骨改良药物在乳腺癌骨转移治疗中的应用进展

骨改良药物包括在临床上应用的双膦酸盐及2010年FDA批准上市的新药地诺单抗,是目前治疗恶性肿瘤骨转移、高钙血症及骨质疏松症的主要药物。该类药物在临床上应用广泛,种类较多,近年来在药物的应用时机、用法及毒副反应方面有一定进展和争议。本文就骨改良药物在乳腺癌骨转移治疗中的临床应用进行探讨。     

Biochemical markers of bone turnover in breast cancer patients with bone metastases: a preliminary report

BACKGROUND: Some biochemical markers of bone turnover are expected to reflect the disease activity of metastatic bone tumor. In the present study six biochemical markers were evaluated to determine appropriate markers for the detection of metastatic bone tumors from breast cancer (BC). METHODS: A panel of bone turnover markers was assessed in 11 normocalcemic patients with bone metastases from BC and in 19 BC patients without clinical evidence of bone metastases. Bone formation was investigated by measuring serum bone isoenzyme of alkaline phosphatase (BALP), osteocalcin (OC) and carboxy-terminal propeptide of type I procollagen (PICP): Bone resorption was investigated by measuring serum carboxy-terminal telopeptide of type I collagen (ICTP), fasting urinary pyridinoline (Pyr) and deoxypyridinoline (D-Pyr). RESULTS: PICP was influenced by age and menopausal status. Significant correlations were observed between each of bone turnover markers except between BALP and OC. The mean levels of the six bone turnover markers were higher in patients with bone metastases than in those without them and significance was observed except for OC. The best diagnostic efficiency by receiver-operating characteristic (ROC) analysis was provided by ICTP followed by Pyr or D-Pyr, BALP, PICP and OC and significance was observed between ICTP and OC. Multiple logistic regression analysis adjusted by age revealed that the only significant marker related to bone metastases was ICTP. CONCLUSIONS: Serum ICTP appears to be the leading marker of bone metastases from BC. However, to reveal the clinical usefulness of these markers, further examination will be needed to account for the ease and cost-effectiveness of the measurements.     

骨改良药治疗骨转移的研究进展

骨改良药是一类缓解因骨转移引起的疼痛、病理性骨折、脊髓压迫、高钙血症等一系列骨相关事件药物的总称。目前主要有双膦酸盐类药物和地诺单抗。骨改良药应用于证实有骨质破坏的骨转移患者,作为化疗、放疗的辅助用药,可以明显提高疗效,延长患者的生存期。此外,中医中药也可以有效缓解骨转移引起的一系列相关症状,改善预后。临床工作中要选择合理的药物,才能最大限度地降低骨转移患者的痛苦,提高生活质量。     

骨转换标志物在非小细胞肺癌骨转移临床应用价值的研究

Objective  

The purpose of this study was to assess the clinical application value of bone turnover markers in non-small-cell lung cancer (NSCLC) patients with bone metastases. Including diagnosing bone metastases, detecting bone metastatic spread.     

Changes of bone turnover markers and serum PTH after night or morning administration of zoledronic acid in breast cancer patients with bone metastases

Persistent circadian rhythm of bone turnover in bone metastatic breast cancer suggests greater skeletal retention of bisphosphonates if administered in the night. We assessed differential effects of night vs morning administration of zoledronic acid (ZA) on bone turnover. Forty-four breast cancer patients with bone metastases were randomised to receive intravenous ZA (4 mg) at 1100 or 2300 hours every 28 days for four times. Urinary concentration N-telopeptide of type-I collagen (NTX) and deoxypyridinolines, and serum C-telopeptide of type-I collagen (CTX), bone alkaline phosphatase (ALP), osteocalcin and Parathyroid hormone (PTH) was measured in the morning at baseline and after 4, 7, 14, 28, 56 and 84 days. Urinary ZA concentration was also measured. Zoledronic acid caused significant decreases of NTX and CTX (P<0.001), without any difference in percent changes between night and morning arms. Bone ALP and osteocalcin were also significantly affected by ZA (P=0.001), without any difference between arms. Parathyroid hormone significantly increased in both the arms; PTH increase was lower in the night arm (P=0.001). From the second administration onwards, urinary ZA level was significantly higher in the night arm (P<0.01). Administration of ZA at two opposite phases of the circadian cycle causes similar changes of bone-turnover marker levels, but has differential effects on the level of serum PTH.     

