Serum tartrate-resistant acid phosphatase 5b (TRACP 5b) as a marker of skeletal changes in prostate cancer

Skeletal metastases are a significant problem in prostate cancer (PC). The patients are also exposed to treatment-related skeletal changes. This cross-sectional study evaluated a marker of bone resorption, TRACP 5b in relation to the standard analyte total alkaline phosphatase (tALP) as a marker of skeletal changes. Serum levels of TRACP 5b, tALP and PSA were measured in 130 prostate cancer patients. Comparison was made between patients with (BM+, n = 25) and without (BM-, n = 105) skeletal metastases, and between those treated with (n = 64) or without (n = 66) androgen deprivation (AD). Sensitivities and specificities were calculated for each marker and diagnostic accuracy was evaluated by ROC curve analysis. ROC curves indicated the superior accuracy of tALP, whereas TRACP 5b and PSA were comparable. With tALP the best combination of sensitivity (96%) and specificity of (91%) was reached at a cut-off point 224 U/L, the corresponding values were for TRACP 5b sensitivity (76%), specificity (89%) with a cut-off point 4.89 U/L, and for PSA sensitivity (65%), specificity (81%) at 23 ng/L for skeletal metastases. Patients treated with AD showed with increasing duration an increase in TRACP 5b values. TRACP 5b was less specific than tALP as a marker of skeletal metastases. TRACP 5b may have a role in the diagnostics of skeletal changes in PC with a focus on treatment-related skeletal changes.     

A case of hormone/docetaxel-refractory prostate cancer in which PSA level decreased after docetaxel+zoledronic acid treatment

The patient was a 63-year-old man who had a recurrence and bone metastasis of prostate cancer after total prostatectomy. He was diagnosed with prostate cancer refractory to hormones. Subsequently, the PSA level decreased after docetaxel therapy, but then gradually increased. Thus, he was diagnosed with bone metastasis of prostate cancer refractory to therapy with hormones or docetaxel. The PSA level decreased after the start of therapy with docetaxel+ zoledronic acid. Zoledronic acid seems to be effective not only for the prevention but also for the treatment of skeletal related events(SRE)in patients with prostate cancer with bone metastases.     

The relative use of eight collagenous and noncollagenous markers for diagnosis of skeletal metastases in breast, prostate, or lung cancer patients.

The present study was sought to assess the relative use of eight biomarkers for the detection of bone metastases in cancer forms frequently spreading to the skeleton. Participants were 161 patients with either breast, prostate, or lung cancer. The presence and extent of bone metastases was assessed by imaging techniques (computer tomography and/or magnetic resonance imaging) and Technetium-99m scintigraphy. Serum or urinary level of the bone resorption markers (alphaalphaCTX, betabetaCTX, NTX, and ICTP), formation marker (BSAP), and osteoclastogenesis markers (osteoprotegerin, RANKL, and TRAP5b) was measured by commercially available immunoassays. When assessed on a group basis, all biomarkers, except for osteoprotegerin and RANKL, were significantly elevated in patients compared with those without bone metastases (P<0.05). Biomarkers had greater diagnostic value in breast and prostate cancer patients, yet alphaalphaCTX, NTx, and ICTP were able to discriminate lung cancer patients with or without bone metastases (P<0.05). Strong linear associations were seen between the extent of skeletal infiltration and levels of the different biomarkers, except for osteoprotegerin and RANKL. Furthermore, all biomarkers (except for osteoprotegerin and RANKL) were indicative at the early stage of skeletal involvement (one to five metastases). When expressing sensitivity as the percentage increase in biomarker level relative to patients without bone metastases, alphaalphaCTX showed the largest relative increases at each stage of the metastatic disease. These results suggest that closer monitoring of cancer patients with serial measures of biomarkers might facilitate the timely diagnosis of skeletal metastases.     

