Immunological monitoring during combination of patient-oriented peptide vaccination and estramustine phosphate in patients with metastatic hormone refractory prostate cancer

BACKGROUND: Additive antitumor effects could be achieved by combination of immunotherapy and cytotoxic agents with no or minimum suppression. METHODS: Thirteen patients positive for human leukocyte antigen (HLA)-A24 or -A2 with metastatic hormone refractory prostate cancer (HRPC) who had failed to respond to the prior-peptide vaccination were entered in the combined peptide vaccination and estramustine phosphate. Conducted immune monitoring on those 13 patients were mainly peptide-specific cytotoxic T lymphocyte (CTL) precursor analysis by IFN-gamma productions and peptide-reactive IgG by an enzyme-linked immunosorbent assay (ELISA). RESULTS: Grade 3 arrhythmia or cerebral infarction was observed in two cases, and Grade 1 or 2 dermatologic reaction at the vaccination sites was observed in all 13 cases. Eleven patients who received more than one cycle of treatment were eligible for immunological and clinical evaluation. There was no significant immunosuppression in most cases when the peptide and a half dose (280 mg/day) of estramustine were administrated, whereas severe immunosuppression was observed in the first two patients who received both the peptide and a full dose (560 mg/day) estramustine. Augmentation of peptide-specific CTL precursors or peptide-specific IgG was observed in 6 of 11 or 10 of 11 cases, respectively. Ten of 11 patients showed serum prostate-specific antigen (PSA) level decrease from the baseline including 8 patients with a serum PSA level decrease of > or =50%. CONCLUSIONS: These results encouraged the further evaluation of the combination of peptide vaccination and low-dose estramustine phosphate for metastatic HRPC patients.     

A prostate stem cell antigen-derived peptide immunogenic in HLA-A24- prostate cancer patients

BACKGROUND: We attempted to identify prostate stem cell antigen (PSCA)-derived peptides immunogenic in HLA-A24+ prostate cancer patients. METHODS: Peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with each of three different PSCA-derived peptides, which were prepared based on the HLA-A24 binding motif, and their peptide-specific and HLA-A24-restricted anti-tumor responses were examined. Plasma levels of immunoglobulin G (IgG) against PSCA peptides were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Among three PSCA peptides, the PSCA 76-84 peptide most effectively induced peptide-specific cytotoxic T lymphocytes (CTLs) from PBMCs of HLA-A24+ prostate cancer patients. Cytotoxicity was dependent on peptide-specific and CD8+ T cells. The PSCA 76-84 peptide-stimulated PBMCs showed a significant level of cytotoxicity against prostate cancer cells in an HLA-A24-restricted manner. IgG reactive to the PSCA 76-84 peptide was detected in half of patients. CONCLUSIONS: The PSCA 76-84 peptide should be considered for use in clinical trials of immunotherapy for HLA-A24+ patients.     

A randomized study of docetaxel and dexamethasone with low- or high-dose estramustine for patients with advanced hormone-refractory prostate cancer

OBJECTIVE: To test the combination of docetaxel with two different doses of estramustine in patients with hormone-refractory prostate cancer (HRPC), to improve response rates and to lower side-effects, as docetaxel-based chemotherapy is an increasing option for men with advanced HRPC, and alone or combined with estramustine, docetaxel improves median survival. PATIENTS AND METHODS: In all, 72 patients with metastatic HRPC were randomly assigned to receive docetaxel (70 mg/m(2) intravenously, on day 2 every 21 days) and estramustine (3 x 280 mg/day oral starting 1 day before docetaxel, for 5 consecutive days) for arm A, or estramustine (3 x 140 mg/day oral starting 1 day before docetaxel, for 3 consecutive days) for arm B. Premedication with oral dexamethasone at a total daily dose of 16 mg, in divided doses twice a day was administered in arm A on day 1-5 and in arm B on day 1-3. Initially, six cycles were administered. Chemotherapy was restarted after a significant increase in prostate-specific antigen (PSA) level. Patients were monitored for any measurable PSA response and toxicity. RESULTS: Between the arms there was no statistically significant difference in time to progression and overall survival. However, treatment B had less treatment-related toxicity than A. Independent prognostic variables were baseline factors like PSA level, haemoglobin level, Eastern Cooperative Oncology Group performance status, and bone pain at presentation. CONCLUSIONS: In this randomized phase II study the combination of docetaxel and estramustine had substantial activity in HRPC, with a significant incidence of severe toxicity, both haematological and not. Nevertheless, treatment-related toxicity was predictable and manageable. There was no better effect with a higher dose of estramustine with docetaxel than for a lower dose. There was a slight tendency to higher toxicity for high-dose estramustine but this was not statistically significant. The present results support the assertion that estramustine is not necessary in docetaxel-based treatment regimens.     

