Effectiveness of taxanes-based chemotherapy against hormone-refractory prostate carcinoma

We performed an investigative and clinical study of docetaxel, and evaluated its efficacy against hormone-refractory prostate carcinoma (HRPC). In an in vitro experiment, docetaxel suppressed the human prostate cell line proliferation not only in an androgen-dependent cell line, LNCaP, but also in androgen-independent cell line, PC-3, in a dose-dependent manner. In an in vivo experiment applying an SCID mouse xenograft model with PC-3, docetaxel administration suppressed the tumor growth more than 95%. In a clinical study, eight cases were enrolled to low-dose (20 mg/m2/wk) weekly regimen and an other eight to high-dose (60 mg/m2/wk) administration of docetaxel every three weeks. A prostate specific antigen (PSA) decline of more than 50% were observed in 4 (50%) in the low-dose group and 5 (63%) in the high-dose group. The median time to progression and overall survival were 8.5 and 13.2 months in the low-dose group and more than 5.5 and 8.5 months in the high-dose one, respectively. This regimen was well tolerated, and the incidence of adverse effect was relatively low and light. Grade 3 neutropenia or leukocytopenia without fever was seen in three patients (18.8%). Only one patient required administration of granulocyte-colony stimulating factor because of neutropenia. No other grade 3 or 4 toxicity was observed. In conclusion, docetaxel-based chemotherapy was well tolerated and an active treatment for HRPC cases.     

Combination chemotherapy of docetaxel and UFT against hormone refractory prostate cancer

Docetaxel-based chemotherapy has been shown to be effective and well tolerated by Japanese patients with metastatic hormone-refractory prostate cancer (HRPC). This study was undertaken to assess the feasibility of docetaxel in combination with UFT (a combination of tegafur and uracil) in Japanese patients with HRPC. Ten patients aged 60-86 years with HRPC, who were pre-treated with hormonal therapy and expected to have more than 3 month survival and without major organ dysfunction, were included in this study. Treatment consisted of docetaxel 70 mg/m2 every 3 weeks plus UFT 260 mg/m2 /day. The primary end point was prostate-specific antigen (PSA) response, and the secondary end points included progression-free survival and toxicity. Nine patients were evaluable for efficacy and toxicity. The PSA response rate was 50% (1 CR and 4 PR). The most common non-hematological adverse events (of any grade) possibly related to treatment were neutropenia and anorexia. Grade 3/4 neutropenia and anorexia occurred in 50 and 20% of patients, respectively. The combination of docetaxel and UFT was feasible and active in Japanese patients with HRPC, with a manageable adverse-event profile similar to that observed in lung cancer chemotherapy.     

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.     

c-myc and bcl-2 Expression in supraglottic squamous cell carcinoma of the larynx.

OBJECTIVES: To evaluate the expression and prognostic significance of c-myc and bcl-2 oncogenes in squamous cell carcinoma (SCC) of the supraglottic larynx.Study design A retrospective cohort study of 61 patients who underwent surgery for SCC of the supraglottic larynx. Gender, age, TNM status, operative procedure, recurrences, and disease-free survival periods were recorded. METHODS: Hematoxylin and eosin-stained sections were reexamined for grade, invasion of tumor margins, lymphovascular invasion, lymphocyte infiltration, and perineural invasion. Immunohistochemical detection of c-myc and bcl-2 oncogenes was performed using monoclonal antibodies. RESULTS: No correlation was observed between either c-myc or bcl-2 and the clinical and histopathologic parameters. Survival analysis revealed no correlation of either c-myc (P = 0.88) or bcl-2 (P = 0.85) with the disease-free survival. c-myc expression was found to be significantly higher in bcl-2-positive patients (P = 0.001). CONCLUSION: Neither c-myc nor bcl-2 had shown to be prognostic factor for laryngeal carcinoma in this present study. Correlation between c-myc and bcl-2 supports the experimental observations of cooperative action between these two genes in tumorigenesis.     