Oral ibandronate is as active as intravenous zoledronic acid for reducing bone turnover markers in women with breast cancer and bone metastases

Ann Oncol 2007; 18: 1165–1171 On page 1168,     

Detection of bone metastases in patients with breast cancer

Various methods have been evaluated for their ability to detect bone metastases in patients with breast cancer. Bone scanning and hydroxyproline measurements are insensitive and showed metastases in few patients with primary breast cancer despite the fact that most will develop bone metastases. We have therefore investigated the value of examining the bone marrow with immunocytochemical staining for breast carcinoma cells. Initial results in 68 patients with no evidence of bone metastases by conventional means indicated (a) that some patients have breast cancer cells in bone marrow despite having no evidence of dissemination using other tests, and (b) that patients with micrometastases relapse sooner than those patients with normal bone marrows.     

Ⅰ型胶原羧基端前肽和β胶原降解产物在乳腺癌骨转移诊断和随访中的价值

目的探讨Ⅰ型胶原羧基端前肽(PICP)和β胶原降解产物(β-CTx)在乳腺癌骨转移诊断和随访中的应用价值。方法将114例乳腺癌患者分为骨转移组(56例)和无骨转移组(对照组,58例)。对照组根据腋窝淋巴结转移情况分为p N0组(12例)、p N1组(15例)、p N2组(19例)和p N3组(12例),根据激素受体情况分为Lumina型组(30例)和非Lumina型组(28例)。分别测定114例患者血清中PICP和β-CTx的水平。结果骨转移组PICP和β-CTx的水平均高于对照组,差异有统计学意义(P<0.05)。对照组中,p N0组、p N1组、p N2组以及p N3组间的PICP和β-CTx水平比较,差异无统计学意义(P>0.05);非Lumina型组的PICP和β-CTx水平高于Lumina型组,差异有统计学意义(P<0.05)。对照组患者有7例无症状患者在随访过程中出现骨代谢指标异常升高,进一步检查发现有5例出现骨转移。结论骨代谢指标能够早于常规影像学检查提示骨转移的发生,在乳腺癌骨转移的诊断和远期随访中具有重要价值。     

Influence of adjuvant tamoxifen treatment on bone mineral density and bone turnover markers in postmenopausal breast cancer patients in Japan

Molecular prognostic and predictive factors have extensively been studied in different cancers during the past decades, some of which were found to be useful in diagnosis, follow up or even treatment of some malignant tumors. To assess the significance of c-erbB-1, c-erbB-2 and p53 expression in head and neck tumors among Iranian patients and their correlation with known prognostic factors, samples from 53 patients with squamous cell carcinomas of larynx and tongue were studied immunohistochemically. Strong immunoreactivity of c-erbB-1, c-erbB-2 and p53 was observed in 37 (70%), 40 (76%) and 37 (70%) of cases, respectively. The coexpression of these molecules was detected in 27 (50.9%) samples. Neither histological grading nor nodal involvement revealed correlation with c-erbB-1 and/or c-erbB-2 expression. No correlation was found between p53 expression and histological grade. However, a significant positive association was observed between p53 expression and nodal involvement. This data, which is the first report on head and neck squamous cell carcinomas (HNSCC) in Iran, indicates the significance of p53 protein expression which may result from p53 tumor suppressor gene inactivation in lymph node metastasis of HNSCC among Iranian patients.     

Oral ibandronate is as active as intravenous zoledronic acid for reducing bone turnover markers in women with breast cancer and bone metastases.

BACKGROUND: Phase III study comparing the effect of oral ibandronate and intravenous zoledronic acid on bone markers. PATIENTS AND METHODS: Breast cancer patients with bone metastases received ibandronate 50 mg/day (n = 137) or zoledronic acid 4 mg every 4 weeks (n = 138) for 12 weeks. The primary end point was mean percentage change in serum levels of cross-linked C-terminal telopeptide of type I collagen (S-CTX) at week 12. Urinary CTX (U-CTX), bone alkaline phosphatase (ALP), amino-terminal procollagen propeptide of type I collagen (PINP) and osteocalcin (OC) were also measured and bone pain and safety assessed. RESULTS: Both bisphosphonates significantly reduced S-CTX (mean ibandronate 76% +/- 29 (SD) versus mean zoledronic acid 73% +/- 47; P < 0.001 for both versus baseline) and U-CTX (ibandronate 78% +/- 50 versus zoledronic acid 86% +/- 17; P < 0.001). The difference in S-CTX between treatments was 0.6% (confidence interval -1.7% to 3.0%), which was within the prespecified noninferiority margin. Bone ALP, PINP and OC decreased by 26%-47% compared with baseline with both bisphosphonates. Compared with zoledronic acid, ibandronate patients reported fewer adverse events overall (65.0% versus 75.9%), and on days 1-3 (8.0% versus 47.5%), including less pyrexia (overall incidence 0% versus 16.8%) and bone pain (5.8% versus 12.4%). CONCLUSIONS: Oral ibandronate was well tolerated and statistically noninferior to zoledronic acid for percentage change in the bone resorption marker, S-CTX.     

Markers of bone turnover for the management of patients with bone metastases from prostate cancer

Although increased bone formation is a prominent feature of patients with osteosclerotic metastases from prostate cancer, there is also some evidence for increased bone resorption. The aim of this study was to compare the clinical utility of new bone resorption markers to that of bone formation in patients with bone metastases from prostate cancer before and after bisphosphonate treatment. Thirty-nine patients with prostate cancer and bone metastasis, nine patients with prostate cancer without bone metastases, nine patients with benign prostatic hyperplasia and 355 healthy age-matched men were included. Urinary non-isomerized (alpha CTX) and beta isomerized (beta CTX) type I collagen C-telopeptides (CTX) and a new assay for serum CTX were used to assess bone resorption. Bone formation was determined by serum osteocalcin, serum total (T-ALP) and bone (BAP) alkaline phosphatase and serum type I collagen C-terminal propeptide (PICP). Fourteen patients with bone metastases were also evaluated 15 days after a single injection of the bisphosphonate pamidronate (120 mg). Levels of all bone formation and bone resorption markers were significantly (P < 0.006-0.0001) higher in patients with prostate cancer and bone metastasis than in patients with benign prostatic hyperplasia, patients with prostate cancer without bone metastases and healthy controls. In patients with bone metastases the median was increased by 67% for serum osteocalcin, 128% for T-ALP, 138% for BAP, 79% for PICP, 220% for urinary alpha CTX, 149% for urinary beta CTX and 214% for serum CTX. After bisphosphonate treatment all three resorption markers significantly decreased by an average of 65% (P = 0.001), 71% (P = 0.0010) and 61% (P = 0.0015) for urinary alpha CTX, urinary beta CTX and serum CTX, respectively, whereas no significant change was observed for any bone formation markers. Patients with prostate cancer and bone metastases exhibit a marked increase in bone resorption, which decreases within a few days of treatment with pamidronate. These findings suggest that these new resorption markers may be useful for the management of these patients.     

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.     

The role of tumour markers in predicting skeletal metastases in breast cancer patients with equivocal bone scintigraphy

Bone scintigraphy (BS) is commonly performed in the staging and postoperative monitoring of breast cancer. Nevertheless, due to low specificity it often demonstrates hot spots with equivocal interpretation, which may be misleading in the management of these patients. The aim of this study was to assess the value of a serum tumour marker panel in selecting among the patients with equivocal BS those with bone metastases. Between January 1986 and December 1995, 297 breast cancer patients were followed-up after mastectomy with serial determinations of a CEA-TPA-CA15.3 tumour marker panel, BS and liver echography. The tumour marker panel was used to select patients with equivocal BS for examination of suspicious bone areas by further imaging techniques. Up to December 1995, 158 (53%) patients showed an equivocal BS and 47 patients developed bone metastases. In the 158 patients with equivocal BS, prolonged clinical and imaging follow-up over 45 months (mean; range 12-120) was used to ascertain the presence or absence of bone metastases. In these 158 patients the negative predictive value and positive predictive value of the tumour marker panel to predict bone metastases was 97% and 75% respectively. This study shows that in breast cancer patients the CEA-TPA-CA15.3 tumour marker panel has a high value in selecting those patients with bone metastases, or at high risk of developing clinically-evident bone metastases, among the large number of subjects with equivocal BS.     

骨转换生物标记物在乳腺癌骨转移瘤疗效评价与监测中的作用

骨转换生物标记物是近年来探索用于骨转移瘤疗效评价及监测的新方法.这些存在于骨转移患者血液及尿液中的生物标记物让我们更深入了解骨破坏的过程及骨骼与肿瘤之间的相互作用.本文旨在通过回顾常用骨生物标记物在骨转移瘤治疗与监测的相关研究,探讨其潜在的临床价值.     

Zoledronic acid and survival in breast cancer patients with bone metastases and elevated markers of osteoclast activity

OBJECTIVE: Most breast cancer patients with bone metastases will receive bisphosphonate treatment. This post hoc analysis investigated whether early normalization of urinary N-telopeptide of type I collagen (NTX) levels during bisphosphonate therapy correlates with a long-term reduction in skeletal-related event (SRE) risk and mortality in patients with breast cancer. METHODS: This was a retrospective subset analysis of a phase III randomized trial comparing i.v. zoledronic acid with pamidronate treatment in patients with bone metastases from breast cancer or multiple myeloma. Patients with breast cancer who had NTX assessments at baseline and at months 1 and 3 (n = 342) were classified as normal (NTX < 64 nmol/mmol creatinine) or elevated (NTX > or = 64 nmol/mmol creatinine). The relative risk for an SRE or death was estimated with Cox regression models. RESULTS: Among the 328 evaluable patients treated with zoledronic acid, 196 patients (59.7%) had elevated baseline NTX, with 149 of those patients (76.0%) having normalized NTX levels and 31 patients (15.8%) having persistently elevated NTX levels at 3 months. The normalized NTX group had significantly lower risks for a first SRE, a first fracture or surgery to bone, or death than the group that had persistently elevated NTX levels. CONCLUSIONS: These results suggest that early normalization of elevated baseline NTX while receiving zoledronic acid is associated with longer event-free and overall survival times compared with persistently elevated NTX. Further analyses in cancer patients with elevated marker levels are warranted to confirm the implications of these findings.     

乳腺癌骨转移的治疗现状与展望

目的:总结乳腺癌骨转移痛变治疗的新进展.方法:应用Medline及CNKI期刊全文数据库检索系统,以"乳腺癌、骨转移瘤和治疗"等为关键词,检索2004-2009年的相关文献,共检索到731条,纳入标准:1)骨转移瘤的特点和表现;2)骨转移肿瘤的核素治疗、放疗、手术治疗和化疗治疗;根据纳入标准,精选分析25篇文献.结果:乳腺癌患者病程中常见骨转移,治疗有双磷酸盐药物,化疗、放疗、放射性核素治疗和手术等,CT引导下的射频治疗是相对新的治疗方法,也有联合放疗和靶向药物治疗的实验研究在开展中.结论:针对乳腺癌骨转移瘤患者,长期、持续、有效的治疗方法是根据患者情况,选择性采用不同治疗措施的综合治疗.     

Bone metabolic markers in bisphosphonate therapy for skeletal metastases in patients with breast cancer

The use of bisphosphonates for skeletal metastasis of breast cancer is now well established. Although clinical judgement for treating skeletal metastasis is based on symptoms and imaging studies, accurate or quantitative means are few. Various bone metabolic markers have been developed and these were evaluated in patients with metastasis to bone. Bone metabolic markers, especially resorption markers, have been shown to be a good tool for the monitoring the response to therapy for skeletal metastasis. This is also true for bisphosphonate treatment for skeletal metastasis. Bone metabolic markers are produced by different mechanisms. There are some different classes of resorption markers; tartrate-resistant acid phosphatase (TRAP) is secreted by osteoclast, N- and C-terminal cross-linking telopeptide of type I collagen (NTx and CTx) are the degradation the products of type I collagen, mainly produced by cathepsin K, and pyridinoline cross-linked carboxyl-terminal telopeptides of type I collagen (I CTP) is also a degradation product of type I collagen, by matrix metalloproteases. Even though bone resorption markers are a good tool to monitor response to bisphosphonate therapy, there remains the question of which class of bone resorption markers is best suited to the task.