|
1
|
Huang K, Tang X, Tang F. Combined chemotherapy of zoledronic acid and pamidronate in the treatment of bone metastases from nonsmall cell lung cancer and the effects on pain stress and bone metabolic indices. Drug Dev Res 2024; 85:e22147. [PMID: 38349271 DOI: 10.1002/ddr.22147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 12/12/2023] [Accepted: 01/02/2024] [Indexed: 02/15/2024]
Abstract
OBJECTIVE We conducted this paper to decipher the efficacy of the combined chemotherapy of zoledronic acid and pamidronate in treating bone metastases from nonsmall cell lung cancer (NSCLC) and the effects on pain stress and bone metabolic indices. METHODS Patients with bone metastases from NSCLC were allocated into Group A and Group B. Patients in the Group A were administrated with pamidronate combined chemotherapy and patients in the Group B were administrated with zoledronic acid combined chemotherapy. The efficacy, pain symptom scores, quality of life scores, serum inflammatory factor, serum bone metabolic indices, serum pain stress indicators, and the occurrence of adverse effects were compared in patients of the two groups. RESULTS The total effective rate of treatment was higher in the Group B than in the Group A. After treatment, reduced Numerical Rating Scale scores and elevated Karnofsky Performance Score score, reduced serum levels of N-terminal mid-fragment of osteocalcin, N-terminal propeptide of type I procollagen, bone-specific alkaline phosphatase, and type I collagen hydroxyl terminal peptide β special sequence, reduced serum levels of C-reactive protein, procalcitonin, tumor necrosis factor-α, and interleukin-6, as well as decreased levels of bradykinin, substance P, neuropeptide Y, and β-endorphin were found in the Group B versus the Group A. No notable difference was witnessed in the rate of adverse reactions between the Group A and the Group B. CONCLUSION Zoledronic acid combined with chemotherapy can effectively treat bone metastases of NSCLC and improve pain stress and bone metabolic status, which has value that can be promoted and applied in clinical treatment.
Collapse
Affiliation(s)
- Kun Huang
- Department of Orthopaedics, Guiyang Yunyan District People's Hospital, Guiyang, Guizhou, China
| | - Xiao Tang
- Department of Orthopaedics, Guiyang Yunyan District People's Hospital, Guiyang, Guizhou, China
| | - Fang Tang
- Department of Rheumatism, the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| |
Collapse
|
|
2
|
Kim J, Jeong C, Lee J, Ha J, Baek KH, Kim S, An TJ, Park CK, Yoon HK, Lim JU. Bone-modifying agents for non-small-cell lung cancer patients with bone metastases during the era of immune checkpoint inhibitors: A narrative review. Semin Oncol 2023; 50:105-112. [PMID: 37723018 DOI: 10.1053/j.seminoncol.2023.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 09/05/2023] [Accepted: 09/11/2023] [Indexed: 09/20/2023]
Abstract
During the course of lung cancer progression, bone metastases occur in about 40% of patients. Common complications associated with bone metastases in lung cancer patients include musculoskeletal pain, pathologic fractures, spinal cord compression, and hypercalcemia. We discuss the efficacy of bone-modifying agents (BMAs) in reducing skeletal-related events (SREs) and improving cancer-related outcomes, particularly in patients with stage IV non-small-cell lung cancer with bone metastases. In addition, the combined effects of BMAs with radiotherapy or immunotherapy in reducing SREs in patients with lung cancer and bone metastases are explored.
Collapse
Affiliation(s)
- Jinyoung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chaiho Jeong
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeongmin Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeonghoon Ha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ki-Hyun Baek
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seohyun Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Tai Joon An
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chan Kwon Park
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hyoung Kyu Yoon
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeong Uk Lim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
| |
Collapse
|
|
3
|
Evolution of bone metastases in patients receiving at least three months of checkpoint inhibitors. Cancer Immunol Immunother 2022; 71:2609-2618. [DOI: 10.1007/s00262-022-03180-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 02/16/2022] [Indexed: 10/18/2022]
|
|
4
|
Jaipanya P, Chanplakorn P. Prolonged durability of extensive contiguous spinal metastasis stabilization in non-small cell lung cancer patients receiving targeted therapy: two case reports and a literature review. J Int Med Res 2022; 50:3000605221105003. [PMID: 35681249 PMCID: PMC9189544 DOI: 10.1177/03000605221105003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Contiguous spinal metastasis poses a challenge for spine surgeons. In patients with a short remaining life expectancy, surgery may be discouraged. However, in select cases, surgery may be inevitable to eliminate pain and improve the patient’s quality of life. Additionally, with advancements in systemic cancer therapy, the efficacy and duration of tumor control have improved significantly. Consequently, a patient’s life expectancy may be difficult to estimate with existing prognostic scores. Because patients may achieve prolonged survival, spinal metastasis surgery could greatly benefit a patient’s quality of life. In this report, we present the details of two patients with non-small lung cancer with contiguous spinal metastasis who underwent spinal surgery for their metastatic disease. After surgery and targeted therapy with epidermal growth factor tyrosine kinase inhibitors (EGFR TKI), the patients attained substantial healing of their previously lytic spines and achieved prolonged survival of up to 42 months. With modern systemic therapy for lung cancer, the treatment of spinal metastatic disease can achieve decent outcomes, even in poor surgical candidates.
Collapse
Affiliation(s)
- Pilan Jaipanya
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 111 Suwannabhumi Canal Road, Bang Pla, Bang Phli District, Samut Prakan 10540, Thailand
| | - Pongsthorn Chanplakorn
- Department of Orthopedics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270, Rama VI Road, Thung Phaya Thai, Ratchathewi District, Bangkok 10400, Thailand
| |
Collapse
|
|
5
|
Exploration of the Effect of Icariin on Nude Mice with Lung Cancer Bone Metastasis via the OPG/RANKL/RANK System. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:2011625. [PMID: 35669373 PMCID: PMC9167109 DOI: 10.1155/2022/2011625] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 04/18/2022] [Accepted: 04/26/2022] [Indexed: 12/21/2022]
Abstract
Epimedium is a traditional Chinese medicine that is most commonly prescribed by practitioners of Chinese medicine for the clinical treatment of malignant tumor bone metastasis. The main component of Epimedium is icariin (ICA). Studies have shown that ICA inhibits bone resorption of osteoclasts through the OPG/RANKL/RANK signaling pathway. Osteoclasts are the only cells in the body that have a bone-destroying capability. The OPG/RANKL/RANK system consists of cytokines that play major roles in osteoclast formation. Therefore, our study selected the OPG/RANKL/RANK system as the research target to investigate the effect of ICA on nude mice with lung cancer bone metastasis. We established the model of bone metastasis in nude mice, intervened the model with icariin and zoledronic acid, and detected the levels of OPG and RANKL by ELISA and western blot. The results showed that ICA had a significant inhibitory effect on bone metastases in nude mice. ICA achieved its antibone metastasis effect in nude mice with lung cancer via inhibiting RANKL expression and simultaneously increasing OPG expression. ICA not only alleviated osteolytic bone destruction caused by bone metastases, but it also reduced weight loss in tumor-bearing nude mice at the late stage of the experiment. The role of ICA in preventing bone metastasis of lung cancer merits further investigation.
Collapse
|
|
6
|
Brozovich A, Garmezy B, Pan T, Wang L, Farach-Carson MC, Satcher RL. All bone metastases are not created equal: Revisiting treatment resistance in renal cell carcinoma. J Bone Oncol 2021; 31:100399. [PMID: 34745857 PMCID: PMC8551072 DOI: 10.1016/j.jbo.2021.100399] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 10/18/2021] [Accepted: 10/19/2021] [Indexed: 01/05/2023] Open
Abstract
Renal cell carcinoma (RCC) is the most common malignancy of the kidney, representing 80-90% of renal neoplasms, and is associated with a five-year overall survival rate of approximately 74%. The second most common site of metastasis is bone. As patients are living longer due to new RCC targeting agents and immunotherapy, RCC bone metastases (RCCBM) treatment failure is more prevalent. Bone metastasis formation in RCC is indicative of a more aggressive disease and worse prognosis. Osteolysis is a prominent feature and causes SRE, including pathologic fractures. Bone metastasis from other tumors such as lung, breast, and prostate cancer, are more effectively treated with bisphosphonates and denosumab, thereby decreasing the need for palliative surgical intervention. Resistance to these antiresportives in RCCBM reflects unique cellular and molecular mechanisms in the bone microenvironment that promote progression via inhibition of the anabolic reparative response. Identification of critical mechanisms underlying RCCBM induced anabolic impairment could provide needed insight into how to improve treatment outcomes for patients with RCCBM, with the goals of minimizing progression that necessitates palliative surgery and improving survival.
