乳腺癌骨转移的辅助治疗NCCN指南2015v3

Supportive Therapy for Bone Metastases

骨转移瘤的辅助治疗

Treatment targeting osteoclast activity is of value in patients with metastatic breast cancer in bone to prevent bone fractures, bone pain requiring radiation therapy, spinal cord compression, and hypercalcemia (skeletal-related events; SREs).山东省肿瘤医院呼吸肿瘤内科张品良

靶向破骨细胞活性的治疗在乳腺癌骨转移患者中的价值是预防骨折、需要放射治疗的骨痛、脊髓压迫和高钙血症（骨相关事件；SRES）

The bisphosphonates zoledronic acid or pamidronate have been used for this purpose, and there is extensive clinical trial support for their efficacy in prevention of SREs (see section below on Bisphosphonates).

双膦酸盐唑来膦酸或帕米膦酸二钠已用于此目的，有广泛的临床试验支持其预防SREs的疗效（见双膦酸盐章节下）。

Denosumab is a fully human monoclonal antibody directed against RANK ligand, a mediator of osteoclast function.

地诺单抗是一个针对介导破骨细胞功能的RANK配体的全人源性单克隆抗体。

A single, randomized, active, controlled trial in metastatic breast cancer showed equivalency and superiority of time to the occurrence of SRE with denosumab, as compared with zoledronic acid.

转移性乳腺癌的一项单中心、有效性、随机对照研究显示与唑来膦酸相比地诺单抗等效且至发生SRE时间更优。

No study of bisphosphonate or denosumab has demonstrated an impact on OS in patients with metastatic disease.

没有研究证明双膦酸盐或地诺单抗对转移性疾病患者的OS有影响。

The bisphosphonates and denosumab are associated with a risk of development of osteonecrosis of the jaw (ONJ).

双膦酸盐类药物和地诺单抗与发生颚骨坏死（ONJ）风险相关。

Poor baseline dental health or dental procedures during treatment are known risk factors for ONJ.

基线牙齿健康不良或在治疗期间牙科手术是已知的ONJ危险因素。

Thus, a dental examination with preventive dentistry intervention is recommended prior to treatment with intravenous bisphosphonate or denosumab, and dental procedures during treatment should be avoided if at all possible.

因此，在静脉注射双膦酸盐或地诺单抗治疗之前推荐牙科检查口腔预防干预，在治疗期间应尽可能避免牙科手术。

Additional risk factors for the development of ONJ include administration of chemotherapy or corticosteroids and poor oral hygiene with periodontal disease and dental abscess.

对于发生ONJ额外的风险因素包括化疗或激素和不良的口腔卫生习惯合并牙周病、牙脓肿。

Confirmation of metastatic disease by imaging, including x-ray, diagnostic CT, or MRI, and initial evaluation of serum calcium, creatinine, phosphorous, and magnesium levels should be undertaken prior to the initiation of intravenous bisphosphonate treatment or subcutaneous denosumab treatment in patients with metastatic disease.

经X线、诊断性CT或MRI影像确认的转移性疾病患者，在开始静脉注射双膦酸盐或皮下注射地诺单抗治疗之前应检测血清钙、肌酐、磷和镁的水平。

Frequent measurement of calcium, phosphorous, and magnesium may be prudent since hypophosphatemia and hypocalcemia have been reported.

频繁测定钙、磷和镁，因为已有报道可以发生低磷血症和低钙血症。

Bisphosphonates

双膦酸盐类药物

An intravenous bisphosphonate (eg, pamidronate, zoledronic acid) in combination with oral calcium citrate and vitamin D supplementation should be used in women with bone metastasis, especially if lytic and/or in weight-bearing bone, if expected survival is 3 months or longer, and if creatinine levels are below 3.0 mg/dL (category 1).

在骨转移女性中应该使用静脉注射双膦酸盐（如帕米膦酸二钠，唑来膦酸）联合口服枸橼酸钙和维生素D，特别是如果溶骨和/或承重骨、预期生存时间≥3个月、肌酐水平低于3mg/dL（1类）。

Bisphosphonates are given in addition to chemotherapy or endocrine therapy.

除了化疗或内分泌治疗外还要给予双膦酸盐类药物。

Zoledronic acid may be superior to pamidronate in lytic breast metastasis.

在乳腺溶骨性转移中唑来膦酸可能优于帕米膦酸二钠。

There are extensive data from randomized trials in support of the use of bisphosphonates for patients with metastatic disease to bone.

有大量随机对照试验数据支持对骨转移性疾病患者使用双膦酸盐治疗。

The randomized clinical trial data include the use of zoledronic acid and pamidronate in the United States and ibandronate and clodronate in European countries.

随机临床试验的数据包括在美国使用的唑来膦酸与帕米膦酸二钠和在欧洲国家使用的伊班膦酸钠和氯膦酸二钠。

In metastatic bone disease, bisphosphonate treatment is associated with fewer skeletal-related events, fewer pathologic fractures, and less need for radiation therapy and surgery to treat bone pain.

在转移性骨疾病中，双膦酸盐治疗骨骼相关事件更少、病理性骨折更少、骨痛需要放疗和手术较少。

The use of bisphosphonates in metastatic disease is a palliative care measure.

在转移性疾病中使用双磷酸盐是一种姑息性关怀措施。

No impact on OS has been observed in patients treated with bisphosphonates.