Prostate-specific antigen-derived epitopes capable of inducing cellular and humoral responses in HLA-A24+ prostate cancer patients

BACKGROUND: We tried to identify prostate-specific antigen (PSA)-derived epitopes immunogenic in HLA-A24+ prostate cancer patients. METHODS: Peripheral blood mononuclear cells (PBMCs) were in vitro stimulated with each of four different PSA peptides carrying the HLA-A24 binding motif, and their HLA-A24-restricted anti-tumor responses were examined using a parental HLA-A24-negative prostate cancer cell line (PC93) and its HLA-A24-expressing transfectant line (PC93-A24). Serum levels of immunoglobulin G (IgG) against PSA peptides were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: PBMCs, which were in vitro stimulated with either the PSA(152-160) or PSA(248-257) peptide, showed higher levels of IFN-gamma production and cytotoxicity against the PC93-A24 than against the PC93. IgG against the PSA(248-257) peptide was detected in half of the prostate cancer patients tested. CONCLUSIONS: The PSA(152-160) and PSA(248-257) peptides could be appropriate target molecules in use for specific immunotherapy of HLA-A24+ prostate cancer patients.     

Immunological evaluation of neoadjuvant peptide vaccination before radical prostatectomy for patients with localized prostate cancer

BACKGROUND: The purpose of this study was to determine the safety and immune responses of pre-operative personalized peptide vaccine for patients with localized prostate cancer. METHOD: Ten human leukocyte antigen (HLA)-A24(+) patients with localized prostate cancer received weekly personalized peptide vaccine for six times with positive peptides (up to four kinds of peptides) from 16 kinds of vaccine candidates, followed by a retropubic radical prostatectomy (RRP). Eight patients with localized prostate cancer receiving RRP served as the control group. The serum prostate-specific antigen (PSA) level, and peptide-specific cytotoxic T lymphocyte (CTL) precursor analysis by interferon-gamma production, and peptide-reactive immunoglobulin G (IgG) using an enzyme-linked immunosorbent assay were monitored during the treatment. Distributions of CD45RO(+) cells, CD8(+) T cells, and CD20(+) B cells in tissue microarray samples were studied using an immunohistochemical technique. RESULT: The peptide vaccination was safe and well tolerated with no major adverse effects. Increased CTL response and the anti-peptide IgG titer were observed in the post-vaccination samples in 8 of 10 or 8 of 10 patients, respectively. The intensity of CD45RO(+) infiltrating cells in the vaccination group was significantly larger than that in the control group. CD8(+) T cell infiltration was seen only in the vaccinated group. CONCLUSION: Increased immune responses, at both the circulation and tumor sites in the vaccinated group, support the further development of personalized peptide vaccines for patients with localized prostate cancer.     

PSA、PSMA、PAP多肽联合致敏自体DC治疗HRPC的临床研究

目的:观察前列腺特异性抗原(PSA)、前列腺特异性膜抗原(PSMA)与前列腺酸性磷酸酶(PAP)多肽联合致敏自体树突状细胞(DC)治疗激素难治性前列腺癌(HRPC)的安全性与有效性。方法:选择HLA-A201阳性HRPC患者16例,分离患者外周血中单核细胞,加入重组人粒细胞集落刺激因子(rhGM-CSF)与白介素(rhIL-4)诱导成DC。用PSA(KLQCVDLHV)、PSMA(ALDVYNGLL)与PAP(LLHETDSAV)3种多肽联合冲击DC后近腹股沟淋巴结富集区皮内多点接种致敏DC,隔周1次,共进行4次接种,于最后1次接种后1～2周内进行免疫学与近期临床疗效的监测。结果:未见1例出现Ⅱ级以上不良反应(寒颤、发烧、注射部位红肿、皮疹等)。患者接种DC后外周血中IL-2、IL-12和IFN-γ水平呈明显上升趋势(P<0.01);迟发型超敏反应(DTH)试验阳性率为36.4%(4/11);5例患者外周抗原特异性IFN-γ+CD8+T细胞比例明显增加(5/11);6例患者PSA水平下降(6/16);1例患者腹腔积液减少;1例患者颈部淋巴结转移灶缩小。3例患者临床反应达到部分缓解(PR),7例患者稳定(SD),6例患者进展(PD)。结论:PSA、PSMA和PAP多肽联合负载自体DC免疫治疗方法可明显改善HRPC患者免疫功能,有效激发特异性T细胞免疫应答,控制并缓解病情,是治疗晚期HRPC的一种安全与有效的手段。     