Collapse
Affiliation(s)
- Ava Brozovich
- Texas A&M College of Medicine, Bryan, TX, USA
- Department of Regenerative Medicine, Houston Methodist Research Institute, Houston, TX, USA
- Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Benjamin Garmezy
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Tianhong Pan
- Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Liyun Wang
- Department of Mechanical Engineering, Center for Biomedical Engineering Research, University of Delaware, Newark, DE, USA
| | - Mary C. Farach-Carson
- Department of Diagnostic and Biomedical Sciences, UT Health Science Center School of Dentistry, Houston, TX, USA
| | - Robert L. Satcher
- Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| |
Collapse
|
|
7
|
Bozzo A, Deng J, Abbas U, Bhasin R, Deodat M, Wariach S, Sanger S, Axelrod D, Masrouha K, Turcotte R, Wilson D, Ghert M. Which Bone-Modifying Agent is Associated with Better Outcomes in Patients with Skeletal Metastases from Lung Cancer? A Systematic Review and Network Meta-analysis. Clin Orthop Relat Res 2021; 479:2047-2057. [PMID: 33835092 PMCID: PMC8373570 DOI: 10.1097/corr.0000000000001749] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 03/05/2021] [Indexed: 01/31/2023]
Abstract
BACKGROUND Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of cancer-related deaths. Metastatic bone disease occurs in 20% to 40% of patients with lung cancer, and these patients often present with pain or skeletal-related events (SREs) that are associated with decreased survival. Bone-modifying agents such as denosumab or bisphosphonates are routinely used; however, to our knowledge, there has been no quantitative synthesis of randomized controlled trial data to determine the most effective pharmacologic treatment of metastatic bone disease because of lung cancer. QUESTIONS/PURPOSES We aimed to perform a network meta-analysis of randomized trials to identify the bone-modifying agent that is associated with the (1) highest overall survival, (2) longest time to SRE, (3) lowest SRE incidence, and (4) greatest likelihood of pain resolution. METHODS We conducted our study according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol and pre-registered the analysis on PROSPERO (ID: CRD42019124364). We performed a librarian-assisted search of MEDLINE, PubMed, EMBASE, Cochrane Library, and Chinese databases including China National Knowledge Infrastructure and Wanfang Data. We included randomized controlled trials reporting outcomes specifically for patients with lung cancer treated with a bisphosphonate or denosumab. SREs included pathologic fractures, spinal cord compression, hypercalcemia of malignancy, or pain resulting in surgical intervention or radiation therapy. We excluded trials exclusively reporting surrogate outcomes such as changes in bone turnover markers. Screening, data extraction, risk of bias evaluation, and Grading of Recommendations Assessment, Development, and Evaluation evaluations were performed in duplicate. We included 131 randomized controlled trials that evaluated 11,105 patients with skeletal metastases from lung cancer. The network meta-analysis was performed using a frequentist model and the R statistical software. Results are reported as relative risks or mean differences, and the I2 value is reported for heterogeneity. The P-score, a measure of ranking certainty that accounts for standard error, is reported for each outcome. Heterogeneity in the network was considered moderate for overall survival and time to SRE, mild for the incidence of SRE, and low for pain resolution. RESULTS For overall survival, denosumab was ranked above zoledronic acid and estimated to confer a mean of 3.3 months (95% CI 0.3-6.3) of increased overall survival compared with untreated patients (P-score = 89%). For the time to SRE, denosumab was ranked first with a mean of 9.1 additional SRE-free months (95% CI 6.7-11.5) compared with untreated patients (P-score = 99%), while zoledronic acid conferred an additional 4.8 SRE-free months (95% CI 3.6-6.1). Reduction in the incidence of SREs was not different between patients treated with denosumab (relative risk 0.54; 95% CI 0.33-0.87) and those treated with zoledronic acid (relative risk 0.56; 95% CI 0.46-0.67). Patients treated with the combination of ibandronate and systemic therapy were more likely to experience successful pain resolution than untreated patients (relative risk 2.4; 95% CI 1.8-3.2). CONCLUSION In this comprehensive synthesis of all available randomized controlled trial evidence guiding the pharmacologic treatment of bone metastases from lung cancer, denosumab was ranked above zoledronic acid for overall survival and time to SRE and was not different for reducing the incidence of SRE. Both were superior to no treatment for each of these outcomes. Given this, we encourage physicians to consider the use of denosumab or zoledronic acid in treating this patient population. The combination of ibandronate and systemic therapy was the most effective at reducing pain because of metastases. No cost-effectiveness analysis has yet been performed for denosumab and zoledronic acid on patients with metastatic lung cancer, and this represents an avenue for future research. LEVEL OF EVIDENCE Level I, therapeutic study.
Collapse
Affiliation(s)
- Anthony Bozzo
- Division of Orthopaedic Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Jiawen Deng
- Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Umaima Abbas
- Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Richa Bhasin
- Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Marisa Deodat
- Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Sajid Wariach
- Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Stephanie Sanger
- Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Daniel Axelrod
- Division of Orthopaedic Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Karim Masrouha
- Division of Orthopaedic Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
- Hamilton Health Sciences, Juravinski Hospital and Cancer Center, Hamilton, Ontario, Canada
| | - Robert Turcotte
- Division of Orthopaedic Surgery, McGill University, Montreal, Quebec, Canada
| | - David Wilson
- Division of Orthopaedic Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
- Hamilton Health Sciences, Juravinski Hospital and Cancer Center, Hamilton, Ontario, Canada
| | - Michelle Ghert
- Division of Orthopaedic Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
- Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
- Hamilton Health Sciences, Juravinski Hospital and Cancer Center, Hamilton, Ontario, Canada
| |
Collapse
|
|
8
|
Mbese Z, Aderibigbe BA. Bisphosphonate-Based Conjugates and Derivatives as Potential Therapeutic Agents in Osteoporosis, Bone Cancer and Metastatic Bone Cancer. Int J Mol Sci 2021; 22:6869. [PMID: 34206757 PMCID: PMC8268474 DOI: 10.3390/ijms22136869] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/14/2021] [Accepted: 04/20/2021] [Indexed: 12/13/2022] Open
Abstract
Metastatic bone cancer occurs in every type of cancer but is prevalent in lung, breast, and prostate cancers. These metastases can cause extensive morbidity, including a range of skeletal-related events, often painful and linked with substantial hospital resource usage. The treatment used is a combination of chemotherapy and surgery. However, anticancer drugs are still limited due to severe side effects, drug resistance, poor blood supply, and non-specific drug uptake, necessitating high toxic doses. Bisphosphonates are the main class of drugs utilized to inhibit metastatic bone cancer. It is also used for the treatment of osteoporosis and other bone diseases. However, bisphosphonate also suffers from serious side effects. Thus, there is a serious need to develop bisphosphonate conjugates with promising therapeutic outcomes for treating metastatic bone cancer and osteoporosis. This review article focuses on the biological outcomes of designed bisphosphonate-based conjugates for the treatment of metastatic bone cancer and osteoporosis.
Collapse
Affiliation(s)
| | - Blessing A. Aderibigbe
- Department of Chemistry, Alice Campus, University of Fort Hare, Alice 5700, South Africa;
| |
Collapse
|
|
9
|
Xu S, Cao S, Geng J, Wang C, Meng Q, Yu Y. High prognostic nutritional index (PNI) as a positive prognostic indicator for non-small cell lung cancer patients with bone metastasis. CLINICAL RESPIRATORY JOURNAL 2020; 15:225-231. [PMID: 33037791 DOI: 10.1111/crj.13288] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 08/11/2020] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Increasing evidence shows the close association between prognostic nutritional index (PNI) and overall survival (OS) of solid cancers including lung cancer. However, the role of PNI in non-small cell lung cancer patients (NSCLC) with bone metastasis remains unclear. OBJECTIVE To explore the prognostic role of PNI in NSCLC patients with bone metastasis. METHODS A retrospective analysis of 259 initially diagnosed NSCLC with bone metastasis was conducted. Univariate and multivariate analysis were used to assess the potential prognostic roles of parameters. RESULTS The most common symptoms initially presented were cough and chest pain. Two hundred patients (77.2%) received the treatment of bisphosphonates. Patients with low PNI were found in 154 (59.5%) patients. Median survival time for all cases was 286 days. The median OS for patients with low and high PNI was 227 and 389 days, respectively. The 6-month, 1-year and 2-year survival rates for patients with low PNI were 66.2%, 29.9% and 10.4% compared to 79.0%, 52.4% and 26.7% in patients with high PNI level. On univariate analysis, female patients, non-smokers, high PNI and systematic chemotherapy (P < 0.05) were shown to be closely correlated with a better prognosis of NSCLC patients with bone metastasis. Only PNI (P = 0.002), systematic chemotherapy (P = 0.026) and distant metastasis number (P = 0.044) held statistical significance on multivariate analysis. CONCLUSIONS PNI represents a non-invasive, efficiency and convenient biomarker of NSCLC patients with bone metastasis. High PNI, systematic chemotherapy and distant metastasis number <2 are independent positive prognostic factors of NSCLC patients with bone metastasis.
Collapse
Affiliation(s)
- Shanqi Xu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shoubo Cao
- Department of Radiation Oncology, Linyi People's Hospital, Linyi, China
| | - Jianxiong Geng
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Chunyan Wang
- Department of Radiation Oncology, Linyi People's Hospital, Linyi, China
| | - Qingwei Meng
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yan Yu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| |
Collapse
|
|
10
|
Brouns AJWM, De Bie BH, van den Beuken-van Everdingen MHJ, Dingemans AMC, Hendriks LEL. Non-Radiation Based Early Pain Relief Treatment Options for Patients With Non-Small Cell Lung Cancer and Cancer Induced Bone Pain: A Systematic Review. Front Oncol 2020; 10:509297. [PMID: 33194576 PMCID: PMC7642688 DOI: 10.3389/fonc.2020.509297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 09/30/2020] [Indexed: 02/03/2023] Open
Abstract
INTRODUCTION Cancer induced bone pain (CIBP) is frequent in patients with non-small cell lung cancer (NSCLC). Radiation therapy continues to be the gold standard for treatment of painful bone metastases, however only a limited number of metastases can be irradiated. We evaluated non-radiation based early CIBP relief options in NSCLC through a systematic review. METHODS Systematic review including all prospective articles published between 01-1994 and 06-2020 on Pubmed, Cochrane Library and ClinicalTrials.gov database. Inclusion: non-radiation based trials evaluating CIBP early pain relief options (initially defined as pain score evaluated within two weeks, because of no randomized trials, later inclusion broadened to pain score evaluated within six weeks) in ≥10 NSCLC patients. Radioisotope trials were excluded as these treatments have interactions with systemic anticancer therapy. RESULTS 188 articles were found; 10 articles (6 randomized controlled (4 double blinded), 1 phase II single-arm, and 3 prospective trials) fulfilled the inclusion criteria. Six of these trials consisted of ≥2 treatment arms, whereas the others were single-arm studies. In total, 554 NSCLC patients were evaluated in these trials. The included trials were very heterogeneous regarding evaluated treatment options, methods of pain measuring, and endpoints. No high-level evidence for specific early pain relief treatment options was found. DISCUSSION Non-radiation based studies evaluating treatment options to rapidly reduce CIBP in NSCLC are scarce. This systematic review shows that there is no high-level evidence to recommend a specific treatment for early pain relief. Future research should focus on early pain relief treatment options for CIBP in NSCLC.
