotocin in patients with advanced prostatic carcinoma who have had extensive irradiation. Experience with weekly doxorubicin (adriamycin) in hormone-refractory stage D2 prostate cancer. A phase II randomized trial of megestrol acetate or dexamethasone in the treatment of hormonally refractory advanced carcinoma of the prostate Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. Weekly chemotherapy in advanced prostatic cancer. Randomized, multicenter, phase II trial of two multicomponent regimens in androgen-independent prostate cancer. Comparison between continuous and intermittent administration of Estracyt in the treatment of carcinoma of the prostate Concomitant i.v. and oral clodronate in the relief of bone pain--a double-blind placebo-controlled study in patients with prostate cancer. Quality of Life of Patients with Newly Diagnosed Poor Prognosis M1 Prostate Cancer Undergoing Orchiectomy without or with Mitomycin C Combination of LHRH analog with somatostatin analog and dexamethasone versus chemotherapy in hormone-refractory prostate cancer: a randomized phase II study. Comparison of estramustine phosphate, methotrexate and cis-platinum in patients with advanced, hormone refractory prostate cancer. A randomized study on hormone-resistant prostatic cancer: estramustine phosphate versus low dose epirubicin with or without medroxyprogesterone acetate. A Norwegian multicenter study. Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer. Prospective and randomized comparison of combined androgen blockade versus combination with oral UFT as an initial treatment for prostate cancer. Androgen priming and response to chemotherapy in advanced prostatic cancer. Adjuvant mitozantrone chemotherapy in advanced prostate cancer 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 Grou Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. Combined versus sequential chemo-endocrine therapy in advanced prostate cancer: final results of a randomized Southwest Oncology Group study. Cyclophosphamide versus cyclophosphamide, methotrexate, and 5‐fluorouracil in advanced prostatic cancer: A randomized trial A randomized study comparing standard versus moderately high dose megestrol acetate for patients with advanced prostate carcinoma Comparison of estramustine phosphate and vincristine alone or in combination for patients with advanced, hormone refractory, previously irradiated carcinoma of the prostate. Chemotherapy of advanced prostatic cancer. Evaluation of response parameters. Treatment of high-grade, high-stage prostate cancer with estramustine phosphate or diethylstilbestrol. A double-blind study. The SPCG-1 Study Group. Scandinavian Prostate Cancer Group. Sequential hormonal therapy and sequential hormonal and chemotherapy for advanced prostatic cancer. Chemotherapy for hormonally refractory advanced prostate carcinoma. A Comparison of combined versus sequential treatment with mitomycin C, doxorubicin, and 5‐fluorouracil A prospective, randomized controlled study on the treatment of stage C and stage D prostatic cancer with estracyt in combination with other chemotherapeutic agents. National randomized study of chemotherapeutic agents in advanced prostatic carcinoma: a progress report. 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. Phase III trial of cyclophosphamide versus cyclophosphamide, doxorubicin, and methotrexate in hormone‐refractory prostatic cancer: A hoosier oncology group study 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. Chemotherapy of advanced prostatic carcinoma with cyclophosphamide or 5-fluorouracil: results of first national randomized study. A comparison of hydroxyurea, methyl-chloroethyl-cyclohexy-nitrosourea and cyclophosphamide in patients with advanced carcinoma of the prostate. Randomized phase 2 trial of ketoconazole and ketoconazole/doxorubicin in androgen independent prostate cancer. Support ellagic acid therapy in patients with hormone refractory prostate cancer (HRPC) on standard chemotherapy using vinorelbine and estramustine phosphate. High-dose medroxyprogesterone acetate versus estramustine in therapy-resistant prostatic cancer: a randomised study. A comparative clinical trial of adriamycin and 5-fluorouracil in advanced prostatic cancer: prognostic factors and response. Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: A Hoosier Oncology Group and Fox Chase Network phase III trial. A phase II evaluation of a 3-drug combination of cyclophosphamide, doxorubicin and 5-fluorouracil and of 5-fluorouracil in patients with advanced bladder carcinoma or stage D prostatic carcinoma. [Comparison of hormone therapy alone and in combination with chemotherapy of cisplatin and methotrexate in newly diagnosed patients with stage D2 prostatic cancer]. Clinical experimental randomized study of 2.6-cis-diphenylhexamethylcyclotetrasiloxane and estramustine-17-phosphate in the treatment of prostatic carcinoma. Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. Epirubicin plus flutamide and orchidectomy in previously untreated advanced prostatic cancer. The continued evaluation of the effects of chemotherapy in patients with advanced carcinoma of the prostate. Comparison of hormonal therapy and chemohormonal therapy in patients with newly diagnosed clinical stage D prostatic cancer. 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 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. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. Hormone stimulation and chemotherapy in advanced prostate cancer: interim analysis of an ongoing randomized trial. Value of cyclophosphamide or melphalan as combined chemotherapy in hormonally unresponsive prostatic carcinoma. Randomised phase III study of intravenous vinorelbine plus hormone therapy versus hormone therapy alone in hormone-refractory prostate cancer. Prospective randomized Phase II trial of pegylated doxorubicin in the management of symptomatic hormone‐refractory prostate carcinoma 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. Prospective randomised trial comparing diethylstilboestrol and flutamide in the treatment of hormone relapsed prostate cancer. A randomized phase II trial of docetaxel (taxotere) plus thalidomide in androgen-independent prostate cancer. Phase II trial of oral estramustine, oral etoposide, and intravenous paclitaxel in hormone-refractory prostate cancer. [Primary treatment for stage D2 prostate cancer: a randomized study of combined androgen blockade alone versus combined with UFT]. Prostatic carcinoma. relationship between primary tumor, histologic grade, and response to chemotherapy. 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. Comparison of procarbazine, imidazole-carboxamide and cyclophosphamide in relapsing patients with advanced carcinoma of the prostate. Estramustine versus conventional estrogenic hormones in the initial treatment of highly or moderately differentiated prostatic carcinoma. A randomized study. The results of a phase II randomized trial comparing 5-fluorouracil and 5-fluorouracil plus alpha-interferon: observations on the design of clinical trials for androgen-independent prostate cancer. Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer. Adriamycin and cyclophosphamide versus hydroxyurea in advanced prostatic cancer. A randomized Southwest Oncology Group study A comparison of diethylstilbestrol or orchiectomy with buserelin and with methotrexate plus diethylstilbestrol or orchiectomy in newly diagnosed patients with clinical stage D2 cancer of the prostate
PURPOSE To investigate the benefit of chemotherapy in patients with symptomatic hormone-resistant prostate cancer using relevant end points of palliation in a r and omized controlled trial . PATIENTS AND METHODS We r and omized 161 hormone-refractory patients with pain to receive mitoxantrone plus prednisone or prednisone alone ( 10 mg daily ) . Nonresponding patients on prednisone  could receive mitoxantrone subsequently . The primary end point was a palliative response defined as a 2-point decrease in pain as assessed by a 6-point pain scale completed by patients ( or complete loss of pain if initially 1 + ) without an increase in analgesic medication and maintained for two consecutive evaluations at least 3 weeks apart . Secondary end points were a decrease of > or = 50 % in use of analgesic medication without an increase in pain , duration of response , and survival . Health-related quality of life was evaluated with a series of linear analog self- assessment scales ( LASA and the Prostate Cancer-Specific Quality -of-Life Instrument [ PROSQOLI ] ) , the core question naire of the European Organization for Research and Treatment of Cancer ( EORTC ) , and a disease-specific module . RESULTS Palliative response was observed in 23 of 80 patients ( 29 % ; 95 % confidence interval , 19 % to 40 % ) who received mitoxantrone plus prednisone , and in 10 of 81 patients ( 12 % ; 95 % confidence interval , 6 % to 22 % ) who received prednisone alone ( P = .01 ) . An additional seven patients in each group reduced analgesic medication > or = 50 % without an increase in pain . The duration of palliation was longer in patients who received chemotherapy ( median , 43 and 18 weeks ; P < .0001 , log-rank ) . Eleven of 50 patients r and omized to prednisone treatment responded after addition of mitoxantrone . There was no difference in overall survival . Treatment was well tolerated , except for five episodes of possible cardiac toxicity in 130 patients who received mitoxantrone . Most responding patients had an improvement in quality -of-life scales and a decrease in serum prostate-specific antigen ( PSA ) level . CONCLUSION Chemotherapy with mitoxantrone and prednisone provides palliation for some patients with symptomatic hormone-resistant prostate cancer PURPOSE Estramustine and etoposide ( VP-16 ) have been demonstrated to inhibit the growth of prostate cancer cells in experimental models . This led us to evaluate the effectiveness of this combination in the treatment of patients with metastatic prostate carcinoma refractory to hormone therapy . PATIENTS AND METHODS Estramustine 15 mg/kg/d and VP-16 50 mg/m2/d , were administered orally in divided doses for 21 days . Patients were then taken off therapy for 7 days and the cycle then repeated . Therapy continued until evidence of disease progression . RESULTS Forty-two patients have been enrolled onto this trial with a minimum of 40 weeks follow-up . Of 18 patients with measurable soft tissue disease , three demonstrated a complete response ( CR ) and six a partial response ( PR ) for longer than 2 months . Of these 18 patients , pretreatment prostate-specific antigen ( PSA ) levels decreased by at least 75 % in five men ( 28 % ) and by at least 50 % in nine ( 50 % ) . The median survival duration has not been reached in those patients who demonstrated a response either by soft tissue or PSA criteria . Of 24 patients with disease limited to bone , six ( 25 % ) demonstrated improvement and nine ( 38 % ) demonstrated stability in their bone scans . Five men ( 21 % ) demonstrated a decrease of at least 75 % in pretreatment PSA levels and 14 ( 58 % ) demonstrated at least a 50 % decrease ; the median survival duration has not been reached in these patients . Pretreatment performance status is an important predictor of survival . CONCLUSION We conclude that the combination of estramustine and VP-16 is an active oral regimen in hormone-refractory prostate cancer The effect of a medroxyprogesterone acetate ( MPA ) plus epirubicin combination versus estramustine phosphate was evaluated in 149 prospect ively r and omized patients with hormone-resistant prostatic cancer . The estimated probability of being free from progression after 1 year was 17 % for the patients treated with estramustine and 29 % for the MPA-epirubicin group . There is a significant difference between the two groups regarding risk of progression ( p = 0.013 ) . However , no difference in survival was recorded ( p > 0.30 ) with about 60 % of the patients dead during the first year in both groups . Progression was highly correlated to sedimentation rate ( p < 0.001 ) and to performance index ( p = 0.002 ) . Heart failure occurred in a substantial number of patients in both groups which must be considered before starting therapy Single and combination chemotherapy was compared in a clinical trial for men with advanced , metastatic prostate cancer who had received prior pelvic irradiation and had had progression of disease despite hormonal therapy . The 149 patients were r and omized to receive estramustine phosphate or cis-platinum alone or in combination .  Of the 149 patients 25 ( 17 per cent ) were excluded from the study but 124 were evaluated for response and survival . Entry variables were distributed similarly among patients in each treatment arm . There were no complete or partial responders but there were nearly twice as many patients whose disease was stabilized ( 33 per cent ) on the combination regimen compared to estramustine phosphate ( 18 per cent ) and about a third more than for cis-platinum ( 21 per cent ) . Analysis of survival revealed some advantage for patients on combination therapy .  