Vaccination of hormone-refractory prostate cancer patients with peptide cocktail-loaded dendritic cells: results of a phase I clinical trial

BACKGROUND: Immunotherapies might represent promising alternatives for the treatment of patients with hormone-refractory prostate cancer (HRPC). In a Phase I clinical trial, we evaluated a vaccination with dendritic cells (DCs) loaded with a cocktail consisting of HLA-A*0201-restricted peptides derived from five different prostate cancer-associated antigens [prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), survivin, prostein, transient receptor potential p8 (trp-p8)]. METHODS: Eight HRPC patients received a total of four vaccinations every other week. Clinical and immunological responses were monitored by the determination of the serum PSA levels and by enzyme linked immunospot (ELISPOT) analyses, respectively. RESULTS: Apart from local skin reactions no side effects were noted. One patient displayed a partial response (PR; PSA decrease >50%) and three other patients showed stable PSA values or decelerated PSA increases. In ELISPOT analyses, three of four PSA responders also showed antigen-specific CD8+ T-cell activation against prostein, survivin, and PSMA. CONCLUSIONS: The described protocol represents a safe and feasible concept for the induction of clinical and immunological responses. The application of a peptide cocktail-derived from different antigens as a novel treatment modality is supposed to allow for the genetic and biologic heterogeneity of PCa.     

New epitope peptides derived from parathyroid hormone-related protein which have the capacity to induce prostate cancer-reactive cytotoxic T lymphocytes in HLA-A2+ prostate cancer patients

BACKGROUND: Parathyroid hormone-related protein (PTHrP) is produced by cancer cells and has been suggested to be responsible for malignancy-associated hypercalcemia and osteolysis after bone metatsases. Therefore, PTHrP is a promising target in the treatment of metastatic prostate cancer. METHODS: Seven PTHrP-derived peptides were prepared based on the HLA-A2 binding motif. These peptide candidates were screened by their ability to induce peptide-specific cytotoxic T lymphocytes (CTLs), and their ability to be recognized by immunoglobulin G (IgG). RESULTS: Both the PTHrP59-67 and PTHrP42-51 peptides were found to efficiently induce peptide-specific CTLs from peripheral blood mononuclear cells of HLA-A2+ prostate cancer patients with several HLA-A2 subtypes. These CTLs showed HLA-A2-restricted cytotoxicity toward prostate cancer cells. IgG reactive to the PTHrP42-51 peptide was frequently detected in prostate cancer patients. CONCLUSIONS: These results indicate that these two new PTHrP peptides will be useful in the peptide-based immunotherapy of HLA-A2+ prostate cancer patients, especially those with bone metastases.     

Evaluation of docetaxel plus estramustine in the treatment of patients with hormone-refractory prostate cancer

Objectives:   To investigate the feasibility and efficacy of docetaxel-based chemotherapy in patients with hormone-refractory prostate cancer (HRPC).
Methods:   Forty-six consecutive HRPC patients treated between January 2003 and March 2008 were included in this analysis. Docetaxel was given at a dose of 35 mg/m² twice every 3 weeks and oral estramustine concurrently for three consecutive days during weeks 1 and 2 of each cycle. During each treatment week, the dose of estramustine was 1260 mg on the first day, 980 mg on the second day and 840 mg on the third day. Patients were premedicated with 4 mg twice a day of oral dexamethasone for three consecutive days. Treatment was continued until evidence of disease progression or unacceptable toxicity. Prostate-specific antigen (PSA) levels were evaluated at least once every 4 weeks.
Results:   Patients received a median of three cycles of chemotherapy. Of the evaluable 46 patients, 25 (54%) had a ≥50% PSA decline and 12 (26%) had a ≥75% PSA decline. Median time to PSA progression and overall survival time were 10.1 and 27.0 months, respectively. Median follow-up was 15.0 months. Major severe toxicities were grade 3 or 4 leukopenia in five (11%) patients. Mild toxicities included grade 1 or 2 nausea in eight (17%) patients. Two patients could not continue the treatment because of interstitial pneumonitis and a gastric hemorrhage, respectively.
Conclusions:   Docetaxel plus estramustine chemotherapy represents an active and well tolerated treatment for Japanese HRPC patients.     

