Sequential mitoxantrone/prednisone followed by docetaxel/estramustine in patients with hormone refractory metastatic prostate cancer: results of a phase II study

A. Font1,*, A. Murias2, F. R. García Arroyo3, C. Martin4, J. Areal5, J. J. Sanchez6, J. A. Santiago2, M. Constenla3, J. M. Saladie5 and R. Rosell1

1 Medical Oncology Service, Institut Català d'Oncologia, Hospital Germans Trias i Pujol, Badalona, Barcelona; 2 Medical Oncology Service, Hospital Universitario Insular de Gran Canaria, Las Palmas; 3 Medical Oncology Service, Complexo Hospitalario de Pontevedra, Pontevedra; 4 Hospital del Espiritu Santo, Santa Coloma de Grament, Barcelona; 5 Urology Department, Hospital Germans Trias i Pujol, Badalona, Barcelona; 6 Autonomous University of Madrid, Red de Centros de Epidemiologia y Salod Pública (RCESP), Madrid, Spain

* Correspondence to: Dr A. Font, Medical Oncology Service, Institut Català d'Oncologia, Hospital Germans Trias I Pujol, Carretera del Canyet s/n, 08916 Badalona, Barcelona, Spain. Tel: +34-93-4978925; Fax: +34-93-4978950; Email: afont{at}ns.hugtip.scs.es


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: Mitoxantrone/prednisone ameliorates symptoms in hormone refractory prostate cancer (HRPC) but has no effect on survival. Docetaxel (Taxotere)/estramustine improves response but with significant toxicity. We reasoned that a sequential administration of the two regimens could be a viable alternative for delivering full doses of chemotherapy, avoiding overlapping toxicity and preserving dose intensity.

Patients and methods: Thirty HRPC patients were treated with mitoxantrone 10 mg/m2, day 1, every 3 weeks, plus prednisone 5 mg twice daily, for three cycles, followed by estramustine phosphate, 280 mg three times daily, days 1 to 5, plus docetaxel 75 mg/m2, day 2, every 3 weeks for a maximum of 10 cycles.

Results: All patients were assessable for response and toxicity. After mitoxantrone/prednisone treatment, the prostate-specific antigen (PSA) response rate was 23%, which increased to 63% after completion of sequential mitoxantrone/prednisone and docetaxel/estramustine treatment (12 partial and 7 complete responses). With a median follow-up of 18 months, median survival for all patients was 18 months, and median progression-free survival was 10 months. The mitoxantrone/prednisone regimen was well tolerated, and the only grade 3–4 toxicity was grade 3 neutropenia in four (13%) patients. Twenty-nine patients received a total of 173 cycles of docetaxel/estramustine (median, 6 cycles/patient). Six (20%) patients had grade 3–4 neutropenia and two (6%) patients had febrile neutropenia episodes. The most frequent non-hematological toxic effects were asthenia, nausea and vomiting, edemas and onycholysis. Two (6%) patients had deep venous thrombosis.

Conclusions: Mitoxantrone/prednisone followed by docetaxel/estramustine is a well-tolerated and active regimen in HRPC. Sequential therapy is feasible and can be used to integrate novel, more active regimens.

Key words: docetaxel, mitoxantrone, prostate cancer, sequential, efficacy


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Prostate cancer is the most common cancer in men in Western countries and is the second leading cause of cancer death, after lung cancer [1Go]. Approximately 30–35% of patients with prostate cancer present with regional or metastatic tumors, whereas an additional 25% will develop metastases in the course of the disease. Androgen deprivation remains the standard treatment for metastatic disease, and the majority of patients initially respond to hormone therapy. However, an irreversible progression to hormone-refractory status occurs in virtually all treated patients. Later remissions with additional hormone therapies are less frequent and last for only a short time. Treatment in hormone-refractory prostate cancer (HRPC) is usually palliative, and median survival ranges from 6 to 12 months.