Weekly docetaxel/estramustine phosphate in patients with increasing serum prostate- specific antigen levels after primary treatment for prostate cancer: a phase II trial of the Minnie Pearl Cancer Research Network

Purpose

Docetaxel alone or in combination with estramustine prolongs survival in patients with metastatic hormone-refractory prostate cancer. The role of chemotherapy is undefined in the treatment of patients who develop an increasing serum prostate-specific antigen (PSA) level after primary therapy but have no detectable metastases. This phase II study was performed as a preliminary evaluation of the feasibility and efficacy of weekly docetaxel/estramustine in patients with prostate cancer and increasing serum PSA levels.

Patients and Methods

Between March 2001 and September 2003, 34 patients entered this phase II trial. All patients had biopsy-proven adenocarcinoma of the prostate and had increasing PSA levels but no clinically or radiographically detected metastases after primary therapy. All patients received docetaxel 35 mg/m² intravenously on days 1, 8, and 15 and estramustine phosphate 140 mg 3 times daily for 7 doses, beginning the evening before each dose of docetaxel. Treatment courses were repeated at 28-day intervals, and responding patients received a total of 6 courses.

Results

Thirty-one patients (91%) completed 6 courses of treatment. Thirty-two of 33 evaluable patients (97%) had a decrease in serum PSA level of > 50% during treatment, and 27 patients (82%) had normalization of serum PSA level. The median progression-free survival was 28 months, with 33% of patients progression free at 3 years. This treatment regimen was well tolerated with no myelosuppression-related complications or uncommon grade 3 nonhematologic toxicity.

Conclusion

Treatment with weekly docetaxel and estramustine is feasible and active in patients with prostate cancer and increasing serum PSA levels. However, the benefit of early treatment versus treatment when clinical metastases are detected requires demonstration in a randomized phase III trial.     

Evaluation of two serum isoenzyme phosphatases as bone metastasis markers

Serum activities of bone alkaline phosphatase (b-ALP) and of tartrate resistant acid phosphatase (tr-ACP) were evaluated in 271 cancer patients; 120 of them had bone metastases (BM) and 151 had none. Correlation coefficients, specificities, sensitivities, negative and positive predicting values were computed. They showed the important contribution that these isoenzymes can bring to the diagnosis of BM in 80 patients with prostate cancer, and to the followup of 191 patients with breast cancer. The assay results were analysed in parallel with bone scan and radiography. They were also compared to those of serum antigens: PSA and PAP for prostate cancer, and CEA and CA15.3 for breast cancer. These results clearly indicate that both isoenzymes are better correlated with BM than antigens, these antigens being markers of the whole tumor burden--primary tumor, metastases, recurrence--whereas b-ALP and tr-ACP are specific markers of bone metabolism.     

Osteonecrosis of the jaw in prostate cancer patients with bone metastases treated with zoledronate: a retrospective analysis

Osteonecrosis of the jaw (ONJ) has recently been reported as a potentially serious complication of prolonged treatment with intravenous bisphosphonates. We studied its frequency in prostate cancer patients receiving intravenous zoledronate. The medical and dental records of 52 consecutive patients with prostate cancer and bone metastases treated at our institute between January 2002 and October 2005 were reviewed. All patients received intravenous zoledronate 4 mg every 3 or 4 weeks and concomitant conventional prostate cancer treatments. We analysed the association of ONJ with the number of administrations of zoledronate and exposure to chemotherapy. At a median follow-up of 7 months (range 1-41) after the initiation of zoledronate, ONJ occurred in six patients (12%, 95% C.I. 5.4-23.0%). All six ONJ cases occurred after the 9^th administration of zoledronate. The median number of zoledronate administrations was 17 (range 9-24) and 8 (range 1-32) for patient developing and not developing ONJ, respectively (p =0.02). Chemotherapy with docetaxel was also associated with a strong, but not statistically significant, trend towards increased risk of ONJ (OR 3.8, 95% C.I. 0.4-35.6, p =0.24). The length of exposure to zoledronate was associated with an increased frequency of ONJ in prostate cancer patients. A possible role of chemotherapy with docetaxel as a cofactor for ONJ merits further evaluation.     

