唑来膦酸在乳腺癌中抗肿瘤作用的研究进展

唑来膦酸(ZOL)是第三代双膦酸盐类药物的典型代表,在已上市的双膦酸盐类药物中应用最广泛、综合疗效最好,现已作为乳腺癌骨转移的常规治疗药物.多项临床前研究及临床研究已证实,唑来膦酸对肿瘤细胞有直接或间接的抑制作用,联合其他辅助治疗(化疗和内分泌治疗)可发挥协同作用,对改善乳腺癌患者术后生存、抑制复发及转移具有重要作用,本文就上述研究进展作一综述.     

唑来膦酸在乳腺癌辅助治疗中的临床应用及机制探讨

第三代双膦酸盐类药物唑来膦酸是治疗乳腺癌骨转移公认的标准药物之一,但其在乳腺癌辅助治疗中的应用地位尚存在争议。目前临床研究结果表明,唑来膦酸辅助治疗不仅可以提高骨密度．而且可以降低乳腺癌的复发和转移。在低雌激素水平环境下,唑来膦酸可使早期乳腺癌患者得到生存获益．而且早期应用的益处优于延迟应用。唑来膦酸通过抑制肿瘤转移过程中的多条途径而发挥抗肿瘤作用。但唑来膦酸的最佳剂量、治疗周期及持续时间尚有待进一步的研究予以确认。     

唑来膦酸在乳腺癌中抗肿瘤作用的研究现状

唑来膦酸作为第3代双膦酸盐药物已广泛用于乳腺癌骨转移相关事件的防治。唑来膦酸在乳腺癌中具有抗肿瘤治疗作用。唑来膦酸通过抑制乳腺癌细胞的增殖和诱导细胞凋亡,降低肿瘤细胞的迁移、侵袭能力,防止有利于肿瘤生长的骨微环境的形成,抑制肿瘤新生血管形成,调节免疫等多种途径直接或间接发挥其抗肿瘤作用,与放化疗及内分泌等辅助治疗有序贯协同增效作用。唑来膦酸在乳腺癌患者辅助治疗中的协同抗肿瘤作用也在几项相关的前瞻性临床试验中进行。     

唑来膦酸在乳腺癌辅助治疗中的作用及其机制

双膦酸盐是治疗恶性肿瘤骨转移的有效药物之一,其作用机制是抑制破骨细胞介导的骨质重吸收.最新研究发现,新一代的双膦酸盐唑来膦酸可以诱导肿瘤细胞凋亡和抑制肿瘤血管新生,从而发挥直接或间接的抗肿瘤作用.有研究发现,对乳腺癌采用常用化疗药物序贯唑来膦酸治疗,可发挥协同抗肿瘤效应.唑来膦酸-弗隆辅助协同试验(Zometa-Femara Adjuvant Synergy Trial, ZO-FAST)和奥地利乳腺癌和结直肠癌研究小组-12(Austrian Breast and Colorectal Cancer Study Group-12, ABCSG-12)的最新研究结果显示,唑来膦酸在辅助治疗中与内分泌药物联用可显著提高患者的无病生存率和总生存率,而与辅助化疗联合使用的效果还有待唑来膦酸联合新辅助化疗降低复发(Neo-Adjuvant Zoledronic Acid to Reduce Recurrence,AZURE)临床试验予以证实.这些结果均表明,唑来膦酸用于乳腺癌的辅助治疗可以降低肿瘤的复发和转移.对唑来膦酸的最佳剂量和疗程尚有待进一步的研究予以确认.     

唑来膦酸治疗恶性肿瘤骨转移研究进展

骨骼是恶性肿瘤常见的转移部位之一,并可带来一系列的并发症,如骨痛、病理性骨折、脊髓压迫症和高钙血症等.二膦酸盐是治疗骨转移最常见的药物,唑来膦酸作为新一代含氮二磷酸盐类药物,是至今已发现的药物中抗骨吸收能力最强的.本文综述了唑来膦酸治疗恶性肿瘤骨转移的研究进展.     

唑来膦酸治疗恶性肿瘤骨转移60例的疗效观察

双膦酸盐类是目前治疗骨转移公认的有效药物.这类化合物通过抑制骨吸收来减少骨并发症的发生.唑来膦酸是一种高效、含氮基的第三代双膦酸盐类药物,能明显缓解骨转移患者疼痛,改善患者的生活质量,防止或减少骨骼相关事件发生,不良反应少.     