Induction of cellular and humoral immune responses to tumor cells and peptides in HLA-A24 positive hormone-refractory prostate cancer patients by peptide vaccination

BACKGROUND: To assess the safety and immune response of a peptide-based immunotherapy for patients with hormone-refractory prostate cancer, a phase I clinical trial was conducted. METHODS: This study first investigated whether cytotoxic T-lymphocyte (CTL) precursors reacting to peptide with vaccine candidates (14 peptides for HLA-A24 positive patients) were detectable in the pre-vaccination peripheral blood mononuclear cells (PBMCs) of ten patients with hormone-refractory prostate cancer. Patients were then vaccinated subcutaneously with only those peptides to which pre-vaccination PBMCs reacted (CTL precursor-oriented peptide vaccine) for up to four kinds of peptides. RESULTS: Overall vaccinations were generally well tolerated, but most patients (nine of ten) developed grade 1 local redness and swelling at the injection site. Increased CTL response to both peptides and cancer cells were observed in four of ten patients. Anti-peptide IgG antibodies were also detected in post-vaccination sera of seven of ten patients. One patient achieved a partial response with an 89% decrease in PSA. Stable disease was demonstrated in five of ten patients (50%) for the median duration of 2 months (range, 2-5 months). There were no objective responses of measurable lesions. CONCLUSIONS: Increase in cellular and humoral immune responses, and decrease in PSA level in some patients support further development of peptide-based immunotherapy for hormone refractory prostate cancer.     

Identification of polycomb group protein enhancer of zeste homolog 2 (EZH2)-derived peptides immunogenic in HLA-A24+ prostate cancer patients

BACKGROUND: Antigens overexpressed in metastatic prostate cancer are appropriate targets in anti-cancer immunotherapy, and one candidate is the polycomb group protein enhancer of zeste homolog 2 (EZH2). METHODS: Eleven EZH2-derived peptides were prepared based on the HLA-A24 binding motif. These peptide candidates were screened first by their ability to be recognized by immunoglobulin G (IgG), and then by their ability to induce peptide-specific cytotoxic T lymphocytes (CTLs). RESULTS: IgGs reactive to three EZH2 peptides (EZH2-243 to -252, EZH2-291 to -299, and EZH2-735 to -;742) were detected in the plasma of almost half of prostate cancer patients. Among them, the EZH2-291 to -299 and EZH2-735 to -742 peptides effectively induced HLA-A24-restricted and prostate cancer-reactive CTLs from prostate cancer patients. The cytotoxicity was mainly dependent on EZH2 peptide-specific and CD8+ T cells. CONCLUSIONS: These EZH2-291 to -299 and EZH2-735 to -742 peptides could be promising candidates for peptide-based immunotherapy for HLA-A24+ prostate cancer patients with metastases.     

Weekly paclitaxel plus estramustine combination therapy in hormone-refractory prostate cancer: A pilot study

