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.     

乳腺癌骨转移的综合治疗(附70例临床分析)

目的骨转移为乳腺癌的常见转移部位，其最大危害是骨痛，应采用一系列方法减轻骨痛，努力提高患者的生存质量。方法７０例乳腺癌骨转移患者采用化疗、放疗、内分泌、同位素和综合治疗，分单一方法治疗组和综合方法治疗组，观察治疗后疼痛缓解和功能障碍恢复情况，经ｔ检验得出结论。结果单一方法治疗中，内分泌和同位素治疗有效率高于单纯化疗和放疗；单一方法治疗有效率为５６．４％，综合治疗有效率为９０％，经统计学处理，Ｐ＜０．０１。结论单纯内分泌和同位素治疗优于单纯化疗和放疗，乳腺癌骨转移患者雌孕激素受体多为阳性，更适于内分泌治疗；综合治疗明显优于单一治疗，综合治疗中大剂量化疗加内分泌治疗效果最佳。     

乳腺癌骨移植的综合治疗：附70例临床分析

骨转移为乳腺癌的常见转移部位,其最大危害是骨痛,应采用一系列方法减轻骨痛,努力提高患者的生存质量。方法７０例乳腺癌骨转移患者采用化疗,放疗,内分泌,同位素和综合治疗,分单一方法治疗组和综合方法治疗组,观察治疗后疼痛缓解和功能障碍恢复情况,经ｔ检验得出结论。     

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.     

乳腺癌骨转移放射治疗临床分析(附32例报告)

目的　探讨乳腺癌骨转移的临床特点及放射治疗效果。方法　回顾分析 3 2例乳腺癌骨转移资料 ,转移灶单发 10例 ,多发 2 2例 ,共 68处病灶 ,其中脊柱占 2 7 9% ,骨盆占 2 2 1% ,肋骨占 13 2 %、股骨占10 3 % ,其余依次为肱骨、颅骨、肩胛骨、胫骨、锁骨。 2 2例行放射治疗 ,放疗前中度疼痛 17例 ,重度疼痛 5例 ,6例功能障碍。结果　 2 2例治疗后完全缓解 16例 ,部分缓解 6例 ,卡氏评分有所改善 ,功能障碍均恢复 ,治疗后的 1、2、3年生存率分别为 5 9 1%、2 2 7%、4 5 % ,中位生存期 15月 ,而未治组 10例的中位生存期为 4 5月 (P <0 0 1)。结论　乳腺癌骨转移行放射治疗 ,止痛作用快而持久 ,提高了患者的生存质量 ,是一种简单有效的治疗方法     

乳腺癌骨转移疼痛的综合治疗

目的　探讨缓解乳腺癌骨转移疼痛 ,恢复患者活动能力的方法。方法　 31例乳腺癌骨转移患者采用以CMFP或CAFP方案化疗为主 ,辅以放射性同位素或双磷酸盐类药物综合治疗 ,观察治疗后疼痛缓解、活动能力恢复及骨外转移灶的变化情况。结果　全组骨痛缓解率为 87.1 % (2 7/ 31 ) ,功能活动恢复 85 .7% (6/ 7) ,骨外转移灶的有效率为 67.9% (1 9/ 2 8)。结论　以化疗为主的综合治疗 ,不仅能较好地控制骨外转移灶的发展 ,而且能显著地缓解骨痛 ,恢复患者的活动能力     

Lung cancer with bone metastasis

Lung cancer is one of the most common solid tumors to develop metastases to bone. The prognosis of patients with metastatic lung cancer to bones is short,usually less than 6 months. The treatment requires a multidisciplinary approach that addresses radiotherapy, surgery, chemotherapy, and medical therapy with analgesics and bisphosphonates. Radiotherapy for metastatic bone tumor is a mainstay to relieve pain and control the localized disease. Doses in the range of 20 Gy in 5 fractions, 30 Gy in 10 fractions are acceptable in most circumstances. Prophylactic fixation for long bone fractures is recommended in cases where 30 to 50% of the cortex has been destroyed, pain is present after radiotherapy, or life expectancy is more than 3 months. Systemic chemotherapy has been proved to prolong survival of patients with metastatic non-small-cell lung cancer (NSCLC) as well as extensive small cell lung cancer (SCLC). Combination chemotherapy of platinum and a new drug is recommended in NSCLC patients with good performance status (PS). Gefitinib in upfront or second-line treatment is an optional therapy in adenocarcinoma patients without a history of smoking. Cisplatin combined with etoposide or irinotecan is a standard therapy in SCLC patients with PS 0 or 1. Carboplatin and etoposide is a treatment of choice in SCLC patients with PS 2 or 3. Medical management of cancer pain requires nonsteroidal anti-inflammatory drugs and opioids. Cancer pain that necessitates more than 120 mg of oral morphine is morphine-resistant pain and requires some adjuvant drugs such as corticosteroids, ketamine,anticonvulsants, or local anesthetics. The third generation bisphosphonate zoledronate has been demonstrated to improve cancer pain and to prevent skeletal morbidity in lung cancer patients with metastatic bone disease.     