Major toxicities for all treatments were nausea and vomiting ( 62 to 88 per cent ) and accompanying anorexia ( 72 to 95 per cent ) . Azotemia developed in 45 per cent of the patients receiving combination therapy . In addition an elevation in serum creatinine occurred in 22 per cent of the patients receiving combination therapy and in 17 per cent of those receiving cis-platinum alone . Myelosuppression occurred infrequently BACKGROUND Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive and rogen-independent prostate cancer . We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic , hormone-independent prostate cancer . METHODS We r and omly assigned 770 men to one of two treatments , each given in 21-day cycles : 280 mg of estramustine three times daily on days 1 through 5 , 60 mg of docetaxel per square meter of body-surface area on day 2 , and 60 mg of dexamethasone in three divided doses before docetaxel , or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily . The primary end point was overall survival ; secondary end points were progression-free survival , objective response rates , and post-treatment declines of at least 50 percent in serum prostate-specific antigen ( PSA ) levels . RESULTS Of 674 eligible patients , 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone . In an intention-to-treat analysis , the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone ( 17.5 months vs. 15.6 months , P=0.02 by the log-rank test ) , and the corresponding hazard ratio for death was 0.80 ( 95 percent confidence interval , 0.67 to 0.97 ) . The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone ( P<0.001 by the log-rank test ) . PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients , respectively ( P<0.001 ) , and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease , respectively ( P=0.30 ) . Grade 3 or 4 neutropenic fevers ( P=0.01 ) , nausea and vomiting ( P<0.001 ) , and cardiovascular events ( P=0.001 ) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone .  Pain relief was similar in both groups . CONCLUSIONS The improvement in median survival of nearly two months with docetaxel and estramustine , as compared with mitoxantrone and prednisone , provides support for this approach in men with metastatic , and rogen-independent prostate cancer Cisobitan , an organosilicon compound with estrogenic and antigonadotropic properties has been evaluated clinical ly in comparison with an estrogen preparation . In a multicenter study a total of 140 patients with well and moderately well differentiated prostatic cancer were r and omly allocated to treatment with Cisobitan or Estradurin/Etivex , 70 to each group . Of 34 patients with poorly differentiated prostatic cancer 18 were given Cisobitan--  and 16 were given  Estracyt-treatment . Among the patients with well and moderately well differentiated prostatic cancer there were , disregarding mortality , no major differences in subjective , objective or laboratory response to the two kinds of treatment . The pattern of side effects was similar , but oedema requiring diuretics occurred more often in the estrogen treated group . There was a significant difference in mortality at 12 months between the groups , two in the Cisobitan group and ten in the estrogen treated group . Cancer was the cause of death in two patients in the estrogen treated group . All other patients succumbed in cardiovascular diseases . At 24 months the difference in mortality rate was less pronounced : Another ten patients had died in the Cisobitan treated group and seven among the estrogen treated patients . Cancer was responsible for the deaths in seven of the Cisobitan patients compared to four of the estrogen treated patients . Within three years one more patient in both groups had died . Of the 34 patients with poorly differentiated cancer , twelve were alive at the 24 months ' follow up , six in the Cisobitan group and six in the Estracyt group OBJECTIVES Results of cytotoxic chemotherapy for hormone-resistant prostate cancer are not impressive . One of the substances which seems to have a therapeutic benefit is 5-fluorouracil ( 5-FU ) . The effect of 5-FU can be modulated by addition of folinic acid ( FA ) . We tested in a prospect i ve , r and omized phase II trial monotherapy with 5-FU versus the combination of 5-FU and high-dose FA . METHODS 25 patients received 600 mg/m2 5-FU , and 24 patients 400 mg/m2 FA plus 600 or 400 mg/m2 5-FU .  They were treated for two cycles for 5 days in a 21-day interval followed by a weekly single-day application until progression occurred . Pain remission , toxicity , time to progression and survival were evaluated . RESULTS Both regimens led to a pain remission in nearly 70 % of the patients . Mucosal side effects like diarrhea and stomatitis occurred more often in the combination arm , whereas leukopenias were more frequent in the monotherapy are . We observed no statistically significant difference between the two treatment arms regarding time to progression and survival . CONCLUSIONS Although both regimens led to a pain remission , side effects are too severe to recommend these protocol s for st and ard treatment of hormone-resistant prostate cancer Abstract In this second nationally r and omized cooperative chemotherapy trial of the National Prostatic Cancer Project 125 patients with histologically confirmed progressing advanced carcinoma of the prostate ( clinical stage D ) who had had prior pelvic irradiation of at least 2,000R received as initial therapy 1 of 2 non-myelosuppressive agents — estramustine phosphate or streptozotocin — for comparison with patients r and omized to receive st and ard treatment . Patients whose disease was progressive after 12 weeks on chemotherapy were crossed over to receive the alternate therapeutic agent . Response to treatment was evaluated in 105 patients on the basis of previously established and defined criteria .All known prognostic factors were comparable among the 3 treatment arms . The objective response rates to therapy were 19 per cent in the st and ard arm ( stable only ) , 30 per cent in the estramustine phosphate arm ( stable and partial regression ) and 32 per cent in the streptozotocin arm ( stable arm ) . Thus far , 4 patients One hundred eleven patients with endocrine-refractory Stage D prostate cancer were treated with weekly administration of 20 mg/m2 body surface area of doxorubicin hydrochloride ( Adriamycin ) . Fifty-seven were part of a r and omized study comparing doxorubicin and prednisone to prednisone alone . There were significantly more subjective responders in the doxorubicin group than in the prednisone group ( p less than 0.01 ) . The number of patients with evidence of stable disease was also higher during the chemotherapy arm compared with prednisone alone ( p = 0.02 ) . Patients taking doxorubicin had a slightly longer period of stable disease than did those taking prednisone ( p = 0.08 ) . Overall survival , however , was not prolonged ( p = 0.26 ) . Fifty-four patients took part in an open trial and 69 percent responded to treatment . All of these had clinical improvement . Side effects were minimal with cardiotoxicity noted in less than 15 percent among patients with side effects . Over 35 percent had no side effects . Thus single agent , weekly doxorubicin therapy as evaluated in our experience , while well tolerated and of subjective benefit , does not provide the patient with a significant longer progression-free survival or improved overall survival The results of a r and omized , multicenter , cooperative group trial evaluating hormonal therapy with either megestrol acetate or dexamethasone in advanced , hormonally refractory prostate cancer are reported . Three of 29 patients ( ∼10 % ) on the megestrol acetate arm experienced an objective response lasting 41 , 84 , and 202 days , respectively , whereas two of 29 patients ( ∼7 % ) on the dexamethasone arm achieved an objective response lasting 359 and 512 days , respectively . Twenty of 29 patients ( ∼69 % ) on the megestrol acetate arm had stable disease lasting for a median duration of 117 days , whereas 21 of 29 patients ( 72 % ) on the dexamethasone arm had stable disease for a median duration of 86 days . Median survival of all patients was 9 months from initiation of treatment . The median survival for patients on the megestrol acetate arm was 268 days compared to 246 days for patients on the dexamethasone arm ( P = 0.2 ) . Neither dexamethasone nor megestrol acetate would seem to be of substantive value in altering the progression of advanced , hormonally refractory prostate cancer PURPOSE Prostate-specific antigen ( PSA ) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells . For patients with metastatic disease , changes in PSA will often ante date changes in bone scan . Furthermore , many but not all investigators have observed an association between a decline in PSA levels of 50 % or greater and survival . Since the majority of phase II clinical trials for patients with and rogen-independent prostate cancer ( AIPC ) have used PSA as a marker , we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting . We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters . RESULT We defined four patient groups : ( 1 ) progressive measurable disease , ( 2 ) progressive bone metastasis , ( 3 ) stable metastases and a rising PSA , and ( 4 ) rising PSA and no other evidence of metastatic disease .  The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials . We propose that investigators report at a minimum a PSA decline of at least 50 % and this must be confirmed by a second PSA value 4 or more weeks later . Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period . Some investigators may want to report additional measures of PSA changes ( ie , 75 % decline , 90 % decline ) . Response duration and the time to PSA progression may also be important clinical end point . CONCLUSION Through this consensus conference , we believe we have developed practical guidelines for using PSA as a measurement of outcome . Furthermore , the use of common st and ards is important as we determine which agents should progress to r and omized trials which will use survival as an end point This r and omised phase II study was performed in order to evaluate the effectiveness of a weekly chemotherapy regimen in advanced prostatic carcinoma patients ( stage D2 ) refractory to hormonal therapy . Seventy-two cases were studied : they were r and omised in a 2:1 ratio to receive either epirubicin ( 30 mg m-2 weekly ) or doxorubicin ( 25 mg m-2 weekly ) ; 48 patients received epirubicin and 24 received doxorubicin . After 12 courses of chemotherapy , the 45 evaluable patients in the epirubicin arm showed a response rate of 37.7 % and the 21 evaluable patients in the doxorubicin arm showed a response rate of 33.3 % ( P = 0.51 ) . Pain intensity , bone and prostatic tumour markers rapidly and significantly decreased in responders . An improvement in physical symptoms , functional conditions and in emotional well-being was observed in the majority of the treated patients . The histological analysis of bone metastases , performed before and after 12 courses of chemotherapy showed a significant reduction in neoplastic invasion and in new bone formation in responders . Cardiac performance worsened in five out of 45 patients and in ten out of 21 during the first 12 courses of epirubicin or doxorubicin respectively ( P = 0.014 ) . The median survival was 12.5 months in the epirubicin arm and 8.0 months in the doxorubicin arm ( P = 0.042 ) . Our data indicate that in advanced prostatic carcinoma , a weekly epirubicin regimen may give rapid palliative results , similar to that of doxorubicin , but with less side-effects PURPOSE Several multicomponent regimens have been reported to be useful in advanced and rogen-independent prostate cancer . We used a r and omized phase II design to evaluate and compare two such regimens . Patients were accrued primarily in the community setting . PATIENTS AND METHODS Patients with progressive , and rogen-independent prostate cancer were r and omly assigned to one of two treatments : either ketoconazole/doxorubicin alternating with vinblastine/estramustine ( KA/VE ) or paclitaxel , estramustine , and oral etoposide ( TEE ) . Patients were prospect ively stratified on the basis of disease volume . The primary end points were response and overall survival time . RESULTS A total of 75 patients were registered ; 71 are included in the analysis . By the criterion of an 80 % prostate-specific antigen reduction maintained for at least 8 weeks , 11 ( 30 % ) of 37 patients in the TEE arm responded , whereas 11 ( 32 % ) of 34 assigned to KA/VE responded . Median survival was 16.9 months ( 95 % confidence interval [ CI ] , 10.5 to 21.2 months ) in the TEE arm and 23.4 months ( 95 % CI , 12.9 to 30.6 months ) for patients treated with KA/VE . Many patients ( 24 % ) failed to complete at least 6 weeks of therapy , including five ( 8 % ) treatment-related early deaths . CONCLUSION Each of these regimens produced clinical ly significant responses , and the observed median survival ( 18.9 months for all 71 patients ) compares favorably with previously published results , especially in the community setting . Nonetheless , it is apparent that these first-generation regimens must be applied judiciously , and thus we view efforts at better patient selection and the development of more tolerable therapies as higher priorities than carrying either of these regimens to phase III evaluation in the cooperative group setting Summary Ninety-five patients with prostatic carcinoma , stages A-D and of all histological grade s were r and omized between a continuous and an intermittent treatment regimen of EstracytR ( estramustine phosphate ) .  