|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 1999 American Society for Clinical Oncology Vinblastine Versus Vinblastine Plus Oral Estramustine Phosphate for Patients With Hormone-Refractory Prostate Cancer: A Hoosier Oncology Group and Fox Chase Network Phase III TrialFrom the The Fox Chase Network and Division of Biostatistics, Fox Chase Cancer Center, Philadelphia, PA; and Hoosier Oncology Group, Walther Cancer Institute, and Division of Biostatistics, Indiana University, Indianapolis, IN. Address reprint requests to Gary Hudes, MD, Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA 19111.
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 antiandrogen withdrawal (if prior antiandrogen treatment), were randomized to receive vinblastine (V) 4 mg/m2 by intravenous bolus weekly for 6 weeks followed by 2 weeks off, either alone or together with estramustine phosphate (EM-V) 600 mg/m2 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 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.
AS THE LEADING CAUSE of noncutaneous malignancy and the second leading cause of cancer death in men, adenocarcinoma of the prostate has attracted increasing attention in the past decade. Although prostatic carcinoma is diagnosed earlier because of the widespread use of serum prostate-specific antigen (PSA), the mortality rate from this tumor remains relatively constant at approximately 40,000 deaths per year.1 Virtually all deaths are a consequence of metastatic disease most often involving skeletal sites. Although symptomatic improvement and control of metastatic disease is obtained in most patients after androgen ablation, disease progression occurs at a median of 12 to 18 months. Secondary remissions with additional hormonal maneuvers are less frequent and usually of shorter duration. Chemotherapy with cytotoxic agents has not extended the median survival of approximately 10 months for patients with hormone-refractory metastatic prostate cancer. Consequently, identification of active agents and combinations will be necessary for progress against both "hormone-sensitive" and hormone-refractory disease. Effective therapies must target androgen-independent tumor cells. Estramustine (EM) is a nornitrogen mustard-estradiol conjugate, with both hormonal and nonhormonal effects in man. EM inhibits microtubule function by binding to tubulin2,3 and microtubule-associated proteins.4 As a single agent, EM has limited activity in patients with hormone-refractory prostate cancer (HRPC). In a contemporary phase II trial using PSA and other clinical criteria to gauge response, 14% of 44 patients with HRPC responded to oral EM 15 mg/kg daily.5 The antimicrotubule properties of EM, especially the unique interaction with microtubule-associated proteins, led to the hypothesis that synergistic antimicrotubule effects and cytotoxicity could be achieved by combining EM with other microtubule inhibitors.6 In support of the hypothesis, additive or greater antimicrotubule effects were observed in vitro with the combination of EM plus vinblastine (V).7 The lack of clinical myelotoxicity or neurotoxicity associated with EM and the differing patterns of resistance for EM and V in vitro8 provided further impetus for clinical trials of EM combined with V (EM-V). A total of 83 patients were treated with the EM-V combination in three nonrandomized trials.9-11 Although the response criteria varied, a PSA decrease greater than 50% occurred in 42% of the patients, and objective responses were observed in six (31%) of 17 patients with measurable soft tissue disease. This interesting activity formed the basis for randomized trials conducted to determine if the two-drug combination was superior to the single agents. Although there was considerable (and generally disappointing) experience with EM as a single agent, less was known about the activity of V in HRPC. In the only published phase II trial, Sella et al12 reported eight objective responses in 39 patients (20.5%; 95% confidence interval [CI], 6.3% to 34.7%) treated with V 1.5 to 1.7 mg/m2/d for 5 days by continuous intravenous infusion every 3 weeks. With this background, the Hoosier Oncology Group and the Fox Chase network initiated a phase III trial of V alone versus EM-V for patients with metastatic HRPC.
