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© 1999 American Society for Clinical Oncology Phase I Trial of Docetaxel With Estramustine in Androgen-Independent Prostate CancerFrom the Divisions of Medical Oncology, Departments of Medicine, Urology, Radiology, and Biostatistics, Columbia Presbyterian Medical Center, New York, NY. Address reprint requests to Daniel P. Petrylak, MD, Columbia Presbyterian Medical Center, 161 Fort Washington Ave, New York, NY 10032; email dpp5{at}columbia.edu
PURPOSE: To evaluate the toxicity, efficacy, and pharmacokinetics of docetaxel when combined with oral estramustine and dexamethasone in a phase I study in patients with progressive metastatic androgen-independent prostate cancer. PATIENTS AND METHODS: Thirty-four men were stratified into minimally pretreated (MPT) and extensively pretreated (EPT) groups. Estramustine 280 mg PO tid was administered 1 hour before or 2 hours after meals on days 1 through 5, with escalated doses of docetaxel from 40 to 80 mg/m2 on day 2. Treatment was repeated every 21 days.
RESULTS: Thirty-four patients were assessable for toxicity and 33 for response. In the MPT patients, dose-limiting myelosuppression was reached at 80 mg/m2, with six patients experiencing grade 3/4 granulocytopenia. In EPT patients, escalation above 70 mg/m2 was not attempted. Fourteen MPT (70%) and six EPT (50%) patients had a CONCLUSION: The recommended phase II dose of docetaxel combined with estramustine is 70 mg/m2 in MPT patients and 60 mg/m2 in EPT patients. This combination is active in men with androgen-independent prostate cancer.
TWO REVIEWS IN 1988 and 1993 of phase II single-agent chemotherapy trials in androgen-independent prostate cancer, demonstrating objective response rates of 6.5% and 8.7%, respectively, indicated a clear need for the development of new agents and drug targets.1,2 Since the publication of these reviews, combination therapy using estramustine, a nor-nitrogen mustard linked to an estrogen, has emerged as one therapeutic lead. As a single agent in patients with hormone-refractory prostate cancer, estramustine administered at 560 to 840 mg/day in two or three divided doses produced objective responses in 19% to 69% of patients and reduced the level of serum prostate-specific antigen (PSA) in 14%.3 Although estramustine was designed to exert antitumor activity through an estrogen and alkylating agent moiety, preclinical studies demonstrated that estramustine depolymerizes cytoplasmic microtubules and microfilaments,4 binds to microtubule-associated proteins,5 inhibits P-glycoprotein function,6,7 and disrupts the nuclear matrix.8 Antitumor activity was additive or synergistic in vitro when estramustine was combined with the vinca alkaloids,4 paclitaxel,9 or polypodopyotoxins.8 In men with hormone-refractory prostate cancer, combinations of estramustine and vinblastine,10-12 paclitaxel,13 or etoposide,14 produced objective responses in soft tissue, reductions in serum PSA levels, and relief from bone pain. Speicher et al9 demonstrated the synergistic cytotoxicity of prostate cancer cell lines exposed to combinations of estramustine and paclitaxel at levels below those commonly achieved clinically. The duration of exposure to paclitaxel was essential to maximizing cytoxicity, prompting the use of 96-hour infusions of paclitaxel, rather than shorter schedules, in combination with estramustine in phase I and II trials. Docetaxel, a semisynthetic taxane derived from the needles of Taxus baccata, has significantly longer cellular affinity and uptake, as well as slower cellular efflux, than paclitaxel, effectively prolonging the duration of cell drug exposure.15 Moreover, docetaxel is approximately twice as efficient as paclitaxel in stabilizing microtubules against cold-induced disassembly.16 We have observed greater-than-additive cytoxicity in vitro when docetaxel is combined with estramustine (Petrylak et al, manuscript in preparation). To assess the toxicity and efficacy of estramustine and docetaxel in vivo, a phase I study was designed to define the maximum-tolerated dose (MTD) of this combination and to begin to define its activity as measured by PSA-level reductions and objective responses in those patients with bidimensionally measurable disease. In contrast to previous estramustine-based combination studies, in which estramustine was administered continuously, we limited estramustine administration to a 5-day period starting 1 day before docetaxel therapy. The purpose of this short course of estramustine was to minimize estramustine-related toxicities while allowing maximal interaction between estramustine and docetaxel.