Use of antisense oligonucleotides targeting the cytoprotective gene, clusterin, to enhance androgen- and chemo-sensitivity in prostate cancer

The discovery and targeting of genes mediating androgen-independence may lead to the development of novel therapies that delay progression of hormone refractory prostate cancer (HRPC). Clusterin is a stress-associated cell survival gene that increases after androgen ablation. Here, we review clusterins functional role in apoptosis and the use of antisense oligonucleotides (ASOs) against clusterin to enhance apoptosis in prostate cancer models. Immunostaining of tissue microarrays constructed from untreated and post-hormone treated radical prostatectomy specimens confirm that clusterin is highly expressed in virtually all HRPC cells, 80% of prostate cancer cells after neoadjuvant hormone therapy, but is low or absent (<20%) in untreated specimens. Overexpression of clusterin in LNCaP cells confers resistance to both androgen ablation and chemotherapy. Clusterin ASOs reduced clusterin levels in a dose-dependent and sequence-specific manner. Adjuvant treatment with murine clusterin ASOs after castration of mice bearing Shionogi tumors decreased clusterin levels, accelerated apoptotic tumor regression, and significantly delayed the recurrence of androgen-independent tumors. A human clusterin ASO targeting the translation initiation site and incorporating MOE-gapmer backbone (OGX-011) synergistically enhanced the cytotoxic effects of paclitaxel in human xenografts of prostate, renal cell, bladder, and lung cancer. Clusterin, is an anti-apoptosis protein upregulated in an adaptive cell survival manner by androgen ablation and chemotherapy that confers resistance to various cell death triggers. Suppression of clusterin levels using ASOs enhances cell death following treatment with androgen ablation, radiation, and chemotherapy.     

Anti-interleukin-6 monoclonal antibody induces regression of human prostate cancer xenografts in nude mice

BACKGROUND: Despite clinical associations and in vitro data suggesting that autocrine interleukin-6 (IL-6) production contributes to prostate cancer progression or chemotherapy resistance, there have been no reports that explore the role of IL-6 on prostate tumors in vivo. In the present study, we investigated the effect of IL-6 inhibition on the growth of human prostate cancer xenografts in nude mice. METHODS: To determine if autocrine IL-6 production contributes to prostate cancer growth and chemotherapy resistance in vivo, xenografts of a human prostate cancer cell line that produces IL-6 (PC-3) were established in nude mice. The mice were randomly divided into four treatment groups: (1) saline (vehicle control) + murine IgG (isotype control); (2) etoposide + murine IgG; (3) saline + anti-IL-6 monoclonal antibody; and (4) etoposide + anti-IL-6 monoclonal antibody. Tumors were measured twice weekly during a 4-week treatment period. At the conclusion of the study, all mice were sacrificed, and in addition to final volume, tumors were evaluated for the degree of apoptosis by TUNEL analysis. RESULTS: Anti-IL-6 Ab (with saline or etoposide) induced tumor apoptosis and regression ( approximately 60% compared to initial tumor size). Etoposide alone did not induce tumor regression or apoptosis in this animal model, and there was no synergy between anti-IL-6 Ab and etoposide. CONCLUSIONS: These studies suggest that IL-6 contributes to prostate cancer growth in vivo, and that targeting IL-6 may contribute to prostate cancer therapy.     

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.     

Docetaxel-based chemotherapy with zoledronic acid and prednisone in hormone refractory prostate cancer: Factors predicting response and survival

Objectives:   To evaluate the efficacy of docetaxel/prednisone and zoledronic acid in hormone refractory prostate cancer (HRPC) patients and to analyze prognostic factors predicting overall survival.
Methods:   Forty-four HRPC patients were given docetaxel (75 mg/m²), prednisone and zoledronic acid (4 mg) every three weeks. Overall and progression-free survival curves were calculated. Using the log–rank test, variables predicting overall survival (age, Gleason score, baseline prostate-specific antigen [PSA], percentage PSA decline, nadir PSA, number of chemotherapy cycles) were calculated.
Results:   Median age was 66 years and mean PSA 171.25 ng/mL. The average number of given cycles was 6.3. A good PSA response (>50% decline) was observed in 26/44 cases (59.1%). A total of 17/44 (38.6%) patients expired with a median overall survival of 62.4 weeks. Patients with a Gleason score less than 7, who received more than four cycles and with a more-than-50% decline in PSA had significantly better survival. Variables like age, baseline PSA and nadir PSA did not significantly affect survival.
Conclusion:   The combination of docetaxel/zoledronic/prednisone is safe and effective in the management of HRPC. Patients with a Gleason score <7, PSA decline >50% and those who receive more than four cycles have significantly better survival.     