唑来膦酸联合放疗治疗恶性肿瘤骨转移的临床疗效观察

骨骼是恶性肿瘤转移的常见部位.骨转移后常出现顽固性疼痛、运动功能障碍、高血钙等,严重影响患者生存质量.放射治疗是治疗恶性肿瘤骨转移性疼痛的传统常规治疗手段.而唑来膦酸(zoledronic acid)是1种新型含氮的双膦酸盐类骨重吸收抑制剂,可明显缓解骨转移患者的疼痛,改善其生活质量和活动能力.我们使用国产唑来膦酸联合放疗治疗恶性肿瘤骨转移疼痛,取得了较好疗效,现报告如下.     

唑来膦酸与化疗联用治疗恶性肿瘤骨转移疼痛30例

目的 观察唑来膦酸注射液并化疗对恶性肿瘤骨转移疼痛、生活质量及肿瘤疗效的影响.方法 将64例有骨转移的恶性肿瘤患者分为二组,治疗组(30例)和对照组(34例).治疗组在化疗间歇期使用唑来膦酸注射液,对照组为单纯化疗.化疗2个疗程后观察骨痛、生活质量的变化、肿瘤疗效及不良反应.结果 治疗组治疗恶性肿瘤骨转移引起的疼痛起效迅速,总有效率86.6%,对照组总有效率55.8%,两组比较差异有统计学意义.治疗组治疗后生活质量改善情况明显优于对照组.两组肿瘤疗效的变化差异无统计学意义,两组不良反应相似.结论 唑来膦酸注射液是第三代双膦酸盐类药物,其对于恶性肿瘤骨转移引起的疼痛有明确的止痛作用,能改善患者的生活质量,与化疗联用不增加化疗的不良反应.     

唑来膦酸治疗恶性肿瘤骨转移临床应用新进展

唑来膦酸属于第三代双膦酸盐.治疗恶性肿瘤骨转移临床疗效确切,应用前景广泛.唑来膦酸在体外可抑制破骨细胞活动,诱导破骨细胞调亡;还可以抑制由肿瘤释放的多种刺激因子引起的破骨细胞活动增强和骨钙释放;缓解实体瘤患者骨转移引起骨痛,起效迅速,效果明显.     

双膦酸盐治疗骨转移癌骨痛及对血清钙磷的影响

背景与目的:恶性肿瘤骨转移发生率有上升趋势,双膦酸盐已广泛应用于治疗骨转移癌.本研究旨在评价唑来膦酸与帕米膦酸治疗骨转移癌骨痛及对血清钙磷的影响.方法:对病理及影像确诊的100例骨转移癌患者分别使用唑来膦酸或帕米膦酸进行治疗,评价患者治疗1、2个月后疼痛缓解情况及血清钙、磷变化.结果:双瞵酸盐治疗1、2个月后,疼痛较前无明显变化(P＞0.05),双膦酸盐治疗后中度疼痛似有下降趋势(x2=3.48,P=0.062).骨转移癌患者血钙和血磷间存在直线正相关关系.双膦酸盐治疗1个月后,低钙血症的发生率为54%,治疗2个月后的发生率(56%)较治疗前(36%)显著增加(x2=6.55,P=0.011;x2=8.05,P=0.005).治疗1个月后,血钙、血磷较治疗前显著降低(t=4.39,P=0.000;t=2.50,P=0.014);治疗2个月后,血钙、血磷较治疗前仍低(t=4.32,P=0.000;t=2.49,P=0.010).唑来膦酸和帕米膦酸相比,对骨痛缓解及血钙、血磷、碱性磷酸酶的影响差异无统计学意义(P＞0.05).结论:唑来膦酸与帕米膦酸能缓解骨转移癌患者骨痛,引起低钙血症,打破原有钙磷相关关系.唑来膦酸与帕米膦酸比较对骨痛缓解及血钙、血磷及碱性磷酸酶的影响差异无统计学意义.     