Collapse
Affiliation(s)
- Anita J. W. M. Brouns
- Department of Pulmonary Diseases, Zuyderland Medical Center, Sittard-Geleen, Netherlands
- Department of Pulmonary Diseases, GROW—School for Oncology and Developmental Biology, Maastricht University Medical Center+ (MUMC+), Maastricht, Netherlands
| | - Ben H. De Bie
- Department of Anesthesiology, Maastricht University Medical Center+ (MUMC+), Maastricht, Netherlands
| | | | - Anne-Marie C. Dingemans
- Department of Pulmonary Diseases, GROW—School for Oncology and Developmental Biology, Maastricht University Medical Center+ (MUMC+), Maastricht, Netherlands
- Department of Pulmonary Diseases, Erasmus MC, Rotterdam, Netherlands
| | - Lizza E. L. Hendriks
- Department of Pulmonary Diseases, GROW—School for Oncology and Developmental Biology, Maastricht University Medical Center+ (MUMC+), Maastricht, Netherlands
| |
Collapse
|
|
11
|
Hu Z, Tian Y, Li W, Ruan Y, Zeng F. The efficacy and safety of zoledronic acid and strontium-89 in treating non-small cell lung cancer: a systematic review and meta-analysis of randomized controlled trials. Support Care Cancer 2019; 28:3291-3301. [PMID: 31754835 DOI: 10.1007/s00520-019-05096-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 09/20/2019] [Indexed: 01/06/2023]
Abstract
BACKGROUND Zoledronic acid (ZA) and strontium-89 have been widely used to treat lung cancer with bone metastases. The authors perform this meta-analysis to better evaluate the clinical outcome of ZA and strontium-89 for non-small cell lung cancer (NSCLC) patients. METHODS We carried out standard meta-analysis and network meta-analysis based on a comprehensive data retrieval of EMBASE, PubMed, and Cochrane Library databases (up to March 2019). Random and fixed effects models were used where indicated and between-study heterogeneity was assessed. The primary endpoints were overall survival (OS) and skeletal-related events (SREs). The second endpoints were progression-free survival (PFS) and overall response rate (ORR). RESULTS Seven randomized clinical trials, including 1426 NSCLC patients with seven studies of zoledronic acid and two studies of strontium-89, met the inclusion criteria. Compared with the control group, ZA is associated with a OS benefit (1-year survival rate: RR = 1.76, 95% CI 1.36-2.27; and 24-month survival rate: RR = 2.38, 95% CI 1.35-4.19) and a reduction of SREs (RR = 0.57, 95% CI 0.40-0.84) for the patients with bone metastases. No statistical differences were found in PFS and ORR. Network meta-analysis for the patients with bone metastases showed that ZA + strontium-89 and ZA harbored significantly clinical benefits than strontium-89 and placebo in terms of 1-year survival rate and SREs. Both head-to-head study and network meta-analysis showed that strontium-89 had no statistical impact on OS and SREs compared with placebo. CONCLUSION Our analysis demonstrates that ZA +strontium-89 can be considered a priority for NSCLC patients with bone metastases, followed by ZA.
Collapse
Affiliation(s)
- Zhigang Hu
- Department of Respiratory Medicine, The First College of Clinical Medicine Science, Three Gorges University, No. 183 Yiling Road, Yichang, 443003, People's Republic of China. .,Department of Respiratory Medicine, Yichang Central People's Hospital, Yichang, China.
| | - Yufeng Tian
- Clinical Research Center, Three Gorges University, No. 183 Yiling Road, Yichang, 443003, People's Republic of China
| | - Wenxin Li
- Department of Respiratory Medicine, The First College of Clinical Medicine Science, Three Gorges University, No. 183 Yiling Road, Yichang, 443003, People's Republic of China.,Department of Respiratory Medicine, Yichang Central People's Hospital, Yichang, China
| | - Yushu Ruan
- Department of Respiratory Medicine, The First College of Clinical Medicine Science, Three Gorges University, No. 183 Yiling Road, Yichang, 443003, People's Republic of China.,Department of Respiratory Medicine, Yichang Central People's Hospital, Yichang, China
| | - Fanjun Zeng
- Department of Respiratory Medicine, The First College of Clinical Medicine Science, Three Gorges University, No. 183 Yiling Road, Yichang, 443003, People's Republic of China.,Department of Respiratory Medicine, Yichang Central People's Hospital, Yichang, China
| |
Collapse
|
|
12
|
Ning H, Wu X, Wu Q, Yu W, Wang H, Zheng S, Chen Y, Li Y, Su J. Microfiber-Reinforced Composite Hydrogels Loaded with Rat Adipose-Derived Stem Cells and BMP-2 for the Treatment of Medication-Related Osteonecrosis of the Jaw in a Rat Model. ACS Biomater Sci Eng 2019; 5:2430-2443. [PMID: 33405751 DOI: 10.1021/acsbiomaterials.8b01468] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Severe adverse reactions of bisphosphonates and anti-resorptive or anti-angiogenic medications, termed medication-related osteonecrosis of the jaw (MRONJ), have been reported. MRONJ are difficult to completely cure and could cause great pain to patients. Recent studies have shown that mesenchymal stem cell (MSC) therapies are effective for treating MRONJ, but the method of intravenous injection is unstable and increases the risk of producing tumors. In the present study, low-acyl gellan gum (LAGG) hydrogels were modified with hemicellulose polysaccharide microfibers (PMs) to improve the performance of supporting three-dimensional (3D) cell growth. LAGG-PM composite hydrogels were found to be nontoxic to rat adipose-derived stem cells (rADSCs) in vitro. The hydrogels also promoted the secretion of angiogenic factors, induced osteoclastogenesis by conditioned medium, and supported osteogenic marker expression after the addition of human bone morphogenetic protein-2 (BMP-2). Due to its injectability, the LAGG-PM composite hydrogel incorporated with rADSCs and BMP-2 could be applied into the MRONJ lesion site, which promoted mucosal recovery, bone tissue reconstruction, and osteoclastogenesis. This study confirms the potential applications of LAGG-PM composite hydrogels as 3D cell culture platforms and delivery vehicles for the treatment of MRONJ in a rat model.
Collapse
Affiliation(s)
- Haoran Ning
- Department of Prosthodontics, School & Hospital of Stomatology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji University, Shanghai 200072, China
| | - Xiaowei Wu
- Department of Prosthodontics, School & Hospital of Stomatology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji University, Shanghai 200072, China.,Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing 10081, China
| | - Qing Wu
- Department of Prosthodontics, School & Hospital of Stomatology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji University, Shanghai 200072, China
| | - Wanlu Yu
- Department of Prosthodontics, School & Hospital of Stomatology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji University, Shanghai 200072, China
| | - Huaiji Wang
- Shanghai Tenth People's Hospital, The Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, Shanghai 200092, China
| | - Shang Zheng
- Department of Prosthodontics, School & Hospital of Stomatology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji University, Shanghai 200072, China
| | - Yunong Chen
- Department of Prosthodontics, School & Hospital of Stomatology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji University, Shanghai 200072, China
| | - Yongyong Li
- Shanghai Tenth People's Hospital, The Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, Shanghai 200092, China
| | - Jiansheng Su
- Department of Prosthodontics, School & Hospital of Stomatology, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Tongji University, Shanghai 200072, China
| |
Collapse
|
|
13
|
Mitsuhashi A, Okuma Y, Zenke Y, Hosomi Y. Prognostic effects of osteoclast inhibitors in extensive stage small cell lung cancer patients with bone metastases. Mol Clin Oncol 2018; 9:561-565. [PMID: 30345052 DOI: 10.3892/mco.2018.1710] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 08/31/2018] [Indexed: 11/06/2022] Open
Abstract
Bone metastases (BM) often induce skeletal-related events (SREs) and contribute to poor prognoses in patients with cancer. Osteoclast inhibitors (OIs), such as bisphosphonates (BPs) and denosumab, reportedly prevent SREs and improve quality of life in patients with non-small cell lung cancer and BM, but have not been tested in extensive stage small cell lung cancer (ES-SCLC) patients. From 238 SCLC patient records, the present study reviewed those of 58 BM patients, including 23 who were treated with OIs (OIs group) and 35 who were untreated (untreated group). Patient backgrounds were balanced between groups using propensity score matching, and survival curves were compared using the log-rank test. The median overall survival (OS) times were 8.41 and 12.52 months in untreated and OIs groups, respectively, but these did not differ significantly between groups (log-rank test, P=0.409). The 1-year OS rate was higher in the OIs group (56.1%) when compared with the control group (22.6%). The results indicated that OIs tend to prolong the short term survival of ES-SCLC patients with BM. To the best of our knowledge, this is the first study to examine the prognostic effects of OIs in SCLC patients. The results of the present study may highlight the possibility that OIs improve the prognosis of ES-SCLC patients with BM.
Collapse
Affiliation(s)
- Atsushi Mitsuhashi
- Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo, Tokyo 113-8677, Japan
| | - Yusuke Okuma
- Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo, Tokyo 113-8677, Japan.,Division of Oncology, Research Center for Medical Sciences, Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan
| | - Yoshitaka Zenke
- Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo, Tokyo 113-8677, Japan
| | - Yukio Hosomi
- Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo, Tokyo 113-8677, Japan
| |
Collapse
|
|
14
|
Izumi H, Yamasaki A, Takeda K, Kodani M, Touge H, Tanaka N, Yanai M, Ueda Y, Sakamoto T, Nishii-Ito S, Makino H, Yamaguchi K, Igishi T, Shimizu E. Acute-phase reaction induced by zoledronate and its effect on prognosis of patients with advanced non-small cell lung cancer. Lung Cancer 2018; 122:200-205. [DOI: 10.1016/j.lungcan.2018.06.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 06/14/2018] [Accepted: 06/17/2018] [Indexed: 12/31/2022]
|
|
15
|
Elsayed R, Abraham P, Awad ME, Kurago Z, Baladhandayutham B, Whitford GM, Pashley DH, McKenna CE, Elsalanty ME. Removal of matrix-bound zoledronate prevents post-extraction osteonecrosis of the jaw by rescuing osteoclast function. Bone 2018; 110:141-149. [PMID: 29408511 PMCID: PMC5878730 DOI: 10.1016/j.bone.2018.01.030] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 01/06/2018] [Accepted: 01/25/2018] [Indexed: 12/25/2022]
Abstract
Unlike other antiresorptive medications, bisphosphonate molecules accumulate in the bone matrix. Previous studies of side-effects of anti-resorptive treatment focused mainly on systemic effects. We hypothesize that matrix-bound bisphosphonate molecules contribute to the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ). In this study, we examined the effect of matrix-bound bisphosphonates on osteoclast differentiation in vitro using TRAP staining and resorption assay, with and without pretreatment with EDTA. We also tested the effect of zoledronate chelation on the healing of post-extraction defect in rats. Our results confirmed that bisphosphonates bind to, and can be chelated from, mineralized matrix in vitro in a dose-dependent manner. Matrix-bound bisphosphonates impaired the differentiation of osteoclasts, evidenced by TRAP activity and resorption assay. Zoledronate-treated rats that underwent bilateral dental extraction with unilateral EDTA treatment showed significant improvement in mucosal healing and micro-CT analysis on the chelated sides. The results suggest that matrix-bound bisphosphonates are accessible to osteoclasts and chelating agents and contribute to the pathogenesis of BRONJ. The use of topical chelating agents is a promising strategy for the prevention of BRONJ following dental procedures in bisphosphonate-treated patients.
