Bone Metastasis Of Lung Cancer Research Articles

Clinical applications of strontium-89 therapy for bone metastases of lung cancer

Strontium-89(89Sr)therapy has been recognized as an effective method for treating bone metastases. It functions as a calcium analog that binds with collagen matrix produced by the MC3T3-E1 cells during collagen mineralization. 89Sr emits pure β rays which palliate bone pains and reduce the number of new metastasis sites. Response to 89Sr is affected by factors such as the location, size and histological type of lung cancer, the type of metastasis and the duration of treatment, and can be predicted by relief of bone pain, elimination of metastasis, CD4 +/CD8 +, ALP, and others. 89Sr therapy is safe and effective. Repeat administration or combined used with other treatments can improve the therapeutic effect of 89Sr. Key words: Strontium; Radiotherapy; Lung neoplasm; Bone neoplasms

Serum tartrate-resistant acid phosphatase 5b (TRACP5b) activity as a biomarker for bone metastasis in non-small cell lung cancer patients

Background Diagnosis and follow-up of bone metastasis (BMet) in non-small cell lung cancer (NSCLC) patients usually rely on symptoms and image studies. A serum marker of bone resorption may improve the quality of treatment in such patients. Tartrate-resistant acid phosphatase 5b (TRACP5b) is a specific marker for osteoclasts and we proposed it can be used as a marker of BMet in NSCLC patients. Methods In November 2002 till August 2008 serum samples were obtained from 141 newly diagnosed stage IIIA, IIIB or IV NSCLC patients and 41 normal subjects. All patients received baseline bone scintinography examination and evaluation of clinical symptoms as a standard of BMet diagnosis. Patients were divided into 2 groups by having BMet (Group I, n = 72) or not (Group II, n = 69). An in-house immunoassay using a TRACP-specific monoclonal antibody, 14G6, was used to measure the serum TRACP5b activity at pH 6.1. Results The mean serum TRACP5b activities of Group I, Group II and normal subjects were 3.50 ± 2.23 U/l, 2.09 ± 0.72 U/l and 2.33 ± 0.52 U/l, respectively. After adjusting for age, stage, gender, and histology in a generalized linear model, Group I has significantly higher TRACP5b activity than Group II ( p < 0.001). The receiver operating characteristic analysis established a cutoff value of 2.551 U/l to identify BMet in NSCLC patients with a sensitivity of 63.9% and a specificity of 76.8%. TRACP5b activity declined in patients who responded to treatment ( p = 0.047), and elevated in patients who developed new BMet ( p = 0.05). Conclusions Serum TRACP5b activity test is a potentially useful adjunct in diagnosing and monitoring BMet in NSCLC. Further study is warranted to establish its real value in diagnosis and monitoring of BMet in NSCLC patients.

The relationship between the serum collagen-type1 n-telopeptide (NTx) levels and bone metastasis of lung cancer.

e18095 Background: Bone metastasis is an important factor for determining the appropriate treatment for lung cancer patients; further bone metastasis influences prognosis as well as the quality of ...

(99m)Tc-MDP wholebody bone imaging in evaluation of the characteristics of bone metastasis of primary lung cancer

To explore the image characteristics of bone metastasis of primary lung carcinoma. Whole-body bone imaging ((99)Tc(m)-MDP) was performed in 258 patients with pathologically proven lung carcinoma. The rate of bone metastasis, distribution of the metastatic lesions and their characteristics were analyzed. Among the 258 cases, 142 patients developed bone metastasis. The overall rate of bone metastasis was 55.0%. The metastases located in axial skeleton were 49.6%, appendicular skeleton 36.0%, trunk bones of the axial skeleton 48.4%, and appendicular girdle skeleton 31.4%. Ribs, thoracic vertebrae, ilium and lumbar vertebrae had a higher rate of bone metastasis, higher than 20%, respectively. 1252 lesions were detected including 406 at the left side of the body, 387 in the axial skeleton and 459 at the right side of the body. There was no significant difference in terms of number of lesions between left side and right side (chi(2) = 3.3, P = 0.072). 1224 bone metastatic foci (97.8%) were presented as strong radioactive, 26 (2.1%) mixed lesion, and 2 (0.2%) low radioactive. According to the shape of the lesions, there were 810 punctate lesions (71.5%), 159 (14.0%) lump form, 108 (9.5%) strip form and 56 (4.9%) lamellar form. The accumulative bone metastasis rate was 28.7% for the patients with one to three lesions. The metastasis rate decreased gradually with the increasing number of metastatic lesions. Bone metastasis is very common in patients with lung cancer. Most bone metastases are characterized by strong radioactive and earlier punctate form, often occurs in the trunk bones of axial skeleton or appendicular girdles. The distribution of earlier metastases has not obvious regularity, and advanced bone metastases are often concurrent, multiple and multiform, widely and randomly distributed in the body.