Exploring the anti-tumour activity of bisphosphonates in early breast cancer

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and are firmly established in the management of breast cancer patients with metastatic skeletal disease. There are extensive data that bisphosphonates, particularly nitrogen-containing bisphosphonates such as zoledronic acid, exhibit anti-tumour activity potentially via both indirect and direct mechanisms in vitro. In vivo studies using animal models of breast cancer induced bone disease have shown that bisphosphonates exert anti-tumour effects via inhibiting osteolysis and reducing skeletal tumour burden. Furthermore, pre-clinical studies have demonstrated synergistic anti-tumour effects between chemotherapy agents commonly used in breast cancer treatment and nitrogen-containing bisphosphonates. This, coupled with emerging evidence from pre-clinical in vivo studies suggesting that bisphosphonates may have additional anti-tumour activity outside of the bone microenvironment, could be of significant importance in the clinical management of breast cancer. The evidence in favour of an anti-tumour effect of bisphosphonates in the clinical setting is inconclusive however, with conflicting evidence from several trials. This review focuses on the anti-tumour activity of bisphosphonates in breast cancer, with particular focus on zoledronic acid. The pre-clinical evidence for anti-tumour activity will be reviewed, followed by the synergistic effects with anti-cancer agents. Finally, the clinical relevance and strategies for the evaluation of anti-tumour activity in breast cancer will be discussed. We are currently exploring the potential synergistic anti-tumour effects of the sequential treatment of neoadjuvant chemotherapy followed by zoledronic acid in a randomised phase II study evaluating biological endpoints including apoptosis, proliferation and angiogenesis in patients with breast cancer.     

Management of bone metastases in breast cancer

Opinion statement Patients with advanced breast cancer who develop bone metastases suffer an ongoing risk of skeletal complications that can have a significant impact on their quality of life (QoL). These complications include bone pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy (HCM), a potentially life-threatening condition. Treatment options include radiotherapy to palliate bone pain and/ or prevent impending fracture, orthopedic surgery to prevent or repair fractures, analgesics, and bisphosphonates, which can significantly reduce the risk of skeletal complications and delay their onset. Of the known bisphosphonates, zoledronic acid is the most potent. Since its regulatory approval in the United States and Europe in 2001, zoledronic acid (4 mg by 15-minute infusion) has become widely used and has replaced pamidronate (90 mg by 2-hour infusion) as the standard of care for treating bone metastases from breast cancer and bone lesions from multiple myeloma. Zoledronic acid has also demonstrated significant long-term benefits in randomized trials in prostate cancer and other solid tumors, whereas other bisphosphonates have failed. In long-term, phase III clinical testing, zoledronic acid provided significant treatment benefits beyond those of pamidronate in patients with breast cancer and demonstrated a safety profile comparable with pamidronate. Therefore, zoledronic acid is now recommended from the first diagnosis of bone metastasis. Other intravenous bisphosphonates include clodronate and ibandronate. Both are approved in Europe, but their efficacy relative to pamidronate and zoledronic acid is not known.     

Efficacy and safety of intravenous bisphosphonates for patients with breast cancer metastatic to bone: a review of randomized, double-blind, phase III trials

Intravenous bisphosphonates are the preferred treatment to prevent skeletal complications for patients with breast cancer and bone metastases. Pamidronate, a single-nitrogen bisphosphonate, was the early standard of care for such patients based on 2 large, placebo-controlled trials involving 754 patients. Zoledronic acid, a new-generation bisphosphonate containing 2 nitrogens, was evaluated in 1130 patients with breast cancer in a large, randomized, comparative, phase III trial with pamidronate. At 25 months, zoledronic acid (4 mg) significantly reduced the overall risk of developing a skeletal-related event (SRE) by an additional 20% versus 90 mg pamidronate by multiple-event analysis. Furthermore, zoledronic acid was at least as effective as pamidronate in reducing the proportion of patients with > or = 1 SRE and in delaying the onset of SREs. Moreover, a retrospective subset analysis of 352 patients with > or = 1 osteolytic lesion proved zoledronic acid more effective than pamidronate in reducing the risk and delaying the onset of SREs. Intravenous ibandronate (6 mg via 1-2-hour infusion) was evaluated in a placebo-controlled, phase III trial of 466 patients and was significantly more effective than placebo in reducing the number of 12-week treatment periods in which an SRE occurred. The safety profiles among all intravenous bisphosphonates were similar; patients treated with intravenous bisphosphonates reported notably less bone pain but a higher incidence of mild to moderate transient infusion-related adverse events (eg, nausea, vomiting, myalgia, and anorexia) compared with placebo. In summary, intravenous bisphosphonates are effective for the treatment of bone metastases in patients with breast cancer and have similar safety profiles, but the shorter infusion time and greater efficacy of zoledronic acid in reducing overall skeletal morbidity provide advantages over other available agents.     