Collapse
Affiliation(s)
- Ranya Elsayed
- Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - Pheba Abraham
- Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - Mohamed E Awad
- Department of Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - Zoya Kurago
- Department of Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, USA
| | | | - Gary M Whitford
- Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - David H Pashley
- Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - Charles E McKenna
- Department of Chemistry, Dana and David Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA, USA
| | - Mohammed E Elsalanty
- Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA.
| |
Collapse
|
|
16
|
Lang J, Zhao Q, He Y, Yu X. Bone turnover markers and novel biomarkers in lung cancer bone metastases. Biomarkers 2018; 23:518-526. [PMID: 29683727 DOI: 10.1080/1354750x.2018.1463566] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
CONTEXT Lung cancer still remains the leading cause of cancer-related mortality worldwide. Bone is one of preferred metastatic sites for lung cancer cells. So far, both accurate diagnosis and effective treatment of lung cancer bone metastases are difficult. OBJECTIVE This review aimed to evaluate roles of bone turnover markers (BTMs), microRNAs (miRNAs), dickkopf1 (DKK1) and insulin like growth factor binding protein 3 (IGFBP-3) in lung cancer bone metastases. METHODS We searched articles about these four biomarkers in lung cancer bone metastases mainly in PubMed. RESULT The levels of bone specific alkaline phosphatase (BALP), cross-linked carboxy-terminal telopeptide of type-I collagen (ICTP) and N-terminal telopeptides of type-I collagen (NTX) were reported to be significantly increased in lung cancer patients with bone metastases. ALP, NTX and bone sialoprotein were thought to be associated with prognosis of lung cancer patients with bone metastases. MiRNA-335, miRNA-33a, miRNA-21, DKK1 and IGFBP-3 were revealed to be novel biomarkers in lung cancer bone metastases. DISCUSSION AND CONCLUSION Current researches have revealed that BTMs, miRNAs, DKK1 and IGFBP-3 may be useful in diagnosis, prognosis evaluation or treatment of lung cancer bone metastases. More studies about these biomarkers in lung cancer bone metastases are needed.
Collapse
Affiliation(s)
- Jiangli Lang
- a Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism , State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu , China
| | - Qian Zhao
- b Department of General practice , West China Hospital, Sichuan University , Chengdu , China
| | - Yuedong He
- c Department of Gynecology , West China Second University Hospital, Sichuan University , Chengdu , China
| | - Xijie Yu
- a Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism , State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu , China
| |
Collapse
|
|
17
|
Boyer A, Pasquier E, Tomasini P, Ciccolini J, Greillier L, Andre N, Barlesi F, Mascaux C. Drug repurposing in malignant pleural mesothelioma: a breath of fresh air? Eur Respir Rev 2018; 27:170098. [PMID: 29540495 PMCID: PMC9488560 DOI: 10.1183/16000617.0098-2017] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 01/13/2018] [Indexed: 01/17/2023] Open
Abstract
Drug repurposing is the use of known drugs for new indications. Malignant pleural mesothelioma (MPM) is a rare cancer with a poor prognosis. So far, few treatments have been approved in this disease. However, its incidence is expected to increase significantly, particularly in developing countries. Consequently, drug repurposing appears as an attractive strategy for drug development in MPM, since the known pharmacology and safety profile based on previous approvals of repurposed drugs allows for faster time-to-market for patients and lower treatment cost. This is critical in low- and middle-income countries where access to expensive drugs is limited. This review assesses the published preclinical and clinical data about drug repurposing in MPM.In this review, we identified 11 therapeutic classes that could be repositioned in mesothelioma. Most of these treatments have been evaluated in vitro, half have been evaluated in vivo in animal models of MPM and only three (i.e. valproate, thalidomide and zoledronic acid) have been investigated in clinical trials, with limited benefits so far. Efforts could be coordinated to pursue further investigations and test promising drugs identified in preclinical experiments in appropriately designed clinical trials.
Collapse
Affiliation(s)
- Arnaud Boyer
- Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Multidisciplinary Oncology and Therapeutic Innovations Dept, Marseille, France
- Centre de Recherche en Cancérologie de Marseille (CRCM, Marseille Cancer Research Centre), Inserm UMR1068, CNRS UMR7258 and Aix-Marseille University UM105, Marseille, France
| | - Eddy Pasquier
- Aix Marseille University, Assistance Publique des Hôpitaux de Marseille, Dept of Haematology and Paediatric Oncology, Marseille, France
| | - Pascale Tomasini
- Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Multidisciplinary Oncology and Therapeutic Innovations Dept, Marseille, France
- Centre de Recherche en Cancérologie de Marseille (CRCM, Marseille Cancer Research Centre), Inserm UMR1068, CNRS UMR7258 and Aix-Marseille University UM105, Marseille, France
| | - Joseph Ciccolini
- Centre de Recherche en Cancérologie de Marseille (CRCM, Marseille Cancer Research Centre), Inserm UMR1068, CNRS UMR7258 and Aix-Marseille University UM105, Marseille, France
| | - Laurent Greillier
- Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Multidisciplinary Oncology and Therapeutic Innovations Dept, Marseille, France
- Centre de Recherche en Cancérologie de Marseille (CRCM, Marseille Cancer Research Centre), Inserm UMR1068, CNRS UMR7258 and Aix-Marseille University UM105, Marseille, France
| | - Nicolas Andre
- Centre de Recherche en Cancérologie de Marseille (CRCM, Marseille Cancer Research Centre), Inserm UMR1068, CNRS UMR7258 and Aix-Marseille University UM105, Marseille, France
| | - Fabrice Barlesi
- Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Multidisciplinary Oncology and Therapeutic Innovations Dept, Marseille, France
- Centre de Recherche en Cancérologie de Marseille (CRCM, Marseille Cancer Research Centre), Inserm UMR1068, CNRS UMR7258 and Aix-Marseille University UM105, Marseille, France
| | - Celine Mascaux
- Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Multidisciplinary Oncology and Therapeutic Innovations Dept, Marseille, France
- Centre de Recherche en Cancérologie de Marseille (CRCM, Marseille Cancer Research Centre), Inserm UMR1068, CNRS UMR7258 and Aix-Marseille University UM105, Marseille, France
| |
Collapse
|
|
18
|
Messer JG, Mendieta Calle JL, Jiron JM, Castillo EJ, Van Poznak C, Bhattacharyya N, Kimmel DB, Aguirre JI. Zoledronic acid increases the prevalence of medication-related osteonecrosis of the jaw in a dose dependent manner in rice rats (Oryzomys palustris) with localized periodontitis. Bone 2018; 108:79-88. [PMID: 29289789 PMCID: PMC5828169 DOI: 10.1016/j.bone.2017.12.025] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 12/15/2017] [Accepted: 12/27/2017] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Investigate role of dose/duration of zoledronic acid (ZOL), a powerful anti-resorptive (pAR), on prevalence of medication-related osteonecrosis of the jaw (MRONJ) in rice rats (Oryzomys palustris), a species with natural susceptibility to food impaction-induced localized periodontitis (FILP). We hypothesize that ZOL induces MRONJ lesions in rice rats with FILP, and that the prevalence of MRONJ rises with increasing dose and duration of ZOL treatment. METHODS We performed a toxicology experiment with clinically-relevant doses of ZOL in female rats (N=230) fed standard (STD) rodent chow. At age 4weeks (baseline), 12 rats were necropsied. The rest were randomized into five groups that began to receive 0, 8, 20, 50 or 125μg/kg ZOL IV/q 4weeks. After 12, 18, 24 and 30weeks, subgroups (N=9-16) from each of the dose groups were necropsied. High-resolution macroscopic photos of all jaw quadrants were given a gross quadrant grade (GQG) (0-4 or MRONJ) that classified FILP lesion severity and determined presence of gross MRONJ. Quadrants with GQG≥1 were examined histopathologically. Logistic regression analysis (ZOL dose/duration) of MRONJ prevalence was completed. RESULTS We found: 1) 75% of 0μg/kg ZOL rats developed FILP lesions; 2) baseline rats and rats treated with 0μg/kg ZOL had no MRONJ; 3) 29 gross MRONJ cases were identified; 4) all gross MRONJ cases were confirmed histopathologically by the observation of exposed necrotic bone, and 53 new cases were discovered (total=82); 5) ZOL dose (P<0.001), but not duration (P=0.326), was a significant predictor of MRONJ prevalence; 6) 13% prevalence of gross MRONJ among all rats, with 22% prevalence among rats exposed to ZOL oncologic doses (20-125μg/kg); 7) 38% prevalence of histopathologic MRONJ among all rats, with 73% prevalence among rats exposed to ZOL oncologic doses. CONCLUSIONS This is the first experiment to show a dose response relationship between clinically relevant doses of ZOL and MRONJ prevalence.