在双膦酸盐治疗的患者中未观察到对OS影响。

The data indicate that zoledronic acid and pamidronate may be given on a 3- to 5-week schedule in conjunction with antineoplastic therapy (ie, endocrine therapy, chemotherapy, biologic therapy).

数据表明，唑来膦酸与帕米膦酸二钠可每3-5周给药1次结合抗肿瘤治疗（即内分泌治疗、化疗、生物治疗）。

Recent data from a phase III study showed zoledronic acid administered once every 12 weeks versus the current standard of once every four weeks does not compromise efficacy among women with breast cancer and bone metastases.

新的III期研究数据显示在乳腺癌骨转移女性当中唑来膦酸每12周给药1次与现行标准的每4周1次相比未降低疗效。

The SRE rate was 22% when zoledronic was administered every 4 weeks versus 23.2% when administered once in 12 weeks.

SRE率唑来膦酸每4周给药1次为22%，而每12周给药1次是23.2%。

The use of bisphosphonates should be accompanied by calcium and vitamin D supplementation with daily doses of calcium of 1200 to 1500 mg and vitamin D3 400 to 800 IU.

使用双膦酸盐类药物应该同时补充钙和维生素D，钙的每日剂量为1200-1500mg，维生素D3 400-800 IU。

Recommended agents for use in the United States are pamidronate 90 mg intravenously over 2 hours or zoledronic acid 4 mg intravenously over 15 minutes.

在美国推荐使用的药物帕米膦酸二钠90 mg静脉滴注2小时以上或唑来膦酸4 mg静脉滴注15分钟以上。

The original studies continued treatment for up to 24 months; however, there are limited long-term safety data indicating treatment can continue beyond that time.

原来的研究继续治疗长达24个月；有限的长期安全性数据表明治疗可以持续至超过该时间。

The risk of renal toxicity necessitates monitoring of serum creatinine prior to administration of each dose and dose reduction or discontinuation if renal function is reduced.

肾毒性风险需要在每次给药前监测血清肌酸酐，如果肾功能降低需减量或停药。

Current clinical trial results support the use of bisphosphonates for up to 2 years.

目前临床试验结果支持使用双磷酸盐类最多至两年。

Longer durations of bisphosphonate therapy may provide additional benefit, but this has not yet been tested in clinical trials.

双磷酸盐治疗持续时间更长可能提供额外获益，但是尚未在临床试验中验证。

ONJ, a complication of bisphosphonate treatment, has been described.

ONJ，双膦酸盐治疗的一个并发症，已被描述。

In a review of more than 16,000 cancer patients, an increased risk for jaw or facial bone surgery along with an increased risk of being diagnosed with inflammatory conditions or osteomyelitis of the jaw with the use of intravenous bisphosphonates was documented.

在一项超过16000例癌症患者的综述中，随着双磷酸盐的静脉使用，诊断为颌骨炎症或骨髓炎的风险以及下颌或面部骨骼手术的风险增加。

An absolute risk of 5.48 events per 100 patients treated was seen, with an increase in risk associated with an increase in cumulative dose of drug.

每100名治疗的患者见到绝对风险5.48个事件，随着累积剂量的增加风险增加。

It is recommended that patients should undergo a dental examination with preventive dentistry prior to initiation of bisphosphonate therapy.

在开始双膦酸盐治疗前建议患者应该接受预防性牙科检查。

Denosumab

地诺单抗

Women with metastatic breast cancer to bone who are candidates for bisphosphonate therapy may also be considered for treatment with denosumab (category 1).

乳腺癌骨转移的妇女适于双膦酸盐治疗也可考虑地诺单抗治疗（1类）。

This recommendation is based on the results of a single randomized trial comparing denosumab to zoledronic acid.

这个建议是基于一项比较地诺单抗与唑来膦酸独立随机试验的结果。

All trial patients were recommended to supplement with vitamin D and calcium.

所有试验患者均建议补充维生素D和钙。

Patients on the experimental arm were given 120 mg of denosumab injected subcutaneously every 4 weeks plus intravenous placebo versus the control arm where patients were given an intravenous infusion of 4 mg of zoledronic acid every 4 weeks, and a subcutaneous placebo.

试验组患者给予地诺单抗120 mg皮下注射每4周1次加静脉注射安慰剂而对照组患者给予唑来膦酸4 mg每4周1次静脉注射和皮下注射安慰剂。

In this trial with non-inferiority as the primary endpoint, denosumab was shown to significantly delay time to first SRE by 18% as compared with zoledronic acid (HR, 0.82; 95% CI, 0.71- 0.95; P < .001 for non-inferiority; P = .01 for superiority) and time to first and subsequent SREs (rate ratio, 0.77; 95% CI, 0.66-0.89; P = .001).

本试验的主要终点是非劣效性，与唑来膦酸相比地诺单抗显著延迟首次SRE18%（HR，0.82；95% CI 0.71-0.95  ；非劣效性P<.001；优势P = .01）和至首次或其次的SREs时间（率比，0.77；95% CI，0.66-0.89；P= .001）。

No difference in time to progression or OS was observed.

至进展时间或OS未观察到差异。

Adverse event profiles were similar for the two groups, including incidence of ONJ, with a reduced risk of renal-related and acute phase adverse events in the denosumab treatment group.

两组不良事件情况相似，包括ONJ发生率，地诺单抗治疗组肾脏相关的以及急性期不良事件风险降低。

Long-term risks of denosumab treatment are unknown.

地诺单抗治疗的长期风险未知。

The optimal duration of treatment with denosumab is not known.

地诺单抗治疗最佳的持续时间不清楚。