Pain outcomes in patients with advanced breast cancer and bone metastases

BACKGROUND:

In this study, the authors evaluated the effect of denosumab versus zoledronic acid (ZA) on pain in patients with advanced breast cancer and bone metastases.

METHODS:

The prevention of pain, reduction in pain interference with daily life activities, and the proportion of patients requiring strong opioid analgesics were assessed in a randomized, double‐blind, double‐dummy phase 3 study comparing denosumab with ZA for preventing skeletal‐related events in 2046 patients who had breast cancer and bone metastases. Patients completed the Brief Pain Inventory‐Short Form at baseline and monthly thereafter.

RESULTS:

Fewer patients who received denosumab reported a clinically meaningful worsening of pain severity (≥2‐point increase) from baseline compared with patients who received ZA, and a trend was observed toward delayed time to pain worsening with denosumab versus ZA (denosumab, 8.5 months; ZA, 7.4 months; P = .08). In patients who had no/mild pain at baseline, a 4‐month delay in progression to moderate/severe pain was observed with denosumab compared with ZA (9.7 months vs 5.8 months; P = .002). Denosumab delayed the time to increased pain interference by approximately 1 month compared with ZA (denosumab, 16.0 months; ZA, 14.9 months; P = .09). The time to pain improvement (P = .72) and the time to decreased pain interference (P = .92) were similar between the groups. Fewer denosumab‐treated patients reported increased analgesic use from no/low use at baseline to strong opioid use.

CONCLUSIONS:

Denosumab demonstrated improved pain prevention and comparable pain palliation compared with ZA. In addition, fewer denosumab‐treated patients shifted to strong opioid analgesic use. Cancer 2013. © 2012 American Cancer Society.     

The analgesic effect of calcitonin on breast cancer patients with bone metastases

Lately it has been reported that calcitonin is effective for the treatment of hypercalcemia and for the relief of pain caused by osteolytic bone metastasis. Thus we have studied the analgesic effect of synthetic eel calcitonin (ECT) on 8 breast cancer patients with bone metastases. ECT was administered in the dose of 20 or 40 I.U. twice a day intramuscularly for 7 days without other antineoplastic treatment, and the laboratory data of its analgesic effect and change has been examined. An analgesic effect was obtained on all 8 patients who had received ECT. However, an improvement of radiological findings of metastatic osteolysis and a decrease in urine hydroxyproline were not found after short term (7 days) treatment with calcitonin. These results suggest that the effect of ECT on the relief from pain due to bone metastasis is not caused by an improvement of the osteolytic metastatic lesions.     

Acquisition of metastatic tissue from patients with bone metastases from breast cancer

Biopsies of metastatic tissue are increasingly being performed. Bone is the most frequent site of metastasis in breast cancer patients, but bone remains technically challenging to biopsy. Difficulties with both tissue acquisition and techniques for analysis of hormone receptor status are well described. Bone biopsies can be carried out by either by standard posterior iliac crest bone marrow trephine/aspiration or CT-guided biopsy of a radiologically evident bone metastasis. The differential yield of these techniques is unknown. Results from three prospective studies of similar methodology were pooled. Patients underwent both an outpatient posterior iliac crest bone marrow trephine/aspiration and a CT-guided biopsy of a radiologically evident bone metastasis. Samples were assessed for the presence of malignant cells and where possible also for estrogen (ER) and progesterone receptor (PgR) expression. 40 patients were enrolled. Bone marrow aspiration/trephine biopsy was completed in 39/40 (97.5%) and CT-guided biopsy was completed in 34/40 (85%) of patients. Sufficient tumor cells for hormone receptor analysis were available in 19/39 (48.8%) and 16/34 (47%) of and bone marrow aspiration/trephine and CT-guided biopsies, respectively. Significant discordance in ER and PgR between the primary and the bone metastasis was also seen. Nine patients had tissue available from both bone marrow and CT-guided bone biopsies. ER and PgR concordance between these sites was 100 and 78%, respectively. Performing studies on human bone metastases is technically challenging, with relatively low yields regardless of technique. Given resource issues and similar success rates when comparing both techniques, bone marrow examination may be utilized first and if inadequate tissue is obtained, CT-guided biopsies can then be used.     