Patient Selection Eligibility required histologically proven adenocarcinoma of the prostate and disease progression after primary hormonal therapy. A trial of antiandrogen withdrawal for a minimum of 4 weeks with continued evidence of progression was required for patients taking antiandrogen therapy before registration. Because patients on this trial had not received bicalutamide or nilutamide, longer periods of withdrawal were not required. The presence of metastatic tumor with either bidimensionally measurable disease or assessable disease (eg, bone metastases on radionuclide bone scan) was required. Patients with an elevated tumor marker (eg, PSA) as the sole evidence of tumor were not eligible. For protocol entry, progressive disease was considered to be either increasing palpable or radiographic tumor (eg, bone metastases or soft tissue lesion), increasing PSA, or a combination of radiographic and PSA progression, with or without worsening disease symptoms. Other requirements were no prior chemotherapy; Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; adequate organ function (defined as WBC  4,000/µL, platelets 100,000/µL, serum creatinine 2.0 mg/dL, and bilirubin 2.0 mg/dL); no history of myocardial infarction, active angina pectoris, or uncontrolled congestive heart failure within 6 months of registration; no clinically apparent CNS metastases; and no history of deep venous thrombosis. Patients with bidimensionally measurable soft tissue metastases were eligible, regardless of serum PSA value. Serum PSA 20 ng/mL was required for patients without measurable disease. Radiotherapy had to be completed at least 4 weeks before enrollment, and strontium-89 therapy completed at least 12 weeks before enrollment. The institutional review board of each participating institution approved the study protocol. All patients were required to give written informed consent before enrollment, according to institutional and federal guidelines.
Randomization and Treatment
Doses of the drugs were modified each week for specific toxicities as follows: for WBC
Evaluations Toxicity was graded according to the National Cancer Institute common toxicity criteria (Bethesda, MD). Standard solid tumor response14 criteria were used to monitor the effect of treatment on measurable soft tissue metastases. The following criteria were used to evaluate the effect of treatment on PSA: Partial response required 50% or greater decrease from baseline for three successive measurements obtained every 4 weeks; progression was defined as 50% or greater increase above baseline or the lowest value achieved for three consecutive measurements, with or without new symptomatic lesions on bone scan or increase in measurable disease. In addition to progression defined by PSA increase, patients with other signs or symptoms of cancer-related deterioration were removed from the study at the discretion of the treatment physician and were considered to have progressive disease. PSA stabilization was defined as neither partial response nor progression for at least 90 days. Overall survival and time to progression were determined for each patient from the time of registration.
Statistical Considerations
The primary end point of the trial was overall survival. Assuming a median survival of 10 months for the V arm, the trial had 80% power to detect a 50% increase in overall survival for EM-V patients with type I error of 0.05 (one-sided log-rank test), with planned accrual of 100 assessable patients per arm. Secondary end points were time-to-disease progression, response in measurable disease and PSA, and change in QOL measures. Progression-free survival and overall survival curves were estimated by the product-limit method.15 Survival duration was defined as time of registration until death or was censored on the date of last follow-up evaluation. In respect to time-to-progression measurement, individuals who died before progression occurred (n = 3, one on V, two on EM-V) were considered censored at the time of death. Comparisons of progression-free and overall survival distributions between treatment arms were conducted using one-sided stratified log-rank tests. The proportion of patients in each arm that achieved partial response in measurable disease,
Between March 1993 and June 1995, 201 patients were registered at 19 Hoosier Oncology Group Institutions and 12 Fox Chase Network Institutions. A total of eight patients (4%) that registered were subsequently found to be ineligible (three on the V arm and five on the EM-V arm), which left 98 and 95 eligible patients on the two arms. The reasons for ineligibility were CNS metastases (two patients), ECOG performance status 3 (three patients), and failure to meet laboratory criteria for entry (three patients). The number of patients in each arm who completed at least one 8-week cycle of treatment was similar, 75 (77.3%) for V and 71 (74.7%) for EM-V. As listed in Table 1, patients in each group had similar median age, performance status, baseline hemoglobin, lactate dehydrogenase, and PSA values. The number of patients in each arm with measurable disease was also similar. Of the 193 eligible patients, 110 were enrolled after first-line hormonal therapy. Of the remaining 83 patients, 70 had second-line and 13 had third-line hormonal treatment (excluding flutamide withdrawal) before enrollment.