BACKGROUND: Paclitaxel used in combination with estramustine has been shown to exert synergistic cytotoxicity in patients with hormone-refractory prostate cancer (HRPC). There have been few reports of this therapy in an Asian male population. METHODS: Nine patients with progressive metastatic HRPC completed at least one cycle of combination therapy employing weekly paclitaxel plus estramustine. Paclitaxel was given weekly for 3 weeks as a 2-h intravenous infusion at a dose of 100 mg/infusion. The cycle was repeated every 4 weeks. A dose of 280 mg of oral estramustine was administrated twice daily for 21 days from the first day of each cycle. Both efficacy and toxicity were recorded. RESULTS: Grade 1 sensory neuropathy was seen in three patients (33%) and grade 4 thrombopenia/anemia was seen in one patient (11%). Performance status improved in three of seven patients (43%), while six patients (67%) showed a 50% or greater decline in prostate-specific antigen levels. Two of these patients experienced significant improvement in bone pain. One patient died of cardiac infarction during this trial and another died of disseminated intravascular coagulopathy subsequent to gastrointestinal bleeding. An additional patient suffered non-fatal pulmonary infarction. The one-year median survival rate was 22.2% and the overall survival period was 36 weeks. CONCLUSION: Although weekly paclitaxel plus estramustine may pose a significant risk, this combination may have a beneficial effect on the quality of life HRPC patients. A well-designed phase I-II trial in an Asian male population is highly recommended.     

Safety and efficacy of docetaxel,estramustine phosphate and hydrocortisone in hormone‐refractory prostate cancer patients

Objective: To assess the combination of docetaxel (DTX), estramustine phosphate (EMP) and hydrocortisone for patients with hormone‐refractory prostate cancer (HRPC). Methods: A total of 63 patients with HRPC were treated with a chemotherapeutic regimen including DTX, EMP, and hydrocortisone. Clinical and pathological features were correlated to serum prostate‐specific antigen (PSA) recurrence and survival rates. Incidence and degree of toxicities were also retrospectively reviewed. Results: A median of 11 courses of chemotherapy was administered per patient. PSA levels decreased by >50% in 32 (51%) patients and >90% in 18 (29%) patients. Median time to PSA progression was 6 months (range from 1 to 41 months) and median time of overall survival was 14 months (range from 1 to 56 months). In a univariate analysis to predict overall survival, PSA, hemoglobin, alkaliphosphatase, and performance status prior to the chemotherapy were significant factors. Despite grade 3–4 neutropenia in 87% of patients, grade 5 interstitial pneumonia in one patient and grade 4–5 myocardial infarction in two patients were recognized, the regimen seemed to be relatively safe. Conclusions: Combination chemotherapy with DTX, EMP and hydrocortisone provides survival benefits for patients with HRPC with an acceptable toxicity profile. We need to further evaluate who might benefit most from this regimen.     

A phase I/II dose-escalation study of exisulind and docetaxel in patients with hormone-refractory prostate cancer

OBJECTIVE: To determine the safety and efficacy, in a dose-escalation study, of exisulind (an oral sulphone metabolite of sulindac thought to induce apoptosis in malignant cells by inhibiting cGMP-phosphodiesterase) combined with docetaxel in men with hormone-refractory prostate cancer (HRPC), as pre-clinical studies suggested activity against prostate cancer and synergy with cytotoxic agents. PATIENTS AND METHODS: Thirty-four patients with HRPC were treated with oral exisulind twice daily for 21-day cycles and intravenous docetaxel given for 1 h on the first day of each cycle. Three dose levels were assessed, combining exisulind 150 and 250 mg twice daily with docetaxel at 60 or 75 mg/m2. Toxicity was then evaluated using standard criteria. RESULTS: The recommended phase II dose was determined to be exisulind 250 mg and docetaxel 60 mg/m2, with escalation to 75 mg/m2 after cycle 1, as tolerated. The most common grade 3-4 toxicities among all patients were neutropenia (56%), infection (24%) and hyperglycaemia (18%). Twelve of 32 evaluable patients (38%, 95% confidence interval, CI, 23-55%) had a decline in PSA by at least half. Only four of 17 evaluable patients (95% CI, 1-47%) treated at the phase II dose level had such a decline in PSA. The median (95% CI) overall survival of all patients was 16 (12.9-19.7) months and median progression-free survival 4.7 (2.7-5.2) months. CONCLUSION: The combination of exisulind and docetaxel was tolerable in patients with HRPC. The PSA response rates do not suggest an improvement over historical data with single-agent docetaxel in this population.     