乳腺癌合并皮肤转移的治疗进展

恶性肿瘤的皮肤转移相对少见,乳腺癌是女性最常见合并皮肤转移的恶性肿瘤。大部分皮肤转移的乳腺癌均合并其他部位转移,也有少数患者以皮肤转移为首发或唯一表现。单发或少发局限于胸壁的结节型皮肤转移病灶,通过局部为主的综合治疗,部分患者有望获得长期生存或临床治愈;而广泛的皮肤转移以及合并内脏、骨转移的皮肤转移患者,临床上难以治愈,预后不佳,系统治疗联合局部治疗可以减轻肿瘤负荷、缓解痛苦、改善患者生存质量。本文将就乳腺癌合并皮肤转移基本特征及治疗进展进行综述。      

Bone metastases in hypernephroma. Frequency of scapular involvement

A consecutive series of 95 patients with hypernephroma was studied retrospectively after it was clinically suspected that there was a propensity for this tumor to metastasize to the scapula. Fifteen patients (15.8%) have developed scapular metastases which account for 36.6% of all bone metastases in this series, the majority of which required radiotherapy for pain relief. The scapula was a solitary site of bone metastasis in the majority of patients, and, even when associated with other bone lesions, was frequently an isolated site of pain. A comparative series of 40 consecutive patients with breast cancer metastatic to bone was retrospectively studied. Twenty-five percent of these showed scapular metastases but these were all in association with multiple (greater than 3) other bone metastases; none was symptomatic or required treatment. There was a suggestion that hypernephromas spread more often to the ipsilateral scapula, but the trend did not reach statistical significance. Scapular metastasis in hypernephroma is a common and clinically significant problem, sometimes giving a clue to the primary site. The cause for this predilection is not known.     

89SrCl2 联合99Tc-MDP对乳腺癌骨转移骨痛治疗疗效

目的:观察放射性核素氯化锶（89SrCl 2）联合锝- 99- 亚甲基二膦酸盐（99Tc-MDP）治疗乳腺癌骨转移的临床效果。方法:将80例乳腺癌骨转移患者随机分为89SrCl 2 治疗组30例、99Tc-MDP 治疗组22例、89SrCl 2 与99Tc-MDP 联合治疗组28例3 组,观察各组骨痛缓解、骨转移病灶好转和生活质量评分提高情况。结果:骨痛缓解总有效率、生活质量评分提高率在联合治疗组为92.9%（26/ 28）、78.6%（22/ 28）,均明显高于89SrCl 2 治疗组的73.3%（22/ 30）、53.3%（16/ 30）和99Tc-MDP 治疗组的63.6%（14/ 22）、45.5%（10/ 22）,差异具有统计学意义（P < 0.05）。 骨转移病灶好转有效率在联合治疗组为46.4%（13/ 28）,明显优于99Tc-MDP 治疗组的18.2%（4/ 22）,差异具有统计学意义（P < 0.05）;但与89SrCl 2 治疗组的33.3%（10/ 30）比较差异无统计学意义（P > 0.05）。 结论:89SrCl 2 联合99Tc-MDP 治疗可显著提高乳腺癌骨转移骨痛疗效,且无明显不良反应。      

Local irradiation in combination with bevacizumab enhances radiation control of bone destruction and cancer-induced pain in a model of bone metastases

