Randomized, Double-Blind, Controlled Trial of Mitoxantrone/Prednisone and Clodronate Versus Mitoxantrone/Prednisone and Placebo in Patients With Hormone-Refractory Prostate Cancer and Pain

Ernst, D. Scott; Tannock, I. F.; Winquist, Eric; Venner, Peter; Reyno, Leonard; Moore, Malcolm J.; N., Kim; Ding, Keyue; Elliott, C. Gregory; Parulekar, Wendy R.

doi:10.1200/jco.2003.03.042

Cited by 227 publications

(122 citation statements)

References 21 publications

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“…This may also explain the pain control obtained in a randomised controlled trial that favoured intravenous pamidronate over oral clodronato. 20 The severity of the disease may be an important issue for debate when 21 who failed to show improvement in pain control after adjuvant clodronate vs mitoxantrone. He had an analgesic response (450% decrease in analgesic intake from baseline) in 33% out of 104 cases using clodronate and 30% in the placebo group.…”

Section: Discussionmentioning

confidence: 99%

Use of bisphosphonates can dramatically improve pain in advanced hormone-refractory prostate cancer patients

Rodrigues

Hering

Campagnari

2004

Prostate Cancer Prostatic Dis

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Introduction: Approximately 85% of patients who die from prostate cancer present the spread of bone metastases. Even though the radiological appearance of such metastases is osteoblastic, it is now known that these lesions coexist in their microenvironment with blastic and lytic lesions. The process always begins with bone lysis by osteoclast proliferation, paralleling nearby bone deposition. The treatment options are palliative and have poor clinical response with short-lived improvement. We have studied the clinical effect of bisphosphonates (clodronate) in the treatment of skeletal complications from prostate cancer. Materials and Methods:In an open prospective study, 58 patients with hormonerefractory prostate cancer with bone metastases were assessed from November 2000 to September 2003. The mean age was 70.3 y (range: 51-87 y). Bone scintigraphy, plain X-ray, assaying of prostate-specific antigen (PSA) and biochemical tests were requested before and following treatment. Patients were previously and subsequently assessed using the visual pain scale (0-10) and Karnofsky's index after the first and second intravenous (i.v.) infusions (administration of i.v. clodronate every 28 days) and every 4-6 months thereafter. Student's t-test was used for statistical analysis. Results: A total of 53 patients (91.4%) showed improvement after the first and/or second cycle, which persisted for at least 4 months (average 6.3 months). The averages on the visual pain scale improved from 7.4 (range: 2-8) to 2.4 (0-7) and on Karnofsky's index from 43 (32-58) to 73 (50-82). The radiological appearance of the metastases improved in 27 patients (46.5%) and there were few relapses (six patients; 10.3%). Conclusions: Clodronate was effective in the treatment of skeletal complications from prostate cancer. There was an objective response in 91.4% of treated patients, with a marked improvement in the subjective visual pain scale evaluation as well as on Karnofsky's index, with low side effects.

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Section: Discussionmentioning

confidence: 99%

Use of bisphosphonates can dramatically improve pain in advanced hormone-refractory prostate cancer patients

Rodrigues

Hering

Campagnari

2004

Prostate Cancer Prostatic Dis

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“…Most cancers are sensitive to treatment with hormones, although they all within time become insensitive or independent to hormone therapy. Similar to other solid tumours, PC has recently been found to be sensitive to treatment with chemotherapy [2]. Castrate refractory PC is defined as that state of disease, where clinical progression and/or increasing PSA is observed, in spite of castrate level of plasma-testosterone.…”

Section: Introductionmentioning

confidence: 99%

Phase I/II study on docetaxel, gemcitabine and prednisone in castrate refractory metastatic prostate cancer