77 patients were evaluated ( 46 with continuous and 31 with intermittent therapy ) .  Remissions were seen in 13 ( 28 % ) and ( 13 % ) , respectively . Stable disease was recorded in 30 ( 65 % ) and 24 ( 77 % ) , respectively . Progression experienced 3 ( 6 % ) and 3 ( 10 % ) respectively . 19 % were unable to continue therapy due to intolerable gastrointestinal side effects ( 7 patients receiving continuous and 8 patients receiving intermittent therapy ) Fifty-seven patients with advanced prostate cancer resistant to first-line hormonal therapy were treated with estramustine and additionally r and omized for treatment with clodronate or placebo . Clodronate treatment was started with 5 days intravenous administration ( 300 mg day[-1 ] ) and followed by oral treatment ( 1.6 g day[-1 ] ) for 12 months . Skeletal pain relief was only about 10 % better in the clodronate than in the placebo group . The results do not support the superiority of combined intravenous and oral treatment with  clodronate  compared with oral administration only Objectives : To compare the quality of life ( QL ) of patients with poor prognosis M1 prostate cancer treated with orchiectomy alone ( ORCH ) or orchiectomy combined with adjuvant mitomycin C ( MMC ;  15 mg/m2 i.v . q 6 weeks : ORCH+MMC ; EORTC trial 30893 ) . Methods : Patients with newly diagnosed M1 poor prognosis prostate cancer completed a truncated version of the EORTC QLQ – C30 ( V 1.0 ) at r and omization ( baseline ) and every 6–12 weeks thereafter until going off the protocol . Five ad hoc questions assessing lower urinary tract symptoms were included in the QL question naire . Results : At least one QL form was completed by 177 of the 189 patients included in the trial , with baseline question naires available for 113 patients ( ORCH n = 52 ; ORCH+MMC n = 61 ) . In both arms , pain and urinary dysfunction improved during treatment . Compared with patients from the ORCH arm , the use of adjuvant MMC was associated with a significant reduction in global health status/QL and with impairment in 7 of 11 QL dimensions covered by the question naire . Some improvement in QL was observed after discontinuation of MMC . A survival benefit was not observed in the ORCH+MMC arm . Conclusions : Intravenous MMC ( 15 mg/m2 q 6 weeks ) can not be recommended as adjuvant treatment in M1 poor prognosis prostate cancer due to its negative impact on QL and lack of efficacy . In general , QL assessment s should be m and atory when adjuvant chemotherapy is evaluated in patients with metastatic prostate cancer OBJECTIVES To evaluate prospect ively the combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone in patients with hormone-refractory prostate cancer ( HRPC ) in a r and omized Phase II study . HRPC presents a challenging therapeutic problem . Salvage chemotherapy is the usual approach at this stage of the disease . The combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone has produced objective clinical responses in HRPC . METHODS Forty patients with HRPC were r and omized to receive one of two treatments . Group 1 underwent chemotherapy ( estramustine 140 mg three times daily and etoposide 100 mg orally for 21 days ) and group 2 the combination of a somatostatin analog ( lanreotide 30 mg intramuscularly every 14 days ) and dexamethasone ( 4 mg tapered to 1 mg ) , in addition to and rogen ablation by orchiectomy or a luteinizing hormone-releasing hormone analog ( triptorelin 3.75 mg intramuscularly every 28 days ) . The clinical and prostate-specific antigen ( PSA ) response , overall survival , time to progression , and toxicity were compared between the two groups . RESULTS The data of 20 patients in group 1 and 18 in group 2 were analyzed . The demographic and clinical data were similar in the two groups at study entry . A PSA response ( decrease of greater than 50 % ) was observed in 45 % of group 1 and 44 % of group 2 . The difference was not statistically significant . A partial clinical response was observed in 29 % and 30 % of groups 1 and 2 , respectively . Again , the difference was not statistically significant . Changes in performance status and pain score during treatment were not significantly different in the two groups . Hematologic toxicity was more frequent in group 1 ( 80 % of patients ) , and mild diabetes was more frequent in group 2 ( 22 % of patients ) . The overall survival was 18.8 months in group 1 and 18 months in group 2 ( not statistically significant ) . The time to progression was 6 versus 4 months and , in the PSA responder subgroup , it was 8 versus 7.7 months in groups 1 and 2 , respectively ( neither difference was statistically significant ) . CONCLUSIONS The results of our r and omized Phase II study indicated that the new combination treatment ( luteinizing hormone-releasing hormone analog , somatostatin analog , and dexamethasone ) may be equally effective as salvage chemotherapy in patients with HRPC in terms of the clinical and PSA response , overall survival , and time to progression . A larger prospect i ve Phase III trial is required to confirm our observations In this clinical trial of men with advanced prostatic cancer no longer responsive to hormone therapy 189 were r and omized to receive estramustine phosphate , methotrexate or cis-platinum . Response evaluations were done in 158 cases .  Objective response rates ( complete , partial or stabilization of disease ) were 34 per cent for estramustine phosphate , 36 per cent for cis-platinum and 41 per cent for methotrexate . Subjective parameters indicated a substantial advantage for pain improvement with methotrexate or cis-platinum over estramustine phosphate . Probabilities of continued response indicated some advantage for methotrexate and median response duration s at this time were twice as long for methotrexate ( 32 weeks ) as for cis-platinum ( 16 weeks ) , with estramustine phosphate intermediate ( 23 weeks ) . Survival rates for the original treatment r and omization groups were not different at this time . Side effects of estramustine phosphate consisted primarily of nausea and vomiting and /or anorexia but to a lesser extent than with cis-platinum . These effects were somewhat less for methotrexate , for which the major side effects were stomatitis and leukopenia , as well as hepatic toxicity reflected by elevated serum glutamic oxaloacetic transaminase levels . Other side effects of cis-platinum were less than for methotrexate ( no stomatitis ) , except for signs of renal toxicity ( elevations in blood urea nitrogen and serum creatinine ) , which were greater . Methotrexate had a relatively high level of activity against metastatic , progressive , hormone nonresponsive prostatic cancer , with side effects that were substantial but manageable A prospect i ve r and omized study has been carried out in order to compare three different treatment modalities for symptomatic metastatic hormone-resistant prostatic cancer . A total of 79 patients were included . One group was treated with estramustine phosphate , another with Epirubicin plus Medroxyprogesterone acetate ( MPA ) , while the third arm consisted of Epirubicin plus placebo .  Best palliation was obtained by the combination of Epirubicin and MPA . This combination also seemed to be associated with the longest response duration PURPOSE Both docetaxel and thalidomide have demonstrated activity in and rogen-independent prostate cancer ( AIPC ) . We compared the efficacy of docetaxel to docetaxel plus thalidomide in patients with AIPC . METHODS Seventy-five patients with chemotherapy-naïve metastatic AIPC were r and omly assigned to receive either docetaxel 30 mg/m(2 ) intravenously every week for 3 consecutive weeks , followed by a 1-week rest period ( n = 25 ) ; or docetaxel at the same dose and schedule , plus thalidomide 200 mg orally each day ( n = 50 ) . Prostate-specific antigen ( PSA ) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decline , and time to progression . RESULTS After a median potential follow-up time of 26.4 months , the proportion of patients with a greater than 50 % decline in PSA was higher in the docetaxel/thalidomide group ( 53 % in the combined group , 37 % in docetaxel-alone arm ) . The median progression-free survival in the docetaxel group was 3.7 months and 5.9 months in the combined group ( P = .32 ) . At 18 months , overall survival in the docetaxel group was 42.9 % and 68.2 % in the combined group . Toxicities in both groups were manageable after administration of prophylactic low-molecular-weight heparin in the combination group . CONCLUSION In this r and omized phase II trial , the addition of thalidomide to docetaxel result ed in an encouraging PSA decline rate and overall median survival rate in patients with metastatic AIPC . After the prophylactic low-molecular-weight heparin was instituted to prevent venous thromboses , the combination regimen was well tolerated . Larger r and omized trials are warranted to assess the impact of this combination OBJECTIVE This prospect i ve and r and omized clinical study was initiated to compare the efficacy and safety of combined and rogen blockade with combination with UFT in patients with untreated prostate cancer . METHODS A total of 142 patients were entered in this study between April 1990 and December 1992 . All patients received bilateral orchiectomy and 200 mg/day of diethylstilbestrol diphosphate . Of these patients , 70 patients were administered an additional 400 mg/day of UFT after r and omization . Either treatment was continued for at least 1 year or until objective progression occurred if the initial response was equal to or better than no change . The endpoints of this study were progression-free survival , cancer-specific survival and change of QOL scores . RESULTS A total of 136 patients were evaluable and 131 patients ( 96.3 % ) could be followed up with a median follow-up period of 1469 days . Both groups showed similar initial treatment response at 12 weeks , adverse effect and change of quality of life score during the first year after initiation of the treatment . There was a significantly longer progression-free survival and better but not significant cancer-specific survival in the endocrine chemotherapy group . The patients with earlier stage and initial serum prostate-specific antigen values < 40 ng/ml showed a good indication for this endocrine chemotherapy . CONCLUSION This endocrine chemotherapy was confirmed to be tolerable and significantly effective in the delay of disease progression , which leads to longer survival in patients with prostate cancer A total of 67 patients with progressive stage D2 prostatic cancer refractory to orchiectomy was entered in a controlled clinical trial to test whether and rogen priming enhances the efficacy of cytotoxic drugs .  All patients were treated continuously with aminoglutethimide and hydrocortisone to lower adrenal and rogen secretion and were given cyclic intravenous chemotherapy . In addition , the 34 patients r and omized to the stimulation arm received fluoxymesterone for 3 days before and on the day of chemotherapy . There was 33 controls . The median duration of followup was 24 months . A modestly higher response rate ( objective remission plus disease stabilization ) was observed in the stimulation arm ( 85 versus 72 per cent , p less than 0.05 ) when the analysis was restricted to the evaluable patients . However , a larger fraction of unevaluable patients was present in the stimulation group ( 41 versus 16 per cent ) , mostly as a result of toxicity from fluoxymesterone , which prompted early discontinuation of treatment . Thus , when data analysis included all patients the response rate actually was slightly higher in the control than in the stimulation arm ( 60 versus 50 per cent , p not significant ) . No difference was observed in median duration of response ( 9 months in both groups ) or over-all survival . Our data suggest that at least in those patients with advanced disease and rogen priming does not seem to enhance significantly the antitumor effect of the combination of amino-glutethimide and chemotherapy , and is associated with significant toxicity . These largely negative results may be explained by the large number of hormone-resistant cells present in tumors that have become refractory to orchiectomy Objective To assess the role of mitozantrone , active in relapsed prostate cancer , as an adjuvant to hormonal treatment in patients with advanced prostate cancer Despite improvements in early detection of prostate cancer when it is clinical ly localized-- and therefore most amenable to curative local therapies-- approximately 33 % of men with early prostate cancer will develop biochemical failure with a rising prostate-specific antigen ( PSA ) during follow-up . The early use of and rogen suppression in this group of men has changed the clinical picture of and rogen-independent disease . Now , there are men on and rogen suppression who will develop biochemical failure and remain free of clinical or radiographic evidence of metastatic disease for a period of time . There is no st and ard approach to this group of men , who have a rising PSA on and rogen deprivation , because there are little or no data about strategies that may improve survival , delay time to progression , or improve quality of life . Therefore , current management of this population remains controversial . In an effort to determine which of these 2 approaches -- second-line