镇痛药联合双膦酸盐治疗恶性肿瘤骨转移的相关进展

骨转移是晚期恶性肿瘤最常见的并发症之一.最常见的发生骨转移的恶性肿瘤,主要包括肺癌、乳腺癌、前列腺癌、肾癌、胃肠道肿瘤等.晚期肿瘤一旦发生骨转移,会引起局部的骨质破坏,从而引起骨痛、病理性骨折、神经压迫、高钙血症等一系列骨相关事件(SREs),严重影响患者的生活质量,甚至导致患者脊髓压迫,引起截瘫.晚期恶性肿瘤骨转移的...     

Management of bone health in solid tumours: From bisphosphonates to a monoclonal antibody

Patients with solid tumours are at risk of impaired bone health from metastases and cancer therapy-induced bone loss (CTIBL). We review medical management of bone health in patients with solid tumours over the past 30 years, from first-generation bisphosphonates to the receptor activator of nuclear factor κB ligand (RANKL)-targeted monoclonal antibody, denosumab. In the 1980s, first-generation bisphosphonates were shown to reduce the incidence of skeletal-related events (SREs) in patients with breast cancer. Subsequently, more potent second- and third-generation bisphosphonates were developed, particularly zoledronic acid (ZA). Head-to-head studies showed that ZA was significantly more effective than pamidronate for reducing SREs in patients with breast and castrate-resistant prostate cancer (CRPC), becoming the standard of care for more than a decade. The RANKL inhibitor denosumab was licensed in 2010, and head-to-head studies and integrated analyses confirmed its superiority to ZA for preventing SREs, particularly in breast cancer and CRPC. Bisphosphonates and denosumab have also been investigated for prevention of CTIBL in patients receiving hormonal therapy for breast and prostate cancer, and denosumab is licensed in this indication. Despite advances in management of bone health, several issues remain, notably the optimal time to initiate therapy, duration of therapy, and dosing frequency, and how to avoid toxicity, particularly with long-term treatment. In summary, introduction of ZA and denosumab has protected patients with bone metastasis from serious bone complications and improved their quality of life. Ongoing research will hopefully guide the optimal use of these agents to help maintain bone health in patients with solid tumours.     

Osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: a retrospective study

OBJECTIVE: Bone metastases are a major cause of morbidity in cancer patients. Treatment includes bisphosphonates, which are also associated with avascular osteonecrosis of the jaw (ONJ). Our aim was to evaluate the correlation between bisphosphonates and ONJ. PATIENTS AND METHODS: Of the 539 patients with bone metastases treated in our department from June 2002 to December 2006 with i.v. bisphosphonates, eight (1.5%) developed ONJ. RESULTS: The eight patients with ONJ had all been given zoledronic acid, and two had also been treated with pamidronic acid. In four of the patients, ONJ was diagnosed during treatment, while in the remaining four it was diagnosed several months after therapy with bisphosphonates had ended. Six of these patients received local noninvasive treatment, of whom five progressed. Two showed apparent autolimitation of the disease. The remaining two patients underwent surgical resection and currently show no signs of relapse. All eight ONJ patients presented with various concomitant risk factors such as paradontopathy, dental extraction, or spontaneous avulsion. CONCLUSIONS: Our results show that ONJ can appear months after interruption of treatment and that a surgical approach can be used in suitable cases. Closer cooperation is needed among specialists to define guidelines for the prevention of ONJ in patients with bone metastases.     

恶性肿瘤合并高钙血症22例临床特点及预后分析

目的：分析恶性肿瘤伴高钙血症患者的临床诊治特点以及预后情况。方法：回顾性分析我科2004年1月-2008年6月收治的22例晚期恶性肿瘤合并高钙血症患者的临床资料,并随访观察其生存情况,分析其临床特点、诊治规律及影响预后的主要因素。结果：22例患者血钙浓度为2．78～4．37mmol／L,经双膦酸盐治疗后血钙均降至正常;发现高钙血症后生存时间为3～153天,中位生存时间仅为36天。单因素分析显示,血钙浓度〉3．0mmol／L及远处转移部位／〉3处的患者预后差（P=0．02和P=0．008）;多因素分析提示血钙最高值与远处转移部位的数目均可视为独立的危险因素（P=0．017和P=0．007）,血钙值的升高和远处转移部位数目的增加均将增加死亡的风险。结论：高钙血症多见于恶性肿瘤晚期,预后差,应早期诊断,积极予双膦酸盐类药物降血钙治疗。血钙最高值与远处转移部位的数目是独立的预后因素。     