Buch-Hansen

Bentzen

Hansen

et al. 2009

Cancer Chemother Pharmacol

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Purpose:We assessed the efficacy and toxicity of a fixed dose of docetaxel and prednisone, combined with escalating doses of gemcitabine (DGP). The primary endpoint was PSA response. Methods:Fifteen patients (pts) were enrolled in the phase I and 50 pts entered the phase II. Pts were given DGP, maximum of 8 courses, until progression or unacceptable toxicity. Docetaxel 75 mg/m 2 was administered intravenously day 1, gemcitabine was given day 1 and 8 in doses increasing from 600 to 1,000 mg/m 2 every third week. Pts had castrate refractory metastatic prostate cancer (CRMPC), adequate function of liver, kidney and bone marrow; ECOG performance status ≤2 and were chemotherapy-naïve. Results:Median age was 64 range (49-77). Twenty-one (42%) were PS 0, 26 (52%) were PS 1 and 3 (6%) were PS 2. The median pre-treatment PSA was 448 (12-4.580). No dose limiting toxicity was observed even with the highest dose level in the phase I part of the study. In the phase II part, PSA response was observed in 37(74%) pts. Twenty-four (48%) pts had measurable disease; 12 (50%) had partial remission, 5 (21%) had stable disease, 7 (29%) were not evaluable. Time to progression (TTP) was 7.9 months and overall survival (OS) was 13.9 months. Thirty-seven pts (74%) developed neutropenia, non-haematological toxicity was modest. Conclusions:The PSA response rate was promising and the toxicity of DGP was manageable; however OS was comparable to results of treatment with single agent docetaxel.

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“…Placebo-controlled trials with other bisphosphonates, including pamidronate and clodronate, have failed to demonstrate improvement in quality of life, pain scores, skeletal events, or survival in prostate cancer. 5,6 Endothelin-1 (ET1) is a secreted protein with a potent vasoconstrictive effect, found in the highest concentrations in seminal plasma. 7 ET1 exerts its effects through 2 receptors, ETa and ETb.…”

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confidence: 99%

Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer

Michaelson

Kaufman

Kantoff

et al. 2006

Cancer

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BACKGROUND. Metastatic prostate cancer is characterized by the presence of osteoblastic bone metastases. Bone metastases account for most of the morbidity from this disease. Inhibition of osteoclast activity with the potent bisphosphonate zoledronic acid reduces skeletal complications and decreases serum levels of biochemical bone turnover markers compared with placebo. Atrasentan is an investigational agent that inhibits endothelin‐1 receptor, resulting in decreased osteoblast activity. METHODS. The effects of atrasentan alone versus combination therapy with atrasentan and zoledronic acid were investigated on bone turnover markers in men with bone metastases from prostate cancer. Forty‐four men were randomized to receive either atrasentan alone or combination therapy, and 33 completed at least 12 weeks of treatment and were included in the primary analysis. RESULTS. Treatment with the combination resulted in significantly lower serum levels of N‐telopeptide, a marker of bone resorption, compared with treatment with atrasentan alone. There was no difference between groups in serum levels of bone‐specific alkaline phosphatase, a marker of bone formation, at 12 weeks. Commonly observed adverse effects were edema, rhinitis, fatigue, and shortness of breath, most of which were NCI CTC (version 3.0) Grade 1. No Grade 4 or 5 treatment‐related toxicities were observed. There was minimal clinical efficacy, with no objective responses and only 1 prostate‐specific antigen (PSA) response. CONCLUSIONS. There is no evidence for additive or synergistic effects of combination therapy with atrasentan and zoledronic acid on bone turnover markers in men with metastatic prostate cancer. Cancer 2006. © 2006 American Cancer Society.

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Randomized, Double-Blind, Controlled Trial of Mitoxantrone/Prednisone and Clodronate Versus Mitoxantrone/Prednisone and Placebo in Patients With Hormone-Refractory Prostate Cancer and Pain

Abstract: MP provides useful palliation in symptomatic men with HRPC. Clodronate does not increase the rate of palliative response or overall quality of life. Clodronate may be beneficial to patients who have moderate pain, but this requires further confirmation.

Cited by 227 publications

References 21 publications

Use of bisphosphonates can dramatically improve pain in advanced hormone-refractory prostate cancer patients

Use of bisphosphonates can dramatically improve pain in advanced hormone-refractory prostate cancer patients

Phase I/II study on docetaxel, gemcitabine and prednisone in castrate refractory metastatic prostate cancer

Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer

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