Collapse
Affiliation(s)
- J G Messer
- Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States.
| | - J L Mendieta Calle
- Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States.
| | - J M Jiron
- Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States.
| | - E J Castillo
- Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States.
| | - C Van Poznak
- University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, United States.
| | - N Bhattacharyya
- Department of Oral & Maxillofacial Diagnostic Sciences, College of Dentistry, UF, United States.
| | - D B Kimmel
- Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States
| | - J I Aguirre
- Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States.
| |
Collapse
|
|
19
|
Fanale D, Amodeo V, Bazan V, Insalaco L, Incorvaia L, Barraco N, Castiglia M, Rizzo S, Santini D, Giordano A, Castorina S, Russo A. Can the microRNA expression profile help to identify novel targets for zoledronic acid in breast cancer? Oncotarget 2017; 7:29321-32. [PMID: 27081088 PMCID: PMC5045398 DOI: 10.18632/oncotarget.8722] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 03/31/2016] [Indexed: 01/27/2023] Open
Abstract
Zoledronic acid (ZOL), belonging to third generation bisphosphonate family, is a potent inhibitor of osteoclast-mediated bone resorption, widely used to effectively prevent osteolysis in breast cancer patients who develop bone metastases. Low doses of ZOL have been shown to exhibit a direct anticancer role, by inhibiting cell adhesion, invasion, cytoskeleton remodelling and proliferation in MCF-7 breast cancer cells. In order to identify the molecular mechanisms and signaling pathways underlying the anticancer activity exerted by ZOL, we analyzed for the first time the microRNA expression profile in breast cancer cells. A large-scale microarray analysis of 377 miRNAs was performed on MCF7 cells treated with 10 μM ZOL for 24 h compared to untreated cells. Furthermore, the expression of specific ZOL-induced miRNAs was analyzed in MCF-7 and SkBr3 cells through Real-time PCR. Low-dose treatment with ZOL significantly altered expression of 54 miRNAs. Nine upregulated and twelve downregulated miRNAs have been identified after 24 h of treatment. Also, ZOL induced expression of 11 specific miRNAs and silenced expression of 22 miRNAs. MiRNA data analysis revealed the involvement of differentially expressed miRNAs in PI3K/Akt, MAPK, Wnt, TGF-β, Jak-STAT and mTOR signaling pathways, and regulation of actin cytoskeleton. Our results have been shown to be perfectly coherent with the recent findings reported in literature concerning changes in expression of some miRNAs involved in bone metastasis formation, progression, therapy resistance in breast cancer. In conclusion, this data supports the hypothesis that ZOL-induced modification of the miRNA expression profile contributes to the anticancer efficacy of this agent.
Collapse
Affiliation(s)
- Daniele Fanale
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Valeria Amodeo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Viviana Bazan
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Lavinia Insalaco
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Lorena Incorvaia
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Nadia Barraco
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Marta Castiglia
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Sergio Rizzo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Daniele Santini
- University Campus Bio-Medico, Department of Medical Oncology, Rome, Italy
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
| | - Sergio Castorina
- Fondazione Mediterranea "G.B. Morgagni", Catania, Italy.,Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Antonio Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| |
Collapse
|
|
20
|
Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug. Sci Rep 2017; 7:5987. [PMID: 28729550 PMCID: PMC5519590 DOI: 10.1038/s41598-017-05553-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 05/31/2017] [Indexed: 01/20/2023] Open
Abstract
Bisphosphonates have benefits in breast cancer and multiple myeloma patients and have been used with adoptive immunotherapy with γδ T cells expressing Vγ2 Vδ2 TCRs. Although treatment with γδ T cells is safe, it has shown limited efficacy. Present bisphosphonates stimulate γδ T cells but were designed to inhibit bone resorption rather than treating cancer and have limited oral absorption, tumor cell entry, and cause bone side effects. The development of phosphate and phosphonate nucleotide prodrugs has led to important drugs for hepatitis C and HIV. Using a similar approach, we synthesized bisphosphonate prodrugs and found that they efficiently limit tumor cell growth. Pivoxil bisphosphonate esters enter cells where esterases convert them to their active acids. The bisphosphonate esters stimulated γδ T cells to secrete TNF-α in response to a variety of tumor cells more efficiently than their corresponding acids. The most active compound, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1- bisphosphonate (7), specifically expanded γδ T cells and stimulated them to secrete interferon-γ and kill tumor cells. In preclinical studies, combination therapy with compound 7 and γδ T cells prolonged survival of mice inoculated with either human bladder cancer or fibrosarcoma cells. Therefore, bisphosphonate prodrugs could enhance the effectiveness of adoptive cancer immunotherapy with γδ T cells.
Collapse
|
|
21
|
Sunaga T, Shimamoto K, Nakamura S, Takahashi N, Higashino M, Hozumi T, Matsui M, Nagatani A, Kokubu F, Kogo M, Sasaki T. The Association between Fever and Prognosis in Lung Cancer Patients with Bone Metastases Receiving Zoledronic Acid. Chemotherapy 2017; 62:327-333. [PMID: 28605733 DOI: 10.1159/000476055] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 04/25/2017] [Indexed: 11/19/2022]
Abstract
Zoledronic acid is an established agent used in the management of metastatic bone disease. The administration of zoledronic acid improves overall survival (OS) of lung cancer patients with bone metastases receiving chemotherapy. However, it is currently unknown whether zoledronic acid-induced fever is associated with OS. The purpose of this study was to examine the association between zoledronic acid-induced fever and prognosis in lung cancer patients with bone metastases. We retrospectively analyzed 98 lung cancer patients with bone metastases who had received zoledronic acid. The end point outcome measure was OS. Multivariate analyses were used to estimate the hazard ratio (HR) for OS due to fever after adjusting for covariates. In multivariate analysis, white blood cell (WBC) count, lactate dehydrogenase (LDH) level, fever, chemotherapy, and hypercalcemia were independent prognostic factors, with HRs of 2.834 for WBC count (<10 × 103/μL vs. ≥10 × 103/μL, p < 0.001), 3.044 for LDH level (<250 vs. ≥250 IU/L, p < 0.001), 0.603 for fever (<37.0 vs. ≥37.0°C, p = 0.039), 0.481 for chemotherapy (chemotherapy not administered vs. administered, p = 0.006), and 2.453 for hypercalcemia (<11.0 vs. ≥11.0 mg/dL, p = 0.001). Zoledronic acid-induced fever was the most important prognostic factor in this cohort of lung cancer patients with bone metastases.
Collapse
Affiliation(s)
- Tomiko Sunaga
- Department of Hospital Pharmaceutics School of Pharmacy, Showa University, Tokyo, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Zhang G, Cheng R, Zhang Z, Jiang T, Ren S, Ma Z, Zhao S, Zhou C, Zhang J. Bisphosphonates enhance antitumor effect of EGFR-TKIs in patients with advanced EGFR mutant NSCLC and bone metastases. Sci Rep 2017; 7:42979. [PMID: 28211502 PMCID: PMC5314405 DOI: 10.1038/srep42979] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 01/17/2017] [Indexed: 12/13/2022] Open
Abstract
Whether bisphosphonates could enhance the effect of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) patients with EGFR mutation and bone metastases (BM) remains unknown. EGFR mutation status were collected from 1560 patients with NSCLC and BM. 356 NSCLC patients with EGFR mutation and BM were identified. Among them, 91 patients received EGFR-TKIs alone and 105 patients received EGFR-TKIs plus bisphosphonates as first-line therapy. Comparing to TKIs alone, EGFR-TKIs plus bisphosphonates had a statistically significant longer progression-free survival (PFS: 11.6 vs. 9.3 months; HR = 0.68, P = 0.009), while a similar overall survival (OS: 20.5 vs. 19.5 months; HR = 0.95, P = 0.743) in patients with EGFR-mutant NSCLC and BM. The incidence of skeletal-related events in combined group was numerically lower than that in EGFR-TKIs alone group (29.7% vs. 39.4%, P = 0.147). In multivariate analysis, EGFR mutation was found to be a significant independent prognostic factor for OS in NSCLC patients with BM (HR = 0.710, P = 0.021). In conclusion, EGFR mutation was the significant independent prognostic factor for OS and the addition of bisphosphonates to EGFR-TKIs could enhance the antitumor effect of EGFR-TKIs in patients with EGFR-mutant NSCLC and BM.
Collapse
Affiliation(s)
- Guowei Zhang
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450003, China
| | - Ruirui Cheng
- Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, China
| | - Zengli Zhang
- Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, China
- Department of Respiratory, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Tao Jiang
- Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, China
| | - Shengxiang Ren
- Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, China
| | - Zhiyong Ma
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450003, China
| | - Sha Zhao
- Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, China
| | - Caicun Zhou
- Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, China
| | - Jun Zhang
- Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, Iowa
| |
Collapse
|
|
23
|
Xu JY, Murphy WA, Milton DR, Jimenez C, Rao SN, Habra MA, Waguespack SG, Dadu R, Gagel RF, Ying AK, Cabanillas ME, Weitzman SP, Busaidy NL, Sellin RV, Grubbs E, Sherman SI, Hu MI. Bone Metastases and Skeletal-Related Events in Medullary Thyroid Carcinoma. J Clin Endocrinol Metab 2016; 101:4871-4877. [PMID: 27662441 PMCID: PMC5155685 DOI: 10.1210/jc.2016-2815] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
CONTEXT Bone metastases (BM) can lead to devastating skeletal-related events (SREs) in cancer patients. Data regarding medullary thyroid carcinoma (MTC) with BM are lacking. OBJECTIVE We evaluated the natural history of BM and SREs in MTC patients identified by a cancer center tumor registry. SETTING The study was conducted at a tertiary cancer center. PATIENTS AND MAIN OUTCOME MEASURES We retrospectively reviewed the charts of MTC patients with BM who received care from 1991 to 2014 to characterize BM and SREs. RESULTS Of 1008 MTC patients treated, 188 were confirmed to have BM (19%), of whom 89% (168 of 188) had nonosseous distant metastases. Median time from MTC to BM diagnosis was 30.9 months (range 0-533 mo); 25% (45 of 180) had BM identified within 3 months of MTC diagnosis. Median follow-up after detecting BM was 1.6 years (range 0-23.2 y). Most patients (77%) had six or more BM lesions, most often affecting the spine (92%) and pelvis (69%). Many patients (90 of 188, 48%) experienced one or more SREs, most commonly radiotherapy (67 of 90, 74%) followed by pathological fracture (21 of 90, 23%). Only three patients had spinal cord compression. Patients with more than 10 BM lesions were more likely to experience SREs (odds ratio 2.4; P = .007), with no difference in 5-year mortality after MTC diagnosis between patients with (31%) and without SREs (23%) (P = .11). CONCLUSIONS In this large retrospective series, BM in MTC was multifocal, primarily involving the spine and pelvis, supporting screening these regions for metastases in at-risk patients. SREs were common but spinal cord compression was rare. Antiresorptive therapies in this population should be investigated further with prospective trials.