Gender difference in bone metastasis of human small cell lung cancer, SBC-5 cells in natural killer-cell depleted severe combined immunodeficient mice

Lung cancer frequently develops multiple organ metastases, which thus makes this disease a leading cause of malignancy-related death worldwide. A gender difference is reported to affect the incidence and mortality of lung cancer; however, whether and how the gender difference is involved in lung cancer metastasis is unclear. This study evaluated the gender difference in multiple organ metastases in human small cell lung cancer (SBC-5) cells by using natural killer cell-depleted severe combined immunodeficient mice. Among multiple organ metastases, only bone metastasis formation significantly increased in female mice in comparison to males, while no significant difference was observed in the metastases to the liver and lungs. The suppression of androgen by castration or androgen receptor antagonist treatment in male mice also induced a significant increase of bone metastases. The number of osteoclasts in the bone metastatic lesions was greater in female mice and in mice with androgen suppression than in control male. However, there was no significant difference in the serum concentration of parathyroid hormone-related protein (PTHrP) associated with gender or androgen suppression. An in vitro study also indicated that sex steroid treatment had no effect on the proliferation or PTHrP production in SBC-5 cells. These results indicate that the balance of sex steroids therefore plays an important role in the formation of bone metastasis in small cell lung cancer, and suggests diverse mechanisms of interaction between cancer cells and host cells in the bone microenvironment.

Prediction of the Prognosis and Treatment Strategy for Bone Metastases of Lung Cancer

肺癌骨転移に対する予後予測と治療戦略の確立目的で 93 例の生存期間と予後関連因子，ゾレドロン酸水和物の効果について検討した．その結果，後ろ向き検討 30 例では，performance status (以下 PS)， 麻痺，術前予後判定点数総計点数が有意に予後に影響を与えていた．前向き検討 63 例では，PSと visual analogue scale (以下 VAS) が生存 6 ヵ月未満とそれ以上とで有意差があり，Cox 分析では PS だけが有意に予後に影響を与えていた．ゾレドロン酸水和物投与の 64.7%で VAS を 10/100 未満にできた．

Discordant findings in patients with non-small-cell lung cancer: absolutely normal bone scans versus disseminated bone metastases on positron-emission tomography/computed tomography

At present, metastatic bone involvement is usually assessed using bone scintigraphy, which has a high sensitivity but a poor specificity. The objective of our study was to compare the sensibility of the 2-deoxy-2-[18F] fluoro-d-glucose positron emission tomography/computed tomography (F-18 FDG PET/CT) for the detection of bone metastasis in patients with non-small-cell lung cancer (NSCLC) whose technetium 99m methylenediphosphonate (Tc-99m MDP) bone scans were absolutely normal. This study based on the retrospective analysis of 95 consecutive patients with histologically proven NSCLC who underwent F-18 FDG PET/CT and Tc-99m MDP bone scan at the Eskişehir Osmangazi University School of Medicine, Department of Nuclear Medicine between November 2006 and October 2008. Nineteen patients (19 of 95, 20%) with absolutely normal Tc-99m bone scan versus multiple high-grade F-18 FDG avid bony metastases on F-18 FDG PET/CT were selected for the review. Their ages ranged from 46 to 73 years (15 males and four females; mean: 57.2 years). Nine patients had squamous cell carcinoma, six had adenocarcinoma, three had large cell carcinoma and one had adenosquamous cell carcinoma. Tc-99m MDP bone scan that did not reveal bony abnormalities or radiotracer uptake was characteristic of benign disease (defined as absolutely normal) in these patients. Whereas, F-18 FDG PET/CT not only showed extremely disseminated heterogeneous nest-like high-grade FDG avid metastatic foci within the marrow cavity of the upper and lower thoracic spine, lumbar spine, pelvis, rib cages and bilateral proximal long bones, but also showed disseminated osteolytic bony metastases in these areas. Discordant findings of skeletal metastasis between Tc-99m MDP bone scans and F-18 FDG PET/CT imaging may be seen in 20% of the patients with NSCLC. F-18 FDG PET/CT could detect metastatic bone involvement more accurately than bone scintigraphy. Bone scans are insensitive to early bone marrow neoplastic infiltration. Assessment of glucose metabolism with FDG PET/CT can represent a more powerful tool to detect early bone metastases in lung cancer than with traditional bone scans.