Bisphosphonate treatment inhibits the growth of prostate cancer cells

The presence of skeletal metastases in patients suffering from cancer leads to a variety of clinical complications. Bisphosphonates are a class of drugs with a potent bone resorption inhibition activity that have found increasing utility in treating and managing patients with metastatic bone disease. Several clinical trials have demonstrated that bisphosphonates have clinical value in the treatment and management of skeletal metastases derived from advanced prostate cancer. Currently, the mechanism(s) through which bisphosphonates exert their activity is only beginning to be understood. We have studied the effects of bisphosphonate treatment on the growth of prostate cancer cell lines in vitro. Treatment of PC3, DU145, and LNCaP cells with pamidronate or zoledronate significantly reduced the growth of all three cell lines. Using flow cytometry, pamidronate treatment (100 microM) was shown to induce significant amounts of cell death in all three cell lines studied. In contrast, treatment with zoledronate (100 microM) did not induce cell death, instead exerting dramatic effects on cell proliferation, as evidenced by a major increase in cells present in the G0-G1 and S phase. Although both drugs reduced prostate cancer cell growth in the presence of serum, zoledronate was more potent under these conditions, disrupting growth at doses as low as 25 microM in the presence of 5% fetal bovine serum. These results raise the intriguing possibility that the observed clinical utility of bisphosphonates in managing skeletal metastases may in part derive from direct inhibition of prostate cancer cell growth in the bone microenvironment.     

The prognostic impact of cytokeratin-positive cells in bone marrow of patients with localized prostate cancer

Our study evaluates the prognostic significance of the cytokeratin-positive mononuclear cells (CK+ cells) in the bone marrow (BM) and peripheral blood (PB) as detected by immunocytochemistry in patients with locoregionally confined prostate cancer. BM and PB samples were obtained from 66 newly diagnosed patients with T1-4pN0M0 prostate cancer. All samples were analyzed by standardized immunocytochemical methods (anticytokeratin mononuclear antibody; AE1/AE3) applying a negative immunomagnetic cell enrichment technique. A second sampling was obtained in 60 of the 66 patients >or=2 years after definitive radiotherapy. The median follow-up after high-dose radiotherapy of the patients was 65 months. For the analysis of the postradiotherapy clinical progression-free survival (PFS) treatment, failure was defined as pelvic tumor growth or development of distant metastases. At diagnosis CK+ cells were found in BM in 14 of 66 (21%) prostate cancer patients. This was not associated with an increased risk of progression. On the other hand, the presence of CK+ cells in 12 of 60 (20%) patients at the second BM aspiration was significantly related to a shorterPFS (p = 0.02). In the multivariate analysis, the presence of CK+ cells in the posttreatment BM did not remain as an independent variable of PFS assessment if posttreatment PSA was entered into the analysis. CK+ cells in PB were found in 12% of the patients. After therapy, none of the patients had detectable CK+ cells in PB. The presence of CK+ cells in the posttreatment but not in the pretreatment BM was associated with decreased PFS in patients irradiated for pelvis-confined nonmetastatic prostate cancer. Although this association was not retained in multivariate analysis, our observations indicate that the presence of CK+ cells after local therapy define a group of patients that have a high risk of developing distant metastases.     