hormone therapy or chemotherapy -- is optimal in delaying the time to progression , the Eastern Cooperative Oncology Group ( ECOG ) developed protocol E1899 . Although both approaches offer the potential for response ( reduction in PSA and prolonging the time to clinical progression ) , they have very different toxicity profiles , making impact on quality of life another important end point . This r and omized trial evaluating second-line hormonal therapy using ketoconazole and hydrocortisone versus docetaxel and estramustine combination chemotherapy on progression-free survival in asymptomatic men with a rising PSA on and rogen ablation for prostate cancer is the subject of this article PURPOSE To compare the incidence of palliative response in patients with hormone-resistant prostate cancer ( HRPC ) treated with mitoxantrone and prednisone ( MP ) plus clodronate  with that of patients treated with MP plus placebo . MATERIAL S AND METHODS Men with HRPC , bone metastases , and bone pain were r and omly assigned to receive clodronate 1,500 mg administered intravenously ( IV ) or placebo every 3 weeks , in combination with mitoxantrone 12 mg/m2 IV every 3 weeks and prednisone 5 mg orally bid . Patients completed the present pain intensity ( PPI ) index and Prostate Cancer-Specific Quality -of-Life Instrument at each treatment visit and used a diary to record analgesic use on a daily basis . The primary end point was a reduction to zero or of two points in the PPI or a decrease of 50 % in analgesic intake , without increase in either . RESULTS The study accrued 209 eligible patients over 44 months . One hundred sixty patients ( 77 % ) had mild PPI scores ( 1 or 2 ) , and 49 ( 24 % ) had moderate PPI scores ( 3 or 4 ) . The primary end point of palliative response was achieved in 46 ( 46 % ) of 104 patients on the clodronate arm and in 41 ( 39 % ) of 105 patients on the placebo arm ( P = .54 ) . The median duration of response , symptomatic disease progression-free survival , overall survival , and overall quality of life were similar between the arms . Subgroup analysis suggested possible benefit in patients with more severe pain . CONCLUSION MP provides useful palliation in symptomatic men with HRPC .  Clodronate does not increase the rate of palliative response or overall quality of life .  Clodronate may be beneficial to patients who have moderate pain , but this requires further confirmation BACKGROUND Mitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced , hormone-refractory prostate cancer , but it does not improve survival . We compared such treatment with docetaxel plus prednisone in men with this disease . METHODS From March 2000 through June 2002 , 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily  and were r and omly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks , 75 mg of docetaxel per square meter every three weeks , or 30 mg of docetaxel per square meter weekly for five of every six weeks . The primary end point was overall survival . Secondary end points were pain , prostate-specific antigen ( PSA ) levels , and the quality of life . All statistical comparisons were against mitoxantrone . RESULTS As compared with the men in the mitoxantrone group , men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 ( 95 percent confidence interval , 0.62 to 0.94 ; P=0.009 by the stratified log-rank test ) and those given weekly docetaxel had a hazard ratio for death of 0.91 ( 95 percent confidence interval , 0.75 to 1.11 ; P=0.36 ) . The median survival was 16.5 months in the mitoxantrone group , 18.9 months in the group given docetaxel every 3 weeks , and 17.4 months in the group given weekly docetaxel . Among these three groups , 32 percent , 45 percent , and 48 percent of men , respectively , had at least a 50 percent decrease in the serum PSA level ( P<0.001 for both comparisons with mitoxantrone ) ; 22 percent , 35 percent ( P=0.01 ) , and 31 percent ( P=0.08 ) had predefined reductions in pain ; and 13 percent , 22 percent ( P=0.009 ) , and 23 percent ( P=0.005 ) had improvements in the quality of life . Adverse events were also more common in the groups that received docetaxel . CONCLUSIONS When given with prednisone , treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain , serum PSA level , and quality of life , as compared with mitoxantrone plus prednisone Cytotoxic chemotherapy has not provided survival benefit in metastatic prostate cancer , although it has been used most frequently in patients with far-advanced , refractory disease . To evaluate the effects of chemotherapy given earlier in the course of the disease , the Southwest Oncology Group ( SWOG ) performed a r and omized trial between September 1982 and October 1986 comparing endocrine therapy ( diethylstilbestrol [ DES ] or orchiectomy ) alone followed by cyclophosphamide-Adriamycin ( doxorubicin ; Adria Laboratories , Columbus , OH ) chemotherapy at progression versus initial combined chemo-endocrine therapy .  One hundred forty-three patients were registered , and only six were declared ineligible . Patients on the combined chemo-endocrine therapy arm  had a slightly higher response rate ( 63 % ) compared with endocrine therapy alone ( 48 % ) . A log-linear model of tumor response and treatment arm adjusted for the stratification factors favored the combination arm ( P = .059 ) . Only three of 27 patients on the endocrine therapy alone arm had an objective partial response when crossed over to chemotherapy , while two others had stable disease . Despite the difference in initial response rate , time to treatment failure and survival were identical in the two treatment arms . Seventy-seven percent of patients on the initial endocrine therapy alone arm have died ( median survival , 25.6 months ) compared with 78 % on the chemo-endocrine therapy arm ( median survival , 22.0 months ) . No significant effect of treatment on survival was observed even after adjustment for the stratification variables in a Cox regression model . Exploratory survival analyses with patients on both arms combined did show a marginally significant time to treatment failure and survival advantage for patients treated with DES rather than orchiectomy as initial endocrine therapy . Eighty-six percent of patients treated by orchiectomy have died compared with only 65 % of those treated with DES . These data do not support the addition of cytotoxic chemotherapy to initial endocrine therapy in patients with metastatic prostate cancer Thirty‐two evaluable patients with metastatic carcinoma of the prostate were entered into a prospect i ve r and omized trial comparing cyclophosphamide ( CYC ) with a combination of cyclophosphamide , methotrexate , and fluorouracil ( CMF ) .  Progressive disease after endocrine manipulation was noted in 97 % ( 31/32 ) of patients before entry . Stable disease ( S ) was observed in 9 of 17 patients treated with CYC . One partial response ( PR ) and seven stable responses occurred in the 15 CMF patients . Median duration of stable response was 4.5 months for CYC and 4.5 months on CMF . Median survival of patients with PR and S receiving CYC was 10.1 and for CMF 8.8 months . Patients with progressive disease survived a median 1.7 and 2.6 months with CYC and CMF , respectively . Toxicity was moderate , and no deaths were attributable to sepsis or bleeding . Almost all patients in this study had bone lesions as the dominant site of disease ; this made objective assessment of response difficult . There was no significant improvement in response conferred by the combination regimen . Although patients with metastatic prostatic cancer may benefit from chemotherapy , impressive clinical responses are uncommon Megestrol acetate ( MA ) is a synthetic progestin with reported activity in both hormone‐sensitive and hormone‐refractory prostate carcinoma ( HRPC ) . Based on limited data suggesting a possible dose‐response effect , a trial was initiated to compare st and ard versus moderately high dose MA in HRPC There were 121 men with hormonally refractory metastatic cancer of the prostate who were r and omized to receive estramustine phosphate or vincristine , or the combination of these 2 agents . All patients had received prior radiation therapy ( greater than 2,000 rad ) . There were 90 patients who could be compared for response . The objective response rates ( partial regression or stabilization of disease ) for the 3 treatment groups were 26 per cent for estramustine phosphate , 24 per cent for estramustine phosphate plus vincristine and 15 per cent for vincristine .  Subjective parameters varied little among the 3 regimens . The median duration of response for those responding to estramustine phosphate was similar ( 20 weeks ) to that for vincristine ( 22 weeks ) and greater than that for the combination ( 13 weeks ) . The probability of survival did not differ significantly for patients r and omized to each of the 3 regimens . The addition of vincristine to estramustine phosphate did not enhance the response rate achieved by estramustine phosphate alone and vincristine alone produced the lowest response rate . Estramustine phosphate continues to be the most active agent in previously irradiated patients with hormonally refractory metastatic cancer of the prostate A total of 125 patients with progressing advanced prostatic cancer were entered into a chemotherapy study comparing cyclophosphamide , 5-fluorouracil , and st and ard therapy . Parameters of response were studied in 110 patients who could be evaluated . Thirty-six patients ( 33 per cent ) were considered to have an objective response , that is becoming stable ( 29 patients ) or in partial regression ( 7 patients ) . Negative response parameters ( predictors of a poor response to chemotherapy or st and ard theraphy leading to progress ) included ( 1 ) bone marrow evidence of prostatic cancer , ( 2 ) abnormal liver scan , ( 3 ) prior radiation therapy ( indirectly through increased toxicity to chemotherapy ) , and ( 4 ) lack of bilateral orchiectomy prior to r and omization . Positive indicators ( predictors of good responses ) included ( 1 ) reduction of primary tumor mass , especially after administration of 5-fluorouracil or cyclophosphamide , and ( 2 ) hemoglobin values . There were more objective responders to cyclophosphamide than st and ard therapy whether the hemoglobin was initially normal or low . Indeterminate parameters of response included weight gain , presence of bony or soft tissue metastases , relief of pain , performance status , excretory urography , and biochemical determinations of liver and renal function Between 1984 and 1989 , 197 patients with T1 - 4 , NX , M1 , G2 - 3 or G3 prostate cancer were r and omized to treatment with 560 mg estramustine phosphate ( EMP , Estracyt , Emcyt ) or 3 mg diethylstilbestrol ( DES ) per day in a double blind study with stratification on presence or absence of cancer pain at start . A total of 194 patients were evaluated for efficacy of therapy . Time to progression ( p = 0.054 ) , to treatment failure ( p = 0.036 ) , cancer-specific survival ( p = 0.068 ) as well as overall survival ( p = 0.021 ) were longer in the DES group . There were more patients with prognostic parameters indicating bad prognosis in the EMP group . This trial was design ed to study whether EMP had better effect than DES as the primary treatment of high- grade , disseminated prostate cancer . The results did not confirm this hypothesis . On the contrary , treatment with DES had relatively good effect on this very aggressive form of prostate cancer Ninety-two patients with D2 prostatic cancer were studied . Initial treatment was with either diethylstilboestrol ( DES ) or orchidectomy . Response to DES ( 5/63 , 81 % ) was significantly higher than for orchidectomy ( 18/29 , 62 % ; p less than 0.01 ) . However , duration of response and duration of survival were not significantly different for the 2 forms of hormonal therapy . Fifty-seven patients were r and omised to receive second-line treatment with either medroxyprogesterone acetate ( MPA ) , oral chlorambucil or combination chemotherapy ( adriamycin + cyclophosphamide + 5-fluoro-uracil ) . Response to second-line treatment was similar for all 3 regimens ( 46 % overall response ) . Most of the responses were disease stabilisation and , although there was symptomatic benefit , response to second-line therapy did not significantly improve survival compared to the survival experience of the group as a whole . It is concluded that palliative second-line treatment for advanced prostatic cancer should consist of the least toxic form of treatment which in this study was second-line hormone administration ( MPA ) One hundred forty‐two patients with progressive , hormonally refractory advanced prostate carcinoma who had not received prior chemotherapy were r and omized to receive either combination chemotherapy with 5‐fluo‐rouracil ( 5‐FU ) , doxorubicin , and mitomycin C ( FAM ) or sequential chemotherapy with the same agents , i.e. , mitomycin C , followed by doxorubicin on disease progression , followed by 5‐FU .  