Skeletal metastases are a major source of morbidity for cancer patients. The purpose of this study was to evaluate the effects of megavoltage irradiation and antiangiogenic therapy on metastatic bone cancer. A tumor xenograft model was prepared in C3H/Scid mice using 4T1 murine breast carcinoma cells. Twenty-eight mice bearing tumors were treated with either bevacizumab (15 mg/kg), local megavoltage irradiation (30 Gy in 1 fraction), combination of bevacizumab and local megavoltage irradiation or physiologic saline solution (control group). Tumor area, bone destruction, tumor microvessel density, pain-associated behaviors and expression of substance P were assessed. Combined modality treatment reduced the frequency of pain-associated behaviors, decreased levels of nociceptive protein expression in the spinal cord, maintained cortical integrity and decreased the density of microvessels as compared to single modality treatments. We conclude that concurrent antiangiogenic therapy and localized radiotherapy for the treatment of bone metastases warrants further evaluation in human clinical trials.     

脊柱转移癌的认识与诊治

骨骼系统是恶性肿瘤最常见的转移部位之一,仅次于肝、肺之后居第三位,而脊柱为最多见的骨转移部位,约占骨转移的2／3。脊柱转移癌以胸腰椎多见,颈椎和骶椎则少见,发病年龄多为40～65岁。其中最易发生脊柱转移的肿瘤为乳腺癌、肺癌及前列腺癌。     

Combining Src inhibitors and aromatase inhibitors: A novel strategy for overcoming endocrine resistance and bone loss

Aromatase inhibitors have largely replaced tamoxifen as the first-line treatment for postmenopausal women with metastatic, hormone receptor-positive (HR+) breast cancer. However, many patients develop clinical resistance with prolonged treatment, and oestrogen deprivation following aromatase inhibition can result in loss of bone mineral density. Furthermore, most patients with metastatic breast cancer develop bone metastases, and the resulting adverse skeletal-related events are a significant cause of patient morbidity. Src, a non-receptor tyrosine kinase, is a component of signalling pathways that regulate breast cancer cell proliferation, invasion and metastasis as well as osteoclast-mediated bone turnover. Preclinical evidence also suggests a role for Src in acquired endocrine resistance. As such, Src inhibition represents a logical strategy for the treatment of metastatic breast cancer. In vitro, combination therapy with Src inhibitors and endocrine agents, including aromatase inhibitors, has been shown to inhibit the proliferation and metastasis of both endocrine-responsive and endocrine-resistant breast cancer cell lines more effectively than either of the therapy alone. Src inhibition has also been shown to suppress osteoclast formation and activity. Combination therapy with aromatase inhibitors and Src inhibitors therefore represents a novel approach through which the development of both acquired resistance and bone pathology could be delayed. Data from clinical trials utilising such combinations will reveal if this strategy has the potential to improve patient outcomes.     

双膦酸盐治疗乳腺癌骨转移患者的临床病理特征及预后分析*

目的：探讨乳腺癌骨转移患者的临床、病理、治疗及预后因素。方法：收集2005年1 月至2013年4 月天津医科大学肿瘤医院收治的183 例至少接受6 个月双膦酸盐治疗的乳腺癌骨转移患者的临床资料,根据双膦酸盐类型分为帕米膦酸二钠组、唑来膦酸组及帕米膦酸二钠序贯唑来膦酸组,探讨骨转移的特点、骨相关事件（skeletal-related events,SREs）、治疗及预后特征。结果：胸椎和肋骨为骨转移的常见转移部位,骨转移至发生首次SREs的中位时间为4.2 个月,51.9%（95/ 183）患者发生SREs,累计SREs事件数达167 次,其中110 次（65.9%）发生在骨转移后1 年内,SREs类型以骨放疗为主。患者在不同双膦酸盐药物组的SREs发生率差异无统计学意义（P > 0.05）。 183 例患者骨转移后的中位生存期为43.1 个月,激素受体状态、无病生存期、是否合并内脏转移及脊柱转移与否是乳腺癌骨转移患者的独立预后因素（P < 0.05）。 结论：胸椎和肋骨是乳腺癌骨转移的常见转移部位,SREs主要发生在骨转移后1 年内并以骨放疗为主。激素受体阴性、无病生存期短、合并内脏及脊柱转移是影响乳腺癌患者骨转移不良预后的独立因素。     

