A phase II Hoosier Oncology Group study of vinorelbine and estramustine phosphate in hormone-refractory prostate cancer

C. J. Sweeney, F. J. Monaco, S.-H. Jung, M. J. Wasielewski, J. Picus, R. H. Ansari, W. M. Dugan and L. H. Einhorn+

Hoosier Oncology Group, 3202 North Meridian, Indianapolis IN, USA

Received 19 April 2001; revised 3 August 2001; accepted 6 September 2001.


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background

The purpose was to evaluate the combined anti-microtubular regimen of vinorelbine and estramustine phosphate (EMP) in hormone refractory prostate cancer.

Patients and methods

Weekly vinorelbine 20 mg/m2 (or 15 mg/m2 if a history of prior pelvic radiotherapy) was combined with EMP at 280 mg orally tds for 3 days (the day before, the day of and the day after vinorelbine infusion). After 8 weeks of therapy the combination was given every other week.

Results

From February 1998 to February 1999, 23 men were enrolled with a median age of 69 years (range 50–83 years). The median prostate-specific antigen (PSA) at entry was 160 ng/ml (range 0–802 ng/ml). A median of 13 weeks of therapy was administered and the median follow-up was 14.8 months. Eleven patients (48%) had lower extremity edema requiring diuretic therapy, two (9%) had grade 2 granulocytopenia and four patients [17%; 95% confidence interval (CI) 5% to 39%] had a thromboembolic episode. There was no treatment-related mortality. Fifteen of 21 patients (71%; 95% CI 49% to 89%) had at least a 50% decrease in the PSA for at least 2 months with a median time to serologic progression of 3.5 months (range 0.75–10.5 months). One of eight patients (12.5%; 95% CI 0% to 53%) with measurable disease had a confirmed partial response. The estimated median survival was 15.1 months and the actual one year overall survival was 71% (95% CI 51% to 88%).

Conclusions

Weekly vinorelbine with short course oral EMP is an active regimen as evaluated by rate of PSA response, time to progression and median survival. However, the toxicities of EMP, even when given as a short course, are still problematic.

Key words: estramustine, hormone refractory prostate cancer, vinorelbine


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Metastatic prostate cancer is a common male malignancy that is initially treated with androgen ablation, which induces remissions for a median duration of ~18 months. No therapy is known to prolong the survival of patients with hormone-refractory disease. The regimen of mitoxantrone and low-dose corticosteroid has been shown in phase III studies to be more effective in decreasing pain and/or narcotic requirements without prolonging survival when compared with the steroid alone [1, 2].

A variety of agents that block the microtubule apparatus have been evaluated as single agents and combined with each other. Estramustine phosphate (EMP), a nor-nitrogen mustard carbamate derivative of estradiol-17ß-phosphate, is cytotoxic. The cytotoxicity was initially thought to be due to a combination of the estrogenic and alkylating effects but later work revealed that cell death was due to the drug interfering with the microtubule apparatus [3, 4]. With the emergence of preclinical data demonstrating synergy for combined anti-microtubular therapy (EMP–taxane or vinca alkaloid plus taxane) [58] multiple phase II studies have been conducted demonstrating that this is a promising approach [913]. The Hoosier Oncology Group (HOG), in collaboration with the Fox Chase Cancer Network, completed a phase III trial comparing vinblastine 4 mg/m2 weekly x 6, with the same vinblastine dose plus EMP on days 1–42 with cycles repeated every 8 weeks [14]. Although the combination arm was associated with an increased incidence of nausea and edema, there was a statis-tically significant improvement in response, defined as a prostate-specific antigen (PSA) decline of at least 50% for at least two consecutive months and an improvement in median time to progression (2.2 compared with 3.7 months, P <0.001). It is noteworthy that there was also a trend toward improved survival as the median survival was increased by 2.7 months in the combination arm (9.2 compared with 11.9 months, P = 0.08). It should also be noted that vinblastine was inactive as a single agent with only 4% of patients having a PSA decline >50% for at least two consecutive months compared with 27.5% for the combination arm.

Vinorelbine is a vinca alkaloid that has shown improved activity in non-small-cell lung cancer compared with vinblastine and vindesine. Moreover, it has less neurotoxicity because its effects on the axonal microtubules are limited. Also of significance is the fact that vinorelbine, as a single agent, has documented activity in hormone-refractory prostate cancer (HRPC). In a phase II study of 37 evaluable patients, six patients received 30 mg/m2 weekly and 31 patients received 22 mg/m2 weekly because of dose delays due to granulocytopenia in the higher dose cohort [15]. Doses were weekly x 8 and then every other week. Fourteen of 37 evaluable patients (39%) had a clinical benefit response (improvement in Karnofsky Performance Status [KPS], 25% or greater improvement in pain visual analog scale or at least a 50% decrease in analgesics, all lasting for a minimum of 12 weeks). Eleven of these 14 patients were able to discontinue all analgesics. Four of these 14 patients had a concomitant reduction in serum PSA of at least 50%. Therapy was well tolerated with no unanticipated toxicity.

