Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preclinical studies with zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ) have shown its potential in malignant bone disease. Clinical studies in the treatment of hypercalcemia of malignancy have been completed, as have phase I and II trials in patients with cancer and pre-existing bone metastases. Three randomized, double-blind, controlled phase III trials are ongoing to establish the efficacy and safety of zoledronic acid in the treatment of osteolytic and osteoblastic bone metastases. In one study, 4 mg zoledronic acid is compared with the standard therapy, 90 mg pamidronate, in treatment of osteolytic lesions in patients with breast cancer and multiple myeloma. Two other studies, one in patients with prostate cancer and bone metastases and another in patients with non-small cell lung cancer and other tumor types, are placebo-controlled. The primary end point in all three studies is the frequency of skeletal complications resulting from bone metastases. Adjuvant trials that assess the ability of zoledronic acid to prevent or reduce the incidence of bone metastases in patients at high risk for future skeletal metastasis are also planned or ongoing. The rationale and design of these ongoing and planned studies is discussed.
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PMID:The role of zoledronic acid in cancer: clinical studies in the treatment and prevention of bone metastases. 1134 60

Bisphosphonates (BPs) are potent inhibitors of osteoclast-mediated bone resorption, and it is well accepted that tumor cells in bone, especially breast cancer and myeloma cells, can stimulate osteoclast formation and activity leading to the release of growth factors or cytokines, which will further stimulate cancer cells' growth and their secretion of osteolytic factors. BPs are now the standard treatment for cancer hypercalcemia, for which a dose of 90 mg of pamidronate or 1500 mg of clodronate is recommended; the former compound is more potent and has a longer lasting effect. Repeated pamidronate infusions exert clinically relevant analgesic effects in more than half of patients with metastatic bone pain. Recent data suggest that non-responding patients should perhaps be treated with higher doses. The optimal dose actually remains to be defined, especially as it is thought that it is probably a function of the disease stage. Regular pamidronate infusions can also achieve a partial objective response according to conventional UICC criteria and they can almost double the objective response rate to chemotherapy. Lifelong administration of oral clodronate to patients with breast cancer metastatic to bone reduces the frequency of morbid skeletal events by more than one-fourth. Two double-blind randomized placebo-controlled trials comparing monthly 90 mg pamidronate infusions to placebo infusions for 1-2 years in addition to hormone or chemotherapy in patients with at least one lytic bone metastasis have shown that the mean skeletal morbidity rate could be reduced by 30-40%. The results obtained with intravenous BPs are generally viewed as better than those obtained with oral clodronate. However, preference can be given to the oral route when BPs are started early in the process of metastatic bone disease in a patient receiving hormone therapy. According to the recently published ASCO guidelines, pamidronate 90 mg i.v. delivered over 2 h every 3-4 weeks can be recommended in patients with metastatic breast cancer who have imaging evidence of lytic destruction of bone and who are concurrently receiving systemic therapy with hormonal therapy or chemotherapy. Furthermore, the ASCO Panel considered it "reasonable" to start i.v. BPs in women with localized pain whose bone scans were abnormal and plain radiographs normal, but not when an abnormal bone scan is asymptomatic. The pertinence of these criteria is discussed below. Because BPs are providing supportive care, reducing the rate of skeletal morbidity but evidently not abolishing it, the criteria for stopping their administration have to be different from those used for classic antineoplastic drugs, and they should not be stopped when metastatic bone disease is progressing. However, criteria to determine whether and for how long an individual patient benefits from their administration are lacking. New biochemical markers of bone resorption might help identify those patients continuing to benefit from therapy. Even better results have been achieved in patients with multiple myeloma, and the general consensus is that BPs should be started as soon as the diagnosis of lytic disease is made in myeloma patients. On the other hand, data are scanty in prostate cancer, but large-scale trials with potent BPs are ongoing or planned in such patients. Similar results to those achieved with pamidronate have been obtained with monthly 6-mg infusions of the newer BP ibandronate in patients with breast cancer metastatic to bone. The tolerance of ibandronate could be better, and the drug has the potential to be administered as a 15- to 30-min infusion. Zoledronate can also be administered safely as a 15-min 4-mg infusion, and large scale phase III trials have just been completed. These newer BPs will simplify the current therapeutic schemes and improve the cost-effectiveness ratio; they also have the potential to improve the therapeutic efficacy, at least in patients with an aggressive osteolytic disease or when given as adjuvant therapy. For that matter, initial data with clodronate indicate that they have the potential to prevent the development of bone metastases, but the use of BPs in the adjuvant setting must still be viewed as experimental.
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PMID:Bisphosphonates for cancer patients: why, how, and when? 1213 23