骨转移瘤的综合治疗

目的：研究骨转移瘤的发病特点、诊疗方法及进展。方法：回顾性分析2004年1 月～2009年12月福建医科大学附属第一医院骨科收治的295 例骨转移瘤患者,治疗前、后对患者进行Karnofsky 生活质量评估及疼痛VAS 评分,并对治疗结果进行研究。结果：295 例患者中,男184 例,女111 例;年龄13~86岁,平均年龄56.9 岁;原发肿瘤按发生率依次为：肺癌、未明部位恶性肿瘤、肝癌、消化道癌、甲状腺癌、乳腺癌、前列腺癌等;骨转移部位依次为：脊柱、骨盆、四肢近端、肋骨、颅骨等。单发性转移52例,多发性转移243 例,其中109 例患者行手术治疗,其他的治疗方法包括化疗、放疗、激素治疗、二磷酸盐治疗、止痛等综合治疗。治疗后患者疼痛程度及生活质量均有明显改善,Karnofsky 评分：治疗前50分,治疗后70分;疼痛VAS 评分：治疗前5.6 分,治疗后2.7分,治疗有效率达63.8% 。结论：骨转移瘤作为一种全身性疾病,应采取积极的综合治疗,根据患者情况进行系统评估,制定个体化的治疗方案,才能取得较好的疗效。     

Osseous metastases of breast cancer. Clinical, biochemical, radiographic, and scintigraphic evaluation of response to therapy

Serial bone scans and radiographs were assessed in 50 patients with breast cancer metastatic to bone treated with combination chemotherapy. In 34 patients evaluable nonosseous metastases were present in addition to bone lesions. Clinical and biochemical changes also were assessed serially, independent of skeletal disease. Pretherapy bone scans were more sensitive but less specific than radiographs for detection of osseous metastasis. Response to therapy in nonosseous metastasis correlated well with radiographic improvement of bone lesions (91%), but less well with changes in bone scans (57%). There was concordance between clinical and radiographic findings, suggesting progression of metastatic disease, in 81% of patients and between scan and clinical findings in 72% of them. Changes in carcinoembryonic antigen levels closely reflected clinical and radiographic changes. Serial bone radiographs are the most useful method of determining response to therapy in breast cancer metastatic to bone. The addition of scintigraphs and carcinoembryonic antigen measurements results in a highly sensitive and accurate method of response evaluation.     

唑来膦酸联合放疗治疗骨转移癌的临床疗效观察

目的 探讨唑来膦酸联合局部放疗治疗恶性肿瘤局限件骨转移的临床疗效.方法 45例局限性骨转移患者随机分为2组,联合治疗组23例,采用唑来膦酸静脉滴注加局部放疗;单纯放疗组22例,只采用局部放疗.结果 联合治疗组和单纯放疗组的疼痛缓解率分别为91.3%和86.4%.差异无统计学意义(P>0.05);联合治疗组和单纯放疗组的溶骨病灶再钙化的有效率分别为52.2%和22.7%,差异有统计学意义(P<0.01);联合治疗组和单纯放疗组出现新的骨转移病灶的患者比例分别为13.0%和40.9%,联合治疗组显著低于单纯化疗组(P<0.05).联合治疗组的不良反应主要为短暂低热和恶心.结论 唑来膦酸联合放疗治疗恶性肿瘤局限性骨转移疗效确切,其控制骨痛作用强,可高效修复溶骨病灶,并能降低新的骨转移灶发生率.     

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.     

博宁加化疗、放疗治疗肺癌骨转移疗效观察

目的;观察博宁对肺癌骨转移的止痛效果。方法：应用博宁治疗及放射治疗对照研究。结果：４０例博宁治疗组患者骨痛的止痛总有效率为８７．５％,显效率达５０．０％。其中,单用博宁组有效率为８４．６％,博宁合并放疗组有效率为９１．６％,博宁合并化疗组有效率为８６．７％,三组间止痛效果无显著性差异。     

放疗在乳腺癌骨转移中的临床应用进展

骨转移是晚期乳腺癌最常见的远处转移,多伴有局部疼痛、肢体功能障碍等症状,常导致患者的生存质量下降。由骨转移引起的病理性骨折等骨相关事件(skeletal-related events,SREs)会显著增加乳腺癌患者的死亡风险。积极有效的骨转移治疗有重要的临床意义,放疗是重要的局部治疗手段。本文就放疗在乳腺癌骨转移中的临床应用进展进行综述,着重阐述放疗实施手段及综合治疗模式的循证医学证据。