Collapse
Affiliation(s)
- Jian Yu Xu
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| | - William A Murphy
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| | - Denái R Milton
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| | - Camilo Jimenez
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| | - Sarika N Rao
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| | - Mouhammed Amir Habra
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| | - Steven G Waguespack
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| | - Ramona Dadu
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| | - Robert F Gagel
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| | - Anita K Ying
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| | - Maria E Cabanillas
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| | - Steven P Weitzman
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| | - Naifa L Busaidy
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| | - Rena V Sellin
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| | - Elizabeth Grubbs
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| | - Steven I Sherman
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| | - Mimi I Hu
- Departments of Endocrine Neoplasia and Hormonal Disorders (J.Y.X., C.J., S.N.R., M.A.H., S.G.W., R.D., R.F.G., A.K.Y., M.E.C., S.P.W., N.L.B., R.V.S., S.I.S., M.I.H.), Radiology (W.A.M.), Biostatistics (D.R.M.), and Endocrine Surgery (E.G.), University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402
| |
Collapse
|
|
24
|
Huang CY, Wang L, Feng CJ, Yu P, Cai XH, Yao WX, Xu Y, Liu XK, Zhu WJ, Wang Y, Zhou J, Lu Y, Wang YS. Bisphosphonates enhance EGFR-TKIs efficacy in advanced NSCLC patients with EGFR activating mutation: A retrospective study. Oncotarget 2016; 7:66480-66490. [PMID: 26624882 PMCID: PMC5341815 DOI: 10.18632/oncotarget.5515] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Accepted: 09/05/2015] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Bisphosphonates have exhibited anti-tumor activity in non-small cell lung cancer (NSCLC). We aimed to evaluate whether the combination of bisphosphonates with tyrosine kinase inhibitors of EGFR (EGFR-TKIs) could obtain a synergistic effect on advanced NSCLC patients with EGFR mutations. METHODS Between January 2008 and October 2013, 114 advanced EGFR mutations NSCLC patients who received EGFR-TKIs as first-line therapy were recruited from two cancer centers. Patients were separated into EGFR-TKIs alone or EGFR-TKIs plus bisphosphonates (combination) group. Median progression free survival (mPFS), median overall survival (mOS) distributions and survival curves were analyzed. RESULTS Among the 114 patients, 62 had bone metastases (19 patients treated with EGFR-TKIs, 43 patients treated with EGFR-TKIs + bisphosphonates). Median PFS and OS were significantly improved in combination group compared with EGFR-TKIs group (mPFS: 15.0 vs 7.3 months, P = 0.0017; mOS: 25.2 vs 10.4 months, P = 0.0015) in patients with bone metastases. Among the 71 patients (19 patients with bone metastases) treated with EGFR-TKIs alone, patients with bone metastases had poor survival prognosis (mPFS:7.3 vs 12.1 months, P = 0.0434; mOS:10.4 vs 22.0 months, P = 0.0036). The survival of patients with bone metastases who received EGFR-TKIs plus bisphosphonates therapy was non-inferior to patients without bone metastases treated with EGFR-TKIs alone (mPFS: 15.0 vs 12.1 months, p = 0.1871; mOS: 25.2 vs 22.0 months, p = 0.9798). CONCLUSIONS Concomitant use of bisphosphonates and EGFR-TKIs improves therapeutic efficacy and brings survival benefits to NSCLC patients with EGFR mutation and bone metastases.
Collapse
Affiliation(s)
- Chu-Ying Huang
- Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Department of Medical Oncology, Enshi Tujia and Miao Autonomous Prefecture Central Hospital, Hubei Province, China
| | - Li Wang
- Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Department of Dermatology, Enshi Tujia and Miao Autonomous Prefecture Central Hospital, Hubei Province, China
| | - Cheng-Jun Feng
- Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Ping Yu
- Department of Oncology, The Second People's Hospital of Sichuan, Chengdu, China
| | - Xiao-Hong Cai
- Department of Oncology, The Second People's Hospital of Sichuan, Chengdu, China
| | - Wen-Xiu Yao
- Department of Oncology, The Second People's Hospital of Sichuan, Chengdu, China
| | - Yong Xu
- Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao-Ke Liu
- Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wen-Jiang Zhu
- Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Wang
- Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Department of Oncology, The First People's Hospital of Longquanyi District, Chengdu, China
| | - Jin Zhou
- Department of Oncology, The Second People's Hospital of Sichuan, Chengdu, China
| | - You Lu
- Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yong-Sheng Wang
- Department of Thoracic Oncology, Cancer Center, and State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
25
|
Rennert G, Pinchev M, Gronich N, Saliba W, Flugelman A, Lavi I, Goldberg H, Fried G, Steiner M, Bitterman A, Landsman K, Rennert HS. Oral Bisphosphonates and Improved Survival of Breast Cancer. Clin Cancer Res 2016; 23:1684-1689. [PMID: 27683176 DOI: 10.1158/1078-0432.ccr-16-0547] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 08/19/2016] [Accepted: 08/28/2016] [Indexed: 11/16/2022]
Abstract
Purpose: Bisphosphonates are used for treatment or prevention of osteoporosis and of bone metastases. The use of oral bisphosphonates was suggested to be associated with reduced risk of developing breast cancer, and their positive influence on breast cancer survival was only demonstrated with third-generation bisphosphonates. We studied the association of use of oral bisphosphonates after breast cancer diagnosis on overall and breast cancer survival.Experimental Design: A nested case-control analysis was performed using data from the population-based Breast Cancer in Northern Israel Study (BCINIS). Participants were postmenopausal women with newly diagnosed breast cancer insured by Clalit. Use of second-generation bisphosphonates (alendronate and/or risedronate) was identified using computerized prescription records. The analysis was restricted to women who did not use bisphosphonates prior to diagnosis.Results: In a cohort of 3,731 postmenopausal women with breast cancer, followed up for an average of 70 months, there were 799 cases of death which were matched to 15,915 control periods of living breast cancer cases. Use of bisphosphonates after diagnosis for at least 18 months was significantly more common among survivors than among their matched controls who died, adjusted for tumor stage/grade (overall survival: OR = 0.63, 0.41-0.96, P = 0.03; breast cancer-specific survival: OR = 0.28, 0.09-0.91, P = 0.035). A similar advantageous effect, but statistically underpowered, was found in estrogen receptor (ER)-positive, ER-negative, and HER2neu-positive tumors.Conclusions: The use of oral bisphosphonates, by postmenopausal, probably osteoporotic, women initiated after diagnosis of breast cancer was associated with a significant improvement in overall and breast-specific odds of survival. Clin Cancer Res; 23(7); 1684-9. ©2016 AACR.
Collapse
Affiliation(s)
- Gad Rennert
- Department of Community Medicine and Epidemiology, Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and Clalit National Cancer Control Center, Haifa, Israel.
| | - Mila Pinchev
- Department of Community Medicine and Epidemiology, Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and Clalit National Cancer Control Center, Haifa, Israel
| | - Naomi Gronich
- Department of Community Medicine and Epidemiology, Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and Clalit National Cancer Control Center, Haifa, Israel
| | - Walid Saliba
- Department of Community Medicine and Epidemiology, Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and Clalit National Cancer Control Center, Haifa, Israel
| | - Anath Flugelman
- Department of Community Medicine and Epidemiology, Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and Clalit National Cancer Control Center, Haifa, Israel
| | - Idit Lavi
- Department of Community Medicine and Epidemiology, Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and Clalit National Cancer Control Center, Haifa, Israel
| | | | - Georgeta Fried
- Oncology Institute, Rambam Medical Center, Haifa, Israel
| | | | - Arie Bitterman
- Department of Surgery A, Carmel Medical Center, Haifa, Israel
| | - Keren Landsman
- Department of Community Medicine and Epidemiology, Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and Clalit National Cancer Control Center, Haifa, Israel
| | - Hedy S Rennert
- Department of Community Medicine and Epidemiology, Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology and Clalit National Cancer Control Center, Haifa, Israel
| |
Collapse
|
|
26
|
LeVasseur N, Clemons M, Hutton B, Shorr R, Jacobs C. Bone-targeted therapy use in patients with bone metastases from lung cancer: A systematic review of randomized controlled trials. Cancer Treat Rev 2016; 50:183-193. [PMID: 27716496 DOI: 10.1016/j.ctrv.2016.09.013] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Revised: 12/11/2015] [Accepted: 09/14/2016] [Indexed: 11/25/2022]
Abstract
BACKGROUND Patients with advanced lung cancer commonly have bone metastases. Compared with other malignancies, the use of bone-targeted agents (e.g. bisphosphonates and denosumab) is less common in lung cancer patients. This may be due to the perception that bone-targeted agents are less effective in this population. OBJECTIVE To perform a systematic review to evaluate data from randomized trials of bone-targeted agents in lung cancer patients with bone metastases. METHODS A systematic search of Medline, Embase and the Cochrane Register of Controlled Trials through May 2015 was performed. Randomized trials of bone-targeted therapies in lung cancer patients with bone metastases were sought. Outcomes studied included skeletal related events (SREs), pain, quality of life, progression-free survival and overall survival. Random effects meta-analyses were planned if studies were judged homogeneous. RESULTS Of 632 abstracts, 17 publications describing 13 studies were included. Sample sizes ranged between 50 and 1776. Of 3379 patients, 1903 had lung cancer, with subgroup data available for 8 of 13 studies. Patient demographics were comparable, but enrollment criteria and endpoints were heterogeneous across studies, precluding meta-analysis. Study-specific results suggested that bone-modifying agents reduce the incidence of SREs and bone pain in lung cancer patients. Three studies suggested a survival benefit. CONCLUSION Data from included trials suggests benefit of bone-targeted agents in lung cancer for the prevention of SREs and bone pain. There is a trend toward improvement in overall survival and progression-free survival, although further research is needed. Impact on quality of life and key subgroups for benefit both require future research.
