Bisphosphonate treatment and radiotherapy in metastatic breast cancer

Patients with advanced breast cancer frequently develop metastasis to bone. Bone metastasis results in intractable pain and high risk of pathologic fractures due to osteolysis. The treatment of breast cancer patients with bone metastases requires a multidisciplinary approach. Radiotherapy is an established treatment for metastatic bone pain. It may be delivered either as a localized low dose treatment for localized bone pain or systemically for more widespread symptoms. Bisphosphonates have been shown to reduce morbidity and bone pain from bone metastases when given to patients with metastatic bone disease. In vivo studies indicate that early bisphosphonates administration in combination with radiotherapy improves remineralization and restabilization of osteolytic bone metastases in animal tumor models. This review focused on a brief discussion about biology of bone metastases, the effects of radiotherapy and bisphosphonate therapy, and possible mechanisms of combination therapy in metastatic breast cancer patients.     

Bisphosphonate as an adjuvant therapy for the pain of bone metastases, 3 cases

Pain from bone metastases limits mobility and may cause pathological fractures that can seriously impair the patient's quality of life. Conservative treatments such as orthopedic fixation, radiotherapy, and opioids sometimes fail to give satisfactory pain relief. Bisphosphonates have been reported to reduce the severity of pain from bone metastasis due to breast cancer, prostate cancer, and multiple myeloma. Recent clinical reports demonstrated the effectiveness of bisphosphonates in reducing pain from bone metastases in various malignancies. This study presents 3 cases of refractory pain from bone metastases due to thyroid, colorectal and hepatocellular carcinoma. Primary treatment included orthopedic fixation, radiotherapy, and/or parenteral opioids that failed to reduce bone pain. Bisphosphonate therapy was considered at the start of pain control treatment using opioids. All 3 cases showed gradual reduction in pain after i.v. pamidronate administration and allowed physicians to control further pain with opioids. In 1 case, the patient was successfully withdrawn from opioids. The role of bisphosphonates in painful bone metastases remains unclear. However, recent encouraging reports have indicated that bisphosphonate may become one of the adjuvant treatments available to control refractory bone pain from various malignancies.     

Metastatic bone disease: clinical features, pathophysiology and treatment strategies.

Metastatic bone disease develops as a result of the many interactions between tumour cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all, tumour types providing a rational target for treatment. The clinical course of metastatic bone disease in multiple myeloma, breast and prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone pain, fractures, hypercalcaemia and spinal cord compression, all of which may profoundly impair a patient's quality of life.External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate in metastatic bone disease and in the prevention and treatment of osteoporosis in cancer patients. In vitro suggestions of direct anticancer activity and some promising clinical data in early breast cancer have resulted in considerable interest in the possible adjuvant use of bisphosphonates to inhibit the development of bone metastases.     

骨膦在肿瘤性骨转移综合治疗中的作用

我院１９９３．２－１９９５．１０用骨膦治疗骨转移癌３２例，以评价骨膦在肿瘤骨转移综合治疗中的作用。其中肺癌１７例，乳腺癌１１例，鼻咽癌３例，肝癌１例。３２例经骨膦治疗后止痛总的有效率为８１．２５％，其中ＣＲ８例（２５％），ＰＲ１０例（３１．２５％），ＭＲ８例（２５％）。与治疗前相比，有明显疗效。有效患者的Ｋａｒｎｏｆｓｋｙ状况分级法分别提高２０－４０分，由于治疗后患者疼痛减轻，症状缓解，生存质量得到明显提高。我们认为骨膦联合放疗对控制广泛骨转移性骨痛，提高晚期肿瘤患者生存质量有实际意义。     