Survival and Time to Progression
Increasing bone metastases was the reason for progressive disease in 44 patients (23.2%) at a median of 3.1 months from registration. Progression in bidimensionally measurable disease defined disease progression in 24 patients (12.6%) at a median of 2.1 months. Worsening symptoms, such as pain or decline in performance status considered to be poor subjective response, occurred in 41 patients (21.6%), and discontinuation of therapy was required at a median of 2.1 months. In addition, 51 patients (26.9%) stopped protocol treatment at their request or at the discretion of the treating physician at a median of 3.2 months. Disease progression classified solely by PSA increase, as defined by the protocol criteria, occurred in 29 patients (15.3%) at a median of 3.2 months from registration. To investigate possible antigonadotrophic effects of EM metabolites in nonorchiectomized patients, some of whom may have had residual serum testosterone above the surgically castrate level, we compared time to progression and overall survival by treatment arm and orchiectomy status. For EM-V, median survival durations for orchiectomy (n = 65) and nonorchiectomy patients (n = 30) were 14.5 months and 10.0 months, respectively; and the survival function estimates for orchiectomy and nonorchiectomy patients differed significantly (P = .005, two-sided stratified log rank test) in favor of orchiectomy. For V alone, the median survivals for surgically castrated patients (n = 57) and medically castrated patients (n = 41) were 9.6 months and 7.8 months, respectively, with no difference between the estimated overall survival distributions (P = .869). Considering only patients who had orchiectomy, the overall survival function estimates were significantly different in favor of EM-V (P = .0439). In contrast to overall survival, treatment effect on time to progression was not influenced by orchiectomy.
Measurable Disease
Effect of Treatment on Serum PSA
Pain and QOL
Toxicity
Nonhematologic toxicities are summarized in Table 4. Nausea and leg edema of grade 2 or higher were significantly more common in patients receiving EM-V (P = .0001 and P = .028, respectively), whereas constipation was significantly more common in patients receiving V alone (P = .049). Other neurotoxicity and fatigue occurred with equal frequency on the two treatment arms. Intolerable nausea led to reduction of EM dosage during the initial two cycles of treatment for 28 patients on the EM-V arm.
Serious cardiovascular toxicity was uncommon in both arms. Three EM-V patients had deep venous thrombosis in a lower extremity. Three EM-V patients developed congestive heart failure (two grade 3 and one grade 4), compared with one V patient (grade 4). Other cardiovascular adverse events in the EM-V arm were grade 1 hypotension, grade 1 palpitations, and grade 1 atrial fibrillation in one patient each. In the V arm, four additional patients experienced grade 1 cardiac events, which consisted of palpitations, atrial flutter, atrial tachycardia, and hypotension in one patient each.