伊班膦酸钠联合化疗对肺癌骨转移的临床疗效

目的观察伊班膦酸钠(艾本)联合化疗对肺癌骨转移的止痛效果和不良反应。方法将67例患者分为A、B两组,A组为伊班膦酸钠联合化疗组,B组为单用伊班膦酸钠组。结果A、B两组止痛有效率分别为79.4%和72.7%,差异无显著性(P>0.05)。结论伊班膦酸钠可与化疗联合应用治疗肺癌骨转移性疼痛,且安全有效。     

前列腺癌骨转移临床诊疗专家共识(2008版)

在前列腺癌的发展过程中,至少有65%～75%的患者发生骨转移[1].在死于前列腺癌的患者中,有85%～100%的患者存在骨转移[2].目前,国内虽无确切的资料,但前列腺癌患者在初诊时骨转移却较常见,发生率甚至高达85%.前列腺癌骨转移可导致患者发生骨痛、病理性骨折等骨相关事件(skeletal related events,SREs).     

双膦酸盐辅助治疗骨巨细胞瘤的临床研究

目的：探讨双膦酸盐作为辅助治疗方法降低四肢骨巨细胞瘤复发率的可行性。方法：２００１年２月～２００７年８月我院及香港中文大学威尔士亲王医院收治的３９例四肢骨巨细胞瘤患者,男性２８例,女性１１例,年龄１８～４５岁。肿瘤影像学分级按Ｃａｍｐａｎａｃｃｉ分级标准,其中Ⅱ级１８例,Ⅲ级２１例。所有患者治疗前均经过病理活检诊断为骨巨细胞瘤。分为治疗组和对照组。对照组２０例患者,未予双膦酸盐治疗。治疗组１９例患者,于手术前给予１～３疗程的双膦酸盐治疗（唑来膦酸４ｍｇ,２～３周１次）,术后继续给予３个疗程以上的双膦酸盐治疗。所有患者均接受了手术治疗,手术方式包括囊内切除＋骨水泥或骨移植重建,瘤段切除＋骨移植或人工关节重建。结果：随访１９～３４个月。双膦酸盐治疗后患者疼痛减轻,ＶＡＳ疼痛评分由８.１９±１.３３减轻至２.４２±１.０１,差异有显著性意义（ｔ＝１５.３０４Ｐ＝０.０００）。７８.９％的患者肿胀减轻,６３.２％的患者在唑来膦酸治疗２～３疗程后Ｘ线片上肿瘤内出现明显的骨矿化增加或骨生成。治疗组的复发率为５.３％,低于对照组３５％,差异有显著性意义（χ２＝５.２８４,Ｐ＝０.０２２）。３级骨巨细胞瘤对照组的复发率为５０.０％,治疗组为９.１％,差异有显著性意义（χ２＝４.２９５,Ｐ＝０.０３８）。结论：双膦酸盐作为辅助治疗能够显著降低四肢骨巨细胞瘤的复发率。用药后症状与体征的改善,影像学中骨矿化或骨生成都可作为双膦酸盐疗效的评价方法。     

依班膦酸钠治疗97例骨转移瘤疼痛的临床观察

目的:评价国产依班膦酸钠(Ibandronate)治疗恶性肿瘤高钙血症和骨转移骨痛的疗效和不良反应;同时和帕米膦酸二钠进行疗效和不良反应比较.方法:高钙血症患者应用依班膦酸钠4mg,单次静脉滴注,观察3周内血钙变化;骨痛患者随机分配至A组或B组,A组单次静脉滴注依班膦酸钠4mg,B组单次静脉滴注帕米膦酸二钠90mg,观察3周内骨痛变化情况.结果:97例患者入组,可评价疗效93例,5例高钙血症患者依班膦酸钠治疗后血钙水平均明显下降,有效率为100%(5/5).骨转移疼痛患者中A组治疗有效率为73.5%,B组为59.0%,经统计学处理两组之间无明显差异.两组不良反应基本类似,B组发热发生率略高于A组.结论:依班膦酸钠对于恶性肿瘤骨转移所引起的骨痛和高钙血症具有较好的治疗作用,不良反应较轻,与帕米膦酸钠比较,骨痛缓解率和不良反应基本相似.     

Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases

Background:

The presence of bone metastases in patients with metastatic renal cell carcinoma treated with oral tyrosine kinase inhibitors (TKIs) is associated with poorer outcome as compared with patients without bone involvement. Concomitant bisphosphonates could probably improve outcomes but also induce osteonecrosis of the jaw (ONJ).

Methods:

Retrospective study on all the renal cell carcinoma patients with bone metastases treated with sunitinib or sorafenib between November 2005 and June 2012 at the University Hospitals Leuven and AZ Groeninge in Kortrijk.

Results:

Seventy-six patients were included in the outcome analysis: 49 treated with concomitant bisphosphonates, 27 with TKI alone. Both groups were well balanced in terms of prognostic and predictive markers. Response rate (38% vs 16% partial responses, P=0.028), median progression-free survival (7.0 vs 4.0 months, P=0.0011) and median overall survival (17.0 vs 7.0 months, P=0.022) were significantly better in patients receiving bisphosphonates. The incidence of ONJ was 10% in patients treated with TKI and bisphosphonates.

Conclusion:

Concomitant use of bisphosphonates and TKI in renal cell carcinoma patients with bone involvement probably improves treatment efficacy, to be confirmed by prospective studies, but is associated with a high incidence of ONJ.     

Optimizing clinical benefits of bisphosphonates in cancer patients with bone metastases

Bisphosphonates are important treatments for bone metastases. Considerations for optimizing the clinical benefits of bisphosphonates include efficacy, compliance, and safety. Several bisphosphonates are approved for clinical use; however, few have demonstrated broad efficacy in the oncology setting and been compared directly in clinical trials. Among patients with bone metastases from breast cancer, the efficacy of approved bisphosphonates was evaluated in a Cochrane review, showing a reduction in the risk of skeletal-related events (SREs) ranging from 8% to 41% compared with placebo. Between-trial comparisons are confounded by inconsistencies in trial design, SRE definition, and endpoint selection. Zoledronic acid has demonstrated clinical benefits beyond those of pamidronate in a head-to-head trial that included patients with breast cancer or multiple myeloma. Compliance and adherence also have effects on treatment efficacy. In a comparison study, the adherence rates with oral bisphosphonates were found to be significantly lower compared with those of intravenous bisphosphonates. The safety profiles of oral and intravenous bisphosphonates differ. Oral bisphosphonates are associated with gastrointestinal side effects, whereas intravenous bisphosphonates have dose- and infusion rate-dependent effects on renal function. Osteonecrosis of the jaw is an uncommon but serious event in patients receiving monthly intravenous bisphosphonates or denosumab. The incidence of this event can be reduced with careful oral hygiene. A positive benefit-risk ratio for bisphosphonates has been established, and ongoing clinical trials will determine whether individualized therapy is possible.     

Long-term effects of parenteral dichloromethylene bisphosphonate (CL2MBP) on bone disease of myeloma patients treated with chemotherapy

Data on the long-term treatment of myeloma bone disease with bisphosphonates are scanty. In a prospective pilot trial we evaluated the effect of long-term parenteral administration of dichloromethylene bisphosphonate (Clodronate), in addition to standard chemotherapy, in 30 patients with active myeloma bone disease. Patients were treated with a mean of 4 courses (range 2-8) of Clodronate: 300 mg/day i.v. for seven days followed by 100 mg/day i.m. for 10 days, administered at a mean interval of 4 months (range 3-6). The median follow-up was 24 months (range 8-36). Clodronate reduced bone pain rapidly and significantly, and reduced the mean values of the biochemical indices of bone resorption to within normal limits; these effects were maintained throughout the follow-up. In three hypercalcemic episodes serum calcium became normal after 2-5 days of treatment with Clodronate. No toxic or side effects were noticed. The occurrence of skeletal morbidity in patients treated with Clodronate was compared with that observed in the control group of myeloma patients (p less than 0.001) in severe bone pain as well as in the incidence of new osteolytic lesions and pathological fractures (p less than 0.001). Supportive Clodronate therapy contributes significantly in controlling the progression of myeloma bone disease.     