Until recently, chemotherapy was considered an ineffective approach to HRPC. Two reviews from the mid-1980s showed that chemotherapy had little impact on the prognosis of HRPC [2Go, 3Go]. More recently, two randomized trials [4Go, 5Go] compared mitoxantrone plus corticosteroids to corticosteroids alone and found that although mitoxantrone improved symptom palliation, median survival remained at 12 months in both arms. While mitoxantrone/prednisone has long been considered the standard treatment for HRPC, its lack of effect on survival has spurred the search for more effective cytotoxic agents.

Approaches targeting cytoplasmic microtubules and the anti-apoptotic protein bcl-2 have demonstrated significant activity in human prostate cancer cell lines. Estramustine, which dysregulates normal microtubule assembly by binding with ß-tubulin and microtubule-associated proteins, has been used successfully in combination with other antimicrotubular agents, such as vinblastine, etoposide and taxanes [6Go–8Go]. Phase I and II trials [9Go–11Go] of 3-weekly docetaxel/estramustine in HRPC reported prostate-specific antigen (PSA) response rates of 50%–82% and objective response rates of 28%–50%. However, significant toxicity was observed in all three studies, including grade 3–4 neutropenia in 38%–62% of patients, grade 3–4 asthenia in 24%, and grade 3–4 edema in 22% of patients [9Go–11Go].

Although a phase I study determined the recommended doses of weekly mitoxantrone/docetaxel [12Go], the impact of a combination of the standard mitoxantrone/prednisone with a docetaxel-based regimen has not yet been established in HRPC. However, the significant toxicity observed with the docetaxel/estramustine regimen alone essentially rules out any possibility of a concurrent administration of this regimen with other cytotoxic drugs. We hypothesized that a sequential administration of regimens proven to be active in HRPC could be a viable alternative for delivering full doses of chemotherapy, avoiding overlapping toxicity and preserving dose intensity. Given the established activity of docetaxel in HRPC and the possibility of using a sequential administration to give both mitoxantrone/prednisone and docetaxel/estramustine at full doses, we designed this multicenter phase II study to evaluate the efficacy and toxicity of docetaxel/estramustine when sequentially combined with the standard first-line treatment of mitoxantrone/prednisone in HRPC patients.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility criteria
Criteria for study entry were as follows: histologically documented adenocarcinoma of the prostate with metastatic disease; progressive systemic disease after effective androgen deprivation with castrate testosterone serum levels; discontinued prior treatment with antiandrogen therapy by at least 4 weeks; no prior chemotherapy (prior therapies with corticosteroid and estramustine were allowed); measurable disease or ‘bone-only’ disease with rising PSA levels; progressive disease, defined as the appearance of a new lesion, >25% increase in size of an existing lesion, or doubling of the nadir PSA value documented by two successive determinations for patients with only bone metastases; life expectancy >3 months; Karnofsky Index ≥70%; adequate bone marrow (leucocytes >3000/ml, absolute neutrophil count >1500/ml and platelets >100 000/ml), liver [serum bilirubin level <1.0 upper limit normal value (ULN), ASAT and ALAT <2.5 ULN, alkaline phosphatase <5 ULN] and renal functions. Signed informed consent was obtained from all patients and institutional review board approval was obtained at each participating institution.

Patients were excluded from the study if they had: (i) clinically evident brain metastases; (ii) symptomatic peripheral neuropathy higher than grade 1 according to National Cancer Institute Common Toxicity Criteria (NCI-CTC); (iii) concurrent treatment with other experimental drugs or anticancer therapy; (iv) active uncontrolled infection; or (v) radiotherapy completed less than 4 weeks before enrollment.

Treatment plan
Eligible patients were treated with mitoxantrone 10 mg/m2 by intravenous infusion (i.v.) on day 1 every 3 weeks plus prednisone 5 mg orally twice daily for three courses, followed by estramustine phosphate, 280 mg orally three times daily on days 1 to 5 plus docetaxel 75 mg/m2 i.v. on day 2 every 3 weeks for a maximum of 10 courses or until progressive disease or unacceptable toxicity. During docetaxel therapy, patients received dexamethasone 8 mg orally every 12 h, from 12 h before until 36 h after the docetaxel dose. Therapy was withheld for 1 week if platelet count <100 000/mm3 or neutrophil count <1500/mm3. The chemotherapy dose was reduced by 25% for neutropenic fever or for any other grade 3–4 toxicity excluding anemia, alopecia or nausea and vomiting. Prophylactic use of growth factors was not allowed during the study. Primary androgen suppression with gonadotropin-releasing hormone analog was continued at the investigator's discretion.