Therapeutic options in androgen-independent prostate cancer: building on docetaxel

Of men with metastatic prostate cancer who undergo androgen ablation, 70-80% respond rapidly to therapy, as manifested by a reduction in prostate cancer-related symptoms and declines in serum prostate-specific antigen (PSA) level. Unfortunately, after a median of 18-24 months, nearly all patients with metastatic prostate cancer will progress to androgen independence. Until recently the standard of care for treating hormone-refractory prostate cancer (HRPCa) was the combination of mitoxantrone and prednisone, which palliated bone pain but did not extend survival. Two randomized trials with > 1700 patients showed for the first time a survival benefit for patients with HRPC treated with chemotherapy; when compared with mitoxantrone-based therapy, docetaxel based-therapy reduced the risk of death by 20-24%. Future trials in HRPC are attempting to improve the efficacy of docetaxel by incorporating new agents targeting angiogenesis, apoptosis, and signal transduction pathways; there is promising activity for these novel combinations in phase I and II studies. Concepts are also being refined about definitions of response and progressive disease, patient eligibility criteria, and the validity of surrogate markers of efficacy and survival, as shown by changes in PSA level.     

Patupilone (epothilone B, EPO906) inhibits growth and metastasis of experimental prostate tumors in vivo

BACKGROUND: Microtubule agents appear promising for the treatment of prostate cancer. Patupilone (epothilone B), a highly potent non-taxane microtubule stabilizing agent, was evaluated in models of androgen-independent prostate cancer. METHODS: Patupilone was administered to athymic mice bearing human prostate cancer xenografts (subcutaneous DU 145 and PC-3M, orthotopic PC-3M). RESULTS: One 4 mg/kg patupilone administration produced transient regression of DU 145 tumors, while two weekly administrations of 2.5 mg/kg produced stable disease followed by protracted regression, however with more pronounced body weight loss. Taxol (15 mg/kg every other day) weakly inhibited tumor growth, but with less body weight loss. Patupilone (5 mg/kg) produced protracted growth inhibition of subcutaneous PC-3M tumors, with transient body weight loss. In mice with orthotopic PC-3M tumors, 4 or 5 mg/kg/week patupilone impaired primary tumor growth, abrogated metastases and enhanced survival, with only transient body weight loss. CONCLUSIONS: These data suggest that patupilone holds promise for prostate cancer treatment.     

Current indications for chemotherapy in prostate cancer patients

Recently, data from two randomized studies, TAX327 and SWOG 9916, which compared docetaxel-based chemotherapy to mitoxantrone-based therapy, have demonstrated that treatment with docetaxel can prolong life in a statistically significant way in patients with hormone refractory prostate cancer (HRPC). In the TAX237 trial the median overall survival rates for patients treated with docetaxel every 3 wk was 18.9 mo, compared with 16.4 mo for the patients in the control arm (p=0.009). Patients treated with the combination of docetaxel and estramustine in the SWOG trial had a significant improvement in median survival (18 mo vs 16 mo, p=0.01), longer progression-free survival (6 mo compared with 3 mo, p<0.0001), and a 20% reduction in the risk of death. The optimal timing of docetaxel-based chemotherapy is still unknown because there are no prospective clinical trials indicating whether earlier treatment is more effective than delayed treatment. There are now increasing options also for second-line therapies in the palliative treatment of HRPC, and ongoing studies on new drugs such as satraplatin and ixabepilone will define the role of these agents in this setting. Preliminary neoadjuvant and adjuvant chemotherapy studies in high-risk prostate cancer patients have demonstrated that these approaches are feasible and do not add morbidity to surgery or radiotherapy, but their impact on survival still needs to be proven in randomized studies.     