Management of bone metastases in breast cancer

Opinion statement Patients with advanced breast cancer who develop bone metastases suffer an ongoing risk of skeletal complications that can have a significant impact on their quality of life (QoL). These complications include bone pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy (HCM), a potentially life-threatening condition. Treatment options include radiotherapy to palliate bone pain and/ or prevent impending fracture, orthopedic surgery to prevent or repair fractures, analgesics, and bisphosphonates, which can significantly reduce the risk of skeletal complications and delay their onset. Of the known bisphosphonates, zoledronic acid is the most potent. Since its regulatory approval in the United States and Europe in 2001, zoledronic acid (4 mg by 15-minute infusion) has become widely used and has replaced pamidronate (90 mg by 2-hour infusion) as the standard of care for treating bone metastases from breast cancer and bone lesions from multiple myeloma. Zoledronic acid has also demonstrated significant long-term benefits in randomized trials in prostate cancer and other solid tumors, whereas other bisphosphonates have failed. In long-term, phase III clinical testing, zoledronic acid provided significant treatment benefits beyond those of pamidronate in patients with breast cancer and demonstrated a safety profile comparable with pamidronate. Therefore, zoledronic acid is now recommended from the first diagnosis of bone metastasis. Other intravenous bisphosphonates include clodronate and ibandronate. Both are approved in Europe, but their efficacy relative to pamidronate and zoledronic acid is not known.     

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.     

Role of breast surgery in T1-3 breast cancer patients with synchronous bone metastases

The impact of breast surgery on survival of metastatic breast cancer (MBC) patients is controversial. We addressed the question in a mono-institutional series of MBC patients with synchronous bone metastases. We identified 187 consecutive women diagnosed between 2000 and 2008 with locally operable (T1–T3) MBC, synchronous bone metastases, with no other distant sites being involved. Progression-free survival (PFS) and overall survival (OS) were compared between operated and non-operated patients. Median age was 51 years; 92 % of the women had a hormone-positive tumor. At the time of diagnosis, 131 patients out of 187 (70 %) underwent surgery. Operated and non-operated patients differed in terms of number of bone metastatic sites: a single metastasis was detected in 35 (28 %) operated, and 6 (11 %) non-operated cases (P = 0.01). No other significant differences were observed. The multi-adjusted hazard ratio was 0.63 (95 % CI 0.43–0.92) for PFS and 0.64 (95 % CI 0.41–0.99) for OS in favor of surgery. The 5-year cumulative incidence of ipsilateral breast skin progressions among non-operated patients was 18 %. In this large and homogeneous series of MBC patients with synchronous bone metastases, the role of breast surgery had a favorable impact on both disease progression and mortality.     

乳腺癌术后骨转移临床分析

目的 对191例乳腺癌术后骨转移患者进行临床分析。方法 对进行全身骨核素显像的742例中的191例乳腺癌术后有骨转移者的发病年龄，淋巴结转移、雌、孕激素（ER、PR），骨转移的部位，术后距骨转移的时间、部位等进行临床分析。结果 191例骨转移年龄25－73岁，中位年龄41．8岁，35－45岁发病最多，1至5年内发生骨转移者占116／191（60．7％），ER阴性者108／138（78．3％），有淋巴结转移者136／191（71．2％）。乳腺癌术后距骨转移的平均时间为32．7个月，骨转移部位以脊柱、骨盆为多，分别为51．3％和25．7％。有骨痛者127／191（66．5％），血清AKP异常者109／191（57．1％）。结论 对病期晚、有淋巴转移，ER阴性的中年妇女应高度重视，术后1至5年内定期作全身骨核素显像，以尽早发现骨转移，为早期诊断、早期治疗赢得时间。     

Detection of bone metastases in routine follow-up after treatment for primary breast cancer

BACKGROUND AND OBJECTIVES: The effect of follow-up after primary treatment for breast cancer on overall survival remains highly questionable, and controversy still exists regarding the benefits of regular follow-up. We therefore attempted to assess the role of intensive follow-up in patients with bone metastases. METHODS: We analyzed the survival of 87 breast cancer patients who relapsed first in bone diagnosed either with or without symptoms, from 1985 to 1998. Overall survival (OS) was the main outcome. Recurrence was coded as either asymptomatic, elevated tumor marker, or symptomatic. RESULTS: The median disease free interval was 33 months in the asymptomatic group, 42 months in the elevated tumor marker group, and 43 months in the symptomatic group. Overall survival did not differ significantly between the groups. The median OS was 77 months in the asymptomatic group, 78 months in the elevated tumor marker group, and 79 months in the symptomatic group. CONCLUSIONS: Our study showed that intensive testing, including assessment of serum tumor markers and bone scans, did not improve OS. The results of our study supported the American Society of Clinical Oncology (ASCO) recommendations that routine use of bone scans is not recommended.     