Evaluations
Pretreatment evaluation included medical history, physical examination, serum PSA, serum testosterone, serum biochemistry, complete blood count (CBC), chest X-rays, bone scan, and computed tomography (CT) of the abdomen and pelvis. Before each chemotherapy cycle, physical examination, assessment of adverse events, CBC, serum biochemistry and serum PSA were carried out. In patients with measurable disease by radiologic assessment, CT scans were repeated every 9 weeks. Bone scans were repeated as clinically indicated.

Assessment of outcome
The primary end point of the study was PSA response according to the criteria of the Prostate-Specific Antigen Working Group [13Go]: complete response with confirmed normalization (PSA <4 ng/ml); partial response with a confirmed decrease of >50% from baseline; stable disease with a confirmed decrease of <50% from baseline or an increase of <25%; and progressive disease with an increase of >25%. Secondary end points included analysis of response in measurable disease according to World Health Organization criteria, time to progression, survival and toxicity (NCI-CTC).

Statistical analyses
This study was designed as a prospective, non-randomized, multicenter, phase II study, where PSA response was considered the primary end point. Patients who received at least one dose of mitoxantrone were assessable for toxicity. Overall response rate was calculated from all patients entered with no attempt to exclude patients whose response was not evaluated or who progressed early. Time to progression was calculated from the first treatment infusion to the first objective evidence of tumor progression, final follow-up, or start of other antitumor therapy. Overall survival was measured from initial treatment to death. Time to progression and overall survival were analyzed using the Kaplan–Meier method. All patients entering the trial were included in the survival analysis.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
From February 2001 to May 2003, 30 patients from four institutions were enrolled on to the study. Median age was 69 (range 57–85), and 17 patients (56%) had a Karnofsky Index >80%. The median PSA was 151 ng/ml (range 12.5–682 ng/ml). All patients had radiographic evidence of metastatic disease; 29 (97%) patients had bone metastases, and nine (30%) had measurable disease (six with metastatic lymph nodes, two with lung metastases, and one with liver metastases). Eight (27%) patients had received prior radiotherapy to the primary tumor (Table 1).


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Table 1. Patient characteristics

 
Treatment delivery
A total of 85 cycles of mitoxantrone/prednisone were administered to 30 patients. Twenty-five patients received the planned three cycles and five received two cycles. Nine (10%) cycles of mitoxantrone/prednisone were delayed in seven (23%) patients due to neutropenia. A total of 173 cycles of docetaxel/estramustine were administered to 29 patients, with a median of six cycles per patient. Twenty-one patients received six or more cycles of docetaxel/estramustine. One patient did not proceed to docetaxel treatment because of progressive disease with significant clinical deterioration after two cycles of mitoxantrone/prednisone. Eighteen (10%) cycles of docetaxel/estramustine were delayed in 10 (33%) patients mainly due to hematological toxicity. The median number of days of treatment delay was 10 (range 4–28). Dose reduction of docetaxel was required in four (13%) patients due to hematological toxicity (three patients) or non-hematological toxicity (one patient); estramustine was reduced or omitted in seven (24%) patients due to digestive intolerance.

Toxicity
All patients were assessable for toxicity to mitoxantrone/prednisone. Overall, this regimen was well-tolerated and no unexpected toxic effects were observed (Table 2). No grade 3–4 non-hematological toxicity was reported, while the only significant hematological toxicity was grade 3 neutropenia, detected in four (13%) patients.