Induction of human cytotoxic T lymphocytes specific for prostate-specific antigen

Prostate-specific antigen (PSA), a tissue-specific protein expressed by most adenocarcinomas of the prostate, might be a useful target for T-cell-mediated immunotherapy of prostate cancers. The current study examined whether it is possible to elicit human cytotoxic T lymphocytes (CTL) with specificity for PSA. A synthetic nonamer peptide, corresponding to residues 146–154 of PSA and containing a canonical HLA-A2-binding motif, was shown to stabilize the expression of HLA-A2 on the T2 antigen-processing mutant cell line. Repeated in vitro stimulation of peripheral blood lymphocytes from a normal HLA-A2⁺ donor induced CTL with specificity for the PSA 146–154 peptide. The peptide-induced CTL expressed the CD4⁻ CD8⁺ cell surface phenotype and were restricted by HLA-A2. A large portion of patients with prostate cancer express the HLA-A2 phenotype, implying that many prostate cancers might be targeted by HLA-A2-restricted CTL with specificity for the PSA 146–154 epitope. Prostate 30:73–78, 1997. © 1997 Wiley-Liss, Inc.     

Failing to achieve a nadir prostate-specific antigen after combined androgen blockade: Predictive factors

Objectives:   To determine the optimal cut-off of a nadir prostate-specific antigen (PSA) for prediction of progression within 24 months after combined androgen blockade (CAB) and to analyze predictive factors of failing to achieve the nadir PSA.
Methods:   We retrospectively reviewed the medical records of 343 patients with prostate cancer treated with CAB from 2000 to 2005. We determined the nadir PSA level that predicts progression to hormone refractory prostate cancer (HRPC) at 24 months after CAB. Predictive factors for failing to achieve a determined nadir PSA were analyzed.
Results:   Mean age was 74.0 years. Mean follow up was 42.1 month. Seventy-seven patients experienced progression to HRPC. A nadir PSA of 1.0 ng/mL predicts progression to HRPC at 24 months. Predictive factors for failing to achieve a nadir PSA of 1.0 ng/mL or less include pretreatment PSA, percentage positive biopsy core, Gleason score, serum hemoglobin, stage, and extent of bone metastasis in univariate analysis. Pretreatment PSA (>50 ng/mL) and serum hemoglobin (<12 g/dL) were significant factors to predict failing to achieve a nadir PSA of 1.0 ng/mL or less in logistic regression analysis.
Conclusions:   A nadir PSA of 1.0 ng/mL can predict progression to HRPC after CAB. Pretreatment PSA and serum hemoglobin are significant predictors of failing to achieve a nadir PSA of 1.0 ng/mL or less.     

激素抵抗性前列腺癌(附39例报告)

目的探讨激素抵抗性前列腺癌的诊断和治疗,以提高其诊治水平。同时比较中国人和欧美人激素抵抗性前列腺癌生存期的差异。方法回顾性分析1995年6月～2004年10月39例激素抵抗性前列腺癌患者的临床资料。结果确诊激素抵抗性前列腺癌时,38例血PSA值较最低点均有不同程度升高,血PSA值0．2ng/ml～200ng/ml,平均(51．16±54．71)ng/ml,其中有4例血PSA值一直在4ng/ml以下,升高很少,主要靠转移灶来诊断。化疗是主要的治疗方法,常用的有磷酸雌二醇氮芥,磷酸雌二醇氮芥 足叶乙甙,环磷酰胺 足叶乙甙,磷酸雌二醇氮芥 环磷酰胺等。PSA有效率为44．4%～57．8%,平均有效时间3,8月～7．5月,软组织灶有效率为28．6%～50%。39例中已死亡21例,这21例诊断激素抵抗性前列腺癌后,中位生存期为16个月。结论绝大多数激素抵抗性前列腺癌患者可用PSA诊断和随访,但极少数患者PSA变化很小,需用癌灶和症状来随访。化疗是治疗激素抵抗性前列腺癌的主要方法,有一定的疗效。本组患者生存时间似较欧美患者长。     

Response to docetaxel/carboplatin-based chemotherapy as first- and second-line therapy in patients with metastatic hormone-refractory prostate cancer

OBJECTIVES

To evaluate the efficacy of docetaxel/carboplatin (DC)‐based chemotherapy as first‐ and second‐line chemotherapy for patients with hormone‐refractory prostate cancer (HRPC).