Cost-effectiveness of denosumab compared with zoledronic Acid in patients with breast cancer and bone metastases

BackgroundResults from a phase III clinical trial showed that denosumab significantly reduced the risk of first on-study and subsequent skeletal-related events (SREs) compared with zoledronic acid. This study aims to assess the cost-effectiveness of denosumab vs. zoledronic acid in the prevention of SREs in patients with advanced breast cancer and bone metastases.Materials and MethodsA Markov model was developed with 4-week model cycles and a 1-year time horizon. The health states were defined by SRE status (no SRE, first on-study SRE, subsequent SRE, no SRE but history of SRE) and SRE type (pathologic fracture, radiation to the bone, surgery to the bone, spinal cord compression). Costs (in 2011 US dollars) included drug, SRE treatment, and adverse event (AE) costs and were assessed from a third-party payer perspective. The primary outcome was incremental total cost per SRE avoided; the secondary outcome was incremental total cost per pathologic fracture avoided. One-way and probabilistic sensitivity analyses were used to assess the robustness of the model.ResultsDuring the 1-year treatment period, denosumab incurred $7522 higher costs ($30,033 for denosumab and $23,511 for zoledronic acid), 0.06 fewer SREs, and 0.02 fewer pathologic fractures per patient, which led to an incremental total cost per SRE and pathologic fracture avoided of $114,628 and $290,136, respectively, compared with zoledronic acid. Results were robust to 1-way and probabilistic sensitivity analyses.ConclusionAlthough denosumab demonstrated superiority in preventing SREs in the phase III trial, it may not be cost-effective compared with zoledronic acid because of its high cost.     

Association of the vitamin D receptor genotype with bone metastases in breast cancer patients

This study was designed in order to evaluate specific vitamin D receptor (VDR) genotypes as indicators of the likelihood of developing osseous metastases in breast cancer patients. Therefore, we determined polymorphisms of the VDR gene in a study group comprising 183 breast cancer patients. Specific fragments spanning over intron 8 and exon 9 of the VDR gene were amplified by polymerase chain reaction. The fragments were then incubated with each of the specific endonucleases APAI, BSMI or TAQI, respectively. The VDR gene polymorphisms were detected by the presence or absence of the particular restriction site using agarose gel electrophoresis. Statistical analyses revealed a significant correlation between both the VDR gene polymorphisms indicated as AA (absence of the APAI restriction site in both alleles) or TT (absence of the TAQI restriction site in both alleles), respectively, and the occurrence of bone metastases. Patients with the AA genotype have a 1.7-fold increased risk of developing bone metastases, whereas patients with the TT genotype have a 0.5-fold risk. Neither other genotypes nor allelic combinations displayed any further correlation with the clinical stage. The data suggest that the AA genotype of the VDR gene might be useful to identify breast cancer patients with a high probability of forming occult bone metastases who are considered to benefit from an adjuvant bone-protective therapy.     

Simulated bone metastases: A case study of two patients with breast cancer

Two case studies are used to discuss topical issues current in follow-up management of patients with early stage breast cancer. These issues include the role of screening and diagnostic bone scintigraphy and patient self-advocacy in clinical management.     

Two bedridden patients with bone metastases from breast cancer effectively treated with pamidronate therapy

Case 1: A 43-year-old woman underwent mastectomy because of locally advanced breast cancer with multiple bone metastases. She was treated with CMF therapy but developed a compression fracture of a thoracic vertebra after 10 months and received pamidronate therapy. Pamidronate administration relived her back pain after 2 months and she was able to walk again after 3 months. However, she developed a resistance to the treatment, and then refused another treatment. She was found to have hypercalcemia 6 months later and received pamidronate again, but died 9 months after the treatment. Case 2: A 52-year-old woman underwent mastectomy because of breast cancer (T2) and was diagnosed as having multiple bone metastases 24 months after the operation. She could not turn over in bed due to progressing bone pain and received pamidronate therapy with CMF therapy at home 23 months after the diagnosis. After 2 months, pamidronate administration relieved her bone pain and she was free of pain after 4 months. After 5 months, X-rays revealed that lytic lesions showed sclerosis, and the pamidronate therapy was assessed as producing a PR. Pamidronate therapy improved her quality of life and activities of daily living, and she continues to receive it this time as an outpatient. Pamidronate therapy is promising as an effective treatment for bedridden patients with bone metastasis from breast cancer.     

Double-blinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases

One hundred forty-four patients with breast cancer and osteolytic bone metastases were randomized to receive either oral clodronate 1,600 mg/d (73 patients) or placebo (71 patients), in addition to either chemotherapy or hormonal therapy, for up to 12 months. Patients were withdrawn from the study when the 12 months of treatment had been achieve or a new bone event occurred, which was defined as: hypercalcemia (> 3 mmol/l), increase in, or onset of new bone pain due to metastases, requirement of radiotherapy for bone pain relief, pathological fractures (including vertebral collapse, spinal cord compression) or death due to bone metastases. Patients are well balanced according to age, performance status, bone condition, except for fractures, more frequent in the clodronate group (25% vs 12%). Of the 137 evaluable patients, 69 received oral clodronate and 68 placebo. Clodronate significantly delayed the median time to onset of new bone events compared to placebo, respectively 244 days and 180 days (p = 0.05). Hypercalcemia did not occur in the clodronate group but was observed in four placebo-treated patients. Clodronate-treated patients had a significant reduction in pain intensity compared to placebo (p = 0.01; measured using a visual pain scale) and significantly fewer patients receiving clodronate required analgesics (p = 0.02). The evaluation of global efficacy by physicians and patients indicated that clodronate was more efficacious than placebo (respectively p = 0.02 and p = 0.01). No significant difference in incidence of adverse effects was observed between the two groups. Clodronate therapy significantly delayed the occurrence of new bone events in these patients with bone metastases from breast cancer and adds to treatment of malignant osteolysis.     