Optimising treatment of bone metastases by Aredia™ and Zometa™

Metastatic bone disease develops as a result of the many interactions between tumour cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all, tumor types providing a rational target for treatment. The clinical course of metastatic bone disease in multiple myeloma, breast and prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone pain, fractures, hypercalcaemia, and spinal cord compression, all of which may profoundly impair a patient's quality of life. External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement. Pamidronate (Aredia(TM)) is the most widely evaluated bisphosphonate and is recommended for most patients with multiple myeloma or breast cancer with bone metastases. Current research aims include the evaluation of new potent bisphosphonates such as zoledronic acid (Zometa(TM)). It is hoped that this compound is not only more convenient and easier to administer but also more effective in inhibiting skeletal morbidity. Zometa may also have some direct anticancer activity. Preclinical studies with Zometa have demonstrated its potential in malignant bone disease. Clinical studies in 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 now ongoing to establish the efficacy and safety of Zometa in treatment of bone metastases in patients with osteolytic and osteoblastic lesions. Additionally, new specific molecules such as osteoprotogerin have been developed that are based on our improved understanding of the cellular signalling mechanisms involved in cancer induced bone disease. These potent molecules are now entering clinical trials. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate in metastatic bone disease and their use in the prevention and treatment of osteoporosis in cancer patients. In vitro suggestions of direct anti-cancer activity and some promising clinical data in early breast cancer have resulted in considerable interest in the possible adjuvant use of bisphosphonates to inhibit the development of bone metastases.     

Bisphosphonate zur Behandlung tumorinduzierter Knochenveränderungen

The treatment of metastatic bone disease requires multimodality management including effective anti-tumour therapy and long-term treatment with bisphosphonates. When local complications are manifest or seem imminent radiotherapy or surgical treatment can also be used. Basically, bisphosphonates are indicated for all patients with tumour-induced bone manifestations, but their early administration without confirmation of tumour-induced bone changes does not seem justified except in the context of clinical trials. Bisphosphonates do lead to significant prevention of bone complications and to slowing of tumour progression, and they also contribute to the attenuation of bone pain. Even though they have only a modest influence on overall survival, the impact of consistent multimodal treatment of bone metastases associated with the administration of bisphosphonates is substantial, as it can dampen the patient’s sometimes long decline into general illness as a result of the bone metastases and thus contribute to retention or even improvement of the quality of life.     

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.     

Management of bone metastases

Metastatic bone disease develops as a result of the many interactions between tumor cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all, tumor types providing a rational target for treatment. The clinical course of metastatic bone disease in multiple myeloma, breast and prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone pain, fractures, hypercalcemia, and spinal cord compression, all of which may profoundly impair a patient's quality of life. External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement. Additionally, new specific molecules such as osteoprotogerin have been developed that are based on our improved understanding of the cellular signaling mechanisms involved in cancer-induced bone disease. These potent molecules are now entering clinical trials. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate in metastatic bone disease and its use in the prevention and treatment of osteoporosis in cancer patients. In vitro suggestions of direct anticancer activity and some promising clinical data in early breast cancer have resulted in considerable interest in the possible adjuvant use of bisphosphonates to inhibit the development of bone metastases.     

Influence of parasternal radiotherapy for breast carcinoma on thoracic vertebral metastases

A retrospective study was performed of 109 women who had died with breast carcinoma metastatic to bone. Both radiologically demonstrated metastases and the requirement for palliative radiotherapy to the upper two thirds of the thoracic spine occurred significantly less in those patients who had received exit dose irradiation to this region from parasternal radiotherapy given for apparently localised disease. This finding is in agreement with a previous report that such low dose irradiation can exert a clinically important effect on minimal metastatic disease. Systemic (double hemi-body) radiotherapy might be an effective and quick adjuvant treatment for patients with breast carcinoma.     