Clinical trials of immunotherapy for advanced prostate cancer

There is a lack of effective therapeutic regimens for advanced hormone-refractory prostate cancer (HRPC). Recent combination regimens of chemotherapy have improved management of HRPC. Neither systemic chemotherapy nor radiation regimens have significantly improved survival. Conventional systemic cytokine therapy has had limited efficacy in the treatment of advanced prostate cancer patients and its toxicity is severe. Combinations of multiple biological response modifiers for treatment of this disease also have limited efficacy. Results from phase II trials have shown that the combination of interferon- and interleukin-2 therapy and the infusion of dendritic cells primed with peptides of prostate specific membrane antigen are promising. The former showed 31% response using the National Prostatic Cancer Project criteria, and the latter showed 27% of objective partial response with a reduction of >50% prostate specific antigen level. The toxicity of these two regimens was tolerated by patients. New approaches with tumor vaccines in conjunction with cytokine gene therapy have also been investigated. The clinical responses of these trials have been limited but promising. Immunotherapy may become an effective modality of prostate cancer treatment in the future.     

Combination chemotherapy with docetaxel and cisplatin in patients with hormone-refractory prostate cancer

We investigated the efficacy of docetaxel and cisplatin for hormone-refractory prostate cancer (HRPC). Thirteen patients with HRPC were treated with 30 mg/m2 docetaxel weekly for 3 weeks and 70 mg/m2 cisplatin on day 1. Treatment was repeated every 21 days. They received 2 cycles and were evaluated for the responses to serum prostate-specific antigen (PSA) and tumor size. Ten (77%) of the 13 patients showed a 50% or greater decrease in PSA with a median time to progression of 3 months. One of the 2 patients with measurable soft tissue disease showed a reduction in disease. No severe toxicity of this regimen was observed. Combination chemotherapy with docetaxel and cisplatin in patients with HRPC was well tolerated and efficatious with a significant decrease in serum PSA and measurable disease.     

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.     

Combination chemotherapy with docetaxel, estramustine and suramin for hormone refractory prostate cancer

PURPOSE: To investigate more effective chemotherapy against hormone refractory prostate cancer (HRPC) with the combination of estramustine (EM), docetaxel, and suramin. PATIENTS AND METHODS: A total of 42 patients with symptomatic, progressive HRPC were included in this study. We evaluated the activity of the following schedule: EM 10 mg/kg orally daily on Days 1 to 21 every 28 days, docetaxel 70 mg/m(2) IV on Day 2 every 28 days and a total doses of 2150 mg of suramin in every cycle. Treatment was continued until disease progression or excessive toxicity. RESULTS: Median follow-up was 23.4 months. A median of 8.8 consecutive cycles was administered per patient. In the 25 patients with lymphadenopathy, there were three (12%) complete and 18 (72%) partial responses for a measurable disease response rate of 84%. Levels of prostatic specific antigen (PSA) decreased by greater than 50% in 100% of patients and by greater than 90% in 76.2%. The median time to progression was 57 weeks and median overall survival was 132 weeks. A decline in PSA of > or =50% lasting > or =30 days was significantly associated with a prolonged median time to progression and median overall survival. Tumor volume reduction and/or antitumor treatment effects were observed in 88% of patients. A significant decrease in mean pain score from 7.8 (range, 6-10) to 2.2 (range, 0-4) (P < 0.001) was achieved in 78%. Of patients with bone metastasis, 30.5% demonstrated a partial response. The mean Eastern Cooperative Oncology Group (ECOG) performance score improved from 2.8 to 1.5 at the end of treatment period. There was no therapy-related death. The predominant toxicities were Grade 3 or 4 leukopenia in 33.3%, anemia in 21%, thrombocytopenia in 21.4%, cardiac ischemia in 4.7%, and rash in 4.7%. CONCLUSION: The combination of docetaxel, EM, and suramin is a highly effective regimen for HRPC. Although hematologic and gastrointestinal toxicities were modest, these were easily managed medically.     