Management of Metastatic Bone Disease and Hypercalcemia of Malignancy

Thirty years of research have established bisphosphonates as the most effective agents for the inhibition of osteoclast-mediated bone resorption, and they play an important role in the management of malignant bone disease. Bisphosphonates have been systematically improved through chemical engineering, and the newest nitrogen-containing compounds, including zoledronic acid and ibandronate, are 1000-fold more potent than first-generation compounds. Consequently, they can be administered at low molar doses via short intravenous infusions without compromising renal safety. Bisphosphonates have a variety of metabolic effects on osteoclasts. Nitrogen-containing bisphosphonates inhibit protein prenylation via the mevalonate pathway, thereby inhibiting osteoclast activation and inducing apoptosis. Preclinical studies suggest that bisphosphonates also have direct and indirect antitumor activity. In animal models, bisphosphonates reduced skeletal tumor burden and bone metastases. Currently, intravenous bisphosphonates are the standard therapy for hypercalcemia of malignancy, and they have become an integral part of the treatment of bone metastases in conjunction with standard antineoplastic agents. Intravenous bisphosphonates quickly normalize serum calcium, reduce skeletal complications, and palliate bone pain in patients with bone metastases. Intravenous pamidronate (90mg via 2-hour infusion every 3–4 weeks) has, until recently, been the international standard for the treatment of osteolytic bone lesions from breast cancer or multiple myeloma. However, 4mg zoledronic acid (via 15-minute infusion) is quickly becoming the new standard based on evidence that it is as safe and effective as 90mg pamidronate in patients with breast cancer and multiple myeloma and significantly more effective for hypercalcemia of malignancy. Consequently, the American Society of Clinical Oncology guidelines for breast cancer and multiple myeloma recommend pamidronate or zoledronic acid for patients with radiographic evidence of osteolytic bone destruction. Moreover, 4mg zoledronic acid is the only bisphosphonate that has demonstrated significant clinical benefit in patients with other solid tumors, including lung cancer, and prostate cancer patients with primarily osteoblastic bone metastases. Bisphosphonates also may have activity in the adjuvant setting to prevent or delay the development of bone metastases. Studies with oral clodronate in early breast cancer have provided clinical evidence that bone metastases can be inhibited, and the studies are ongoing with more potent bisphosphonates. Bisphosphonates have also been shown to prevent cancer treatment-induced bone loss. These and other studies continue to redefine the role of bisphosphonates in the treatment of malignant bone disease and the management of bone health in cancer patients.     

Bisphosphonates: from preclinical evidence to survival data in the oncologic setting

Bisphosphonate therapy has become a standard of therapy for patients with malignant bone disease. In vivo pre-clinical data suggest that bisphosphonates may exert an antitumor effect and preliminary clinical data show promising activity on metastatic disease in cancer patients. This review will describe the pre-clinical evidence of action of bisphosphonates on osteoclasts and tumor cells, in both in vitro and animal models. In addition, the effects of principal bisphosphonates on skeletal disease progression in patients with cancers in different sites, including breast cancer, prostate cancer and non-small cell lung cancer will be reported. The preliminary clinical data from retrospective trials on the effect of bisphosphonates on survival will be described and the ongoing adjuvant phase III trial will be analyzed. This review will describe the preliminary clinical evidences from prospective studies on the effect of zoledronic acid treatment on the prevention of bone metastases.     

Zoledronic acid: past, present and future roles in cancer treatment

Bisphosphonates are widely used to stabilize the bone and prevent devastating skeletal complications in patients with malignant bone disease from breast cancer or multiple myeloma. Bisphosphonates work by inhibiting osteoclast-mediated bone resorption and have also demonstrated antitumor activity in preclinical models. Of the available bisphosphonates, intravenous zoledronic acid has demonstrated the broadest clinical activity and is approved for the treatment of bone metastases from any solid tumor in many countries throughout the world. Clinical trials in breast and prostate cancer are also investigating zoledronic acid for the prevention of bone metastasis and bone loss associated with hormonal therapy. Due to its unique pharmacologic profile, zoledronic acid has activity in a variety of clinical settings at low doses and with infrequent intravenous dosing.     

Skeletal complications of prostate cancer: pathophysiology and therapeutic potential of bisphosphonates

Patients with prostate cancer are at risk for skeletal complications resulting from treatment-induced bone loss and for bone metastases. The therapeutic potential of zoledronic acid for the treatment of prostate cancer has been demonstrated in both preclinical and clinical studies. In patients receiving androgen-deprivation therapy, zoledronic acid increases bone mineral density, and, in patients with bone metastases, it reduces the incidence of skeletal complications. Preclinical studies have also demonstrated the antitumor potential of bisphosphonates. Specifically, zoledronic acid inhibits proliferation and induces apoptosis of human prostate cancer cell lines in vitro and has enhanced antitumor activity when combined with taxanes. Animal models have further shown that bisphosphonates decrease tumor-induced osteolysis and reduce skeletal tumor burden. In a model of prostate cancer, zoledronic acid significantly inhibited growth of both osteolytic and osteoblastic tumors and reduced circulating levels of prostate-specific antigen. These studies suggest that zoledronic acid has the potential to inhibit bone metastasis and bone lesion progression in patients with prostate cancer.     