Samarium lexidronam (153Sm-EDTMP): skeletal radiation for osteoblastic bone metastases and osteosarcoma

Radiation therapy can be an effective means to treat bone metastases, which occur in more than 50% of cancer patients. (153)Samarium lexidronam ((153)Sm-EDTMP; Quadramet, Cytogen) is a radiopharmaceutical designed for deposition into bone metastases. Bone scans can identify patients that may benefit from targeted radiation therapy with (153)Sm-EDTMP. As an unsealed source of radiation therapy, (153)Sm-EDTMP is simple to administer: 1 mCi/kg is given in a similar fashion to a bone scan injection ((99m)Tc-MDP bone scan injection is given at 0.2-0.35 mCi/kg. Therefore, both are administered intravenously. However, the radiation-absorbed dose and radiopharmaceutical energy are different). Nevertheless, despite simplicity of administration, (153)Sm-EDTMP is underutilized for improving cancer pain in the skeleton. Repeated cycles and combined treatment with other modalities such as bisphosphonates, chemotherapy and/or external beam radiation are possible. (153)Sm-EDTMP combined with bisphosphonates, chemotherapy and/or radiation may provide better palliation of bone metastases and also in bone-forming tumors (osteosarcoma). Encouraging experience using high-dose (153)Sm-EDTMP for total marrow irradiation in hematologic malignancies involving the bones (e.g., myeloma or acute leukemia) is also reviewed.     

Treatment strategies for skeletal complications of cancer

Skeletal complications are a common result of many cancers, particularly of multiple myeloma and bone metastases of solid tumors originating in the breast, prostate or lung. A number of treatment options are available, including radiotherapy, radiopharmaceuticals, surgery and chemotherapy. Recently, bisphosphonates have emerged as a promising new treatment option for bone complications of cancer. These agents are potent inhibitors of osteoclast activity that bind to the bone matrix, are released during bone resorption, and are subsequently internalized by osteoclasts, where they interfere with biochemical pathways and induce osteoclast apoptosis. Bisphosphonates also antagonize osteoclastogenesis and promote the differentiation of osteoblasts. As a result, bisphosphonates inhibit tumor-induced osteolysis and reduce skeletal morbidity. Bisphosphonates are generally well tolerated, although they have recently been associated with osteonecrosis of the jaw, a painful and debilitating side effect that is only beginning to be understood. Despite this concern, bisphosphonates are an important tool in the management of skeletal complications of cancer, providing benefits for the treatment of hypercalcemia, osteolytic lesions and fractures, as well as offering amelioration of pain and improvement in quality of life.     

The role of bisphosphonates in the management of advanced cancer with a focus on non-small-cell lung cancer. Part 1: Mechanisms of action, role of biomarkers and preclinical applications

With recent advances in cancer management, patients with metastatic bone disease are likely to have a prolonged clinical course, with skeletal-related events such as pain, hypercalcemia, pathologic fractures, spinal cord and nerve compression. Bisphosphonate use has resulted in the reduction of skeletal-related complications for a number of tumors including breast, prostate and myeloma, and improvements in the quality of life for patients. There is now evidence that newer, highly potent, nitrogen-containing bisphosphonates reduce skeletal complications in patients with bone metastases from other solid tumors (including lung cancer). The early identification of patients at high risk for developing bone metastases may help curtail a complex and costly clinical problem--skeletal-related events. In this article, we review the different mechanisms of bisphosphonates and the potential role of newer-generation bisphosphonates, such as zoledronic acid, in the management of advanced, metastatic bone disease. We include a review of mechanistic studies and preclinical data. Additionally, the utility of evolving concepts such as bone markers and imaging of bone metastases are discussed.     

Clinical efficacy of bisphosphonate therapy for bone metastasis from breast cancer

Bisphosphonates inhibit osteoclastic bone resorption and are being used as treatment for bone metastases from breast cancer. Intravenous bisphosphonate therapy can significantly reduce skeletal related events (SREs) when administered concurrently with chemotherapy or endocrine therapy. In addition, intravenous bisphosphonate monotherapy is also able to alleviate cancer induced bone pain, and to improve bone metastases in some patients. Oral bisphosphonates are not routinely used for the treatment of bone metastases due to their low bioavailability. However, minodronate, a bisphosphonate 100-fold more potent than pamidronate, is now in phase II clinical studies in Japan, and may alter the role of oral bisphosphonates in the treatment of bone metastasis from breast cancer. The ASCO guidelines recommend that patients with osteolytic bone metastases be treated not with bisphosphonate monotherapy, but with concurrent bisphosphonate and systemic therapy. In addition, it is also recommended that current standards of care for cancer pain, analgesics and radiotherapy, should not be replaced with bisphosphonate therapy.     