A Bone Metastasis Model With Osteolytic and Osteoblastic Properties of Human Lung Cancer ACC-LC-319/bone2 in Natural Killer Cell-Depleted Severe Combined Immunodeficient Mice

Lung cancer is commonly associated with multiple-organ metastasis, and bone is a frequent metastatic site for lung cancer. Lung cancer frequently develops osteolytic, and less frequently osteoblastic, metastasis to bone. Osteolytic metastasis models of lung cancer have been reported, but no osteoblastic metastasis model is available for lung cancer. In the present study, we established a reproducible model of human lung cancer with both osteolytic and osteoblastic changes in natural killer cell-depleted severe combined immunodeficient mice. Intravenous inoculation of ACC-LC-319/bone2 cells resulted in the development of metastatic colonies in the lung, liver, and bone of the mice. As assessed sequentially by X-ray photographs, osteolytic bone lesions were observed by day 28, and then osteoblastic lesions were detected by day 35. Histological examination revealed the presence of bony spurs, a hallmark of osteoblastic bone metastasis, where osteoclasts were hardly observed. Treatment with an anti-human vascular endothelial growth factor antibody, bevacizumab, as well as zoledronate, inhibited the number of experimental bone metastases, including osteoblastic changes produced by ACC-LC-319/bone2 cells. These results indicate that our bone metastasis model by ACC-LC319/bone2 might be useful to understand the molecular pathogenesis of osteolytic and osteoblastic metastasis, and to identify molecular targets to control bone metastasis of lung cancer.

Treatment of Bone Metastases in Lung Cancer: The Actual Role of Zoledronic Acid

Approximately 30-40% of NSCLC patients develop bone metastases. Bone metastases are associated with a significant increase in skeletal-related events (SREs), including severe bone pain, hypercalcemia, pathological fractures, spinal cord compression. These SREs result in impaired mobility, reduced quality of life, and frequently require therapeutic intervention (radiation therapy, surgery and systemic treatments). The normal balance of formation of new bone by osteoblasts and the resorption of old bone by osteoclasts becomes imbalanced and/or uncoupled, leading to the development of lesions that are osteolytic, osteoblastic, or a combination of both. The current National Comprehensive Cancer Network (NCCN) Clinical Practice Giudelines in Oncology recommend palliative external-beam radiotherapy for the treatment of bone metastases in patients with NSCLC and healthcare professionals treating such patients are urged to consider bisphosphonate therapy. Zoledronic acid is the first and only bisphosphonate that has proven efficacy for the treatment of bone metastases from a broad range of solid tumor types, including lung cancer.

Bone metastasis in patients with non-small cell lung cancer: The diagnostic role of F-18 FDG PET/CT

Purpose To evaluate the performance of F-18 FDG PET/CT in the detection of bone metastasis in non-small cell lung cancer (NSCLC) patients. Materials and methods Three hundred and sixty-two consecutive NSCLC patients who underwent F-18 FDG PET/CT scanning were retrospectively analyzed. Each image of PET/CT, combined CT, and PET was performed at 10 separate areas and interpreted blindly and separately. The sensitivity, specificity and accuracy of F-18 FDG PET/CT, combined CT and F-18 FDG PET were calculated and the results were statistically analyzed. Results Bone metastasis was confirmed in 82 patients with 331 positive segments based on the image findings and clinical follow-up. On patient-based analysis, the sensitivity of F-18 FDG PET/CT (93.9%) was significantly higher than those of combined CT (74.4%) and F-18 FDG PET (84.1%), respectively ( p < 0.05). The overall specificity and accuracy of combined CT, F-18 FDG PET, and F-18 FDG PET/CT were 90.7%, 93.2%, 98.9% and 87.0%, 91.2%, and 97.8%, respectively (compared with PET/CT, p < 0.05). On segment-based analysis, the sensitivity of the three modalities were 79.5%, 94.3%, and 98.8%, respectively (compared with PET/CT, p < 0.05). The overall specificity and accuracy of the three modalities were 87.9%, 89.2%, 98.6% and 84.5%, 91.2%, 98.7%, respectively (compared with PET/CT, p < 0.05). Conclusion F-18 FDG PET/CT is superior to F-18 FDG PET or combined CT in detecting bone metastasis of NSCLC patients because of the complementation of CT and PET. It is worth noting that the added value of F-18 FDG PET/CT may beneficially impact the clinical management of NSCLC.