Objective tumor regressions were observed in 10 of 70 ( 14 % ) patients receiving the FAM treatment arm and 10 of 72 ( 14 % ) patients initially receiving mitomycin C. Of the 24 patients who received secondary therapy with doxorubicin alone , 3 ( 12.5 % ) achieved objective tumor regression . There were no responses among five patients who received tertiary therapy with 5‐FU alone . The median survival time for all patients treated with the combination arm was 8.7 months , compared with 7.1 months for patients who received the FAM arm ( P = 0.025 ) . However , this modes ! survival advantage in favor of the FAM treatment arm must be weighed against significantly more myelosuppression experienced by these patients . The chemotherapeutic regimens used in this study have only minor clinical value in the treatment of hormonally refractory advanced prostate cancer . Cancer 1992 ; 69:1440‐1444 The present study was design ed to investigate the efficacy of various combinations of chemotherapeutic agents in the treatment of prostatic cancer in a group refractory to anti and rogenic therapy ( Group 1 ) and in a previous untreated group ( Group 2 ) . Therapeutic combinations of Estracyt ( E ) + Peplomycin ( P ) + Doxorubicin ( Do ) and P + Do + 5 FU ( F ) in Group 1 and E + P , Honvan ( Ds ) + P and E in Group 2 were carried out . The main objectives of this study were estimations of the efficacy of E and P in relation to the refractory cases of Group 1 and the efficacy of the combination E + P , in Group 2 . This is the first such prospect i ve , r and omized , controlled study to be carried out in Japan in relation to prostatic cancer . The results obtained in the present study indicated that chemotherapeutic regimens including E provide some enhanced efficacy , but that the efficacy with regard to refractory cases is poor ( 23.1 - 27.3 % ) , as has been reported of studies conducted in the USA and Europe . With regard to previously untreated cases , the E + P regimen achieved a relatively higher response rate than the other treatments ( 72.7 vs 44.5 or 50.0 % ) . In the comparison of survival times and survival curves , there were no statistically significant differences among the various treatment subgroups . A comparison of survival curves revealed the interesting finding that the PAP-related response showed a clear correlation to the survival curves of Group 2 patients In the 36 months since its inception , the National Prostatic Cancer Project treatment subgroup has r and omly assigned over 360 patients with progressive advanced prostatic cancer who were no longer responsive to endocrine manipulation to either one of four different clinical studies . The initial study demonstrated a clear superiority for 5-fluorouracil ( 5-FU ) and cyclophosphamide over continued conventional therapy . Beneficial responses were documented and are associated with increased survival rates and relief from pain and other symptoms . A proportionately larger number of patients obtained clinical benefit ( stable and partial regression ) on cyclophosphamide than on st and ard or 5-FU therapy . The criteria for evaluation of patients are supported by the survival data , ie , responders have survived for a longer period of time than those patients who continued in progression . Preliminary data from the subsequent protocol s have documented a 30 % response ( stable and partial regression ) in patients receiving oral estramustine phosphate and definite responses in patients treated with DTIC ; Too few patients have been treated with Leo 1031 to offer total response rates at this time , although the early results are promising . These clinical studies have firmly established a place for chemotherapy in the management of prostatic cancer .  New trials will introduce single- and multiple-drug chemotherapy at earlier phases of the clinical course of prostatic cancer patients PURPOSE Time to progression ( TTP ) , overall survival , and quality of life ( QL ) were compared in patients with hormone-resistant prostate cancer ( HRPC ) treated with prednisone ( 5 mg orally , four times a day ) or flutamide ( 250 mg orally , three times a day ) . PATIENTS AND METHODS Symptomatic patients were r and omized to receive either prednisone ( 101 patients ) or flutamide ( 100 patients ) . Subjective response was assessed based on performance status , the use of analgesics , and the need to apply alternative palliative treatment . Prostate-specific antigen (PSA)-based biochemical response ( > or= 50 % reduction of baseline PSA ) was recorded . At baseline and at 6-week intervals during follow-up , patients completed the European Organization for Research and Treatment of Cancer Quality of Life Question naire C-30 . RESULTS There was no difference between the groups in median TTP  ( prednisone , 3.4 months ; flutamide , 2.3 months ) or overall survival  ( prednisone , 10.6 months ; flutamide , 11.2 months ) . In the prednisone group , 56 % of the patients experienced a subjective response , compared with 45 % in the flutamide group ( P : = .18 ) . The median response duration was 4.8 months for prednisone and 4.2 months for flutamide . A biochemical response was observed in 21 % and 23 % of the prednisone and flutamide groups , respectively . Gastrointestinal toxicity was the reason for trial discontinuation in seven patients receiving flutamide and two patients receiving prednisone . The QL assessment parameters favored the use of prednisone with statistically significant differences in pain , fatigue , role functioning , appetite loss , gastrointestinal distress , and overall QL . CONCLUSION In symptomatic HRPC , treatment with prednisone or flutamide leads to similar rates of TTP and overall survival and no difference in subjective or biochemical response . The QL results favor the use of low-cost prednisone in patients with HRPC Background . Between August 1984 and November 1989 , the Hoosier Oncology Group conducted a Phase III study comparing cyclophosphamide ( CTX ) with cyclophosphamide , doxorubicin , and methotrexate ( CAM ) in patients with hormone‐refractory metastatic prostatic cancer to determine whether the addition of doxorubicin and methotrexate to the cyclophosphamide regimen conferred any survival advantage Currently , approximately 30,000 men die annually of metastatic , hormone-refractory prostate cancer . And rogen blockade is palliative and is generally effective for an average of 2 to 3 years until a patient develops and rogen-independent disease . Newer chemotherapeutic regimens can induce remissions in approximately 50 % of patients ; however , median survival for patients with and rogen-independent disease is still 8 to 12 months . The strategy of using chemotherapy regimens after and rogen blockade has been proved noncurative , and new approaches are needed to attempt to cure patients with advanced disease . It has been demonstrated in the pre clinical setting that and rogen withdrawal induces apoptosis in cancer cells in both the Shinogi breast cancer model and the LNCaP prostate cancer model . In both of these models , and rogen withdrawal was not curative , and the tumors grew back in a hormone-independent state . It is possible that the addition of chemotherapy at the time of initial and rogen ablation will improve cell kill by potentiating apoptosis , thereby killing cells that might otherwise have mutated to the and rogen-independent state if allowed to continue to cycle and grow . The rationale behind Radiation Therapy Oncology Group ( RTOG ) P-0014 is to demonstrate in a r and omized phase 3 trial that giving patients chemotherapy at the beginning of and rogen blockade may improve patient survival The National Prostatic Cancer Project has r and omized this study for endocrine-resistant prostatic cancer patients for treatment with st and ard hormonal or other therapies compared to 5-fluorouracil and cyclophosphamide . Both agents were found at the probability level of 0.05 to have a significant advantage over st and ard treatment in terms of objective response , subjective improvement and minimal toxicity . Additional chemotherapy protocol s are currently under way . This r and omized trial is the first report of such a national study completed to date . We are much encouraged by this program and believe that additional agents now under consideration will provide additionally encouraging results This is the fifth completed r and omized clinical trial of the National Prostatic Cancer Project . There were 125 patients with histologically confirmed relapsing clinical stage D prostatic cancer r and omized to receive hydroxyurea , methyl-chloroethyl-cyclohexy-nitrosourea or cyclophosphamide .  All patients had received and failed previous hormonal therapy . Patients whose disease progressed after 12 weeks on the initial therapy were crossed over or r and omized to receive an alternate drug . There were 98 patients available for comparison of treatments . Objective responses included patients with complete or partial regression as well as stable disease . The response rates were 35 per cent for cyclophosphamide , 30 per cent for methyl-chloroethyl-cyclohexy-nitrosourea and 15 per cent for hydroxyurea . Subjective response parameters included improvement in performance status and relief of pain . Pain was improved in a fifth of the patients on each treatment area . Methyl-chloroethyl-cyclohexy-nitrosourea and hydroxyurea showed activity in advanced prostatic cancer patients but at the expense of excessive toxicity .  Cyclophosphamide continues to be the most active single agent in this type of patient , particularly with regard to duration of response and survival . There was a statistically demonstrable advantage for cyclophosphamide over hydroxyurea and a marginal advantage over methyl-chloroethyl-cyclohexy-nitrosourea in survival experience Eighty-nine patients with progressive prostate cancer despite suppression of testosterone and withdrawal of anti- and rogens were studied . This was a relatively advanced population , with 63 of 89 having either osseous metastases ( mets ) beyond the axial skeleton or visceral mets . Patients were r and omly assigned to receive either ketoconazole alone , or ketoconazole with weekly doxorubicin . All patients received replacement hydrocortisone . The primary endpoints were response and survival . Based on PSA reduction criteria ( > /= 80 % maintained for at least 8 weeks ) , 14 of 45 patients ( 31 % ) in the single-agent ketoconazole arm responded . Sixteen of 44 patients ( 36 % ) in the combination ketoconazole/doxorubicin arm responded . There were no important differences between the two treatments in any outcome measure . The median overall survival for all patients was 12.5 months ; median time to progression was 3.3 months . Toxicity was significant with both regimens , and more severe in the doxorubicin arm . Fully 20 % of patients in each arm discontinued therapy due to intolerable side effects . Each of these regimens is toxic , and produced responses in fewer than half of treated patients . Although the observed median survival does compare favorably with reports from similar cohorts treated in the community , the potential benefit is only modest . In our view , neither of these regimens is sufficiently promising to justify phase 3 evaluation BACKGROUND Recent phase III studies in hormone refractory prostate cancer ( HRPC ) showed an improvement in terms of overall survival ( OS ) , objective response ( OR ) and biochemical response ( BR ) ; however , chemotherapy is usually accompanied by negative side effects that determines poor quality of life ( QoL ) and only marginally improves individual clinical response ( ICR ) in terms of pain relief and performance status . Ellagic acid is a polyphenol that is found in many species of flowering plants . It is an antioxidant that determines apoptosis , down regulation of IGF-II , activates p21 ( waf1/Cip1 ) , mediates the cumulative effect on G1/S transition phase and prevents destruction of p-53 gene by cancer cells . ENDPOINTS The aim of this study was to assess the effects of ellagic acid support therapy on toxicity , OR , ICR and BR in HRPC patients treated with estramustine phosphate and vinorelbine .  