手术去势间断联合多西他赛治疗晚期前列腺癌的疗效观察

目的：探讨手术去势间断联合多西他赛治疗晚期前列腺癌的临床疗效。方法收集75例转移性前列腺癌患者的病历资料。按照临床治疗方法不同将患者分为实验组和对照组,实验组28例,对照组47例。实验组患者采取睾丸切除去势＋多西他赛治疗,对照组患者采取睾丸切除去势治疗。观察患者的临床疗效、PSA水平、疼痛评分及不良反应发生情况,观察患者生活质量评分变化情况。结果实验组患者治疗后PSA水平、疼痛评分低于治疗前和对照组,差异有统计学意义（P＜0．05）;治疗后,对照组患者PSA水平、疼痛评分低于治疗前,差异有统计学意义（P＜0．05）。实验组患者红细胞、白细胞减少,恶心呕吐,骨髓抑制,手足综合征,脱发发生率显著低于对照组,差异有统计学意义（P＜0．05）。实验组患者生活质量评分高于治疗前和对照组,差异有统计学意义（P＜0．05）;治疗后,对照组患者生活质量评分高于治疗前,差异有统计学意义（ P＜0．05）。实验组患者中位生存时间、无进展生存时间、2年生存率均高于对照组,差异有统计学意义（P＜0．05）。结论手术去势间断联合多西他赛治疗晚期前列腺癌效果较好,能改善患者PSA水平、疼痛情况,减少不良反应发生情况,提高患者的生活质量,临床应用价值较高。     

The prognostic significance of prostate specific antigen in metastatic hormone-resistant prostate cancer.

Twenty-seven of 152 patients (18%) with progressing hormone resistant prostate cancer had normal serum levels of prostate specific antigen (PSA less than or equal to 10 micrograms l-1), when referred for secondary treatment. PSA was significantly correlated with the extent of skeletal metastases (R: 0.35) and the levels of hemoglobin (R: -0.19) and serum alkaline phosphatase (R: 0.30). In a multivariate Cox regression analysis the survival of the 152 patients was not correlated with the PSA level but with the patients performance status, the level of hemoglobin, and the time between primary hormone treatment and relapse. The lack of serum PSA to predict survival may be explained by a heterogenous composition of hormone resistant prostate cancer as regards differentiated and/or PSA producing vs undifferentiated and/or PSA non-producing cells.     

Efficacy of androgen deprivation therapy (ADT) in patients with advanced prostate cancer: association between Gleason score, prostate-specific antigen level, and prior ADT exposure with duration of ADT effect

BACKGROUND: The purpose of this study was to compare predictive factors for the efficacy of androgen deprivation therapy (ADT) in men with hormone-sensitive prostate cancer (HSPC) either with (M+) or without (M-) metastases. METHODS: A cohort of prostate cancer patients was identified from a medical oncology practice treated with ADT for presumed nonlocalized prostate cancer, evaluated the efficacy of ADT using prostate-specific antigen (PSA) time to progression (TTP) and compared factors associated with TTP in M- and M+ patients. RESULTS: In this 553 patient cohort 51% were M- and 49% M+. The median TTP on ADT for the M- group was 33.2 months, versus 15.9 months in the M+ group (P<.0001). In multivariate analyses, lower biopsy Gleason score (GS), the absence of metastases, and lower serum PSA at ADT initiation all were associated with the efficacy of ADT. The association between GS and TTP was confined to M+ patients, whereas the association between PSA at ADT initiation and TTP was confined to M- patients. Use of ADT as part of local treatment was associated with a shortened TTP in both groups (hazard ratio [HR], 1.45, 95% confidence interval [CI], 1.10-1.91). CONCLUSIONS: In this large, retrospective study of HSPC patients in a medical oncology practice treated with ADT for nonlocalized prostate cancer, we found factors predicting efficacy of this treatment differed based on whether metastases were present at ADT initiation. The use of ADT as a part of local therapy was associated with a significantly decreased TTP, regardless of metastatic disease status.     