The Markers of Bone Turnover in Patients with Lung Cancer

Bone metastases may change the primary treatment modality, especially if the bone is the only site of metastasis in patients considered to be in the early stage of lung cancer. It is usually diagnosed by imaging techniques. However, the diagnostic yields of imaging methods are limited. Some bone markers such as propeptides of type-1 collagen, pyridinoline cross-links and deoxypyridinoline (D-PYD) cross-links, serum osteocalcin, alkaline phosphatase are thought to be useful in the detection of bone metastasis in lung cancer. Thus, we aimed to determine the clinical usefulness of bone turnover markers in the assessment of bone metastases in patients with lung cancer. Urinary D-PYD, calcium, and serum osteocalcin, calcium and total alkaline phosphatase (T-ALP) were measured in 60 lung cancer patients. Patients were evaluated by technetium 99 (99Tc) bone scintigraphy. The comparisons of measured values in patients with and without bone metastasis were done by using appropriate statistical methods. Fifty-four males and six females were included into study. Twenty-two patients had bone metastases, while 38 did not. Forty-two patients were nonsmall-cell lung cancer, whereas 18 were small-cell carcinoma. Urinary D-PYD level was the unique value that was statistically significantly higher in patients with bone metastases than that level in patients without bone metastasis (p < 0.05). Our study suggests that urinary measurement of D-PYD might be helpful in detecting bone metastasis in lung cancer. The high urinary D-PYD level may be an early sign of occult metastases in patients with no bone metastasis assessed by scintigraphic techniques.

Predictors of Survival in Patients With Bone Metastasis of Lung Cancer

The prognosis of patients with bone metastasis from lung cancer has not been well documented. We assessed the survival rates after bone metastasis and prognostic factors in 118 patients with bone metastases from lung cancer. The cumulative survival rates after bone metastasis from lung cancer were 59.9% at 6 months, 31.6% at 1 year, and 11.3% at 2 years. The mean survival was 9.7 months (median, 7.2 months; range, 0.1-74.5 months). A favorable prognosis was more likely in women and patients with adenocarcinoma, solitary bone metastasis, no metastases to the appendicular bone, no pathologic fractures, performance status 1 or less, use of systemic chemotherapy, and use of an epithelial growth factor receptor inhibitor. Analyses of single and multiple variables indicated better prognoses for patients with adenocarcinoma, no evidence of appendicular bone metastases, and treatment with an epithelial growth factor receptor inhibitor. The mean survival period was longer in a small group treated with an epithelial growth factor receptor inhibitor than in the larger untreated group. The data preliminarily suggest treatment with an epithelial growth factor receptor inhibitor may improve survival after bone metastasis.

Molecular pathogenesis and its therapeutic modalities of lung cancer metastasis to bone

Bone metastasis is a critical problem of lung cancer patients. Reproducible animal models of lung cancer bone metastasis, like NK-cell depleted SCID mouse model with SCB-5 cells, are useful to explore the molecular mechanism and search of molecular targets. SBC-5 cells overexpressed PTHrP and that treatment with anti-PTHrP neutralizing antibody inhibited the production of bone metastases of SBC-5 cells in the NK-cell depleted SCID mouse model, indicating the critical role of PTHrP in bone metastasis in this model. In addition, we demonstrated that several compounds, including bisphosphonates and reveromycin A, potentially suppress osteoclast-activity were beneficial for the treatments of bone metastasis. Multi-modality therapy may be necessary for further augmenting the therapeutic efficacy against lung cancer bone metastasis.