Patients Between February 1996 and February 1997, 34 patients with pathologically confirmed adenocarcinoma of the prostate signed informed consents and were entered onto the study. Eligibility required the progression of disease after androgen ablation, as defined by at least one of three criteria: (1) two consecutive increased PSA measurements taken at least 1 week apart; (2) a greater than 25% increase in bidimensionally measurable soft tissue metastases or the appearance of new lesions; or (3) the appearance of new foci on a radionuclide bone scan. To control for the effects of androgen ablation, luteinizing hormone–releasing hormone therapy was maintained. All patients had serum testosterone levels  50 ng/mL at the time of entry. Antiandrogen therapy was discontinued for at least 4 weeks for patients being treated with flutamide and 6 weeks for patients treated with bicalutamide.
Other criteria included an Eastern Cooperative Oncology Group performance status of 0 to 2, granulocyte count greater than 1500/µL, platelet count greater than 100,000/µL, serum aspartate aminotransferase level 2.5x the institutional upper limit of normal, bilirubin level
Patient Stratification The pretreatment evaluation included a complete medical history and physical examination, serum chemistry evaluations, automated blood and platelet counts, sequential multiple analysis of 20 chemical constituents, serum PSA level measurement, ECG, and chest x-ray, computed tomography of the abdomen and pelvis, and radionuclide bone scan.
Pharmacokinetics The docetaxel concentration-time data were analyzed for basic parameters (area under the concentration-time curve [AUC] extrapolated from time 0 to infinity [AUC0-inf], maximum drug concentration [Cmax], time to maximum concentration [tmax]) and were analyzed using noncompartmental methods. Subsequently, the data were fit to a three-compartment model, using model 19 in the WinNonlin Standard Version 1.1 personal computer package (Scientific Consulting, Inc., Apex, NC). The constants volume, K21, K31, alpha, beta, and gamma were determined by WinNonlin. From the computer-generated estimates, values for total clearance (Cl), volume of distribution at steady-state (Vdss), and the triphasic plasma half-lives (alpha, beta, and gamma) were calculated according to standard equations. The AUC0-inf was calculated using the linear trapezoidal rule.
Response Criteria An improvement in bone scan was defined as the disappearance of one or more lesions.
Treatment Regimen
Dose-Escalation Parameters and Statistical Methods
Patient Characteristics Table 2 summarizes the clinical characteristics for the 21 MPT and 13 EPT patients entered onto the study. The median age for all patients treated was 68 years, and the median Eastern Cooperative Oncology Group performance status was 1. Eighteen patients had measurable soft tissue metastases, whereas 29 patients had metastases to bone. At baseline, 15 patients had symptomatic bone pain and required narcotic analgesics. Of all patients treated, 20 (59%) failed other chemotherapeutic regimens. Fifteen patients had prior estramustine-based therapy: treatment with estramustine (one patient) or estramustine combined with vinblastine (five patients), etoposide (three patients), or both vinblastine or etoposide (six patients). Twenty-four patients had prior radiation therapy (71%), whereas three patients received isotope therapy for symptomatic bone pain.