Ibandronate: its role in metastatic breast cancer

Bisphosphonates are the most effective agents for treating and/or preventing complications of bone metastases and are the standard of care in this setting. Currently, four bisphosphonates are available for metastatic bone disease (MBD): clodronate, pamidronate, zoledronic acid, and ibandronate. Although all four of these bisphosphonates have been shown to reduce the incidence of skeletal-related events in patients with bone metastases, there are substantial differences among these agents in their potency, dose and route of administration, and side effects. Ibandronate and zoledronic acid, the two newer aminobisphosphonates, appear to have similar biochemical efficacies when phase III trial data are compared. Both agents were equally effective in reducing markers of bone resorption in the only prospective comparative trial carried out to date, but no data on relative clinical efficacy are available from head-to-head comparisons. Both the oral and i.v. formulations of ibandronate have also shown long-term efficacy in managing metastatic bone pain (MBP), but the onset of action of standard bisphosphonate treatment is not sufficient when rapid relief of pain is required. Because of its favorable renal safety profile, i.v. ibandronate can be administered daily for 3 days, as a so-called "loading dose." This dosing regimen has allowed rapid and effective relief of MBP without the unwanted side effects associated with opioids and other analgesics. Ibandronate is thus an effective, flexible, and well-tolerated bisphosphonate that can meet the varying requirements of patients with MBD.     

Metastatic Bone Disease

The cancer patient with skeletal metastases now has a much improved range of treatment options with major advances in bone-specific drug therapy as well as radiotherapy and radiopharmaceuticals, orthopaedic surgery, and systemic anticancer therapy with cytotoxic and endocrine agents. Recent advances in the understanding of bone remodeling mechanisms and the interdependence of cancer cells and bone have been closely associated with development of the bisphosphonate drugs and newer agents such as osteoprotegerin (OPG). The bisphosphonates are potent inhibitors of osteoclast mediated bone resorption and appear to function either by induction of apoptosis in mature osteoclasts or by inhibition of formation of osteoclasts from progenitor cells. Bisphosphonates are the treatment of choice in tumor-induced hypercalcemia. Bisphosphonates have a clear role in reducing bone pain and skeletal complications, such as pathological fracture and are being evaluated in the prevention of bone metastases. Until recently, intravenous (IV) pamidronate has been the drug most commonly prescribed for oncological indications and oral clodronate has also been widely used in some countries outside the US. However, newer and more potent drugs, such as zoledronate, are increasingly having a major impact on routine therapy. Three of the largest ever bisphosphonate trials, using zoledronate in metastatic bone disease have recently been completed. In a breast and multiple myeloma trial in 1648 patients, zoledronate (4mg IV) was shown to be equivalent to pamidronate (90mg IV) in reducing skeletal events and was more convenient to administer. In trials in prostate cancer and a wide range of other solid tumor types affecting bone, both the number of patients with skeletal-related events and the rate of bone complications were reduced. The indications for bisphosphonates are, therefore, no longer constrained by tumor type. The assessment of response to therapy is a vital part of management of metastatic bone disease. Plain radiographs and the isotope bone scan remain widely used but have many limitations. Newer imaging techniques such as computerized tomography, magnetic resonance imaging, and positron emission tomography may be useful in selected situations. Recent research suggests that measurement of tumor markers and bone-specific markers will play an increasingly important role in assessment of response. In particular, bone resorption markers measuring collagen breakdown have potential as rapid, convenient, and inexpensive measures of response, with suppression of bone resorption into the normal range being an important aim of bone-specific treatments.     