双膦酸盐治疗恶性肿瘤骨转移新进展

恶性肿瘤骨转移可以引起多种骨并发症,包括病理性骨折、需要放射治疗的严重骨骼疼痛、脊髓压迫以及危及生命的恶性高钙血症（骨相关事件）。本文回顾了双膦酸盐在多种恶性肿瘤骨转移中的临床研究结果及安全性。结果表明,双膦酸盐在多种恶性肿瘤骨转移所引起的骨相关事件的治疗中意义明确,然而其不良反应及治疗也值得进一步研究。     

重视特殊情况下肿瘤骨转移的诊治

恶性肿瘤骨转移是十分常见的现象,诊断和治疗并不十分困难。但在特殊的情况下,如骨病灶和其他部位占位病灶同时出现;或仅有骨的单发或多发病灶,但疾病的良恶性较长时间内难以确定;或骨病灶的性质大致明确,其他部位无病灶可寻;或原发肿瘤已消失多年,新出现骨病灶,此时诊断需要慎重。对于单纯肿瘤骨转移引起的疼痛,有可能出现麻醉性止痛药的过度使用和放疗的应用不足,也需要引起重视。     

Antiresorptive treatment options and bone health in cancer patients-safety profiles and clinical considerations

Antiresorptive therapies are the standard of care for maintaining bone health in patients with advanced cancers involving bone. In the absence of antiresorptive therapies, many patients with bone metastases from solid tumors will experience potentially debilitating skeletal-related events. Furthermore, older age is associated with decreased bone integrity both in female and male patients and also with increased risk for malignancies, such as breast and prostate cancer, which have a high risk of metastasis to bone. Although antiresorptive therapies are generally well tolerated, there have been reports of associated serious adverse events. Hypocalcemia, osteonecrosis of the jaw, renal events, and acute-phase reactions have been reported in patients with cancer receiving all types of antiresorptive therapies. Because the clinical indications of antiresorptive agents continue to expand, and new options are becoming available, it is important for clinicians to recognize adverse events so that they may be prevented or properly treated and managed. Moreover, the risk-benefit profiles of those agents must be considered on a per-patient basis.     

New treatment strategy for bone metastases from breast cancer

Breast cancer patients frequently develop bone metastasis. Parathyroid hormone-related protein, an osteoclast activating factor, might be necessary for tumorto erode bone and grow at skeletal site. Bisphosphonates have an affinity for bone and are potent inhibitors of osteoclastic bone resorption. In light of this,53 patients with bone metastasis from breast cancer were treated with chemoendocrine(mainly high-dose medroxyprogesterone acetate as the endocrine therapy) therapy + bisphosphonate (pamidronate, Aredia (R)). During the previous 6 years (median 27 months), 53 breast cancer patients with bone metastasis were treated with pamidronate + chemoendocrine therapy. The regimen consisting of pamidronate + chemoendocrine agent was administered to 27 patients as a post relapse first-line regimen and to the remaining 26 cases, which failed first- or second-line treatment as a second or third line regimen. As a result of the combination therapy, sclerotic changes were observed in the osteolytic lesions in 31 of the 53 patients (59%). The effect on the osteolytic lesions did not correlate with the duration of disease free interval, estrogen receptor (ER) status, presence/absence of previous therapy or number of " hot spot(s) ] on bone scintigraphy. Lessening of pain from the bone metastasis was achieved in 83% of the patients after 3 months of pamidronate administration. Pamidronate + chemoendocrine therapy seems highly promising.     

Challenges in the differential diagnosis of hypercalcemia: A case of hypercalcemia with normal PTH level

The hypercalcemias are a common and heterogeneous group of disorders, ranging from the occasional detection of a high level of serum calcium to a life-treating condition. In a patient presenting with hypercalcemia, a differential diagnosis can be established easily by measuring serum calcium and parathyroid hormone (PTH) concentrations. We describe the case of an 83-year-old man presenting with a severe symptomatic hypercalcemia with high-normal PTH level due to the coexistence of primary hyperparathyroidism and malignancy-associated hypercalcemia. The presence of two conditions producing hypercalcemia was revealed only during in-hospital stay and after the administration of an intravenous bisphosphonate, when the PTH concentration increased rapidly after bisphosphonate treatment with a decrease in serum calcium. The occurrence of two conditions producing hypercalcemia is a rare event in the literature, and should be considered in the presence of an abnormally high serum calcium level associated with normal or high-normal PTH, in order to establish a correct diagnosis and appropriate interventions.     

博宁治疗恶性肿瘤骨转移疼痛的疗效观察

目的：观察博宁（帕米膦酸二钠APD）对骨转移疼痛的临床疗效。方法：22例晚期恶性肿瘤骨痛患者静脉点滴博宁90mg一疗程,连用1－2个疗程,部分病例合并化(n=1）或内照射治疗（n=5)。结果：博宁对骨痛的总有效率为86.3%(19/22),合并化疗、^153Sm(钐）－EDTMP（乙二胺四甲基膦酸）治疗和单纯博宁治疗的有效率分别为90.9％、80.0％、66.7％。获效时间1－20天,83.3％患者在两周内获效,无明显毒副作用。结论：博宁是一种治疗恶性肿瘤骨转移骨痛的有效药物,能有效地缓解骨痛和活动功能障碍、提高患者的生活质量,与化疗、^153Sn-EDTMP内照射治疗联用,疗效更好。     

双膦酸盐类在实体肿瘤骨转移中的临床应用

实体瘤骨转移所致一系列症状较难处理,严重影响患者生活质量.双膦酸盐类是重要的姑息治疗手段.现就近年来双膦酸盐类控制实体瘤骨转移疼痛、骨相关事件(SRE)、高钙血症以及预防骨转移发生等方面的临床研究进展作一综述.     

Iodine-125 radioactive seed brachytherapy as a treatment for spine and bone metastases: A systematic review and meta-analysis

AimTo evaluate the analgesic efficacy, safety, and local tumor control of iodine-125 (¹²⁵I) seed brachytherapy (BT) for the management of spine and bone metastases.MethodsA systematic literature search was conducted using PubMed, the Cochrane Library, and Scopus databases. Data regarding patient demographics, tumor characteristics, procedural parameters, and clinical outcomes were extracted and analyzed.ResultsFourteen studies (7 prospective, 7 retrospective) were included, accounting for 689 patients, in our review. Analgesic efficacy was assessed at baseline and various postoperative time points. Significant improvement in pain was noted at 4- and 24-week follow-ups (p < 0.01). Interestingly, all studies that combined ¹²⁵I seed BT with cement augmentation reported relatively higher levels of pain reduction (mean pain reduction ≥4 points) as compared to the studies which applied ¹²⁵I seed BT as a stand-alone therapy (mean pain reduction ≥2 points), at the last follow-up. Local tumor control rates ranged widely from 14% to 100% at varying follow-ups. Median overall survival ranged between 10 months and 25 months. The overall complication rate was 19% (130/689) and mainly included minor subcutaneous hemorrhage, fever, myelosuppression, and seed displacement. Metrics assessing performance and quality of life demonstrated significant improvements from baseline to posttreatment.Conclusion¹²⁵I seed BT, alone or in conjunction with cement augmentation, may be a viable salvage therapy in appropriately selected patients. However, further studies are needed to analyze the long-term efficacy of this intervention as a palliative and curative modality.     

放疗联合内生场热疗对骨转移癌疗效的临床研究

目的观察热疗联合放疗治疗骨转移癌的疗效。方法经X线、CT、MRI或ECT证实的骨转移癌患者56例,随机分为治疗组和对照组,各28例;对照组行单纯放疗,治疗组在放疗后采用迈达NRL-002型内生场肿瘤热疗机加热60min,每周2次;观察疼痛缓解、体力状况、骨病灶好转情况及不良反应。结果治疗组疼痛缓解总有效率（显效＋有效）82.14%,明显优于对照组（57.14%）;治疗后1周内起效者20例（71.42%）,体力改善总有效率78.57%,骨病灶疗效总有效率75%,无严重不良反应发生。结论放疗配合内生场热疗治疗骨转移癌较单纯放疗更为有效,能明显地缓解疼痛,提高患者的生活质量。