Treatment and Toxicity
Twenty-seven patients discontinued treatment because of progression of disease after a median of eight cycles of therapy. Six patients continue to be treated (five MPT patients, one EPT patient), five of whom were entered at the 70 mg/m2 level. One patient discontinued therapy because of a CVA, which could possibly be attributed to estramustine. Six patients (five MPT patients, one EPT patient) required dose reduction to the previous level because of toxicity resulting from asthenia in four patients, neutropenia in one patient, and neutropenic fevers in one patient. Table 4 summarizes the major toxicities (grade 3/4) observed during the first three cycles of treatment. For the MPT patients, neutropenia was dose-limiting at 80 mg/m2, with three patients demonstrating grade 3 toxicity and three patients demonstrating grade 4 toxicity. Grade 4 neutropenia was observed at a lower dose (40 mg/m2) in one EPT patient. One episode of neutropenic fever without a documented source was observed in one MPT patient entered at the 70 mg/m2 level; he subsequently received 10 cycles of treatment at 60 µg/m2, with only grade 2 neutropenia. Based on the observed dose-limiting neutropenia at 80 mg/m2 in the MPT patients and the lower threshold for grade 4 neutropenia in the EPT patients, the recommended phase II dose of docetaxel when combined with estramustine is 70 mg/m2 in MPT patients and 60 mg/m2 in EPT patients.
Table 5 summarizes all of the toxicities observed for all treatment cycles in both patient groups. Only two episodes of grade 4 granulocytopenia were observed in patients who received more than three cycles of therapy. The first episode occurred in an MPT patient after his fourth cycle and was not considered to be dose-limiting because the duration of the episode was shorter than 1 week. His dose was reduced on cycle 5 because of asthenia. The second patient had grade 4 neutropenia after cycle 9, which lasted for less than 1 week. He subsequently received five treatments without significant neutropenia.
The incidence of thromboembolic events (8.8%) was lower than that reported for single-agent estramustine studies.3 In addition to the patient who had a CVA, two patients who had previous histories of deep venous thrombosis (DVT) developed a new thrombosis while on the study. Both were successfully treated with intravenous and then subcutaneous heparin in addition to their prior anticoagulation therapies. One patient was able to continue therapy without extension of his DVT; the second was not continued on treatment because of disease progression. No myocardial infarctions or pulmonary emboli were reported on the study. Gastrointestinal toxicity was observed, primarily nausea in 29% of the patients and vomiting in 12%. Of all patients treated, 47% developed a transient elevation of liver-function enzymes, with four patients' levels elevated to grade 3. Hyperbilirubinemia was observed in 15% of patients, with one grade 3 event. Fluid retention, generally of minimal severity, was observed in 65% of the patients treated and was graded as grade 3 in only one case. Consistent with previous reports of fluid retention secondary to estramustine treatment, the majority of patients reported edema during or immediately after estramustine administration, with edema resolving several days after the cessation of estramustine therapy. Ten patients required furosemide treatment at some point in their treatment. Two episodes of pleural effusions were observed. In one patient, the pleural effusion was associated with a viral syndrome. Thoracentesis of his pleural fluid demonstrated an exudate with a negative cytology for adenocarcinoma, which was inconsistent with docetaxel-induced effusions. The patient subsequently received six more treatments without reaccumulation of the pleural effusion. Grade 3 or 4 granulocytopenia was observed in 62% and 38% of MPT and EPT patients, respectively, but only resulted in neutropenic fever in one patient. Thrombocytopenia was reported in 24% of patients but was not severe in any case. Extravasation reactions, which occurred in four patients, were graded as severe in two. Severe reactions resulted in skin desquamation and digital parasthesias, with the desquamation in two patients healing after approximately 8 weeks. The unilateral hand parasthesias persisted in one patient.
Pharmacokinetics
PSA Response
Response to estramustine and docetaxel was not affected by prior estramustine-based chemotherapy. Of the 15 patients previously treated with estramustine or estramustine-based regimens, 8 (53%) had a PSA-level decrease of more than 50%.
Response in Bidimensionally Measurable Disease
Pain and Bone Scan Response Of the 34 patients entered onto the study, 29 had positive bone scans at entry. Two MPT patients (7%) had improvements on their bone scans after 6 and 12 cycles of therapy. One patient was asymptomatic, whereas the second required morphine analgesics to control his bone pain. He discontinued all pain medications after three cycles of estramustine plus docetaxel and did not require any pain medications for 12 weeks.