The results of this randomized trial demonstrate differences in time to progression and improvements in PSA that favor the combination of V and EM. Despite these differences in secondary outcome measures, overall survival for patients on the two treatments was not significantly different. With a sample size adequate to detect a 50% or greater difference in survival, this trial was not designed to detect smaller differences that might also be considered clinically meaningful. For example, the power of statistically detecting a 25% difference in overall survival (the approximate difference observed in median survival), assuming a one-sided test with the available sample sizes, was estimated to be only 51% using the methods of Schoenfeld and Richter.16 As predicted from previous trials, a greater proportion of patients who received EM-V experienced nausea and fluid retention; the latter usually consisted of mild to moderate peripheral edema. The incidence of other cardiovascular toxicity was not significantly different between the two arms. An unexpected observation was the striking difference in granulocytopenia, with grade 3 or 4 toxicity in 27% of patients receiving V alone compared with only 7% of patients receiving EM-V. The mechanism of this apparent protective effect of EM on V-induced granulocytopenia is unclear. Patients receiving single-agent EM often demonstrate increased WBC and granulocyte counts,17 an observation that is consistent with increased mobilization or production of granulocytes. Alternatively, a pharmacologic interaction of EM and V, which might have caused reduced plasma concentrations or cumulative exposure to V, cannot be excluded. EM has both hormonal and nonhormonal cytotoxic effects in vivo.18 Approximately 20% of the administered dose of EM is metabolized to estrone and estradiol, resulting in concentrations sufficient to lower serum testosterone to castrate levels.19 The hormonal effects of EM may be particularly relevant for patients with incomplete suppression of testosterone. Approximately 60% of patients in each arm of this trial had bilateral orchiectomy, and the remaining patients continued on luteinizing hormone-releasing hormone agonist or diethylstilbestrol (two patients) during protocol treatment. Although it is unlikely that significant elevations of serum testosterone were common in either group, we did not require measurement of serum testosterone to document castrate levels. To examine the potential effects of EM metabolites on outcomes in the EM-V arm, we compared time to progression and overall survival in medically and surgically castrated patients. In this retrospective analysis, time to progression was not affected by orchiectomy, whereas an interaction of orchiectomy and treatment was observed for overall survival. However, the greater survival for EM-V compared with V in the orchiectomy subgroup rather than in nonorchiectomy patients is evidence that further lowering of testosterone was not an important factor on treatment outcome. Because estrogens may be active by mechanisms other than antigonadotrophic action, we cannot definitely exclude the possibility that estrogenic metabolites of EM contributed to the outcomes favoring EM-V. The present trial and three other recently completed phase III trials20-22 in patients with HRPC demonstrate that achieving pain relief, measurable disease response, and reduction of PSA may not translate into major improvement in overall survival (eg, a 50% increase) for an entire treatment group. Although it is possible that crossover of patients to the more active arm in each of these trials could obscure differences in overall survival between two treatments, the lack of a major increase in survival is more likely because of the modest antitumor activity of all of the therapies used in these trials. Future phase III trials that use overall survival as a primary end point should have adequate statistical power to detect smaller differences in overall survival. Although the combination of EM-V was not shown to be significantly better than V alone in overall survival, the superior results of the combination in time to progression and PSA encourage further clinical development of EM-based combination antimicrotubule therapy in HRPC. Preliminary results obtained with paclitaxel-EM23 and docetaxel-EM24,25 combinations suggest activity superior to that of the EM-V combination. Thus, the optimal combination and schedule for EM-based antimicrotubule therapy has yet to be determined. There is increasing evidence that EM and other tubulin/microtubule-binding agents block mitotic progression by a common mechanism of inhibiting the dynamic instability of spindle microtubules.26 For EM and V, inhibition of microtubule dynamics in vitro by the combination is greater than additive, considering the inhibitory effects of each drug alone.27 It is likely that other antimicrotubule drug combinations will demonstrate additive or greater inhibition of microtubule dynamics and clinical antitumor activity. The encouraging clinical results, including the present randomized trial, support further study of antimicrotubule drug combinations to produce more effective treatment for HRPC.
1. Wingo PA, Landis S, Ries LAG: An adjustment to the 1997 estimate for new prostate cancer cases. CA Cancer J Clin47:239-242, 1997[Medline]
2.
Dahllof B, Billstron A, Cabral F, et al: Estramustine depolymerizes microtubules by binding to tubulin. Cancer Res53:4573-4581, 1993 3. Speicher LA, Laing N, Barone LR, et al: Interaction of an estramustine photoaffinity analogue with cytoskeletal proteins in prostate carcinoma cells. Mol Pharmacol46:866-872, 1994[Abstract] 4. Tew KD, Glucker JP, Hartley-Asp B, et al: Preclinical and clinical perspectives on the use of estramustine as an antimitotic drug. Pharmacol Ther56:323-339, 1992[Medline] 5. Yogada A, Smith JA, Soloway MD, et al: Phase II study of estramustine phosphate in advanced hormone-refractory prostate cancer with increasing prostate specific antigen levels. J Urol 145:384A, 1991 (abstr) 6. Tew KD, Stearns ME: Estramustine: A nitrogen mustard/steroid with antimicrotubule activity. Pharmacol Ther43:299-319, 1989[Medline]
7.