The HOG therefore conducted a phase II trial in which vinorelbine replaced vinblastine and the EMP was decreased from 42 days to 3 days immediately surrounding each vinorelbine dose. The rationale for the changes was to mitigate the toxicities associated with 42 days of oral EMP and switch to a more active vinca alkaloid.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Study design
Patients with HRPC were enrolled on this trial from February 1998 to February 1999. Institutional Review Board approval was granted. Written informed consent was obtained and patients were required to have bidimensionally measurable disease, a PSA >20 ng/ml or symptomatic disease requiring narcotic analgesia. Patients were required to have a KPS of >=70. When on an antiandrogen, patients demonstrated progression after discontinuing this class of agent with at least a 50% increase in the PSA or objective evidence of increasing disease. There was no limitation on number of prior hormonal manipulations but patients did have to demonstrate progressive disease after at least one hormonal therapy. Adequate hematologic, renal and hepatic function were required at entry. Chest radiographs, computed tomography (CT) of the abdomen and pelvis, bone scan, PSA level and an electrocardiogram were performed at baseline. There was no central review of pathology and baseline testosterone levels were not obtained. Patients were excluded who had received prior chemotherapy, had active angina, symptomatic congestive heart failure, a history of a myocardial infarction within 6 months or a history of a prior deep venous thrombosis. Patients were assessed on study every 4 weeks; CT scans were repeated every 8 weeks if measurable disease was present, bone scans were repeated every 12 weeks and as clinically indicated.

The primary objectives of this phase II study were to investigate response rate, time to progression, PSA response (>50% decline) and symptom improvement. A response was recorded if a patient had a 50% decrease in the sum of the perpendicular diameters of the measurable disease. In the absence of measurable disease a response was recorded if PSA fell by >50% lasting 2 months without evidence of symptomatic progression. At the time the study was written a response of 20% was considered low and 50% worthy of further study. This study with 22 evaluable patients had 90% power to detect an improvement from 20 to 50% in overall response rate with a 1-sided alpha error of 0.05.

Therapy
Vinorelbine 20 mg/m2 was administered on a weekly basis for the first eight doses and then every other week for a maximum of 26 weeks. Vinorelbine was given intravenously over 6–10 min. If a patient had prior wide-field pelvic irradiation or bone irradiation then vinorelbine was decreased to 15 mg/m2. EMP was taken orally at a dose of 280 mg tds for 3 days, administered the day before, the day of and the day after each vinorelbine infusion. Patients were instructed to take their medication 1 h before or 2 h after food and not to take it with dairy products or calcium-containing drugs. Dose modifications for myelosuppression were based on the evaluation on the day of scheduled treatment. If the white blood cell count was 2000–2999 cells/dl or platelet count was 75 000–99 999/dl then 50% of the vinorelbine dose was given. If the white blood cell count was <2000 cells/dl or platelet count was<75 000/dl then the vinorelbine dose was omitted. For non-hematalogic toxicities 75% of the dose of drug responsible was given if grade 2 and the dose was held if grade 3 or 4 toxicity occurred. There was no coumadin or aspirin prophylaxis. No corticosteroids were administered. Oral anti-emetics were prescribed for nausea as needed.

Definition of response
Measurable disease. A complete response was defined as the complete disappearance of all clinically detectable disease measured by physical examination and/or radiographic studies for a period of at least 4 weeks. A partial remission was defined as >=50% decrease in the sum of the products of the two longest perpendicular diameters of all measurable lesions for a period of at least 4 weeks without an increase >25% in the size of any area known to contain malignant disease and without the appearance of any new areas of malignancy. Progressive disease was defined as an increase of at least 25% in the size of measurable lesions.

Serological disease. A complete serological response was defined as normalization of PSA for three consecutive measurements 4 weeks apart and a partial response was at least a 50% decrease in PSA for three consecutive measurements 4 weeks apart (i.e. a sustained response for 2 months). Serological progressive disease was defined as a 50% increase in PSA from the lowest level recorded and was confirmed 4 weeks later on the study.