Survival
This study demonstrates that docetaxel combined with estramustine is active and well tolerated in patients with hormone-refractory prostate cancer. The predominant toxicities seem to be similar to those reported in other studies using estramustine-based combination therapies. The response rate of treatment regimens using estramustine and docetaxel is encouraging, particularly in light of the extent of pretreatment in some of these patients. It is unclear whether this response rate is the result of true drug synergy or of an additive pharmacologic effect. The toxicities encountered in this trial were tolerable. Fluid retention is a side effect common to both docetaxel and estramustine; however, the mechanism of fluid retention differs significantly in both drugs.3,20 In phase II trials with docetaxel or estramustine, the incidence of any grade of fluid retention was 47% and 40%, respectively.3,21 The appearance of pleural effusions and peripheral edema due to docetaxel is postulated to be the result of a capillary leak syndrome and is dependent on cumulative dosages. The edema, if severe, also resolves slowly, and treatment discontinuation may be necessary because of symptoms. Previous studies have noted that the incidence of docetaxel-induced edema increases with the total cumulative doses administered and can be significantly reduced by the administration of corticosteroids.20 The cumulative doses of this study are similar to those previously reported. The incidence of edema in our trial was 65%, with only one patient having grade 3 fluid retention and two patients developing asymptomatic pleural effusions on chest x-ray. The one patient who developed grade 3 fluid retention had metastatic prostate cancer to the pelvic lymph nodes. Of note, no patients discontinued treatment because of edema. Myelosuppression is the major dose-limiting toxicity of docetaxel.21 In previous phase II studies, grade 4 neutropenia, albeit of short duration, was observed in 88% to 98% of patients.21 The rate of grade 4 neutropenia reported in this study was 32%, with nine episodes occurring within the first three cycles (Table 2). Cumulative myleosuppression did not appear to be a problem; grade 4 neutropenia was considered to be dose-limiting only if it lasted more than 1 week, and this occurred in only two patients, both of whom were initially entered onto the study at the 80 mg/m2 level. Whether the observed myelosupression was an effect of the increase of the AUC of docetaxel or the result of the combination of estramustine and docetaxel is unknown. However, myelosuppression has rarely been a reported toxicity of estramustine in patients treated for hormone-refractory prostate cancer; there is some evidence that estramustine may have a myeloprotective effect in other combination studies. In a phase III study of estramustine combined with vinblastine versus vinblastine alone, the rate of neutropenia was lower in the combination arm versus the monotherapy arm (grades 2, 3, 4 = 7%, 1%, and 1% v 27%, 18%, and 9%, respectively.22 The exact mechanism of this interaction is unclear. The schedule of estramustine administration used in this study, which was limited to the first 5 days of each treatment cycle, offers several advantages over those previously reported in studies that used continuous administration. Although the rates of gastrointestinal toxicity in our study are similar to those previously reported in other estramustine single-agent and combination studies, nausea and vomiting in our study were reported by patients primarily during the period of estramustine administration, which was generally the first 5 to 7 days of a 21-day cycle. Moreover, because estramustine is bound in the gastrointestinal tract by calcium, the concomitant ingestion of dairy products is contraindicated during this time.23 Intermittent estramustine administration allows these patients to eat dairy products during nontreatment periods, which is beneficial for those patients who are nutritionally compromised by their cancer. Only two episodes of DVT were observed; this reduced incidence may be due to the reduced period of estramustine administration. However, future randomized trials are needed to determine whether this effect is significant. Of note, PSA responses were observed in patients who received prior estramustine or estramustine-based therapy, supporting the hypothesis that this combination works by a different mechanism than does estramustine and vinblastine or etoposide. The mechanism of taxane-induced cell death may provide an explanation for this observation. Docetaxel is approximately 100-fold more effective than paclitaxel or vinca alkyloids in inhibiting the antiapoptotic protein Bcl-2.24 It is possible that this in vitro finding is responsible for the observed clinical response pattern.