Management of bone metastases from breast cancer

Bone is the most common of breast cancer metastasis. Bone metastasis causes skeletal-related events(SREs), including pain, bone fractures, spinal cord compression, and hypercalcemia. SREs significantly impair patients' quality of life. The main purpose of treatment for bone metastasis is to prevent or delay SREs and to improve patients' quality of life. Accurate diagnosis of bone metastases is important in order to choose an appropriate treatment. Treatment of bone metastasis requires a multidisciplinary approach. Analgesic medication with NSAIDs and opioids is the first choice for pain control. In addition to bisphosphonate, the receptor activator of the nuclear factor κB ligand(RANKL)inhibitor, denosumab is a novel bone-targeting agent effective in preventing SREs. Prophylactic stabilization of impending fractures provides several advantages compared with fixation of an acute fracture, in terms of short hospitalization and a quick return to baseline. In general, radiation therapy is indicated for patients for whom surgery is suitable. Radiation therapy to palliate pain from bone metastasis can reduce the intake of analgesic medications. Local radiation therapy is indicated for a limited number of bone metastases, and systemic radionuclide therapy is appropriate for multiple lesions. In summary, treatment using these modalities for bone metastasis from breast cancer should be stratified, considering the symptoms, site of bone metastasis, and patients' life expectancy and performance status.     

Cost effectiveness of bisphosphonates in the management of breast cancer patients with bone metastases.

BACKGROUND: Bisphosphonates are recommended to prevent skeletal related events (SREs) in patients with breast cancer and bone metastases (BCBM). However, their clinical and economic profiles vary from one agent to the other. MATERIALS AND METHODS: Using modeling techniques, we simulated from the perspective of the UK's National Health Service (NHS) the cost and quality adjusted survival (QALY) associated with five commonly-used bisphosphonates or no therapy in this patient population. The simulation followed patients into several health states (i.e. alive or dead, experiencing an SRE or no SRE, and receiving first or second line therapy). Drugs costs, infusion costs, SREs costs, and utility values were estimated from published sources. Utilities were applied to time with and without SREs to capture the impact on quality of life. RESULTS: Compared to no therapy, all bisphosphonates are either cost saving or highly cost-effective (with a cost per QALY < or = 6126 pounds sterlings). Within this evaluation, zoledronic acid was more effective and less expensive than all other options. CONCLUSIONS: Based on our model, the use of bisphosphonates in breast cancer patients with bone metastases should lead to improved patient outcomes and cost savings to the NHS and possibly other similar entities.     

乳腺癌骨转移患者溶骨性骨代谢指标与治疗效果的关系

目的 探讨特异性的溶骨性骨代谢指标血I型胶原吡啶交联羧基末端肽(sICTP)、尿I型胶原吡啶交联氨基末端肽(uNTx)和尿吡啶酚(uPyd)与乳腺癌骨转移患者治疗反应的关系.方法 应用酶联免疫吸附试验(ELISA),测定120例乳腺癌患者的sICTP、uNTx和uPyd,比较其在骨转移和无骨转移患者中浓度的差别,并对乳腺癌骨转移患者进行随访,比较患者治疗前后sICTP、uNTx和aPyd指标与治疗效果的关系.结果 骨转移组患者的sICTP、uNTx和uPyd水平均明显高于无骨转移组(P<0.01),56例乳腺癌骨转移患者的sICTP、uNTx和uPyd指标间两两相关(均r>0.5,P<0.01).获得随访的45例乳腺癌骨转移患者中,临床受益组25例,sICTP、uNTx和uPyd治疗3个月后明显下降(P=0.025,P<0.001,P<0.001).病情进展组20例,治疗3个月后,sICTP、uNTx和uPyd无明显变化(P>0.05);而病情进展后,sICTP、uNTx和uPyd明显升高(P=0.011,P=0.002,P=0.002).Logistic回归分析结果显示,uPyd和uNTx治疗后降低的患者治疗收益的概率增加(OR=17.0,P=0.019;OR=16.7,P=0.015),而治疗后sICTP指标下降与治疗受益无关(P=0.841).结论 sICTP、uNTx和uPyd可作为乳腺癌骨转移患者评价疗效和转归监测的辅助指标.     

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。