Time to progression. Patients with measurable disease were deemed to have responded or progressed based on the measurable disease criteria alone. Patients with symptomatic progression of bone metastases requiring bone radiation were deemed to have progressed regardless of measurable disease or serological status. If patients were being followed by the PSA alone, progression was recorded at the date of the first PSA >50% of the lowest result recorded on therapy. Time to progression was measured from the time of initiation of therapy to the time progression was documented and survival was measured from the initiation of therapy to death or the last date the patient was known to be alive.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Twenty-three men with a median age of 69 years (range 50–83 years) were enrolled from February 1998 to February 1999 (Table 1). Survival data were calculated after 15 deaths were recorded and the remaining patients were censored with survival of at least 22 months. Eight patients had measurable disease, 21 patients had a PSA >20 ng/ml and 10 patients required narcotic analgesia. Twelve patients had one prior hormonal manipulation, eight patients had undergone two hormonal manipulations and three patients had received three lines of hormonal therapy. Eight patients had received prior palliative external beam radiation therapy for bony metastases and one had received prior radioisotope injection. The median PSA for all 23 patients was 160 ng/ml (range 0–802 ng/ml). The median number of weeks on therapy was 13 (range 1–26 weeks). Thirteen patients were taken off therapy because of progression, four patients were removed because of toxicity and five patients had reached the specified maximum amount of 26 weeks of therapy. The median KPS was 80 (range 70–100) at the time the patients were entered onto the study.


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Table 1. Patient characteristics
 
Response
One of eight patients (12.5%, 95% CI 0% to 53%) with measurable disease had a confirmed partial response lasting 6 months. This person also had an 82% decrease in his PSA lasting 3 months. Six of the remaining seven patients with measurable disease had stable disease and all six had at least a 50% decline in PSA. The remaining patient with measurable disease had progressive disease in the first month. Fifteen of the 21 patients (71%, 95% CI 48% to 89%) with PSA levels >20 ng/ml (range 28–802 ng/ml) had a serologic partial response lasting at least 2 months. Of the 15 patients with a >50% decline in PSA, the median time to first documented PSA >50% of nadir was 3.5 months. Eight patients (36%) had a 75% decline in the PSA lasting a median of 5 months. No patients with an elevated PSA and measurable disease progressed by the measurable disease first. In the eight patients with measurable disease the median time to progression of the measurable lesions was 5.75 months (range 2–52 weeks).

Survival
With eight patients alive and censored after 22 months, the estimated median overall survival was 15.1 months (Figure 1). The actual 1 year overall survival was 71% (95% CI 51% to 88%).



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Figure 1. Overall survival.

 
Toxicity
All 23 patients were evaluable for toxicity. Grade 2 or greater granulocytopenia was observed in 13% of patients. There were no neutropenic fevers. Lower extremity edema requiring and controlled with diuretic therapy was observed in 11 patients (48%). Lower extremity deep venous thrombosis was observed in four patients (17%, 95% CI 5% to 39%). None of the patients with a thromboembolic complication continued on study with anticoagulation. Four patients (17%) had grade 2 nausea and there were no reports of neuropathy. There was one report of grade 2 hepatic toxicity and this resulted in discontinuance of therapy.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Therapy for HRPC remains palliative and the efficacy of a regimen has to be balanced against the toxicity. The phase III study of vinblastine–EMP compared with vinblastine alone by the HOG and Fox Chase Cancer Network suggested a benefit of combined anti-microtubule blockade with improved PSA response, response rate, time to progression and a trend toward improved survival. In the HOG phase II study presented in this paper we found that vinorelbine–EMP is also an efficacious regimen as assessed by PSA response rate, time to progression and overall survival. The results are impressive considering that the median PSA was 160 ng/ml and this study was performed in a community setting. Although the phase II and phase III HOG studies can not be directly compared, inferences regarding the activity of vinorelbine–EMP can be made when the data from the two trials are evaluated. The PSA response rate was 71% in this phase II study of vinorelbine–EMP compared with 27.5% for vinblastine–EMP in the previous phase III study. The median overall survival in the vinorelbine–EMP and vinblastine–EMP arms were 15.1 and 11.2 months, respectively. The 1-year overall survival for vinorelbine–EMP was 71% and in the phase III trial vinblastine–EMP and vinblastine alone were associated with 50 and 35% 1-year survivals, respectively.

However, the toxicity of oral EMP, even as a short course, is still problematic. In this phase II trial of vinorelbine–EMP almost half of the patients required diuretic therapy and 17% had a thromboembolic complication. The combination arm of vinblastine–EMP in the phase III trial was associated with increased lower extremity swelling and nausea compared with single agent vinblastine. The apparent myeloprotection of a vinca alkaloid plus EMP seen in the phase III trial was also seen in the current phase II trial. Specifically, there was a 56% incidence of grade 2 or greater granulocytopenia in the vinblastine arm, whereas this degree of myelosuppression was seen in only 16% of the vinblastine-EMP arm and only 13% of the patients in the vinorelbine-EMP study.