PATIENTS AND METHODS

We retrospectively identified all patients with HRPC treated with DC‐based chemotherapy at the Dana‐Farber Cancer Institute. Regimens either included estramustine (EDC) or not (DC). We identified patients who received EDC as first‐line chemotherapy and patients who received DC as second‐line or subsequent chemotherapy. Patients treated with EDC received 20–70 mg/m² docetaxel every 1–4 weeks, estramustine 140 mg three times daily and carboplatin (area under the curve, AUC), (4–6) every 3–4 weeks. Patients treated with DC received docetaxel 50–70 mg/m² and carboplatin AUC (4–6) every 3–4 weeks.

RESULTS

In all, the study included 54 patients; 24 received EDC and 30 DC (median age 62.8 and 66.9 years, respectively); their prostate‐specific antigen (PSA) level at the start of chemotherapy was 112.7 and 213.3 ng/mL, respectively. There were declines of ≥50% in PSA level in 88% and 20% in the two groups, respectively. The median overall survival was 17.7 and 14.9 months in the EDC and DC groups, respectively. The most common reversible grade 4 toxicity with either regimen was neutropenia (4% and 7% in EDC and DC, respectively).

CONCLUSIONS

DC‐based chemotherapy is well tolerated and active in HRPC. Adding carboplatin to docetaxel provides an additional activity in 20% of patients as a second‐line or subsequent chemotherapy.     

Docetaxel, with or without estramustine phosphate, as first-line chemotherapy for hormone-refractory prostate cancer: results of a multicentre, randomized phase II trial

OBJECTIVE

To report the results of a randomized phase II trial of docetaxel with and without estramustine phosphate (EP) in patients with hormone‐refractory prostate cancer (HRPC).

PATIENTS AND METHODS

Patients with progressive HRPC were randomized to receive docetaxel 70 mg/m² on day 1 (arm A), or docetaxel 70 mg/m² on day 2 plus oral EP three times daily, at a total daily dose of 840 mg, on days 1–5 (arm B). The primary objective of the trial was to evaluate the activity of the treatments in terms of the response in prostate‐specific antigen (PSA) level.

RESULTS

Forty‐five of the 49 patients centrally randomized to arm A and 44 of the 46 in arm B were evaluable for activity. The PSA level decreased by ≥50% in 40% of the patients in arm A and in 75% of those in arm B. The median time to PSA progression was 20 weeks in arm A and 30 weeks in arm B. The patients in arm B had an improvement in pain over time.

CONCLUSION

These data support the existence of a possible advantage in combining docetaxel and EP, which should be verified in a specific randomized phase III study.     

Prospective study of estramustine phosphate for hormone refractory prostate cancer patients following androgen deprivation therapy

INTRODUCTION: Estramustine phosphate (EMP) in combination with other cytotoxic agents has been widely used in clinical trials as an anti-tumor agent for the treatment of hormone-refractory prostate cancer (HRPC). However, few prospective studies have considered the efficacy of EMP monotherapy for HRPC patients following androgen-deprivation therapy (ADT), given the availability of methods to measure prostate-specific antigen (PSA) levels in the serum. We therefore initiated a prospective study to determine whether EMP is efficient for HRPC following ADT using changes in PSA levels as the major endpoint. METHODS: After a diagnosis of anti-androgen withdrawal syndrome had been excluded, 34 patients with HRPC who showed an elevated serum PSA level in 3 or more sequential tests following ADT were treated orally with 560 mg/day of EMP. The clinical stage and the median PSA value for inclusion in the study were D2 and 25.9 (range 6.5-540.8) ng/ml, respectively. Treatment was continued until evidence of disease progression reappeared or until severe adverse effects appeared. RESULTS: Of the 34 patients enrolled, 29 were evaluated, while the other 5 (15%) patients were discontinued due to severe gastrointestinal side effects. Seven of the 29 patients (24%) showed a decrease of 50% or greater in serum PSA levels from the initially elevated values, with the median duration of PSA response being 8.0 (range 2.2-18.8) months. Baseline PSA, hemoglobin, alkaline phosphatase, lactate dehydrogenase, performance status, and length of time of initial hormonal treatment did not correlate with the PSA response. With a median follow-up time of 20.0 (range 3.2-45.6) months, the cancer-specific survival rate at 2 years was 83% in the PSA responders and 44% in the non-responders. The PSA response was correlated with cancer-specific survival (p = 0.029). CONCLUSIONS: Following ADT one quarter of HRPC patients responded to EMP, with more than 50% of patients showing a decrease in PSA levels and an enhanced survival rate.