Collapse
Affiliation(s)
- Nathalie LeVasseur
- Division of Medical Oncology and Department of Medicine, University of Ottawa, Ottawa, Canada.
| | - Mark Clemons
- Division of Medical Oncology and Department of Medicine, University of Ottawa, Ottawa, Canada; Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada
| | - Brian Hutton
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada; School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Canada
| | | | - Carmel Jacobs
- Division of Medical Oncology and Department of Medicine, University of Ottawa, Ottawa, Canada
| |
Collapse
|
|
27
|
Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2016; 17:1070-1080. [PMID: 27324280 DOI: 10.1016/s1470-2045(16)30096-1] [Citation(s) in RCA: 149] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 04/19/2016] [Accepted: 04/20/2016] [Indexed: 11/23/2022]
Abstract
BACKGROUND Based on preclinical data for the antitumour effect of zoledronate in osteosarcoma, we assessed whether zoledronate combined with chemotherapy and surgery improved event-free survival in children and adults with osteosarcoma. METHODS In this randomised, multicentre, open-label, phase 3 trial (OS2006), patients aged between 5 years and 50 years with newly diagnosed high-grade osteosarcoma were randomly assigned to receive standard chemotherapy with or without ten zoledronate intravenous infusions (four preoperative and six postoperative). Adults older than 25 years received 4 mg zoledronate per infusion, patients aged 18-25 years received 0·05 mg/kg for the first two infusions and 4 mg for the remaining eight infusions, and younger patients received 0·05 mg/kg per infusion. Chemotherapy comprised high-dose methotrexate based chemotherapy in patients younger than 18 years, and doxorubicin, ifosfamide, and cisplatin in adults older than 25 years; patients aged 18-25 years were treated with either regime at the discretion of the treating centre. Balanced randomisation between the two groups was done centrally with online randomisation software, based on a minimisation algorithm taking into account centre, age, combined with chemotherapy regimen, and risk group (resectable primary and no metastasis vs other). Patients and investigators were not masked to treatment assignment, but the endpoint adjudication committee members who reviewed suspected early progressions were masked to group allocation. The primary endpoint was event-free survival, estimated from the randomisation to the time of first failure (local or distant relapse, progression, death) or to the last follow-up visit for the patients in first complete remission, analysed on a modified intention-to-treat population, which excluded patients found not to have a malignant tumour after central review. Three interim analyses were planned. This trial is registered with ClinicalTrials.gov, number NCT00470223. FINDINGS Between April 23, 2007, and March 11, 2014, 318 patients, median age 15·5 years (range 5·8-50·9), were enrolled from 40 French centres; of whom 158 were assigned to the control group (chemotherapy alone) and 160 to the zoledronate group, including 55 (17%) patients with definite metastases. The trial was stopped for futility after the second interim analysis. With a median follow-up of 3·9 years (IQR 2·7-5·1), 125 events occurred (55 in the control group and 70 in the with zoledronate group). Event-free survival at 3 years for all 315 randomly assigned patients was 60·3% (95% CI 64·5-65·9); 3-year event-free survival was 63·4% (55·2-70·9) for the control group and 57·1% (48·8-65·0) for the zoledronate group. The risk of failure was not reduced and was even marginally higher in the zoledronate group than in the control group (hazard ratio [HR] 1·36 [95% CI 0·95-1·96]; p=0·094). No major increase in severe toxic effects of grade 3 or higher associated with zoledronate, barring expected hypocalcaemia (45 [29%] of 153 participants in the zoledronate group vs ten [6%] of 155 participants in the control group; p<0·0001) and hypophosphataemia (61 [40%] of 151 in the zoledronate group vs 26 [17%] of 156 in the control group; p<0·0001). No significant difference in orthopaedic complications was noted between the two groups (27 in the control group and 29 in the zoledronate group). Two treatment-related deaths were reported (one from cardiomyopathy in the control group and one from multiorgan failure in the zoledronate group before the first zoledronate infusion). INTERPRETATION From the results observed in this study, we do not recommend zoledronate in osteosarcoma patients. Further biological studies are required to understand the discordance between the results of OS2006 trial and preclinical data. FUNDING French National Cancer Institute (INCa), Novartis, Chugai, Ligue Nationale contre le Cancer, Fédération Enfants et Santé, Société Française des Cancers et Leucémies de l'Enfant.
Collapse
|
|
28
|
Charpidou A, Tsagouli S, Gkiozos I, Grapsa D, Moutsos M, Kiagia M, Syrigos K. Bone metastases in patients with small cell lung carcinoma: rate of development, early versus late onset, modality of treatment, and their impact on survival. A single-institution retrospective cohort study. Clin Exp Metastasis 2016; 33:453-60. [PMID: 27209468 DOI: 10.1007/s10585-016-9789-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Accepted: 03/04/2016] [Indexed: 10/21/2022]
Abstract
The aim of the present study was to further explore the impact of bone metastases (BMs) and their therapeutic management on the overall prognosis of patients with small cell lung carcinoma (SCLC). We performed a retrospective analysis of medical records of 363 patients with histologically or cytologically confirmed SCLC, diagnosed and treated in the Oncology Unit of Sotiria Athens General Hospital, between January 2003 and December 2012. Demographic and clinicopathological features, including BMs, their time point of development (early onset/at diagnosis versus late onset/at a subsequent time point), treatment modality for BMs (radiotherapy, bisphosphonates or both) and the presence of skeletal-related events (SREs), were correlated with overall survival (OS). Survival analysis was performed using the Kaplan-Meier method, log-rank tests and Cox regression analysis. Overall, 130/363 patients (35.8 %) were diagnosed with either early-onset (97/363 cases, 26.7 %) or late-onset BMs (33/363 cases, 9.1 %). Patients with early-onset BMs had a reduced OS as compared to those with late-onset BMs [Hazard ratio (HR) 0.61; 95 % Confidence interval (CI) 0.41-0.91; p = 0.015) or those without BMs (HR 0.76; 95 % CI 0.6-0.96; p = 0.024). SREs and treatment modality of BMs had no impact on OS. Multiple Cox regression analysis showed that increased age, poor performance status (PS), presence of BMs and early onset BMs were independently associated with reduced OS. The results of our single-institution study suggest that the development of early-onset BMs may represent an independent predictor of a worse prognosis among patients with SCLC, in addition to well-established adverse prognostic factors such as poor PS.
Collapse
Affiliation(s)
- Andriani Charpidou
- Oncology Unit, 3rd Department of Medicine, School of Medicine, "Sotiria" General Hospital, University of Athens, Mesogion 152, 115 27, Athens, Greece
| | - Sofia Tsagouli
- Oncology Unit, 3rd Department of Medicine, School of Medicine, "Sotiria" General Hospital, University of Athens, Mesogion 152, 115 27, Athens, Greece
| | - Ioannis Gkiozos
- Oncology Unit, 3rd Department of Medicine, School of Medicine, "Sotiria" General Hospital, University of Athens, Mesogion 152, 115 27, Athens, Greece
| | - Dimitra Grapsa
- Oncology Unit, 3rd Department of Medicine, School of Medicine, "Sotiria" General Hospital, University of Athens, Mesogion 152, 115 27, Athens, Greece
| | - Michalis Moutsos
- Oncology Unit, 3rd Department of Medicine, School of Medicine, "Sotiria" General Hospital, University of Athens, Mesogion 152, 115 27, Athens, Greece
| | - Maria Kiagia
- Oncology Unit, 3rd Department of Medicine, School of Medicine, "Sotiria" General Hospital, University of Athens, Mesogion 152, 115 27, Athens, Greece
| | - Konstantinos Syrigos
- Oncology Unit, 3rd Department of Medicine, School of Medicine, "Sotiria" General Hospital, University of Athens, Mesogion 152, 115 27, Athens, Greece.
| |
Collapse
|
|
29
|
Ang C, Doyle E, Branch A. Bisphosphonates as potential adjuvants for patients with cancers of the digestive system. World J Gastroenterol 2016; 22:906-916. [PMID: 26811636 PMCID: PMC4716044 DOI: 10.3748/wjg.v22.i3.906] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 11/05/2015] [Accepted: 12/08/2015] [Indexed: 02/06/2023] Open
Abstract
Best known for their anti-resorptive activity in bone, bisphosphonates (BPs) have generated interest as potential antineoplastic agents given their pleiotropic biological effects which include antiproliferative, antiangiogenic and immune-modulating properties. Clinical studies in multiple malignancies suggest that BPs may be active in the prevention or treatment of cancer. Digestive tract malignancies represent a large and heterogeneous disease group, and the activity of BPs in these cancers has not been extensively studied. Recent data showing that some BPs inhibit human epidermal growth factor receptor (HER) signaling highlight a potential therapeutic opportunity in digestive cancers, many of which have alterations in the HER axis. Herein, we review the available evidence providing a rationale for the repurposing of BPs as a therapeutic adjunct in the treatment of digestive malignancies, especially in HER-driven subgroups.