The purpose of this report is to summarize information on drugs recently approved by the U.S. Food and Drug Administration. Three drugs have recently been approved: Gleevec (imatinib mesylate) at a starting dose of 400 or 600 mg daily for the treatment of malignant unresectable and/or metastatic gastrointestinal stromal tumors; Mesnex (mesna) tablets as a prophylactic agent to reduce the incidence of ifosfamide-induced hemorrhagic cystitis, and Zometa (zoledronic acid) for the treatment of patients with multiple myeloma and for patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. The recommended dose and schedule is 4 mg infused over 15 minutes every 3-4 weeks. These three drugs represent three different types of drug approval: Gleevec is an accelerated approval and supplemental new drug application (NDA); Mesnex tablets represent an oral formulation of a drug approved 14 years ago as an intravenous formulation, and Zometa represents a standard NDA for a noncytotoxic, supportive-care drug. Information provided includes rationale for drug development, study design, efficacy and safety results, and pertinent literature references.
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PMID:U.S. Food and Drug Administration drug approval summaries: imatinib mesylate, mesna tablets, and zoledronic acid. 1240 1

Bisphosphonates are the treatment of choice for lytic bone lesions associated with breast cancer. In contrast, bone lesions associated with prostate cancer are predominately osteoblastic. Zoledonic acid (Zol) is a new-generation bisphosphonate that is approximately 2-3 orders of magnitude more potent than pamidronate (Pam) in preclinical models and has demonstrated clinical efficacy in patients with both lytic and blastic lesions. Zoledonic acid (4 mg via 15 min infusion) every 3-4 weeks was directly compared to Pam (90 mg via 2 hr infusion) in 767 patients with breast cancer and bone metastases. The primary endpoint was the proportion of patients experiencing a skeletal-related event (SRE) over 13 months. Zoledonic acid was as effective as Pam, and the proportion of Zol-treated patients with an SRE (42% in the hormonal therapy strata and 44% in the chemotherapy strata) was comparable to the original studies comparing Pam to placebo. Among 371 breast cancer patients receiving hormonal therapy, the proportion of patients with an SRE was 47% for Pam vs. 57% for placebo (P = 0.057), and among 380 patients treated with chemotherapy, the proportions with an SRE were 43% for Pam vs. 56% for placebo (P = 0.008) at 12 months. Zoledronic acid (4 mg) has been compared to placebo in a randomized Phase III trial involving 422 men with hormone-refractory prostate cancer metastatic to bone. Zoledonic acid demonstrated a significant advantage over placebo for median time to first SRE (median not reached for Zol vs. 321 days for placebo; P = 0.011), the proportion of patients with an SRE over 15 months (33 vs. 44% for placebo; P = 0.021), and mean skeletal morbidity rate (number of SREs/time, 0.08 vs. 1.49 for placebo; P = 0.006). In addition, the effects of Zol were apparent early. At 3 months, only 12% of Zol-treated patients had an SRE vs. 23% for placebo (P = 0.003), and at 6 months, the proportions were 21 vs. 31% for placebo (P = 0.025). In contrast, a previous study of Pam in 236 prostate cancer patients found that Pam was no more effective than placebo in reducing bone pain or SREs over 6 months. In these studies, Zol was well tolerated with a safety profile similar to other IV bisphosphonates. In conclusion, Zol is the first bisphosphonate to demonstrate efficacy in both lytic and blastic disease. The unique properties of this novel agent should be further explored in future clinical trials.
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PMID:The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate. 1244 49

Bone metastases are a common feature of a variety of solid tumors and are associated with substantial skeletal morbidity, including severe bone pain and pathologic fractures. Treatment with bisphosphonates, primarily pamidronate, is the current standard of care for patients with breast cancer and multiple myeloma who have predominantly osteolytic lesions. However, until recently no bisphosphonate had demonstrated efficacy in patients with osteoblastic lesions, which are common during the progression of prostate cancer and other solid tumors. Zoledronic acid, a potent, new-generation, nitrogen-containing bisphosphonate, has demonstrated significant benefits for patients with bone metastases resulting from a broad range of primary tumors, including multiple myeloma and breast, lung, kidney, and prostate cancers, and other solid tumors. Benefits include a decreased incidence of pathologic fractures and longer time to the first skeletal complication. Zoledronic acid is the first and only bisphosphonate to be proved effective in patients with all types of bone lesions, from osteolytic to osteoblastic, and therefore represents an important therapeutic advancement in the treatment of bone metastases.
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PMID:Broad clinical activity of zoledronic acid in osteolytic to osteoblastic bone lesions in patients with a broad range of solid tumors. 1256 47

Osteoporosis is an important complication of androgen deprivation therapy for prostate cancer. Androgen deprivation therapy either by bilateral orchiectomies or treatment with a gonadotropin-releasing hormone agonist decreases bone mineral density (BMD) and increases the risk of fracture. Dietary factors and lifestyle may contribute to bone loss. There are limited prospective data about treatment or prevention of osteoporosis in men with prostate cancer and many recommendations are based on studies of postmenopausal osteoporosis. Lifestyle modification including smoking cessation, moderation of alcohol consumption, and regular weight bearing exercise should be encouraged. Supplemental calcium and vitamin D are recommended. Additional treatment may be warranted for men with osteoporosis, fractures, or high rates of bone loss during androgen deprivation therapy. Recent studies have evaluated the efficacy of bisphosphonates to prevent bone loss during androgen deprivation therapy. Pamidronate (pamidronic acid), a second-generation bisphosphonate, prevents bone loss in the hip and spine during androgen deprivation therapy. Zoledronic acid, a more potent third-generation bisphosphonate, not only prevents bone loss but also increases BMD in the hip and spine. Alendronate (alendronic acid) is approved for the treatment of osteoporosis in men although its efficacy and that of other oral bisphosphonates has not been evaluated in men receiving androgen deprivation therapy. Additional prospective studies are needed to evaluate the long-term effects of bisphosphonates on fracture risk and disease-related outcomes.
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PMID:Bisphosphonates to prevent osteoporosis in men receiving androgen deprivation therapy for prostate cancer. 1257 98