MATERIAL S AND METHODS Patients with HRPC were r and omly distributed in two study groups : a  control group ( group A ) who underwent chemotherapy with vinorelbine and estramustine phosphate , and an  experimental group ( group B ) where chemotherapy regimen was associated with ellagic acid . RESULTS The mean number of chemotherapy cycles/patient was 4 ( range 3 - 8 cycles ) and 6.5 ( range 5 - 11 ) in group A and B patients , respectively . A reduction in systemic toxicity , statistically significant for neutropenia , associated with better results in term of OR rate , ICR , and BR were observed in group B compared with group A. On the contrary no significant difference in OS and PFS was detected between groups . CONCLUSIONS our study suggests that the use of ellagic acid as support therapy reduces chemotherapy induced toxicity , in particular neutropenia , in HRCP patients ; however , further studies are required to confirm our results A series of 105 patients with metastatic prostatic cancer , having progressed on first-line hormonal treatment , were r and omised to high-dose medroxyprogesterone acetate ( MPA ) 1000 mg i.m . daily for 15 days , followed by 1000 mg weekly ( 53 patients ) , or to estramustine 280 mg per os twice daily ( 52 patients ) . The treatment was discontinued because of side effects in 3 of 51 evaluable MPA-treated patients and in 8 of 51 evaluable estramustine-treated patients . Progression-free survival was short in both groups and no statistically significant difference between them was observed . After 1 year , 70 % of the patients had died and there was no statistically significant difference between the 2 treatments in the cumulative observed survival rates . According to modified SPCG criteria , remissions lasting from 12 to 56 weeks were noted in 13 MPA-treated patients and in 4 estramustine-treated patients . This difference was statistically significant . After cross-over , 6 of 33 patients in the MPA group had a remission compared with 1 of 24 in the estramustine group . It was concluded that the response rate , considering both subjective and objective response criteria , was better with MPA and the side effects were fewer In patients with metastatic hormone-relapsed adenocarcinoma of the prostate ,  adriamycin was compared to 5-fluorouracil in a r and omized trial in 99 patients and adriamycin alone was studied in an open trial in 48 patients . Response to adriamycin was superior as judged by response of measurable disease ( 25 vs 8 % ; P less than 0.05 ) and survival ( median 29 vs 24 weeks ; Cox analysis , P less than 0.03 ) , but comparable as judged by acid phosphatase response . Ambulatory status and site of metastases influenced rate of response to chemotherapy . Activity level , site of metastases , weight loss , and the symptom of protein aversion were prognostic factors for survival . Hematologic and gastrointestinal toxicity were frequent but were tolerated satisfactorily . Adriamycin therapy may be beneficial in patients with prostatic cancer after hormone therapy PURPOSE To compare vinblastine versus the combination of vinblastine plus estramustine as treatment for patients with hormone-refractory prostate cancer ( HRPC ) . PATIENTS AND METHODS A total of 201 patients with metastatic prostate cancer , progressive after hormonal therapy and anti and rogen withdrawal ( if prior anti and rogen treatment ) , were r and omized to receive vinblastine ( V ) 4 mg/m(2 ) by intravenous bolus weekly for 6 weeks followed by 2 weeks off , either alone or together with estramustine phosphate ( EM-V ) 600 mg/m(2 ) PO days 1 through 42 , repeated every 8 weeks . Of 193 eligible patients , 98 received V , and 95 received EM-V. RESULTS Overall survival trended in favor of EM-V but was not significantly different as determined by Kaplan-Meier analysis ( P = .08 ) . Median survival was 11.9 months for EM-V and 9.2 months for V. EM-V was superior to V for secondary end points of time to progression ( P < . 001 , stratified log rank test ; median 3.7 v 2.2 months , respectively ) and for proportion of patients with > /= 50 % prostate-specific antigen ( PSA ) decline sustained for at least 3 monthly measurements ( 25.2 % v 3.2 % , respectively ; P < .0001 ) . Granulocytopenia was significantly less for EM-V compared with V ( grade 2 , 3 , and 4 = 7 % , 7 % , and 1 % v 27 % , 18 % and 9 % , respectively ; P < .0001 ) ; however , grade 2 or worse nausea ( 26 % v 7 % , respectively ; P = .0002 ) and extremity edema ( 22 % v 8 % , respectively ; P = .005 ) were more frequent for EM-V. CONCLUSION Although overall survival was not significantly greater for the combination , EM-V was superior to V for time to progression and PSA improvement . These results encourage further study of estramustine-based antimicrotubule drug combinations in HRPC The  Southeastern Cancer Study Group has evaluated 5-fluorouracil administered intravenously weekly at a dosage of 600 mg . per M.2 as a single agent , and the 3-drug combination of cyclophosphamide , doxorubicin and 5-fluorouracil in patients with metastatic carcinoma of the bladder and of the prostate previously untreated with cytotoxic chemotherapy in a prospect ively r and omized phase II study . In 4 of 18 patients with bladder carcinoma  5-fluorouracil induced an objective response , and cyclophosphamide , doxorubicin and 5-fluorouracil induced an objective response in 3 of 21 patients . In patients with prostatic carcinoma  5-fluorouracil induced an objective response as measured by a 50 per cent decrease in prostatic acid phosphatase determined in a central reference laboratory in 3 of 25 patients and objective stability by National Prostatic Cancer Project criteria in 14 of 29 patients . Cyclophosphamide , doxorubicin and 5-fluorouracil induced an objective response in 7 of 22 patients and objective stability in 20 of 29 . Thus , 5-fluorouracil administered in an adequate weekly dosage is established as an effective single agent in some patients with stage D carcinoma of the bladder or prostate . However , there is no significant added benefit as measured by survival obtained for these patients by combining cyclophosphamide and doxorubicin with 5-fluorouracil BACKGROUND Prognosis of hormone-refractory prostatic cancer is dismal . We evaluated the efficacy of cytotoxic chemotherapy in combination with hormone therapy in patients with newly diagnosed metastatic prostatic cancer . METHODS From February 1984 to March 1992 , 39 newly diagnosed patients with stage D2 prostatic cancer were r and omized to orchiectomy plus diethylistilbestrol diphosphate or orchiectomy plus diethylstilbestrol diphosphate plus combination chemotherapy with cisplatin and methotrexate . RESULTS There was not significant difference in survival or progression-free survival between the two groups . CONCLUSION Chemotherapy has not been proved to prolong survival or progression-free survival in patients who received hormone therapy Patients with poorly differentiated prostatic carcinoma and skeletal metastases were r and omized to treatment with 2.6-cis-diphenylhexamethylcyclotetrasiloxane ( 2.6-cis ) and estramustine-17-phosphate ( estramustine ) . Parallel with the clinical study a group of non-r and omized patients were treated with 2.6-cis . Cytological regression of the tumor could be registered in half of the estramustine group but not in the 2.6-cis group . There were no drug-related changes in blood chemistry , kidney function tests , hematology or liver enzymes . There was in increase in acid and alkaline phosphatase in both groups but more pronounced in the 2.6-cis group . In both groups follicle-stimulating and luteinizing hormone values were depressed . Testicular and penis atrophy was observed in the 2.6-cis group . Relief of pain and marked improvement of conditions occurred in the majority of the cases in both groups . In general , no tumor regression was observed during administration of 300 mg . 2.6-cis daily for at least 3 months . Some tumor regression was noted during 600 mg . estramustine therapy daily PURPOSE We compared median time to treatment failure of men with asymptomatic , hormone refractory , progressive prostate cancer treated with mitoxantrone plus prednisone versus prednisone alone . MATERIAL S AND METHODS In a multicenter phase III trial 120 men with asymptomatic , progressive , hormone refractory prostate cancer were r and omly assigned to treatment with mitoxantrone and prednisone or prednisone alone . Patients received 12 mg./m . mitoxantrone intravenously once every 3 weeks for 6 cycles and 5 mg . prednisone twice daily with or without mitoxantrone .  Time to treatment failure was assessed as an aggregate end point comprised of time to disease progression , time to toxicity or death , or time to initiation of alternate therapy . RESULTS Median followup was 21.8 months . Median time to treatment failure and median time to progression were the same : time to treatment failure and time to progression in the mitoxantrone and prednisone group was 8.1 months compared to 4.1 months in the prednisone alone group ( p = 0.017 versus p = 0.018 ) . More patients ( 27 or 48 % ) treated with mitoxantrone and prednisone achieved a 50 % or greater reduction in prostate specific antigen levels than those who received only prednisone ( 15 or 24 % , p = 0.007 ) . There was no significant difference in median survival between the 2 groups , which was 23 and 19 months , respectively . Death was mainly attributable to disease progression . CONCLUSIONS Patients with hormone refractory prostate cancer who are asymptomatic but had progressive disease had a significantly higher response rate when treated with mitoxantrone and prednisone as demonstrated by the 50 % or greater decrease in prostate specific antigen compared to treatment with prednisone alone . Time to treatment failure was significantly prolonged in the chemotherapy treated group but survival rates were not different Based on the results of several small clinical studies , the experimental data of J. T. Isaacs , and the theoretical considerations about the heterogeneity of prostatic cancer , we investigated the effect of simultaneous hormone-chemotherapy in previously untreated advanced prostatic cancer . Patients ( n = 145 ; 117 stage D , 28 clinical stage C ) up to an age of 80 years with histologically confirmed and previously untreated prostatic cancer were entered into the study . All patients received hormonal therapy with surgical castration and long-term administration of flutamide . Following castration , the patients were divided r and omly into two groups . Group I patients received simultaneous chemotherapy starting 4 weeks after castration with weekly administration of 25 mg/m2 of 4-epirubicin intravenously for 18 weeks . Patients in group II initially had only hormonal therapy and did not receive chemotherapy until they progressed . Both groups were assessed at intervals of 3 months with respect to subjective and objective response according to the National Prostatic Cancer Project criteria . Quality of life was assessed monthly by the patients during the first 6 months and every 3 months thereafter . Evaluation of the baseline data showed that both groups were comparable with respect to prognostic factors . The first statistical analysis revealed the significant superiority of the combined treatment with respect to response rates ( P = .005 ) , median time to progression ( P = .1 ) , and survival time ( P = .01 ) . Analysis of the patients ' self- assessment data showed that , to date , chemotherapy had not exerted an unfavorable influence on quality of life . These results are very preliminary and should be h and led with care . However , the data suggest that an early combined chemotherapy-hormonal treatment is beneficial for at least a subset of patients , and warrants further clinical investigation The response and duration of survival were evaluated for patients with stage D relapsing prostatic cancer who were r and omized to cyclophosphamide (Cytoxan),5-fluorouracil ( 5-FU ) or st and ard therapy , or to subsequent chemotherapies .  The chemotherapies on initial r and omization were superior to the st and ard therapy in the number of responders and duration of response . Survival was longer for responders ( stable or partial regression ) on chemotherapy by comparison to responders ( stable only ) on st and ard therapy . The survival for patients receiving initial and crossover chemotherapy was significantly improved for patients who responded to therapy . Chemotherapy of advanced relapsing stage D prostatic cancer is more beneficially treated by specific chemotherapy as shown in this r and omized study BACKGROUND In order to examine the usefulness of chemohormonal therapy , we conducted a multicentered r and omized trial comparing hormonal therapy , using a luteinizing hormone-releasing hormone ( LH-RH ) agonist , with chemohormonal therapy , hormonal therapy plus cyclophosphamide ( CPM ) , in patients with newly diagnosed clinical stage D prostatic cancer . METHODS Between January 1991 and March 1995 , 41 evaluable patients with stage D prostatic cancer were r and omized into 2 groups : group A ( hormonal therapy alone ) , goserelin acetate depot 3.6 mg subcutaneously every 4 weeks : group B ( chemohormonal therapy ) , goserelin acetate depot 3.6 mg subcutaneously and CPM 1000 mg/m2 intravenously every 4 weeks . The responses to the therapies were evaluated based on the criteria of The Japanese Urological Association . RESULTS There were no significant differences between the 2 groups with regard to objective and subjective response rates . No advantage in chemohormonal therapy was observed in the survival rate and progression-free survival rate . However , the survival rate and progression-free survival rate of responders were significantly higher than those of nonresponders in both groups . When the results were categorized by histologic grade patients with poorly-differentiated adenocarcinoma had significantly higher response rates , survival rates , and disease-progression-free survival rates in Group B compared to similar patients in Group A. CONCLUSIONS We conclude that chemohormonal therapy does not definitely improve the clinical response and prognosis of patients with stage D prostatic cancer ; however , for patients with poorly-differentiated adenocarcinoma , chemohormonal therapy is a useful treatment Patients with hormone escaped advanced progressive prostate cancer were r and omized either to receive either high-dose Estramustine phosphate orally or Mitomycin C by i.v . injection every 6 weeks until signs of progression or death supervened . Patients on both arms progressed rapidly , with a median time to progression of 5 months and a median length of survival of only 10 months . Toxicity was very considerable in both arms PURPOSE Suramin is a novel agent that has demonstrated preliminary evidence of antitumor activity in hormone-refractory prostate cancer ( HRPC ) . A prospect i ve r and omized clinical trial was design ed to evaluate pain and opioid analgesic intake as surrogates for antitumor response in HRPC patients with significant , opioid analgesic-dependent pain . PATIENTS AND METHODS A double-blind , placebo-controlled trial r and omized patients to receive a 78-day , outpatient regimen of either suramin plus hydrocortisone ( HC , 40 mg/d ) or placebo plus HC .  