Safety and efficacy of bisphosphonates beyond 24 months in cancer patients.

PURPOSE: Bisphosphonate therapy has decreased the risk of skeletal complications associated with osteolytic bone lesions in patients with breast cancer and multiple myeloma. The large prospective studies have used 21 to 24 months of treatment. We studied the safety and efficacy of bisphosphonates in a subset of patients who received therapy for more than 24 months. PATIENTS AND METHODS: Patients who received bisphosphonates (pamidronate or zoledronic acid) were identified. Data on skeletal events and laboratory parameters were gathered by chart review. RESULTS: We studied 22 patients who received intravenous pamidronate or zoledronic acid for a duration of 3.6 years (range, 2.2 to 6.0 years). Prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were encountered. There was a clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine in these patients. The fracture rate beyond 2 years was no greater than during the first 2 years of treatment. There were no stress fractures of long bones with prolonged therapy. CONCLUSION: Prolonged treatment with the potent bisphosphonates pamidronate and zoledronic acid seems to be well tolerated and should be studied in prospective, randomized studies to document prolonged skeletal efficacy.     

Breast tumour growth inhibition in vitro through the combination of cyclophosphamide/metotrexate/5-fluorouracil, epirubicin/cyclophosphamide, epirubicin/paclitaxel, and epirubicin/docetaxel with the bisphosphonates ibandronate and zoledronic acid

Breast cancer has a significant capacity to metastasize to bone. Bisphosphonates are the standard treatment for hypocalcaemia of malignancy (HCM), which is a common complication of bone metastasis. The combination of bisphosphonates with standard anticancer drugs such as paclitaxel or tamoxifen results in a synergistic apoptotic effect greater than that produced by either single agent alone. Potential antitumour effects in vitro of the two bisphosphonates zoledronic acid (Zol) and ibandronate (Ib) (each at 30 microM) combined with different anticancer drug combinations: cyclophosphamide/metotrexate/5-fluorouracil (CMF), epirubicin/cyclophosphamide (EC), epirubicin/paclitaxel (ET), and epirubicin/docetaxel (EDoc) were investigated using ATP-cell viability assay (ATP-CVA). Twenty cases of female primary, invasive breast cancer were assessed. Ibandronate and zoledronic acid alone showed an inhibitory effect on breast cancer tumour cells in vitro. The breast tumour growth inhibition effect for those two drugs amounted to 22 and 25% respectively. Inhibitory effects were clearly visible for all four combinations of anticancer drugs together with both bisphosphonates. Combinations of anticancer drugs with zoledronic acid seem to be more effective with respect to tumour growth inhibition than combinations with ibandronate.     

Bone metastases in breast cancer

Opinion statement Patients with advanced breast cancer who develop bone metastases suffer from longterm skeletal morbidity. Complications of bone metastases include pain, pathologic fractures, and spinal cord compression, which have a significant impact on the quality of life of patients. Treatment options for patients with bone metastases include surgery, radiation, and analgesics to reduce bone pain and to prevent or repair fractures. Intravenous bisphosphonates can delay the onset of bone metastasis and reduce the percentage of patients who experience skeletal complications of bone metastasis, thus reducing skeletal morbidity. For the past 6 years, pamidronate disodium (90 mg administered by 2-hour intravenous infusion) has been the treatment of choice for the prevention of skeletal complications of bone metastases in patients with breast cancer. However, a more potent bisphosphonate, zoledronic acid (4 mg administered by 15-minute intravenous infusion), was approved for use and has improved efficacy in patients with bone metastases. Because of the increased efficacy and more convenient infusion time, zoledronic acid may become the new standard of care for the treatment and prevention of skeletal complications secondary to bone metastases in patients with breast cancer. Phase III clinical trials have shown that patients with an existing skeletal complication are more likely to develop subsequent complications compared with patients who have not experienced a complication. Therefore, zoledronic acid therapy should be initiated when the patient is diagnosed with bone metastasis.