Response in bone turnover markers during therapy predicts overall survival in patients with metastatic prostate cancer: analysis of three clinical trials

Background:

The bone-forming metastases of prostate cancer result from complex stromal–epithelial interactions within the tumour microenvironment. Autocrine–paracrine signalling pathways between prostate cancer epithelial cells, osteoblasts, and osteoclasts stimulate aberrant bone remodelling, and the activity of these three cell populations can be quantitatively measured using prostate-specific antigen (PSA), bone-specific alkaline phosphatase (BAP) and urine N-telopeptide (uNTx), respectively. The purpose of the present study was to test the hypothesis that serial measurements of BAP and uNTx during therapy would facilitate monitoring of disease activity and predict the overall survival (OS) in patients with metastatic prostate cancer receiving therapy.

Methods:

Radionuclide bone scan, PSA, BAP, and uNTx data were retrospectively analysed from three clinical trials in patients with metastatic prostate cancer conducted at our institution. Qualitative changes in bone scans and quantitative changes in PSA, BAP, and uNTx concentrations during therapy were correlated with OS.

Results:

Baseline levels of BAP, but not PSA, were prognostic for OS in both androgen-dependent and castrate-resistant disease. A reduction in PSA, BAP, uNTx, or BAP/uNTx on therapy was predictive of improved OS in both patient groups. Conversely, an increase in PSA, or BAP on therapy was predictive of worse OS in both patient groups. Baseline number of lesions and response on bone scan during therapy were neither prognostic nor predictive of OS in either patient group.

Conclusion:

These observations support the concept that serial measurements of bone turnover metabolites during therapy function as clinically informative predictive biomarkers in patients with advanced prostate cancer and skeletal metastases. PSA measurements and bone scans remain essential to monitor the overall disease activity and determine the anatomic distribution of skeletal metastases.     

89Strontium in bone metastases from hormone resistant prostate cancer: palliation effect and biochemical changes.

Hematological and biochemical parameters were evaluated in 31 patients receiving 150 MBq 89Strontium (89Sr) intravenously due to painful skeletal metastases from hormone resistant prostate cancer. Two and 3 months after the injection prostate specific antigen (PSA) had increased by a median of 36% and 100%, respectively, as compared to the pretreatment value whereas alkaline phosphatase (APHOS) had decreased by about 20% (median). The leucocyte and platelet counts were reduced by about 20-35%, without reaching grade greater than or equal to 2 toxicity. Pain relief was reported in 14 of 29 evaluable patients at 2 months and in 11 of 23 patients at 3 months. It is concluded that 89Sr represents a worthwhile therapeutic modality in the palliation treatment of patients with hormone resistant prostate cancer, though the biological significance of frequently increasing PSA and decreasing APHOS is not yet completely understood.     

Platelet-derived growth factor receptor inhibition and chemotherapy for castration-resistant prostate cancer with bone metastases.

PURPOSE: To further assess preclinical and early clinical evidence that imatinib mesylate, a platelet-derived growth factor receptor (PDGFR) inhibitor, modulates taxane activity in prostate cancer and bone metastases, a randomized study was conducted. EXPERIMENTAL DESIGN: Men with progressive castration-resistant prostate cancer with bone metastases (n = 144) were planned for equal randomization to i.v. 30 mg/m(2) docetaxel on days 1, 8, 15, and 22 every 42 days with 600 mg imatinib daily or placebo, for an improvement in median progression-free survival from 4.5 to 7.5 months (two-sided alpha = 0.05 and beta = 0.20). Secondary end points included differential toxicity and bone turnover markers, tumor phosphorylated PDGFR (p-PDGFR) expression, and modulation of p-PDGFR in peripheral blood leukocytes. RESULTS: Accrual was halted early because of adverse gastrointestinal events. Among 116 evaluable men (57 docetaxel + imatinib; 59 docetaxel + placebo), respective median times to progression were 4.2 months (95% confidence interval, 3.1-7.5) and 4.2 months (95% confidence interval, 3.0-6.8; P = 0.58, log-rank test). Excess grade 3 toxicities (n = 23) in the docetaxel + imatinib group were principally fatigue and gastrointestinal. Tumor p-PDGFR expression was observed in 12 of 14 (86%) evaluable bone specimens. In peripheral blood leukocytes, p-PDGFR reduction was more likely in docetaxel + imatinib-treated patients compared with docetaxel + placebo (P < 0.0001), as were reductions in urine N-telopeptides (P = 0.004) but not serum bone-specific alkaline phosphatase (P = 0.099). CONCLUSIONS: These clinical and translational results question the value of PDGFR inhibition with taxane chemotherapy in prostate cancer bone metastases and are at variance with the preclinical studies. This discordance requires explanation.     

Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: diagnostic and prognostic implications

Our aim was to assess the diagnostic accuracy of bone markers in serum of patients with prostate cancer (PCa) for early detection of bone metastases and their usefulness as predictors of PCa-caused mortality. In sera of 117 PCa patients (pN0M0, n = 39; pN1M0, n = 34; M1, n = 44), 35 healthy men and 35 patients with benign prostatic hyperplasia, bone formation markers [total and bone-specific alkaline phosphatase (tALP, bALP), amino-terminal procollagen propeptides of type I collagen (P1NP), osteocalcin (OC)], bone resorption markers [bone sialoprotein (BSP), cross-linked C-terminal (CTX) and cross-linked N-terminal (NTX) telopeptides of type I collagen, tartrate-resistant acid phosphatase isoenzyme 5b (TRAP)] and osteoclastogenesis markers [osteoprotegerin (OPG), receptor activator of nuclear factor kappaB ligand (RANKL)] were measured. tALP, bALP, BSP, P1NP, TRAP, NTX and OPG were significantly increased in PCa patients with bone metastases compared to patients without metastases. OPG showed the best discriminatory power to differentiate between these patients. Logistic regression analysis resulted in a model with OPG and TRAP as variables that predicted bone metastasis with an overall correct classification of 93%. Patients with concentrations of OPG, P1NP, tALP, bALP, BSP, NTX, TRAP and CTX above cut-off levels showed significantly shorter survival than patients with low marker concentrations. Multivariate Cox proportional hazards regression revealed that only OPG and BSP were independent prognostic factors for PCa-related death. Thus, the importance of serum OPG in detecting bone metastatic spread, alone or in combination with other bone markers, and predicting survival in PCa patients has been clearly demonstrated.     

Survival and PSA response of patients in the TAX 327 study who crossed over to receive docetaxel after mitoxantrone or vice versa

BackgroundThe TAX 327 study compared 3-weekly docetaxel, weekly docetaxel or 3-weekly mitoxantrone, each with prednisone, for 1006 patients with metastatic hormone-refractory prostate cancer. Survival and symptom control were superior following 3-weekly docetaxel as compared with mitoxantrone. At progression, many patients were treated with the other drug. Here, we provide a retrospective report of survival and prostate-specific antigen (PSA) response after second-line therapy.MethodsThe TAX 327 database provided information about treatment after progression on first-line therapy, and survival has been updated. Investigators were asked to provide information about crossover treatment and serial PSA values.ResultsWe identified 232 crossover patients. Median survival after crossover was 10 months and did not depend on direction of crossover. Data on PSA response are available for 96 patients: PSA response (≥50% reduction) occurred in 15% of 71 men receiving mitoxantrone after docetaxel and in 28% of 25 men receiving docetaxel after mitoxantrone. Median PSA progression-free survival was 3.4 months for mitoxantrone after docetaxel and 5.9 months for docetaxel after mitoxantrone.ConclusionsOne quarter of men received crossover therapy and survival was similar in the crossover groups. The PSA response rate to docetaxel after mitoxantrone was higher than that for mitoxantrone after docetaxel.     