Previous results from studies that used paclitaxel as a single agent in the treatment of hormone-refractory prostate cancer have demonstrated minimal activity with significant toxicity.25 Roth et al25 studied 23 men with bidimensionally measurable hormone-refractory prostate cancer treated with taxol 135-170 mg/m2 by continuous infusion over 24 hours every 21 days. Significant myelosuppression was encountered, with 26% of patients experiencing neutropenic sepsis. Only one response was noted in bidimensionally measurable disease, accompanied by a
Dexamethasone administration, starting before and continuing after docetaxel administration, has been found to significantly decrease the incidence of fluid retention associated with docetaxel. A recent randomized trial of docetaxel alone versus docetaxel and methylprednisolone premedication demonstrated a significant delay in the onset of edema in patients treated with the steroid.20 Unfortunately, the necessity of this pretreatment may interfere with the measurement of response in both measurable disease and by PSA. Corticosteroids are active in androgen-independent prostate cancer, with Previous analysis of docetaxel pharmocokinetics demonstrated a proportional increase in the AUC from 2.79 to 5.19 at doses ranging between 70 and 115 mg/m2.31 Our study found that this dose-proportionality was preserved at low dosages; however, when the dosage was increased from 70 to 80 mg/m2, a significant rise in the AUC was observed. Factors that may account for the disproportional increase in AUC, AUC0-inf per dose, and half-life of docetaxel in patients treated in this study include the inhibition of docetaxel metabolism by estramustine or its metabolites or a decrease in its hepatic clearance. Docetaxel is metabolized by CYP3A,32 an enzyme of the cytochrome P450 family that is also known to metabolize paclitaxel. After dephosphorylation, estramustine is oxidized at the 17 position, primarily in the intestine, liver, and prostate, to yield the cytotoxic metabolite estramustine.33 Estromustine is further hydrolyzed, predominantly to estradiol and estrone. It is not known whether the oxidation of estramustine is a cytochrome P450–mediated process that could potentially compete with docetaxel metabolism. Other drugs that are known to inhibit the hydroxylation of docetaxel include ketoconazole, midazolam, erythromycin, and orphenadrine; however, none of the treated patients were being treated with any of these medications during the study. It is also possible that estramustine and its metabolites could inhibit cytochrome P450 metabolism without being metabolized themselves. Hepatic dysfunction has been correlated with decreased docetaxel clearance. Because all patients who had blood samples drawn for pharmakokinetics had normal transaminase and bilirubin levels, it is unlikely that the decreased clearance observed was due to hepatic impairment.34 Two phase III studies in men with hormone-refractory prostate cancer demonstrated a significant reduction in bone pain in those treated with the combination of mitoxantrone plus corticosteroids when compared with those treated with corticosteroids alone.26,35 Unfortunately, the reported median survival in these phase III mitoxantrone studies, as well as in a recent phase III trial of estramustine plus vinblastine versus vinblastine alone, is only 10 to 12 months.22 Based on our observed 1-year survival of 68% and the improvement of bone pain in men treated with estramustine plus docetaxel, further phase II studies are being planned in the Southwest Oncology Group as well as the Cancer and Leukemia Group B. If our results are confirmed, phase III studies are warranted to compare the combination of estramustine and docetaxel to either mitoxantrone plus prednisone or estramustine plus vinblastine.
The median survival, as of the publication date of this article, of all patients treated is 22.8 months.
Supported by General Clinical Research Center/National Institutes of Health grant no. RR00645 from the Irving Cancer Center, Irving Center for Clinical Research, and unrestricted educational grants from Rhone-Poulenc Roher, Upjohn Pharmacia We thank Dr John Kuhn of the University of Texas, San Antonio, for his helpful comments made during the preparation of this manuscript.