Treatment of breast cancer with bone metastasis: bisphosphonate treatment — current and future

There are a variety of treatments for patients with bone metastases from breast cancer. These include bisphosphonates, antitumor endocrine and cytotoxic systemic therapies, radiotherapy to the metastatic site, radionucleotides, and conservative treatment (analgesics). The optimal combination treatment for bone metastases is not clear. Bisphosphonates are effective for reducing skeletal complications such as bone pain, pathological fracture, bone surgery, and hypercalcemia. Bisphosphonates are recommended as the gold standard therapy for breast cancer with bone metastases. Treatment guidelines tend to recommend starting a bisphosphonate at the time of diagnosis of bone metastases. Animal models have supported the prevention of bone metastasis by bisphosphonate therapy, but three major adjuvant clinical trials of the oral bisphosphonate clodronate have yielded conflicting results. However, our preliminary trial of an intravenous bisphosphonate, pamidronate, showed effective inhibition of bone metastases. The use of bisphosphonates, especially zoledronic acid, as adjuvant therapy is promising, but it is still investigational.     

伊班膦酸钠治疗恶性肿瘤骨转移临床评价

蔓伊班膦酸钠为三代含氮双磷酸盐，已被临床应用于治疗恶性肿瘤骨转移及继发的骨相关事件。伊班膦酸钠同时具有口服和静脉两种剂型，临床试验证实二者均能有效降低骨相关事件的发生率、减轻骨转移所致骨痛的程度、改善骨转移病人的生活质量。在安全性评价方面，伊班膦酸钠具有突出的肾脏安全性，即使采用负荷剂量仍然表现出良好的耐受性。本篇综述主要介绍伊班膦酸钠在治疗骨转移瘤方面的有效性和安全性。     

Palliative radiotherapy in plasma cell myeloma.

Pain symptoms caused by bone lesions of multiple myeloma can be relieved by a local irradiation treatment. To estimate the influence of systemic treatment on the palliative effect of local radiotherapy the records of 70 myeloma patients treated with chemotherapy combined with or followed by local irradiation were reviewed. The local response rate, defined as complete pain relief at the irradiated site, was 80% in patients receiving irradiation during chemotherapy (melphalan and prednisone) and this palliative effect endured 31.8 +/- 3.6 months. If irradiation was started in the period without systemic treatment the local response rate was 39.6% and lasted 24.8 +/- 17.9 months. In sites treated with more than one radiotherapy course 94% response rate after the first treatment, 56% after the second treatment and no response after the third course was achieved. The duration of local pain control was positively related to the applied radiation dose. It is concluded that irradiation during concomitant chemotherapy is superior to radiotherapy performed in a period without systemic treatment. Local long-term palliation can only be achieved by a sufficient high radiation dose.     

The present and future role of bisphosphonates in the management of patients with breast cancer

At least 25% of patients with breast cancer develop skeletal metastases, with bone the site of disease producing the greatest morbidity. It is apparent that the bisphosphonates present an important component of the treatment strategy. They are now the treatment of choice in tumour-induced hypercalcaemia, and they can reduce bone pain and skeletal complications such as pathological fractures. In addition, bisphosphonates are being increasingly evaluated in the prevention of bone metastases and to prevent and treat cancer therapy-induced osteoporosis. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate.     

The role of bisphosphonates in breast cancer: The present and future role of bisphosphonates in the management of patients with breast cancer

At least 25% of patients with breast cancer develop skeletal metastases, with bone the site of disease producing the greatest morbidity. It is apparent that the bisphosphonates present an important component of the treatment strategy. They are now the treatment of choice in tumour-induced hypercalcaemia, and they can reduce bone pain and skeletal complications such as pathological fractures. In addition, bisphosphonates are being increasingly evaluated in the prevention of bone metastases and to prevent and treat cancer therapy-induced osteoporosis. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate.