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,     

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.     

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.     

Under usage of zoledronic acid in non-small cell lung cancer patients with metastatic bone disease--a short communication

Background and aim

The use of zoledronic acid (ZA) is now recommended for patients with NSCLC and metastatic bone disease (MBD). We thus examined the rates of ZA administration in NSCLC looking specifically at the use of this drug with systemic chemotherapy (ZCt) and comparing overall survival between patients who had ZCt from diagnosis to those who had chemotherapy (Ct) alone.

Method

In this retrospective audit, we analysed the data of 114 consecutive patients with stage IV NSCLC and MBD at presentation. Forty-three of these patients had received zoledronic acid and chemotherapy (ZCt) and 71 had received chemotherapy alone (Ct).

Results

Forty-three (37.7%, 43/114) of NSCLC patients diagnosed with MBD received ZA with their first chemotherapy (ZCt). Patients on ZCt, after adjustment for the planned prognostic factors (sites of disease, histology and PS), had better overall survival (OS), with a median of 34 weeks, compared to those who received chemotherapy alone, who had a median of 19 weeks (p = 0.03), HR = 0.60 (95%CI: 0.38-0.96). After adjusting for prognostic factors (sex, age. single versus doublet chemotherapy), ZCt patients still maintained a trend to better OS (p = 0.06) HR 0.63 (95%CI: 0.39-1.02) 34 versus 21 weeks.

Conclusions

The percentage of patients with MBD treated with ZA at first chemotherapy (37.7%) is low. The addition of ZA increased OS in NSCLC patients with MBD in this audit. More formal policies and dedicated trials on the treatment of MBD in NSCLC patients need to be put in place.     

非小细胞肺癌孤立性骨转移的治疗

非小细胞肺癌（NSCLC）骨转移的治疗方法有手术、化疗、放疗等。近年来分子靶向治疗如地诺单抗成为NSCLC骨转移新的治疗方法。尽管治疗手段众多,但是NSCLC骨转移患者预后仍未得到明显改善。对于孤立性骨转移患者,积极的治疗可改善患者的生存及预后。     

骨转换标志物在非小细胞肺癌骨转移临床应用中价值的研究

背景与目的:骨转移导致骨质破坏,可引起骨转换标志物(bone turnover markers)水平的改变;因此,本研究旨在探讨骨转换标志物在非小细胞肺癌(non-small cell lung cancer,NSCLC)骨转移诊断及病情评价方面的应用价值.方法:定量检测76例NSCLC骨转移患者血清中碱性磷酸酶(alkaline phosphatase,AKP)、β-Ⅰ型胶原羧基端肽(β-C-terminal telopeptide of type Ⅰ collagen,β-CTx)、骨钙素(osteocalcin,OST)和骨特异性碱性磷酸酶(bone-specific alkaline phosphatase,BALP)水平,并与44例健康人群进行对照.结果:骨转移组患者血清中AKP、β-CTx和BALP水平均明显高于正常对照组.各骨转换标志物之间有很好的相关性,BALP和OST的表达水平与骨转移程度呈正相关性.β-CTx表达水平较高和BALP表达水平较低的患者发生病理性骨折可能性增加.结论:骨代谢标志物在NSCLC骨转移患者诊断及病情判断方面有重要的参考价值,在临床上有广泛的应用前景.     

Predictors of skeletal-related events in non-small cell lung cancer patients with bone metastases

Background

Skeletal-related events (SREs) cause significant pain and morbidity to many non-small cell lung cancer (NSCLC) patients. We try to evaluate the predictive factor of SREs in NSCLC patients with bone metastases.

Patients and methods

We retrospectively examined the medical charts of 273 patients diagnosed with bone metastases secondary to NSCLC. The predictive factor of SREs was analyzed using the first-event analyses and a survival-adjusted multiple-event analysis.

Results

Out of 273 patients with bone metastases, 171 (62.6%) had at least one SRE and 46 of these experienced multiple SREs. In the first-event analyses, a larger proportion of ever-smokers have experienced the SRE compared with never-smokers (odds ratio, 2.80; 95% CI, 1.32-6.00). In addition, ever-smokers (hazard ratio [HR], 1.75; 95% CI, 1.05-2.92), patients without history of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) therapy (HR, 2.12; 95% CI, 1.49-3.00) and patients with histology of nonadenocarcinoma (HR, 1.59; 95% CI, 1.14-2.22) had a shorter median time from bone metastasis to first SRE. In a survival-adjusted multiple-event analysis, clinical characteristics such as ever-smoking, nonadenocarcinoma, poor performance status (ECOG ≥ 2), and no history of EGFR TKI therapy were independent risk factor of development of SRE throughout the course of disease.

Conclusion

Our data indicate that patients with characteristics such as ever-smoking, nonadenocarcinoma, poor performance status, and no history of treatment with EGFR TKI are more likely to have SRE, so more vigilant surveillance and prevention should be considered to these patients.     

Role of zoledronic acid in the setting of bone metastases from non-small-cell lung cancer

Bone metastases are major sequelae of non-small-cell lung cancer and are associated with poor survival, skeletal-related events (SREs), and economic burden. In recent phase III trials, zoledronic acid has demonstrated a potential to prevent or delay SREs, although this has not yet translated into a survival benefit. Zoledronic acid is the first and only bisphosphonate with proven efficacy in the treatment of bone metastases associated with a broad range of tumors, including lung cancer. We report herein a case study that highlights the clinical benefit of zoledronic acid in a patient with squamous cell carcinoma of the lung.     

Biochemical markers of bone turnover and clinical outcome in patients with renal cell and bladder carcinoma with bone metastases following treatment with zoledronic acid: The TUGAMO study

Background:

Levels of bone turnover markers (BTM) might be correlated with outcome in terms of skeletal-related events (SRE), disease progression, and death in patients with bladder cancer (BC) and renal cell carcinoma (RCC) with bone metastases (BM). We try to evaluate this possible correlation in patients who receive treatment with zoledronic acid (ZOL).

Methods:

This observational, prospective, and multicenter study analysed BTM and clinical outcome in these patients. Serum levels of bone alkaline phosphatase (BALP), procollagen type I amino-terminal propeptide (PINP), and beta-isomer of carboxy-terminal telopeptide of type I collagen (β-CTX) were analysed.

Results:

Patients with RCC who died or progressed had higher baseline β-CTX levels and those who experienced SRE during follow-up showed high baseline BALP levels. In BC, a poor rate of survival was related with high baseline β-CTX and BALP levels, and new SRE with increased PINP levels. Cox univariate analysis showed that β-CTX levels were associated with higher mortality and disease progression in RCC and higher mortality in BC. Bone alkaline phosphatase was associated with increased risk of premature SRE appearance in RCC and death in BC.

Conclusion:

Beta-isomer of carboxy-terminal telopeptide of type I collagen and BALP can be considered a complementary tool for prediction of clinical outcomes in patients with BC and RCC with BM treated with ZOL.     

Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid.

PURPOSE: Three large, randomized trials of patients with bone metastases recently demonstrated that zoledronic acid reduces the risk of skeletal-related events. These trials provide an opportunity for investigating the correlation between bone metabolism and clinical outcome during bisphosphonate therapy. PATIENTS AND METHODS: Urinary measurements of N-telopeptide (Ntx) and serum bone alkaline phosphatase (BAP) were obtained in 1,824 bisphosphonate-treated patients-1,462 with zoledronic acid (breast, 490; prostate, 411; myeloma, 210; non-small-cell lung, 183; other, 168) and 362 with pamidronate (breast, 254; myeloma, 108). This exploratory cohort analysis grouped patients by baseline and most recent levels of Ntx as low (< 50 nmol/mmol creatinine), moderate (50 to 99 nmol/mmol creatinine), or high (> or = 100 nmol/mmol creatinine), and BAP as low (< 146 U/L) or high (> or = 146 U/L). The relative risks for negative clinical outcomes were estimated for each group using multiple-event and Cox regression models with time-varying covariates. RESULTS: Patients with high and moderate Ntx levels had 2-fold increases in their risk of skeletal complications and disease progression compared with patients with low Ntx levels (P < .001 for all). High Ntx levels in each solid tumor category were associated with a 4- to 6-fold increased risk of death on study, and moderate Ntx levels a 2- to 4-fold increased risk compared with low Ntx levels (P < .001 for all). Bone alkaline phosphatase also showed some correlation with risk of negative clinical outcomes. CONCLUSION: The bone resorption marker Ntx provides valuable prognostic information in patients with bone metastases receiving bisphosphonates.     

全身骨显像与肿瘤标志物联合检测对NSCLC骨转移的诊断价值

  目的  探讨全身骨显像和血清肿瘤标志物（CEA、CA125、CYFRA21-1）联合检测对非小细胞肺癌（non-small cell lung cancer,NSCLC）患者骨转移诊断的临床应用价值。  方法  回顾性分析广西医科大学附属肿瘤医院2014年1月至2016年6月185例首诊且经病理或细胞学检查确诊为NSCLC患者的全身骨显像及血清肿瘤标志物（CEA、CA125、CYFRA21-1）检测结果,计算单项检查与联合检查诊断骨转移效能。参照Soloway分级标准将NSCLC骨转移患者的全身骨显像结果进行分级。应用Spearman相关分析评价全身骨显像分级与血清肿瘤标志物水平的相关性。  结果  185例NSCLC患者中78例发生骨转移,骨转移发生率为42.16%（78/185）;全身骨显像诊断NSCLC骨转移的灵敏度、特异性分别为91.02%（71/78）、85.98%（92/107）。NSCLC骨转移组CEA、CA125及CYFRA21-1水平高于NSCLC无骨转移组,差异具有统计学意义（P < 0.05）;78例NSCLC骨转移患者中,EOD 0:8.98%（7/78）,EOD 1:50.00%（39/78）,EOD 2:21.79%（17/78）,EOD 3:19.23%（15/78）。Spearman相关分析结果显示,全身骨显像分级与CEA、CA125及CYFRA21-1水平存在相关性（r_s=0.579、0.274、0.327,均P < 0.05）。全身骨显像与肿瘤标志物联合检测NSCLC骨转移诊断效能高于各项单项检测效能（AUC=0.922）,灵敏度及特异性均提高（分别为92.30%、86.00%）。  结论  全身骨显像对诊断NSCLC骨转移的诊断效能较高,适宜作为NSCLC骨转移的首选筛查方法,在临床中具有重要应用价值。全身骨显像联合CEA、CA125、CYFRA21-1检测比单项检测有助于提高NSCLC骨转移病灶检出率,临床实用性更强。      

Iressa治疗非小细胞肺癌脑转移

非小细胞肺癌患者脑转移的发生率为20％～40％，虽然有证据提示含铂类方案的化疗对脑转移灶可获得与脑外转移灶类似的反应率，但姑息性的放射治疗仍是目前肺癌脑转移患者的标准治疗方法。令人失望的是其治疗效果甚差，中位生存时间只有3～4月。靶向治疗的出现是否能给这些患者带来希望?目前没有充足的证据。现报告我院2003年1月至2004年6月期间，Iressa治疗8例非小细胞肺癌脑转移患者的临床效果。     

Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid

BACKGROUND: For patients with bone metastases, high N-telopeptide of type I collagen (NTX) levels correlate with increased risks of skeletal-related events and death. However, the relation between NTX decreases and clinical benefits is unclear. METHODS: Correlations between NTX normalization during treatment and clinical outcome were retrospectively analyzed in 3 large, phase 3 trials. Urinary NTX levels were measured at baseline and at Month 3 in patients with bone metastases from breast cancer (BC; n = 578), hormone-refractory prostate cancer (HRPC; n = 472), or nonsmall-cell lung cancer and other solid tumors (NSCLC/OST; n = 291) who received zoledronic acid or control (pamidronate for BC; placebo for HRPC and NSCLC/OST) for up to 24 months. NTX levels were characterized as normal (N; <64 nmol/mmol creatinine) or elevated (E; > or =64 nmol/mmol creatinine). RESULTS: After 3 months of zoledronic acid, most N-group patients maintained normal levels; however, most E-group patients normalized their NTX levels (BC, 81%; HRPC, 70%; NSCLC/OST, 81%). In contrast, NTX levels normalized with pamidronate in 65% of BC, with placebo in 8% of HRPC, and in 17% of NSCLC/OST E-group patients. Normalized NTX correlated with improved overall survival versus persistently elevated NTX (significant for zoledronic acid-treated patients; trend for placebo-treated patients). Moreover, percentage reductions from baseline NTX levels correlated with benefits regardless of whether patients transitioned from E to N. CONCLUSIONS: Zoledronic acid normalizes or maintains normal NTX levels in most patients with bone metastases. Normalized NTX within 3 months of treatment, versus persistently elevated NTX, was associated with reduced risks of skeletal complications and death.     

Recommendations for zoledronic acid treatment of patients with bone metastases

The introduction of zoledronic acid, a new-generation bisphosphonate, has greatly extended the use of bisphosphonates in the treatment of patients with bone metastases. On the basis of results from three large, randomized, phase III clinical trials enrolling more than 3,000 patients, zoledronic acid (4 mg via 15-minute infusion) was approved in the United States for the treatment of patients with documented bone metastases from solid tumors in conjunction with standard antineoplastic therapy and patients with multiple myeloma. Zoledronic acid is also approved in Europe for the prevention of skeletal-related events in patients with advanced malignancies involving bone. Current treatment guidelines published by the American Society of Clinical Oncology recommend the use of intravenous bisphosphonates at first radiographic evidence of osteopenia in patients with multiple myeloma or osteolytic bone lesions in patients with breast cancer to significantly reduce the occurrence and delay the onset of skeletal complications. Zoledronic acid has also demonstrated efficacy in the treatment of bone metastases in patients with prostate cancer, lung cancer, and other solid tumors. Bisphosphonate therapy is generally well tolerated but can be associated with increases in serum creatinine. Therefore, monitoring renal function is required for all patients receiving bisphosphonate therapy. Serum creatinine should be monitored before each dose and treatment withheld until any serum creatinine elevations have resolved to baseline levels. Caution should be exercised when treating patients who are receiving other potentially nephrotoxic therapies. With these simple precautions, intravenous bisphosphonate therapy is safe for long-term use and provides durable treatment benefits.     

Possible improvement of survival with use of zoledronic acid in patients with bone metastases from renal cell carcinoma

Background

Bisphosphonates play an indisputable role in preventing skeletal-related events (SREs) secondary to bone metastases, and also have a direct effect on tumor cells. However, it remains unclear whether bisphosphonates improve overall survival (OS) for renal cell carcinoma (RCC) patients with bone metastases.

Methods

Between 1978 and 2010, a total of 45 patients who had RCC metastatic to bone and were classified as intermediate risk according to Memorial Sloan-Kettering Cancer Center criteria were included in this retrospective study. In this cohort, 23 patients received zoledronic acid (ZOL) treatment (ZOL-treated group) whereas the other 22 did not (non-ZOL-treated group). The primary endpoint was OS and the secondary endpoint was the SRE rate defined as the total number of SREs divided by the total years under study.

Results

For the cohort of 45 patients, the median OS from diagnosis of bone metastases was 27.2 months. Multivariate analysis showed that lower serum calcium (p = 0.0083) and ZOL treatment (p = 0.0013) were independent factors predicting longer survival. The ZOL-treated group had significantly longer OS than the non-ZOL-treated group (p = 0.0034). Patients in the ZOL-treated group experienced a lower SRE rate than patients in the non-ZOL-treated group (p = 0.0453). In particular, none of the patients in the ZOL-treated group developed spinal compression whereas 6 (28 %) in the non-ZOL-treated group did (p = 0.0479).

Conclusions

The current study indicates that ZOL not only reduces SREs but possibly improves OS in these patients.