Presented at the Thirty-third Meeting of the American Society of Clinical Oncology, Denver, CO, May 17-20, 1997.
1. Yagoda A, Petrylak D: Cytotoxic chemotherapy for advanced hormone-resistant prostate cancer. Cancer 371:1098-1109, 1993 2. Eisenberger MA, Abrams JS: Chemotherapy for prostatic carcinoma. Semin Urol 6:303-310, 1988[Medline] 3. Perry CA, McTavish D: Estramustine phosphate sodium: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer. Drugs Aging 7:149-174, 1995
4.
Dahllof B, Billstrom A, Cabral F, Hartley-Asp B: Estramustine depolymerizes microtubules by binding to tubulin. Cancer Res 53:4573-4581, 1993
5.
Stearns ME, Wang M, Tew K, et al: Estramustine binds a MAP-1 like to inhibit microtubule assembly in vitro and disrupt microtubule organization in DU-145 cells. J Cell Biol 107:2647-2656, 1988
6.
Speicher LA, Barone L, Chipman E: P-glycoprotein binding and modulation of the multidrug resistance phenotype by estramustine. J Natl Cancer Inst 86:688-694, 1994 7. Yang CP, Shen HJ, Horowitz SB: Modulation of the function of p-glycoprotein by estramustine. J Natl Cancer Inst 86:3723-3724, 1994 8. Pienta KJ, Lehr JE: Inhibition of prostate cancer growth by estramustine and etoposide: Evidence for interaction at the nuclear matrix. J Urol 149:1622-1625, 1993[Medline]
9.
Speicher LA, Barone L, Tew KD: Combined antimicrotubule activity of estramustine and taxol in human prostatic carcinoma cell lines. Cancer Res 52:4433-4440, 1992 10. Seidman AD, Scher HI, Petrylak D, et al: Estramustine and vinblastine: Use of prostate specific antigen as a clinical trial end point in hormone refractory prostate cancer. J Urol 147:931-934, 1992[Medline] 11. Amato RJ, Ellenhorst J, Bui C, et al: Estramustine and vinblastine for patients with androgen-independent adenocarcinoma of the prostate. Urol Oncol 2:168-172, 1995
12.
Hudes GH, Greenberg R, Krigel R, et al: Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone refractory prostate cancer. J Clin Oncol 10:1754-1761, 1992 13. Hudes GR, Nathan F, Khater C, et al: Phase II trial of 96-hour paclitaxel plus oral estramustine phosphate in metastatic hormone-refractory prostate cancer. J Clin Oncol 15:3156-3163, 1997[Abstract]
14.
Pienta KJ, Redman B, Hussain M, et al: Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. J Clin Oncol 12:2005-2012, 1994 15. Riou JF, Petitgenet, Combeau C, et al: Cellular uptake and efflux of docetaxel (Taxotere) and paclitaxel (Taxol) in P388 cell line. Proc Am Assoc Cancer Res 35:385, 1994 (abstr 2292) 16. Diaz JF, Andreu JM: Assembly of purified GDP-tubulin into microtubules induced by taxol and taxotere: Reverseability, ligand stoichiometry, and competition. Biochemistry 32:2747-2755, 1993[Medline] 17. Vergniols JC, Bruno R, Montay G, et al: Determination of taxotere in human plasma by a semiautomated HPLC method. J Chromatog 582:273-278, 1992[Medline] 18. Kaplan EL, Meier P: Nonparametric estimations from incomplete observations. J Am Stat Assoc 53:487-491, 1958
19.