Two other studies combining vinorelbine with prolonged oral EMP have also been reported. In one of these, vinorelbine was dosed at 25 mg/m2 on days 1, 8, 22 and 29 with 600 mg/m2 of EMP on days 1–42 with cycles repeated every 52 days. Nine of 24 patients (38%) had >50% PSA decline and the median survival was 10.5 months [11]. In the other study 25 mg/m2 of vinorelbine was given on days 1 and 8 with EMP dosed at 420 mg daily given orally from days 1 to 14. There was a 25% rate of PSA decline >50% of baseline in 25 patients with a median survival of 14.1 months [16]. The vascular toxicities observed in this study were one episode of deep venous thrombosis, one unwitnessed cardiac arrest and one patient with myocardial ischemia. Colleoni et al. [12] have also presented the results of a 25 patient phase II trial of EMP (400 mg/m2 orally days 1–42), etoposide (50 mg/m2 orally days 1–14 and 28–42) and vinorelbine (20 mg/m2 days 1, 8, 28 and 35) with cycles repeated every 8 weeks. Prostate-specific antigen in 14 patients (56%) decreased from baseline by at least 50% and two of three patients with measurable disease had a partial response. Only three patients had grade 3/4 neutropenia, nine patients had grade 1/2 nausea and no thromboembolic events were reported.

The taxanes are another class of drugs that block the microtubule apparatus and have also been evaluated both alone and in combination with EMP. Single-agent paclitaxel given at 130–170 mg/m2 over 24 h every 3 weeks was found to be devoid of any meaningful activity in a phase II Eastern Co-operative Oncology Group study of 23 patients with measurable disease [17]. No patient had a significant shrinkage of their measurable disease and four patients had a decrease of between 16% and 24% in their PSA. In a study of paclitaxel dosed at 150 mg/m2 weekly for 6 weeks with cycles repeated every 8 weeks, four of eight patients had a partial response of measurable disease and seven of 18 had a serological response [18]. Weekly single-agent docetaxel given at a dose of 36 mg/m2 for the first 6 weeks of an 8 week cycle resulted in at least a 50% decline in PSA in 47% of 19 patients. A significant decrease in pain in 33% of patients as measured by the Six Point Present Pain Intensity scale was also reported [19]. Of note is the observation that the PSA decline correlated with a decreased pain response.

Several studies have combined a taxane with EMP with encouraging results. Petrylak et al. [20] enrolled 34 men with HRPC onto a phase I study of docetaxel–EMP. The EMP was dosed at 280 mg orally tds on days 1–5, with docetaxel escalated from 40 to 80 mg/m2 on day 2. Treatment was repeated every 21 days. The overall PSA response rate (>=50% decrease) was 63%. Five of the 18 patients with bidimensionally measurable disease (28%) achieved a partial response. Eight of 15 patients (53%) requiring narcotic analgesics for bone pain discontinued their medications after treatment. The median survival for all patients treated was 22.8 months on this phase I trial. Petrylak et al. [21] followed this up with a phase II trial and dosed the docetaxel at 70 mg/m2 on day 2. There was a 71% rate of PSA decline >50% in 35 evaluable patients with a 1-year survival of 77%. Significant toxicity was also observed in this study. There were two deaths associated with granulocytopenic fevers, two patients experienced cerebrovascular accidents (including one patient who died) and two patients had a deep venous thrombosis. Similar results were reported by Savarese et al. [22] when docetaxel at 70 mg/m2 was given with hydrocortisone and EMP to 47 patients. A 23% objective response rate and 69% serologic response rate was recorded. The thrombotic complications have been a source of concern for many investigators and have resulted in prophylactic regimens being introduced into the trials. Petrylak et al. [21] prescribed aspirin and coumadin to the last nine patients for prophylaxis and no thrombotic problems were observed. Sinibaldi et al. [23] employed docetaxel with 280 mg of EMP given tds for five doses every 3 weeks with 2 mg of daily oral coumadin. No thrombotic events were observed in the 32 patients on study. Taken together these two studies suggest that antithrombotic prophylaxis mitigates this toxicity.

In conclusion, the serologic response rate and the 1-year overall survival data from the HOG vinorelbine–EMP study provide further support to the concept of combined anti-microtubule therapy. However, the high incidence of thrombotic events in the present study and other studies is problematic. It is therefore felt that exploration of a regimen of combined anti-microtubule agents that do not contain EMP is warranted.


    Acknowledgements
 
Supported in part by Glaxo Wellcome and Walther Cancer Institute, Indianapolis, IN. This study was presented in part at the Annual Meeting of American Society of Clinical Oncology, May 20–23, 2000, New Orleans, Louisiana, USA.


    Footnotes
 
+ Correspondence to: Dr L. H. Einhorn, Indiana University, Indiana Cancer Pavilion, Room 473, 535 Barnhill Drive, Indianapolis, IN 46202, USA. Tel: +1-317-274-0920; Fax: +1-317-274-3646; E-mail: leinhorn@iupui.edu Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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