Prostate cancer often metastasizes to bone during disease progression. Patients who develop bone metastases have a high risk of developing skeletal complications, including pathologic fractures, spinal cord compression, and severe bone pain. Bisphosphonate therapy is widely used for the prevention of skeletal complications in patients with bone lesions from multiple myeloma and breast cancer. Until recently, however, no bisphosphonate had ever shown objective clinical benefit in patients with prostate cancer and osteoblastic bone lesions. A recent multicenter, randomized, placebo-controlled trial found zoledronic acid (4 mg) to be a safe and effective therapy in patients with bone metastases from hormone-refractory prostate cancer. Zoledronic acid significantly reduced the proportion of patients who experienced skeletal complications and extended the time to first skeletal complication. Further, zoledronic acid significantly reduced the risk of skeletal complications over this 15-month study and provided consistent reductions in bone pain that were significant at the 3- and 9-month time points compared with placebo. These results suggest that zoledronic acid may become an important advancement in the care of patients with prostate cancer metastatic to bone. The role of zoledronic acid in the treatment of patients with prostate cancer continues to evolve.
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PMID:Treatment of bone complications in advanced prostate cancer: rationale for bisphosphonate use and results of a phase III trial with zoledronic acid. 1258 91

Metastasis to bone is a common feature in advanced prostate cancer patients. Current treatments, while effective in suppressing tumour growth and relieving tumour associated bone pain, do not provide long term remission or 'cure' for the disease. A greater understanding of prostate cancer metastasis is required if new treatment strategies are to be developed. Growth of tumour foci in skeletal sites is a major cause of morbidity in advanced prostate cancer and has required the development of specialised approaches to treatment, including the use of bisphosphonates. These drugs inhibit tumour induced osteoclastic bone resorption, thereby preventing skeletal related events and treatment induced bone loss. Zoledronic acid is currently the only bisphosphonate with proven benefit in prostate cancer. Bisphosphonates may also modify the bone microenvironment so that it becomes less favourable for the growth and survival of metastases. The most recent developments in our understanding of the advantages for growth and survival gained by metastatic prostate cancer cells in the skeleton are reviewed, along with the clinical evidence supporting the use of bisphosphonates in advanced prostate cancer.
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PMID:Pathophysiology of bone metastases from prostate cancer and the role of bisphosphonates in treatment. 1278 13

Osteoporosis is an important and preventable adverse effect of androgen deprivation therapy for prostate cancer. Androgen deprivation therapy by either bilateral orchiectomies or administration of a gonadotropin-releasing hormone agonist decreases bone mineral density and increases fracture risk. Treatment-related osteoporosis can be prevented by intermittent administration of either intravenous pamidronate or zoledronic acid. Pamidronate (60 mg intravenously every 3 months) prevents bone loss during androgen deprivation therapy. Zoledronic acid (4 mg intravenously every 3 months) not only prevents bone loss but also increases bone mineral density. Alendronate and other oral bisphosphonates may be effective but have not been evaluated in men with castrate testosterone levels. Oestrogen replacement therapy and treatment with selective ooestrogen receptor modulators may prevent bone loss during androgen deprivation therapy. Bicalutamide (150 mg daily) monotherapy increases serum ooestrogen levels and maintains bone mineral density.
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PMID:Management of treatment-related osteoporosis in men with prostate cancer. 1278 15

Zoledronic acid is a potent, third generation, nitrogen-containing bisphosphonate, licensed for the management of skeletal metastases and hypercalcaemia of malignancy, both of which cause considerable morbidity. In the preclinical setting, zoledronic acid has demonstrated superior potency regarding inhibition of osteolysis and reduction of hypercalcaemia as compared with other bisphosphonates. Clinical trials have indicated that zoledronic acid is superior to pamidronate in suppressing osteolysis and in reducing hypercalcaemia of malignancy. Its main mechanism of action is induction of osteoclast apoptosis through inhibition of the mevalonate pathway. Zoledronic acid has also demonstrated direct anti-tumour activity both in vitro and in animal models, suggesting it may be of benefit in preventing the formation of bone metastases. Clinical trials are in progress, assessing the benefit of zoledronic acid in the adjuvant setting in both breast and prostate cancer.
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PMID:The use of zoledronic acid in the management of metastatic bone disease and hypercalcaemia. 1452 88


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