Treatment assignment was unblinded when either disease progression or dose-limiting toxicity occurred ; placebo patients were allowed to cross-over to open-label suramin plus HC . In addition to pain and opioid analgesic intake , prostate-specific antigen ( PSA ) response , time to disease progression , quality of life , performance status , and survival were compared . RESULTS Overall mean reductions in combined pain and opioid analgesic intake were greater for suramin plus HC ( rank sum P = .0001 ) . Pain response was achieved in a higher proportion of patients receiving suramin than placebo ( 43 % v 28 % ; P = .001 ) , and duration of response was longer for suramin responders ( median , 240 v 69 days ; P = .0027 ) . Time to disease progression was longer ( relative risk = 1.5 ; 95 % confidence interval , 1.2 to 1.9 ) and the proportion of patients with a greater than 50 % decline in PSA was higher ( 33 % v 16 % ; P = .01 ) in patients who received suramin . Neither quality of life nor performance status was decreased by suramin treatment , and overall survival was similar . Most adverse events were of mild or moderate intensity and were easily managed medically . CONCLUSION Outpatient treatment with suramin plus HC is well tolerated and provides moderate palliative benefit and delay in disease progression for patients with symptomatic HRPC PURPOSE Approximately 40,000 men die each year of hormone-refractory prostate cancer ( HRPC ) . The results of treatment with chemotherapy have been disappointing to date , with no trials demonstrating a benefit with respect to survival duration .  Corticosteroids and mitoxantrone each have been shown to be active agents in this disease . The purpose of this study was to demonstrate an advantage of mitoxantrone and hydrocortisone ( M+H ) over hydrocortisone alone with respect to survival duration . PATIENTS AND METHODS Two hundred forty-two patients with HRPC were r and omized to receive either M+H or hydrocortisone alone . Patients were monitored for survival , time to disease progression , time to treatment failure , response , and quality -of-life ( QOL ) parameters . RESULTS Treatment in both arms was well tolerated . Although there was a delay in time to treatment failure and disease progression in favor of M+H over hydrocortisone alone , there was no difference in overall survival ( 12.3 months for M+H v 12.6 months for hydrocortisone alone ) . There was an indication that QOL was better with M+H , in particular with respect to pain control . CONCLUSION M+H generated more frequent responses and a delay in both time to treatment failure and disease progression compared with hydrocortisone alone . In addition , there was a possible benefit of M+H with respect to pain control over hydrocortisone alone . No improvement in survival was observed . Although M+H could be viewed as a palliative option for patients with HRPC , new drugs and novel strategies are needed to improve survival for this disease We report here in the interim analysis of an ongoing r and omized clinical trial design ed to test whether and rogen priming enhances tumor chemosensitivity in men with stage D prostate cancer refractory to orchiectomy . All patients are continuously treated with aminoglutethimide and hydrocortisone , to lower adrenal and rogen secretion , and are given cyclic chemotherapy . Patients in the stimulation arm receive also the synthetic and rogen , fluoxymesterone , for 3 days before and on the day of chemotherapy .  Of 57 patients entered to date , 41 have received adequate treatment to be evaluable .  Response to therapy ( objective remissions + stabilizations of disease ) occurred in 17 of 18 evaluable patients ( 94 % ) r and omized to the stimulation arm , and in 16 of 23 evaluable patients ( 70 % ) in the control group ( p less than 0.025 ) . Duration of response was not significantly different in the two groups ( median : 9 months in the stimulation and 12 months in the control arm ) . With 30 % of the total of 57 patients still alive , survival is not significantly different in the stimulation ( median : 13 months ) and control arm ( median : 16 months ) . As expected , patients who responded to treatment lived significantly longer than those who failed to benefit . Two episodes of reversible spinal cord compression occurred during and rogen administration . ( The risk of this serious side effect may be reduced by performing a screening myelogram to rule out sub clinical spinal metastasis ) . Our preliminary data suggest that and rogen priming may enhance the tumoricidal effect of cytotoxic drugs in advanced prostate cancer . The lack of improvement in duration of response and survival may be explained by the large fraction of hormone-independent cells probably present in patients with tumors refractory to orchiectomy This prospect i ve r and omized study in nonhormonally responsive adenocarcinoma of the prostate shows that response rates to melphalan vs cyclophosphamide groups were virtually identical BACKGROUND Vinorelbine ( VRL ) has been shown to be active in hormone-refractory prostate cancer ( HRPC ) in phase II studies , alone or in combination . Its moderate toxicity profile is well tolerated in elderly patients . PATIENTS AND METHODS Patients with metastatic prostate cancer , progressive after primary hormonal therapy , were r and omised to receive intravenous VRL 30 mg/m2 on days 1 and 8 every 3 weeks , and hydrocortisone 40 mg/day or hydrocortisone alone until disease progression . Centres could choose to add aminoglutethimide 1000 mg/day to hydrocortisone as second-line hormone therapy ( HT ) for all their patients . R and omisation was stratified by centre . Further chemotherapy was allowed after progression . The primary end point was progression-free survival ( PFS ) . The final analysis was performed on a total of 414 patients . Reported results were all based on intention-to-treat analyses . All progressions and responses were review ed by an independent panel . RESULTS PFS was significantly prolonged in the VRL plus HT arm compared with the HT alone arm , according to the statistical hypothesis of the protocol ( P=0.055 in the two-sided log-rank test with a pre-specified significance level of 10 % ) . The 6-month PFS rates were 33.2 % versus 22.8 % , and the median duration s of PFS were 3.7 versus 2.8 months . In the multivariate Cox analysis , which included age , Karnofsky performance status ( PS ) , haemoglobin , alkaline phosphatase at study entry and number of prior hormonal treatments , the P value was decreased to 0.005 . The prostate-specific antigen ( PSA ) response rate ( > or = 50 % decline sustained for at least 6 weeks ) was significantly higher for VRL plus HT compared with HT ( 30.1 % versus 19.2 % ; P=0.01 ) . Clinical benefit , defined as a decrease in pain intensity or analgesic consumption or an improvement of Karnofsky PS for at least 9 weeks , and at least stable assessment in the other two , was also more frequently observed in patients who received VRL plus HT versus HT alone ( 30.6 % and 19.2 % ; P=0.008 ) . There was no statistical difference in overall survival . Forty-three per cent of patients in the HT arm received at least one line of further chemotherapy after progression , compared with 28 % of patients in the VRL-based arm . Aminoglutethimide did not seem to result in better efficacy for either arm . VRL plus HT was well tolerated , with a median administered relative dose intensity of 90 % ; grade 4 neutropenia occurred in 6.5 % of patients and non-haematological toxicity was rare . CONCLUSIONS The combination of VRL and hydrocortisone compared with hydrocortisone alone result ed in improved clinical benefit , PFS and PSA response rate . This therapeutic gain is similar to that previously reported with mitoxantrone in combination with low-dose corticosteroids . There was no gain in survival ; however , the combination is well tolerated in this elderly group of patients , who often present cardiac co-morbidities , and therefore offers an active and safe therapeutic option for patients with hormone-refractory prostate cancer Liposomal encapsulation of doxorubicin has been shown to reduce nonspecific delivery of this agent to normal tissue and to increase specific delivery to malignant cells . On the basis of doxorubicin 's demonstrated clinical efficacy against hormone‐refractory prostate carcinoma ( HRPCA ) , the authors conducted a prospect i ve , r and omized Phase II clinical trial to evaluate the feasibility , toxicity , and therapeutic efficacy associated with the pegylated form of this agent In a r and omized phase III trial performed by the Urological Group of the European Organization for Research on Treatment of Cancer low dose estramustine phosphate ( 280 mg . twice daily for 8 weeks and 140 mg . twice daily thereafter ) was compared to diethylstilbestrol ( 1 mg . 3 times daily ) in patients with stages T3 to T4 , M0 or M1 prostatic cancer . Of 248 patients entered 227 were evaluable for analysis : 115 received estramustine phosphate and 112 received diethylstilbestrol . The best response of the local tumor as assessed by palpation was seen in patients receiving diethylstilbestrol . There was no significant difference between treatments for response rate of metastases , interval to local progression , distant progression , over-all survival and death of carcinoma of the prostate . Duration of survival was correlated with the assessment of local response as determined by palpation . The response of distant lesions also was correlated closely with survival .  Diethylstilbestrol ( 1 mg . 3 times daily ) was associated with a significantly worse degree of cardiovascular toxicity than estramustine phosphate . This finding was especially obvious in patients who had no history of cardiovascular disease .  Gastrointestinal toxicity occurred in 25 patients treated with estramustine phosphate , including 6 in whom cessation of treatment was necessary . Further studies are required to determine the optimum dose of diethylstilbestrol and estramustine phosphate , and to establish the best form of hormonal treatment for prostatic carcinoma BACKGROUND Patients with hormone relapsed prostate cancer ( HRPC ) are often treated with flutamide or diethylstilboestrol . However , which of these two options is the best treatment for HRPC remains unclear . METHODS We carried out a prospect i ve study to determine and compare the prostate-specific antigen ( PSA ) response and survival in patients with hormone relapsed prostate cancer ( HRPC ) , all of whom had previously shown a good response to medical or surgical castration . The patients were r and omised to treatment with diethylstilboestrol ( DES ) and aspirin , or the anti and rogen flutamide . In addition , quality of life was determined by interview and question naire . RESULTS Twenty-eight patients were r and omised for treatment options . There was a significantly greater fall in the PSA ( 65 % vs 35 % ; P = 0.034 ) after treatment with diethylstilboestrol compared to treatment with flutamide .  Median survival also rose after treatment with diethylstilboestrol ( 18 months ) compared to flutamide ( 11 months ) , but this difference did not reach statistical significance . There was no difference in the quality of life parameters between the two groups . There were no cardiovascular complications in the stilboestrol group . CONCLUSIONS In HRPC , treatment with stilboestrol is associated with a greater PSA fall and an increase in median survival when compared to flutamide treatment New therapeutic alternatives are needed to improve outcomes in patients with and rogen-independent prostate cancer ( AIPC ) . For several years , research ers at the National Cancer Institute have been interested in elucidating the importance of angiogenesis in the pathogenesis of prostate cancer and in identifying inhibitors of this process . Thalidomide has been shown to inhibit the ability of tumors to recruit new blood vessels . In a recent phase II trial of thalidomide in AIPC , 28 % of patients achieved a prostate-specific antigen ( PSA ) decrease of > 40 % . The taxane docetaxel also produces PSA and measurable disease responses when used as monotherapy or as a component of combination chemotherapy for AIPC . Thus , based on the single-agent activity of thalidomide and docetaxel , we initiated a r and omized phase II study of weekly docetaxel with or without thalidomide , 200 mg at bedtime , in patients with chemotherapy-naive metastatic AIPC .  