血清缓激肽与前列腺癌的相关性研究

目的 探讨血清缓激肽在前列腺癌的诊断及鉴别诊断中的临床应用价值.方法 收集68例前列腺癌患者和32例前列腺增生患者,以同期体检的健康男性32例为对照组,收集其血清,酶联免疫吸附试验(enzymelinked immuno sorbent assay,ELISA)法检测血清中的缓激肽水平,比较各组血清缓激肽水平的差异以及前列腺癌患者在不同年龄、临床分期、病理分期(Gleason评分)、前列腺特异抗原(prostate specific antigen,PSA)水平、肿瘤体积以及骨转移、淋巴结转移、局部侵犯与否状态下血清缓激肽水平的差异.比较血清缓激肽与PSA联合诊断前列腺癌和PSA独立诊断前列腺癌的敏感度差异.结果 前列腺癌组血清缓激肽水平[(16.44 ±0.91) μg/L]低于对照组[(19.72±1.10) μg/L]和前列腺增生组[(20.93±1.80) μg/L],差异均具有统计学意义(均P＜0.05).在肿瘤体积较大的前列腺癌患者血清缓激肽水平较低(P＜0.05),而血清缓激肽水平在年龄、肿瘤临床分期、病理分期(Gleason评分)、PSA水平及骨转移、淋巴结转移、局部侵犯与否方面比较差异均无统计学意义(均P＞0.05).血清缓激肽与PSA联合诊断前列腺癌较单独诊断敏感度提高(P＜0.05).结论 前列腺癌患者血清缓激肽表达水平较低,且与肿瘤体积相关.血清缓激肽与PSA联合诊断前列腺癌敏感度较单独诊断高.     

The biochemical markers of bone remodeling in cancer patients with skeletal involvement

The report discusses a study of pyridinoline (Pyd) and deoxypyridinoline (Dpyd) as biochemical markers of bone resorption as well as total bone alkaline phosphatase level (APh) and that of its bone fraction as criteria of osteogenesis in skeletal lesions in breast, prostate and lung cancer and multiple myeloma. The investigation established a significantly enhanced Pyd and Dpyd excretion with urine and increased blood-serum APh levels in skeletal cancers (n = 271) as compared with healthy subjects (n = 173) and patients without bone metastases (n = 94). A case has been made for determination of total excretion of Pyd crosslinks of collagen to diagnose bone metastases. Most pronounced hyperenzymemia was found in prostate cancer which points to the leading role of APh as a bone metastasis marker. Pyd and Dpyd excretion and APh levels were significantly higher among patients multiple metastases with than in those with single bone metastases. The universality of pyridinoline crosslinks as skeletal damage markers has been confirmed by establishing a significant correlation between drug and therapeutic effect for Pyd and Dpyd only, in patients receiving ibandronate.     

Weekly docetaxel and zoledronic acid every 4 weeks in hormone-refractory prostate cancer patients

Objectives: To investigate the safety and efficacy of docetaxel and zoledronic acid in patients with hormone-refractory prostate cancer (HRPC), based on preclinical evidence of synergism between taxanes and bisphosphonates. Methods: Twenty-five patients with advanced HRPC received weekly docetaxel 30 mg/m²: in 18 patients with symptomatic bone metastases and normal renal function, docetaxel was combined with zoledronic acid, 4 mg i.v. every 4 weeks. Premedication consisted of intravenous dexamethasone before docetaxel. No oral steroids were given. Results: Overall, 12 patients (48%) had a PSA response (reduction of 50% or more compared to baseline). A PSA response was achieved in 8/18 patients (44%) receiving concomitant docetaxel and zoledronic acid, and in 7/12 patients (58%) receiving docetaxel and zoledronic acid as first-line therapy. The weekly schedule of docetaxel resulted in a mean received dose intensity of 26 mg/m²/week, or 87% of the planned dose intensity. Toxicity was mild and as expected for docetaxel. The median time to progression was 7 months, and the median overall survival was 16 months. Conclusions: Concomitant treatment with docetaxel and zoledronic acid is safe and has encouraging activity in HRPC. The combination should be evaluated in randomised clinical trials.