Mareel MM, Storme GA, Dragonetti CH, et al: Anti-invasive activity of estramustine on malignant MO4 mouse cells and on DU-145 human prostate carcinoma cells in vitro. Cancer Res48:1842-1849, 1988 8. Speicher LA, Sheridan VR, Godwin AK, et al: Resistance to the antimitotic drug estramustine is distinct from the multidrug resistant phenotype. Br J Cancer64:267-273, 1991[Medline] 9. Amato RJ, Logothetis CJ, Dexeus FH, et al: Preliminary results of phase II trial of estramustine and vinblastine for patients with progressive hormone-refractory prostate carcinoma. Proc Am Soc Clin Oncol7:207, 1988 (abstr) 10. Seidman A, Scher HI, Petrylak D, et al: Estramustine and vinblastine: Use of prostate specific antigen as a clinical trial endpoint for hormone-refractory prostate cancer. J Urol147:931-934, 1992[Medline]
11.
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 Oncol10:1754-1761, 1992 12. Dexeus F, Logothetics CJ, Samuels ML, et al: Continuous infusion of vinblastine for advanced hormone-refractory prostate cancer. Cancer Treat Rep69:885-886, 1985[Medline] 13. Ware JE, Kosinski M, Keller SD: SF-36 Physical and Mental Summary Scales: A User's Manual. Boston, MA, The Health Institute, 1994 14. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol5:649-655, 1982[Medline] 15. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc53:457-481, 1958 16. Schoenfeld DA, Richter JR: Nomograms for calculating the number of patients needed for a clinical trial with survival as an endpoint. Biometrics38:163-170, 1982[Medline] 17. Daponte D, Sylvester R, DePauu M, et al: Change in white cell count during treatment of advanced cancer of the prostate with estramustine phosphate and with stilboestrol. Br J Urol65:408-4112, 1983 18. Hudes GR: Estramustine-based chemotherapy. Semin Urol Oncol15:13-19, 1997[Medline] 19. VanPoppel H, Werbrook PW, Baert L: Effect of estramustine phosphate on free androgens. Acta Urol Belg58:89-95, 1990[Medline]
20.
Tannock IF, Osoba D, Stockler MR, et al: Mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: A Canadian randomized trial with palliative endpoints. J Clin Oncol14:1756-1764, 1996
21.
Kantoff PW, Conaway M, Weiner E, et al: Hydrocortisone with or without mitoxantrone in patients with hormone refractory prostate cancer: Preliminary results from a prospective randomized Cancer and Leukemia Group B Study (9182) comparing chemotherapy to best supportive care. J Clin Oncol14:1743, 1996 (abstr 2013) 22. Small EJ, Marshall ME, Leyno L, et al: Superiority of suramin + hydrocortisone over placebo + hydrocortisone: Results of a multi-center double blind Phase III study in patients with hormone refractory prostate cancer. Proc Am Soc Clin Oncol 17, 1998 (abstr 1187) 23. 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 Oncol15:3156-3163, 1997[Abstract]
24.
Kreis W, Budman DR, Fetten J, et al: Phase I trial of the combination of daily estramustine phosphate and intermittent docetaxel in patients with metastatic hormone-refractory prostate carcinoma. Ann Oncol10:33-38, 1999
25.
Petrylak DP, Macarthur RB, O'Connor J, et al: Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol17:958-967, 1999 26. Wilson L, Jordan MA: Microtubule dynamics: Taking aim at a moving target. Curr Biol2:569-573, 1995
27.
Panda D, Miller HP, Islam K, et al: Stabilization of microtubule dynamics by estramustine by binding to a novel site in tubulin: A possible mechanistic basis for its antitumor action. Proc Natl Acad Sci USA94:10560-10564, 1997 Submitted September 15, 1998; accepted June 14, 1999.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