PD6-3-3: Medical and economical impact of bone metastases in lung cancer patients: a prospective French national, multicentric study (GFPC 06-01 study)

Bone metastases are an important emerging problem in patients with lung cancer and are leading to increasing consumption of health care resources. To assess the epidemiology, the management strategies and the costs of bone metastases in lung cancer; to model the management of these patients by a Markov model in order to evaluate the effectiveness of different therapeutic strategies. prospective, national, multicentric, observational, epidemiological study planned to include 500 patients between may 2006 and may 2007, with a one year follow up, a monthly report of skeletal-related events and resources consumptions. The economic analysis is limited to the direct costs with the health care payer’s perspective. At this time, 404 patients are included by 36 centres: men: 77,2%, median age: 61 (39-84) years, non small cell lung cancer: 90%. Bone diagnosis metastases is made by scintigraphy (59.7%), standard radiology or RMI (3.4%), and bone-scan (36.9%). At inclusion the median number of lesions was 4; 74.4% of patients receive an analgesic treatment, 41.5% a biphosphonates therapy (zoledronate in 83% of cases), 20.5% a radiotherapy and 5%.had a bone-surgery. complete demographic, clinical and economical datas will be presented at the IASCL meeting.

β-CTX and ICTP Act as Indicators of Skeletal Metastasis Status in Male Patients with Non-Small Cell Lung Cancer

Bone metastasis is common in lung cancer patients and associated with reduced quality of life and reduced overall and median survival, so the early detection of bone metastasis and monitoring of its status is very important for clinicians. Serum bone-specific alkaline phosphatase (BAP), osteocalcin (OC), beta isomer of C-terminal telopeptide of type I collagen (beta-CTX) and cross-linked C-terminal telopeptide of type I collagen (ICTP) were compared with regard to their usefulness as indicators of bone metastasis in lung cancer. The serum concentrations of the 4 markers were measured by commercially available tests in 96 male patients with non-small cell lung cancer and 30 male patients with other pulmonary diseases. The levels of both â-CTX and ICTP were significantly higher in 61 lung cancer patients with bone metastases than in 35 lung cancer patients without bone metastases (both p<0.001), and significantly correlated with the extent of bone disease. Although ICTP had a better sensitivity and accuracy than beta-CTX (75.4% vs 65.6% and 72.9% vs 68.8%, respectively), they had a similar area under the receiver operating characteristic curve (0.85 vs 0.83). These results support the use of beta-CTX and ICTP as an adjunct tool for the diagnosis and screening of bone metastasis in lung cancer.

Parathyroid hormone-related protein and ezrin are up-regulated in human lung cancer bone metastases

Lung cancer often metastasizes to bone in patients with advanced disease. Identification of the factors involved in the interactions between lung cancer cells and bone will improve the prevention and treatment of bone metastases. We identified changes in metastasis-related gene expression of human HARA lung squamous carcinoma cells co-cultured with neonatal mouse calvariae using a pathway-specific microarray analysis. Nine genes were up-regulated and two genes down-regulated in HARA cells co-cultured with mouse calvariae. Five of the nine up-regulated genes, including caveolin 1, CD44, EphB2, ezrin, and Parathyroid hormone-related protein (PTHrP), and one down-regulated gene, SLPI, were further confirmed by Reverse transcription-polymerase chain reaction (RT-PCR). A mouse model was subsequently used to study the role of PTHrP and ezrin in bone metastasis in vivo. PTHrP (all three isoforms) and ezrin were up-regulated in HARA cells at sites of bone metastasis as detected by RT-PCR and immunohistochemistry. The PTHrP 141 mRNA isoform was increased by the greatest extent (13.9-fold) in bone metastases compared to PTHrP 139 and PTHrP 173 mRNA. We then generated a HARA cell line in which PTHrP expression was inducibly silenced by RNA interference. Silencing of PTHrP expression caused significant reduction of submembranous F-actin and decreased HARA cell invasion. Ezrin up-regulation was confirmed by Western blots on HARA cells co-cultured with adult mouse long bones. Further, Transforming growth factor beta (TGF-beta) was identified as one of the factors in the bone microenvironment that was responsible for the up-regulation of ezrin. The identification of PTHrP and ezrin as important regulators of lung cancer bone metastasis offers new mechanistic insights into the metastasis of lung cancer and provides potential targets for the prevention and treatment of lung cancer metastasis.