Bruno R, Hille D, Riva A, et al: Population pharmackinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 16:187-196, 1998 20. Piccart MJ, Klijn J, Paridaens R, et al: Corticosteroids significantly delay the onset of docetaxel-induced fluid retention: Final results of a randomized study of the European Organization for Research and Treatment of Cancer investigational drug branch for breast cancer. J Clin Oncol 15:3149-3155, 1997[Abstract] 21. Cortes JE, Pazdur R: Docetaxel. J Clin Oncol 13:2643-2655, 1995[Abstract] 22. Hudes G, Roth BG, Loehrer P, et al: Phase III trial of vinblastine versus vinblastine plus estramustine phosphate for metastatic hormone refractory prostate cancer (HRPC). Proc Am Soc Clin Oncol 16:316A, 1997 (abstr 1127) 23. Gunnarsson PO, Davidsson T, Andersson B, et al: Impairment of estramustine phosphate absorption by concurrent intake of milk and food. Eur J Clin Pharmacol 38:189-193, 1990[Medline]
24.
Haldar S, Basu A, Croce CM: Bcl-2 is the guardian of microtubule integrity. Cancer Res 57:229-233, 1997 25. Roth BJ, Yeap BY, Wilding G, et al: Taxol in advanced hormone-refractory prostate carcinoma phase II trial of the Eastern Cooperative Oncology Group. Cancer 72:2457-2460, 1993[Medline] 26. Tannock IF, Osoboa D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone vs prednisone alone for symptomatic hormone-refractory prostate cancer: A Canadian randomized trial with palliative endpoints. J Clin Oncol 14:1796-1764, 1996
27.
Kelly WK, Curley T, Leibertz C, et al: Prospective evaluation of hydrocortisone and suramin in patient with androgen-independent prostate cancer. J Clin Oncol 13:2208-2213, 1995 28. Dawson NA, Cooper M, Figg W, et al: Antitumor activity of suramin in hormone-refractory prostate cancer controlling for hydrocor-tisone treatment and flutamide withdrawal as potentially confounding variables. Cancer 76:435-461, 1995 29. Storlie JA, Buckner JC, Wiseman GA, et al: Prostate specific antigen levels and clinical response to low dose dexamethasone for hormone-refractory metastatic prostate cancer. Cancer 76:96-100, 1995[Medline] 30. Tannock I, Gospodarowicz M, Meakin W, et al: Treatment of metastatic prostate cancer with low-dose prednisone: Evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol 7:5590-5597, 1989
31.
Extra JM, Rousseau F, Bruno R, et al: Phase I and pharmacokinetic study of Taxotere (RP56976 NCSC 628503) given as a short intravenous infusion. Cancer Res 53:1037-1042, 1993
32.
Royer I, Monsarrat B, Sonnier M, Wright M, Crestiel T: Metabolism of docetaxel by human cytochrome P450: interactions with paclitaxel and other antineoplastic drugs. Cancer Res 56:58-65, 1996 33. Gunnarsson P, Forshell G: Clinical pharmacokinetics of estramustine phosphate. Urology 23:22-27, 1984 (suppl 6) 34. Bruno R, Sanderink GJ: Pharmacokinetics and metabolism of taxotere. Cancer Surv 17:305-313, 1993 (review) [Medline] 35. Kantoff PW, Conoway M, Winer E, et al: Hydrocortisone (HC) with or without mitoxantrone (M) in patients (pts) with hormone refractory prostate cancer (HPRC): Preliminary results from a prospective randomized Cancer and Leukemia Group B Study (9182) comparing chemotherapy to best supportive care. J Clin Oncol 14:1748, 1996 (abstr 2013) Submitted May 12, 1998; accepted November 5, 1998.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50% decline in serum PSA on two consecutive measurements taken at least 2 weeks apart. The overall 50% PSA response rate was 63% (95% confidence interval [CI], 28% to 81%). Of the 18 patients with bidimensionally measurable disease, five (28%; 95% CI, 11% to 54%) achieved a partial response. At the time of entry onto the study, 15 patients required narcotic analgesics for bone pain; after treatment, eight (53%) discontinued their pain medications. The area under the curve for docetaxel increased linearly from 40 to 70 mg/m2. At 80 mg/m2, the measured area under the curve was 8.37 (standard deviation, 0.724), which was significantly higher than the previously reported values. 