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Table 2. Toxicity profile

 
Twenty-nine patients were assessable for toxicity to docetaxel/estramustine (Table 2). The main hematological toxicity associated with this regimen was grade 3–4 neutropenia, detected in six (20%) patients. Neutropenic fever requiring hospitalization occurred in two (6%) patients. The most common grade 2 or higher non-hematological toxic effects included peripheral edema in five (17%) patients, asthenia in five (17%) patients, nausea/vomiting in nine (31%) patients and onycholysis in six (20%) patients. Other non-hematological toxic effects, including mucositis, diarrhea and neurotoxicity, were infrequent. Two patients had deep venous thrombosis. There was one treatment-related death, due to neutropenic sepsis, after the first cycle of docetaxel/estramustine. Docetaxel/estramustine was discontinued in four patients due to toxicity (grade 3 edema in two patients, grade 2 asthenia in two patients).

Efficacy
After mitoxantrone/prednisone treatment, seven of 30 patients (23%; 95% CI 11.7%–41.1%) achieved a PSA response (one complete and six partial responses). Six patients had stable disease and 17 progressive disease. Twenty-nine patients subsequently received docetaxel/estramustine. In these patients, the PSA response rate was 63% (95% CI 47.2%–80.2%), which included seven (23%) complete responses and 12 (40%) partial responses. Three of six patients (50%) with stable disease and 10 of 16 patients (62%) with progressive disease after mitoxantrone/prednisone responded to docetaxel/estramustine (Table 3).


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Table 3. PSA response rate after completion of mitoxantrone/prednisone treatment and after completion of sequential mitoxantrone/prednisone and docetaxel/estramustine

 
A confirmed partial response was observed in three of nine patients (33%) with measurable disease; all of these responses were observed in metastatic lymph nodes. The median duration of response was 8 months (range 2–15 months).

Median follow-up was 18 months. The estimated overall median survival for all 30 patients was 18 months (95% CI 12.6–23.4 months), with 1 year and 2 year survival rates of 66% and 45%, respectively (Figure 1). Median progression-free survival was 10 months (95% CI 8.5–11.5 months) (Figure 2). At the time of this report, 15 patients have died.



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Figure 1. Overall survival.

 


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Figure 2. Time to progression.

 
When baseline characteristics were correlated with survival, only Karnofsky Index, PSA levels, response and alkaline phosphatase levels emerged as significant prognostic factors. Median survival was 27 months in patients with Karnofsky Index >80%, compared to 9 months for those with Karnofsky Index 70%–80% (P=0.0003). In patients with PSA <100 ng/ml, median survival was not reached, whereas for those with PSA >100 ng/ml, median survival was 11 months (P=0.019). Median survival for responders was 27 months, whereas for non-responders, it was 8 months (P=0.0021). Median survival for patients with high serum alkaline phosphatase levels (>120 U/l) was 12 months, compared to 27 months for those with normal levels (<120 U/l) (P=0.005). There was no difference in survival according to age (<70 versus >70 years) or hemoglobin levels (<13 versus >13 g/dl). A multivariate Cox regression model for survival showed a favorable hazard ratio (HR) for patients with Karnofsky Index >80% (HR = 0.140) and for those with normal serum alkaline phosphatase levels (HR = 0.153).


    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The treatment of HRPC has remained controversial because to date few regimens have demonstrated activity in this disease. Mitoxantrone plus corticosteroids is the standard regimen based on its positive impact on symptom mitigation compared with supportive care with steroids alone [4Go, 5Go]. However, the activity of this regimen has proven to be limited. In two randomized trials comparing mitoxantrone plus corticosteroids with best supportive care, the mitoxantrone-based regimens achieved palliative response rates of 38%–42% and PSA response rates of 29%–38% [4Go, 5Go]. However, median survival was around 12 months both for patients receiving chemotherapy and those receiving supportive care alone. Similar results were obtained in a third trial comparing mitoxantrone/prednisone with the same regimen plus clodronate [14Go].