Docetaxel , 30 mg/m(2 ) intravenously , was administered every 7 days for 3 weeks , followed by a 1-week rest period . Both regimens have been well tolerated among the first 59 treated patients , with a near absence of grade ( 3/4 ) myelosuppression . Fatigue , hyperglycemia , and pulmonary toxicity were seen in both groups . Thrombotic events have been seen in the combination arm . Thirty-five percent ( 6 of 17 ) of the patients receiving docetaxel alone and 53 % ( 19 of 36 ) of those receiving docetaxel and thalidomide have had a PSA decrease of at least 50 % . Combining a cytotoxic agent with an angiogenesis inhibitor is a promising area of investigation for prostate cancer management PURPOSE To evaluate the combination of intravenous ( IV ) paclitaxel , oral estramustine , and oral etoposide in patients with advanced hormone-refractory prostate cancer . PATIENTS AND METHODS Forty patients with carcinoma of the prostate that was progressing despite hormonal therapy and who had undergone anti and rogen withdrawal ( if previously treated with an anti and rogen ) were enrolled onto this phase II trial . Patients were treated with oral estramustine 280 mg tid and oral etoposide 100 mg/d for 7 days , with paclitaxel 135 mg/m(2 ) IV over 1 hour on day 2 of each 21-day treatment cycle . Patients received a maximum of six cycles of therapy . RESULTS Thirty-seven patients were assessable for response . Twenty-two had measurable disease at baseline ; response was not assessable in six of these patients . Overall response was 45 % ( 10 of 22 patients ; 95 % confidence interval [ CI ] , 24 % to 68 % ) , and response was 63 % ( 10 of 16 ) in assessable patients . Twenty-six patients had a > or = 50 % decrease from their baseline prostate-specific antigen levels during therapy , for a response rate of 65 % ( 95 % CI , 48 % to 79 % ) by this criterion . Median duration of response was 3.2 months , with an estimated median survival of 12.8 months . Major toxicities of therapy were leukopenia ( eight patients had > or = grade 4 leukopenia ) and anemia . Hematologic toxicity seemed to be associated with liver metastases . Serial measurements in 24 patients using the Functional Assessment of Cancer Therapy-Prostate ( FACT-P ) showed no significant change in quality of life ( QOL ) as a result of therapy . CONCLUSION The combination of IV paclitaxel , oral estramustine , and oral etoposide is active in patients with advanced prostate cancer . The regimen is tolerable and does not have a significant impact on QOL as measured by the FACT-P in a limited sample of patients To evaluate the efficacy of chemoendocrine therapy for the initial treatment of stage D2 prostate cancer , we conducted a prospect i ve r and omized study which compared combined and rogen blockade alone to that combined with UFT . Twenty-one patients received LH-RH agonist and flutamide ( Group-A ) , and 23 patients received LH-RH agonist , flutamide and UFT ( Group-B ) . The overall response rate and the PSA response rate of Group-A was 71.4 % and 100 % respectively , against 65.2 % and 90 % , respectively in Group-B. The median follow-up period was 24 months . The 2-year progression-free survival rate of Group-A was 7.4 % and that of Group-B was 15.9 % . The response rate and progression-free survival rate did not differ significantly between the 2 groups . Liver dysfunction due to flutamide was common in both groups , and a total of 4 patients did not continue the treatment because of this adverse effect . We conclude that in patients with stage D2 prostate cancer , treatment with combined and rogen blockade and UFT is not superior to treatment with combined and rogen blockade alone This National Cooperative Study has r and omly compared the usefulness of 5-fluorouracil ( 5-FU ) , cyclophosphamide ( Cytoxan ) and st and ard therapy in patients with advanced carcinoma of the prostate ( Stage D ) . All patients studied were endocrine failures and were in progression .  Favorable responses were seen with all three treatments regardless of histologic grade . Actual tumor regression occurred only in patients who received either 5-FU or cyclophosphamide . In patients with poorly differentiated or anaplastic tumors treated with cyclophosphamide , progression of disease was significantly less rapid than in patients treated with 5-FU or st and ard therapy . However , favorable responders could not always be identified in advance on the basis of histologic grade alone PURPOSE To test the hypothesis that the efficacy and toxicity of suramin in the treatment of patients with hormone-refractory prostate cancer was dose dependent . PATIENTS AND METHODS Patients were r and omized with equal probability to receive low- , intermediate- , or high-dose suramin ( total doses 3.192 , 5.320 , and 7.661 g/m(2 ) , respectively ) . Overall survival , time to progression , and response rate ( prostate-specific antigen [ PSA ] and objective ) for each treatment arm were compared . Relationships between plasma suramin concentrations and response , toxicity , and survival were also evaluated . RESULTS Three hundred ninety patients were r and omized . For the low- , intermediate- , and high-dose arms , the median survival time was 16 , 14 , and 13 months , respectively ( P = .49 ) . The objective response rate was 9 % , 7 % , and 15 % , respectively ( P = .10 ) . PSA response rates were 24 % , 28 % , and 34 % , respectively ( P = .082 ) . L and mark analyses of a 50 % decline in PSA at 20 weeks showed a significant correlation with survival . There was a dose-response relationship between dose and toxicity . After adjusting for treatment arm , the measured suramin concentration was not associated with clinical response , PSA response , survival , or toxicity . CONCLUSION Although high-dose suramin was associated with higher objective and PSA response rates , these were not statistically significant . Overall , no dose-response relationship was observed for survival or progression-free survival , but toxicity was increased with the higher dose . Patients treated with the low-dose level experienced modest toxicity , making it the preferred arm on this study . The lack of a dose-response relationship and the toxicity profile observed raise questions regarding the utility of suramin , particularly high-dose suramin , as administered on this schedule In this third cooperative chemotherapy trial of the National Prostatic Cancer Project 165 patients with histologically confirmed , relapsing clinical stage D prostatic cancer were r and omized to receive either imidazole-carboxamide , procarbazine or cyclophosphamide .  All patients had received and failed previous hormonal therapy . Patients whose disease progressed after 12 weeks on initial therapy were crossed over or r and omized to receive an alternate drug . There were 129 patients available for comparison of treatments . The objective response rates ( partial regression plus stable disease ) were 26 % for cyclophosphamide , 27 % for imidazole-carboxamide and 14 % for procarbazine . Subjective responses were noted in pain relief , improvement in performance status and weight gain . Procarbazine was associated with excessive toxicity , result ing in many patients ( 28 % ) discontinuing therapy within the first 3 weeks and closure of this particular arm of the study . The regimen of initial imidazole-carboxamide therapy with a later cross-over to cyclophosphamide when the disease continues to progress is associated with the longest increase in survival .  Imidazole-carboxamide and cyclophosphamide appear to be active agents in advanced prostatic cancer and are worthy of continued use in this disease In a prospect i ve r and omized multicenter trial patients with highly or moderately differentiated prostatic carcinoma , previously untreated , were allotted either to oral Estramustine phosphate or to intramuscular polyestradiol phosphate plus oral ethinyl estradiol . As regards frequency and duration of tumour remission there was no statistical difference between the two groups . Nor did they differ significantly with respect to adverse reactions . This is an interim report and will be followed later on by a final evaluation The therapeutic benefit of chemotherapy in and rogen independent prostate cancer is limited . 5-Fluorouracil has been reported to have modest antitumor activity in and rogen independent prostate cancer . Although alpha-interferon is inactive as a single agent in prostate cancer , pre clinical data indicate that it increases the in vitro cytotoxicity of 5-fluorouracil against a variety of malignant cells . We evaluated the relative antitumor activity and tolerance of 5-fluorouracil versus 5-fluorouracil plus alpha-interferon in 50 patients with histologically confirmed metastatic adenocarcinoma of the prostate . These patients had progressive disease in the presence of castrate levels of testosterone . A prospect i ve r and omized phase II open labeled trial was performed because of the difficulty in measuring responses in patients with metastatic prostate cancer . Of 23 patients treated with 5-fluorouracil alone and 28 treated with 5-fluorouracil plus alpha-interferon 17 and 23 , respectively , were evaluable for response and toxicity , and 5 and 5 , respectively , were evaluable for toxicity only . Only 2 of 17 ( 11.7 % ) and 4 of 23 ( 17 % ) patients , respectively , showed a greater than 50 % decrease in serum prostate specific antigen ( no significant difference ) . There was no difference in duration of response or duration of survival between the 2 groups ( mean duration of response 8.64 and 6.17 weeks , respectively , and mean duration of survival 33.70 and 38.65 weeks , respectively ) . Both regimens caused significant morbidity ( mucositis and neurotoxicity ) and 3 treatment related deaths at the high 5-fluorouracil doses . 5-Fluorouracil alone and with alpha-interferon at the doses used have minimal antitumor activity against and rogen independent prostate cancer and , therefore , should not be tested further in these patients . And rogen independent prostate cancer selected using our criteria is a rapidly progressive disease , and these patients are an ideal target population for phase II studies PURPOSE Estramustine phosphate ( EMP ) and vinblastine are two microtubule inhibitors with distinct molecular targets and at least additive antimicrotubule effects in vitro . Their modest single-agent activities in hormone-refractory prostate cancer , nonoverlapping toxicities , and lack of cross-resistance prompted a phase II trial in hormone-refractory prostate cancer . PATIENTS AND METHODS Thirty-six assessable patients at the Fox Chase Cancer Center and seven Fox Chase Cancer Center Network institutions were treated with oral EMP 600 mg/m2 on days 1 to 42 and vinblastine 4 mg/m2 intravenously ( IV ) once a week for 6 weeks . Courses were repeated every 8 weeks . Response assessment was based on a change in serum prostate-specific antigen ( PSA ) levels and was correlated with change in pain scores . RESULTS PSA decreased from baseline by at least 50 % in 22 patients ( 61.1 % ) and by > or = 75 % in eight patients ( 22.2 % ) . A 50 % or more decrease in PSA on three successive 2-week measurements together with an improved or stable pain score , performance status , and measurable soft tissue disease ( if present ) was required for a partial response ( PR ) , which occurred in 11 patients for an overall response rate of 30.5 % ( 95 % confidence interval , 15.6 % to 45.6 % ) . In seven patients with measurable nonosseous disease , there was one PR ( 14 % ) and one minor response ( MR ) . In 28 patients with assessable pain , major pain responses occurred in 12 ( 42.9 % ) . PSA response ( > or = 50 % decrease times three measurements ) was predictive of major pain response with a 93.7 % specificity , a 50 % sensitivity , and a positive predictive value of 85.7 % . CONCLUSION We conclude that EMP and vinblastine is an active combination in hormone-refractory prostate cancer Over a 24‐month period , the Southwest Oncology Group ( SWOG ) conducted a r and omized prospect i ve chemotherapeutic trial in 158 patients with advanced prostatic cancer . Patients were initially r and omized to receive either a combination of Adriamycin and cyclophosphamide ( AC ) or a single agent , hydroxyurea ( H ) , and then crossed over to the other treatment on failure . Of the 137 evaluable patients , 43 ( 31 % ) had classically measurable metastatic disease in the lymph nodes , skin , chest , or liver . Focusing their efforts on this subset of patients with measurable disease , the authors of this report found the combination AC to have a superior response rate to the single agent , hydroxyurea . Objective response to AC was seen in 6 of 19 ( 32 % ) and in only one of 24 ( 4 % ) patients r and omized to hydroxyurea ( P = 0.06 , Fisher 's exact test ) . However , in the larger group of 137 evaluable  patients , a survival advantage was not seen for those individuals treated with AC . Failure to demonstrate a survival advantage for an objective ly superior drug combination would suggest the need for more active phase II agents in this disease From April 1983 to March 1985 , 265 patients with newly diagnosed metastatic prostate cancer were r and omized to one of three treatment protocol s : ( 1 ) diethylstilbestrol ( DES ) or bilateral Orchiectomy , ( 2 ) the leutinizing hormone‐releasing hormone ( LHRH ) analog buserelin , or ( 3 ) methotrexate plus DES or orchiectomy . In 261 evaluable patients there was no significant difference in survival between the three groups . However , progression‐free survival ( PFS ) was significantly different ( P < 0.0005 , log‐rank test ) . Of the possible pairwise comparisons for PFS , two showed significance : buserelin was inferior to DES/ orchiectomy ( P < 0.05 ) and buserelin was inferior to methotrexate plus DES/orchiectomy ( P < 0.0001 )
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 .
AUTHORS ' CONCLUSIONS Patients with HRPC have not traditionally been offered chemotherapy as a routine treatment because of treatment-related toxicity and poor responses .