Calcitriol (1,25-dihydroxycholecalciferol) potentiates activity of mitoxantrone/dexamethasone in an androgen independent prostate cancer model

PURPOSE: Mitoxantrone combined with glucocorticoids is widely used for androgen independent prostate cancer. It is well tolerated, reduces prostate specific antigen, diminishes pain and improves quality of life. Calcitriol (1,25-dihydroxycholecalciferol) inhibits proliferation, modulates cell cycle progression, induces apoptosis and potentiates the cytotoxic effects of a number of agents. Glucocorticoids potentiate the antitumor effects of calcitriol and blunt calcitriol induced hypercalcemia. Therefore, we investigated the effect of calcitriol on the antitumor efficacy of mitoxantrone and dexamethasone or mitoxantrone/dexamethasone in the PC-3 androgen independent prostate cancer model. MATERIALS AND METHODS: We treated PC-3 cells in vitro with various concentrations of mitoxantrone/dexamethasone with and without calcitriol, and assessed growth inhibition by crystal violet assays. We similarly treated mice bearing PC-3 xenografts and performed excision clonogenic assays and tumor outgrowth studies to assess antitumor activity. RESULTS: Calcitriol significantly increased mitoxantrone/dexamethasone mediated growth inhibition in PC-3 cells (p <0.05). Median dose effect analysis indicated that calcitriol is synergistic with mitoxantrone. Adding calcitriol to mitoxantrone/dexamethasone significantly reduced the surviving fraction per gm. tumor compared with mitoxantrone/dexamethasone or untreated controls (p <0.03). Calcitriol plus mitoxantrone/dexamethasone also caused significantly greater tumor regression in PC-3 xenografts compared with treatment with mitoxantrone/dexamethasone or untreated controls (p <0.02). CONCLUSIONS: These preclinical data demonstrate that calcitriol increases the antitumor activity of mitoxantrone/dexamethasone in the PC-3 model system. This combination may be efficacious for prostate cancer.     

Docetaxel, vinorelbine, and zoledronic acid as first-line treatment in patients with hormone refractory prostate cancer: a phase II study

ObjectivesCombining antineoplastic agents is the key to improving the treatment options for men with hormone refractory prostate cancer (HRPC). The current study investigated the combination of docetaxel, vinorelbine, and zoledronic acid as a first-line treatment for HRPC.MethodsPatients were treated repeatedly with docetaxel (25 mg/mq) and vinorelbine (10 mg/mq) intravenously for three consecutive weeks followed by a 1-wk rest until disease progression or side effects. Zoledronic acid was administered every 4 wk. Changes in prostate-specific antigen (PSA) levels and objective responses were evaluated after two and three cycles, respectively. Toxicity and pain evaluation, based on pain intensity reduction and analgesic drug reduction, were assessed every cycle.ResultsForty men with HRPC (median age: 65 yr) were treated. Among 38 evaluable patients, complete and major PSA responses were observed in seven (18%) and 12 (32%), respectively; a partial objective response was observed in six of 15 (40%) patients with measurable disease. Neutropenia (25%) was the most important grade 3 haematologic toxicity observed. Only three patients (7.5%) reported grade 4 neutropenia. Nineteen patients (47.5%) achieved a reduction of pain intensity and analgesic drug use after two cycles. Median progression-free survival was 7 mo (95% CI: 2–10 mo), with a median overall survival of 17 mo (95% CI: 6–22 mo).ConclusionsThe combination of docetaxel, vinorelbine, and zoledronic acid is associated with improvement in biochemical, objective, and pain responses and is well tolerated as a first-line treatment for HRPC.     