Docetaxel given every 3 weeks, plus oral estramustine and daily hydrocortisone, showed significant activity in HRPC, with PSA response rates of 68% overall and 50% in a subgroup of 24 patients with measurable disease; median survival was 20 months and time to progression was 8 months [11Go]. Weekly docetaxel, with or without estramustine, is also active in HRPC [15Go–18Go]. A randomized phase II study comparing two docetaxel/estramustine schedules, weekly or every 3 weeks, with mitoxantrone/prednisone reported a benefit for both docetaxel-based regimens in terms of PSA response rate (65%–77% versus 21%) and time to progression (6–8 months versus 2.5 months); pain control and improvement in performance status were also superior in the docetaxel/estramustine arms [19Go]. Furthermore, two recent phase III trials have confirmed that docetaxel-based regimens obtain superior results to mitoxantrone/prednisone. In both trials, median survival in patients treated with a docetaxel combination was around 18 months, at least 2 months higher than in patients treated with the mitoxantrone/prednisone regimen [20Go, 21Go].

Sequential chemotherapy approaches have been analyzed in different primary tumors [22Go–25Go]. In patients with lymph node-positive breast cancer, the sequential administration of doxorubicin and paclitaxel showed better results than an escalating doxorubicin dose [22Go]. Sequential treatment has also proven superior to an alternating schedule in breast cancer patients [23Go]. In HRPC, however, sequential chemotherapy approaches have not been widely evaluated, although Ellerhorst et al. investigated an alternating schedule of weekly doxorubicin/ketoconazole and vinblastine/estramustine and obtained a 67% PSA response rate and a 19-month median survival in 46 patients [26Go].

This study has shown for the first time that the sequential administration of mitoxantrone/prednisone followed by docetaxel/estramustine confers a meaningful survival benefit with moderate side-effects in HRPC patients. The median survival with this sequential approach was superior to that obtained with mitoxantrone/prednisone alone [4Go, 5Go]. Median survival was 18 months overall and 27 months in patients with Karnofsky Index >80%. The 23% PSA response rate observed after three cycles of mitoxantrone/prednisone was slightly lower than that attained in previous randomized studies [4Go, 5Go, 14Go, 20Go, 21Go], which may have been due to two factors. First, we administered only three cycles of mitoxantrone/prednisone, rather than six or more; secondly, the mitoxantrone dose per cycle in our study was 10 mg/m2, compared with 12 mg/m2 [4Go] and 14 mg/m2 [5Go]. In contrast, the response rate and median survival after docetaxel/estramustine was in line with results in other trials of docetaxel-based regimens [9Go, 11Go, 19Go–21Go]. Moreover, with this sequential treatment, we achieved a progression-free survival of 10 months, whereas in other trials, it has ranged from 6 to 8 months [11Go, 19Go, 20Go], suggesting that sequential treatment with these active regimens can have a positive impact on the prognosis of HRPC patients. Importantly, docetaxel/estramustine was able to reverse the relative drug resistance of patients to mitoxantrone/prednisone. Ten of 16 patients (62%) with progressive disease after mitoxantrone/prednisone responded to docetaxel/estramustine. These two regimens are thus non-cross-resistant, and previous treatment with mitoxantrone will not affect the efficacy of a docetaxel-based regimen.

Our study also demonstrates the feasibility of sequential mitoxantrone/prednisone and docetaxel/estramustine. The mitoxantrone/prednisone regimen was well tolerated, with no limiting grade 3–4 toxic effects. Moreover, the toxicity pattern of docetaxel/estramustine in our study was slightly better than that of previous trials. Grade 3–4 neutropenia occurred in only 20% of patients, whereas in the study by Savarese et al. [11Go], it occurred in 56%, in spite of the lower median number of cycles administered (five versus six cycles). The incidence of non-hematological toxicity in our trial was similar to that in other trials, including the frequency of thromboembolic events. The most significant toxicity in our patients was nausea and vomiting, which was probably related to estramustine.

In summary, our study confirms the benefit of docetaxel/estramustine in the treatment of HRPC patients and demonstrates the feasibility of a sequential approach in the treatment of these patients. Future studies should investigate the use of sequential therapy with a view to integrating novel regimens that may be more active than the standard mitoxantrone/prednisone.

Received for publication August 31, 2004. Revision received November 4, 2004. Accepted for publication November 10, 2004.


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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