Beta-CTX and ICTP act as indicators of skeletal metastasis status in male patients with non-small cell lung cancer

Bone metastasis is common in lung cancer patients and associated with reduced quality of life and reduced overall and median survival, so the early detection of bone metastasis and monitoring of its status is very important for clinicians. Serum bone-specific alkaline phosphatase (BAP), osteocalcin (OC), beta isomer of C-terminal telopeptide of type I collagen (beta-CTX) and cross-linked C-terminal telopeptide of type I collagen (ICTP) were compared with regard to their usefulness as indicators of bone metastasis in lung cancer. The serum concentrations of the 4 markers were measured by commercially available tests in 96 male patients with non-small cell lung cancer and 30 male patients with other pulmonary diseases. The levels of both â-CTX and ICTP were significantly higher in 61 lung cancer patients with bone metastases than in 35 lung cancer patients without bone metastases (both p<0.001), and significantly correlated with the extent of bone disease. Although ICTP had a better sensitivity and accuracy than beta-CTX (75.4% vs 65.6% and 72.9% vs 68.8%, respectively), they had a similar area under the receiver operating characteristic curve (0.85 vs 0.83). These results support the use of beta-CTX and ICTP as an adjunct tool for the diagnosis and screening of bone metastasis in lung cancer.

The diagnostic value of serum β-CTX and urinary CTX/CR in lung cancer with bone metastasis

The study included 24 patients of lung cancer with bone metastasis, 26 patients of lung cancer without bone metastasis and 27 healthy controls. The serum levels of β-crosslaps of type Ⅰ collagen (β-CTX), M-MID and urinary β-CTX/creatinine (CTX/CR) were measured by ELISA. Results showed that the serum levels of β-CTX and urinary CTX/CR in lung cancer patients with bone metastasis were significantly higher than those without bone metastasis (P ＜ 0. 01 ). The findings suggest that the measurement of serum β-CTX and urinary CTX/CR may indicate bone metastasis in lung cancer. Key words: Lung neoplasms ; Neoplasm metastasis ; β-crosslaps of type Ⅰ collagen ;

Analyse médico-économique des métastases osseuses des cancers broncho-pulmonaires: Étude 0601 du Groupe Français de Pneumo-Cancérologie

Bone metastases are common in lung cancer and are leading to increasing consumption of health care resources. The therapeutic choice for the clinician is extensive, from biphosphonates to percutaneous vertebroplasty. In the absence of official guidelines the management varies from centre to centre. There are very few economic analyses of these patients.Study 06-01 of the French Lung Oncology Group is a medico-economic analysis of the management of bone metastases in lung cancer. It is a national, multicentre, observational, epidemiological study. The primary objective is to assess the epidemiology, the management strategies and the costs of bone metastases in lung cancer. The secondary objective is to develop a medico-economic model of the management based on a Markov model in order to evaluate the effectiveness of different therapeutic strategies.The aim of this study is a better understanding of theses patients at a time when few observational studies have been undertaken.

Impact of Skeletal Complications on Total Medical Care Costs among Patients with Bone Metastases of Lung Cancer

Previous studies have estimated the costs of skeletal-related events (SREs) for patients with bone metastases of solid tumors by tallying costs for services specifically attributable to these events. This approach may underestimate costs if SREs indirectly increase use of other services. This is a retrospective observational study using a large health insurance claims database. Patients with bone metastases of lung cancer who experienced > or =1 SRE were matched to similar patients without SREs based on propensity scores. Kaplan-Meier estimated total medical care costs were compared for propensity-matched samples of patients with SREs and without SREs. We identified 534 patients with lung cancer and bone metastases, including 295 (55%) with > or =1 SRE. After matching, there were 162 patients each in the SRE and no-SRE groups with mean follow-up of 5.3 and 3.9 months, respectively. In the SRE group, costs of treatment of SREs were $9,480 (95% CI $7,625 to $11,374) per patient. Total medical care costs were $27,982 (95% CI $15,921 to $40,625) greater for SRE versus no-SRE patients (p < 0.001). The costs of SREs in patients with lung cancer and bone metastases are substantial and potentially greater than previously estimated.