Targeting Bcl-2 with oblimersen for patients with hormone refractory prostate cancer

Patients with metastatic hormone refractory prostate cancer (HRPC) have limited treatment options and new therapies are needed. Advances in the understanding of the molecular mechanisms implicated in prostate cancer progression have identified many potential therapeutic gene targets including Bcl-2, an important pro-survival regulator of apoptotic cell death. Bcl-2 is overexpressed in a variety of human malignancies including prostate cancer where it has also been associated with androgen independent progression and treatment resistance. Oblimersen is a phosphorothioate antisense oligonucleotide complimentary to the Bcl-2 mRNA and a potent inhibitor of Bcl-2 expression which in pre-clinical testing can significantly enhance the therapeutic effect of chemotherapy, hormone and radiation therapy. Clinical trials evaluating oblimersen in combination with chemotherapy in a variety of cancers have shown good tolerability and promising response rates. Randomized trials are required to determine if oblimersen can enhance the effectiveness of docetaxel in patients with HRPC.     

Combined modality radioimmunotherapy for human prostate cancer xenografts with taxanes and 90yttrium-DOTA-peptide-ChL6.

BACKGROUND: Therapy for prostate cancer in the PC3 tumor-nude mouse model with 90yttrium-(90Y)-DOTA-peptide-ChL6 (5.55 MBq;150 microCi) has resulted in durable responses. To make radioimmunotherapy (RIT) more effective, the radiation-enhancing drugs Taxol (paclitaxel) and Taxotere (docetaxel) were tested for synergy with 90Y-DOTA-peptide-ChL6. METHODS: Nude mice bearing human prostate cancer PC3 xenografts were treated with 90Y-DOTA-peptide-ChL6 (2.78 MBq; 75 microCi) and after 24 hr, paclitaxel (300 or 600 microg), or docetaxel (300 microg). Tumor size, survival, blood counts, and pharmacokinetics were monitored to assess efficacy and toxicity. RESULTS: Docetaxel plus RIT had a 67% cure rate, whereas no mice were cured among the RIT alone, chemotherapy alone, or untreated controls. Paclitaxel (600 microg) plus RIT produced a 100% response rate with 20% cures. Average tumor volume was reduced to a greater degree in the combined modality radioimmunotherapy (CMRIT) groups compared to controls and the anti-tumor response was durable. Myelotoxicity in the combined modality groups (RIT plus paclitaxel or RIT plus docetaxel) were similar to groups receiving the same dose of RIT alone. CONCLUSION: In the PC3-tumor nude mouse model, addition of paclitaxel or docetaxel to 90Y-DOTA-peptide-ChL6, in doses clinically achievable in humans, provided therapeutic synergy without increased or excessive toxicity.     

What is the real impact of bone pain on survival in patients with metastatic hormone‐refractory prostate cancer treated with docetaxel?

OBJECTIVES

To determine the benefit of starting early chemotherapy with docetaxel (the recommended first‐line treatment) for patients with asymptomatic metastatic hormone‐refractory prostate cancer (HRPC).

PATIENTS AND METHODS

Data were analysed from 145 patients with HRPC treated with chemotherapy between February 2000 and June 2002 in one French centre. Eligible patients were categorized into three groups according to the bone pain at baseline, i.e. minimal/no pain, mild, and moderate/severe pain. The primary endpoint was the effect of bone pain on overall survival (OS).

RESULTS

Docetaxel was administered to 67% of patients. The risk of death was 1.56 and 2.11 times higher for patients with mild or moderate/severe pain than for those with minimal/no pain (P = 0.027). The median (95% confidence interval (CI)) OS was 23.1 (18.5–27.6) and 14.1 (8.9–19.2) months (P = 0.001, log‐rank‐test) for patients with minimal pain or no pain treated with docetaxel‐based chemotherapy compared with mitoxantrone, respectively. The prostate‐specific antigen doubling time (PSA‐DT) had a significant effect on OS in patients with minimal/no pain, with a median of 32.4 and 16.5 months for a PSA‐DT of ≥45 and <45 days, respectively (P < 0.001).

CONCLUSIONS

Our results suggest that patients with HRPC and minimal or no bone pain could have better survival than those with mild pain or moderate to severe pain, independent of the treatment administered. In addition, patients with HRPC and minimal or no bone pain treated with docetaxel‐based chemotherapy have a significantly better OS than those treated with mitoxantrone. The PSA‐DT can be useful to identify asymptomatic patients who are candidates for early treatment.