Collapse
|
|
30
|
Hendriks LEL, Hermans BCM, van den Beuken-van Everdingen MHJ, Hochstenbag MMH, Dingemans AMC. Effect of Bisphosphonates, Denosumab, and Radioisotopes on Bone Pain and Quality of Life in Patients with Non-Small Cell Lung Cancer and Bone Metastases: A Systematic Review. J Thorac Oncol 2015; 11:155-73. [PMID: 26718881 DOI: 10.1016/j.jtho.2015.10.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 10/01/2015] [Accepted: 10/08/2015] [Indexed: 12/25/2022]
Abstract
Bone metastases are common in patients with non-small cell lung cancer (NSCLC), often causing pain and a decrease in quality of life (QoL). The effect of bone-targeted agents is evaluated by reduction in skeletal-related events in which neither pain nor QoL are included. Radioisotopes can be administered for more diffuse bone pain that is not eligible for palliative radiotherapy. The evidence that bone-targeted agents relieve pain or improve QoL is not solid. We performed a systematic review of the effect of bone-targeted agents on pain and QoL in patients with NSCLC. Our systematic literature search included original articles or abstracts reporting on bisphosphonates, denosumab, or radioisotopes or combinations thereof in patients with bone metastases (≥5 patients with NSCLC), with pain, QoL, or both serving as the primary or secondary end point. Of the twenty-five eligible studies, 13 examined bisphosphonates (one also examined denosumab) and 12 dealt with radioisotopes. None of the randomized studies on bisphosphonates or denosumab evaluated pain and QoL as the primary end point. In the single-arm studies of bisphosphonates a decrease in pain or analgesic consumption was found for 38% to 77% of patients. QoL was included in five of 13 studies, but improvement was found in only two. No high-level evidence that bisphosphonates or denosumab reduce pain or improve QoL was found. Although the data are limited, radioisotopes seem to reduce pain with a rapid onset of action and duration of response of 1 to 3 months. The evidence that bisphosphonates or denosumab reduce or prevent pain in patients with NSCLC and bone metastases or that they have an influence on QoL is very weak. Radioisotopes can be used to reduce diffuse pain, although there is no high-level evidence supporting such use.
Collapse
Affiliation(s)
- Lizza E L Hendriks
- Department of Pulmonary Diseases, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
| | - Bregtje C M Hermans
- Department of Pulmonary Diseases, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | | | - Monique M H Hochstenbag
- Department of Pulmonary Diseases, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Anne-Marie C Dingemans
- Department of Pulmonary Diseases, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| |
Collapse
|
|
31
|
Liu J, Huang W, Zhou R, Jia S, Tang W, Luo Y, Zhang J. Bisphosphonates in the Treatment of Patients With Metastatic Breast, Lung, and Prostate Cancer: A Meta-Analysis. Medicine (Baltimore) 2015; 94:e2014. [PMID: 26579808 PMCID: PMC4652817 DOI: 10.1097/md.0000000000002014] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
The purpose of this meta-analysis was to investigate whether bisphosphonates are a key therapy for bone metastases in lung cancer, breast cancer, and prostate cancer by comparing all randomized controlled trials that appraised the effects of bisphosphonates on risk of skeletal-related events (SREs).PubMed, Embase, and Medline databases (up to December 2014) were used to search all related articles. Using the data from 19 available publications, the authors examined the efficacy in treating or reducing the risk of SREs in lung cancer, breast cancer, and prostate cancer by meta-analysis.Bisphosphonates have demonstrated efficacy in treating or reducing the risk of SREs in lung cancer [odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.69-0.95, P = 0.008], breast cancer (OR = 0.62, 95% CI = 0.54-0.71, P = 0.000), and prostate cancer (OR = 0.62, 95% CI = 0.45-0.86, P = 0.004).This meta-analysis suggests that bisphosphonates have demonstrated efficacy in treating or reducing the risk of SREs in lung cancer, breast cancer, and prostate cancer.
Collapse
Affiliation(s)
- Jing Liu
- Laboratory of Molecular Genetics of Aging and Tumor, Faculty of Medicine, Kunming University of Science and Technology, Kunming, China
| | | | | | | | | | | | | |
Collapse
|
|
32
|
RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs. Br J Cancer 2015; 113:1313-22. [PMID: 26528707 PMCID: PMC4815796 DOI: 10.1038/bjc.2015.352] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 08/27/2015] [Accepted: 09/02/2015] [Indexed: 12/12/2022] Open
Abstract
Background: Bone metastases (BMs) are associated with poor outcome in metastatic clear-cell renal carcinoma (m-ccRCC) treated with anti-vascular endothelial growth factor tyrosine kinase inhibitors (anti-VEGFR-TKIs). We aimed to investigate whether expression in the primary tumour of genes involved in the development of BM is associated with outcome in m-ccRCC patients treated with anti-VEGFR-TKIs. Methods: Metastatic clear-cell renal cell carcinoma patients with available fresh-frozen tumour and treated with anti-VEGFR-TKIs. Quantitative real-time PCR (qRT–PCR) for receptor activator of NF-kB (RANK), RANK-ligand (RANKL), osteoprotegerin (OPG), the proto-oncogene SRC and DKK1 (Dickkopf WNT signalling pathway inhibitor-1). Time-to-event analysis by Kaplan–Meier estimates and Cox regression. Results: We included 129 m-ccRCC patients treated between 2005 and 2013. An elevated RANK/OPG ratio was associated with shorter median time to metastasis (HR 0.50 (95% CI 0.29–0.87); P=0.014), shorter time to BM (HR 0.54 (95% CI 0.31–0.97); P=0.037), shorter median overall survival (mOS) since initial diagnosis (HR 2.27 (95% CI 1.44–3.60); P=0.0001), shorter median progression-free survival (HR 0.44 (95% CI 0.28–0.71); P=0.001) and mOS (HR 0.31 (95% CI 0.19–0.52); P<0.0001) on first-line anti-VEGFR-TKIs in the metastatic setting. Higher RANK expression was associated with shorter mOS on first-line anti-VEGFR-TKIs (HR 0.46 (95% CI 0.29–0.73); P=0.001). Conclusions: RANK/OPG ratio of expression in primary ccRCC is associated with BM and prognosis in patients treated with anti-VEGFR-TKIs. Prospective validation is warranted.
Collapse
|
|
33
|
Terpos E, Confavreux CB, Clézardin P. Bone antiresorptive agents in the treatment of bone metastases associated with solid tumours or multiple myeloma. BONEKEY REPORTS 2015; 4:744. [PMID: 26512321 DOI: 10.1038/bonekey.2015.113] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 07/14/2015] [Indexed: 12/16/2022]
Abstract
Skeletal lesions contribute substantially to morbidity and mortality in patients with cancer. The disease manifestation course during metastatic bone disease is driven by tumour cells in the bone marrow, which alter the functions of bone-resorbing (osteoclasts) and bone-forming (osteoblasts) cells, promoting skeletal destruction. Successful therapeutic strategies for the treatment of metastatic bone disease include bisphosphonates and denosumab that inhibit osteoclast-mediated bone resorption. Inhibitors of cathepsin K, Src and activin A are under clinical investigation as potential anti-osteolytics. In this review, we describe current knowledge and future directions of antiresorptive therapies that may reduce or prevent destructive bone lesions from solid tumours and multiple myeloma.
Collapse
Affiliation(s)
- Evangelos Terpos
- National and Kapodistrian University of Athens, School of Medicine , Athens, Greece
| | - Cyrille B Confavreux
- Department of Rheumatology, Edouard Herriot Hospital, Hospices Civils de Lyon , Lyon, France ; INSERM, Research Unit UMR1033, UFR de Médecine Lyon-Est (domaine Laennec) , Lyon, France ; Université de Lyon , Lyon, France
| | - Philippe Clézardin
- INSERM, Research Unit UMR1033, UFR de Médecine Lyon-Est (domaine Laennec) , Lyon, France ; Université de Lyon , Lyon, France
| |
Collapse
|
|
34
|
Wang X, Wu G, Cao G, Yang L, Xu H, Huang J, Hou J. Zoledronic acid inhibits the pentose phosphate pathway through attenuating the Ras-TAp73-G6PD axis in bladder cancer cells. Mol Med Rep 2015; 12:4620-4625. [PMID: 26126921 DOI: 10.3892/mmr.2015.3995] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 05/29/2015] [Indexed: 11/05/2022] Open
Abstract
Zoledronic acid (ZA) is the current standard of care for the therapy of patients with bone metastasis or osteoporosis. ZA inhibits the prenylation of small guanosine‑5'-triphosphate (GTP)‑binding proteins, such as Ras, and thus inhibit Ras signaling. The present study demonstrated that ZA inhibited cell proliferation and the pentose phosphate pathway (PPP) in bladder cancer cells. In addition, the expression of glucose‑6‑phosphate dehydrogenase (G6PD, the rate‑limiting enzyme of the PPP) was found to be inhibited by ZA. Furthermore, the stability of TAp73, which activates the expression G6PD was decreased in zoledronic acid treated cells. Decreased levels of Ras‑GTP and phosphorylated‑extracellular signal-regulated kinase 1/2 were also observed following treatment with ZA. This may be due to the fact that activated Ras was reported to stabilize TAp73 inducing its accumulation. The inhibition of Ras activity by PT inhibitor II also significantly reduced the levels of TAp73 and G6PD and the PPP flux. Moreover, knockdown of TAp73, attenuated the PPP flux and eliminated the affection of ZA on the PPP flux. In conclusion, it was proposed that ZA can inhibit stability of TAp73 and attenuate the PPP via blocking Ras signaling in bladder cancer cells.
Collapse
Affiliation(s)
- Xiaolin Wang
- Department of Urology, First Affiliated Hospital, Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Guang Wu
- Department of Urology, First People's Hospital of Wujiang, Suzhou, Jiangsu 215200, P.R. China
| | - Guangxin Cao
- Department of Urology, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Lei Yang
- Department of Medical Oncology, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Haifei Xu
- Department of Urology, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Jian Huang
- Department of Urology, Nantong Tumor Hospital, Nantong, Jiangsu 226361, P.R. China
| | - Jianquan Hou
- Department of Urology, First Affiliated Hospital, Soochow University, Suzhou, Jiangsu 215006, P.R. China
| |
Collapse
|
|
35
|
Gampenrieder SP, Rinnerthaler G, Greil R. Bone-targeted therapy in metastatic breast cancer - all well-established knowledge? ACTA ACUST UNITED AC 2015; 9:323-30. [PMID: 25759612 DOI: 10.1159/000368710] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Bone-targeted therapies like bisphosphonates (zoledronic acid or pamidronate) or denosumab are recommended in all patients with metastatic breast cancer and bone metastases, whether they are symptomatic or not. The choice between these 2 different agents, however, remains open. In this review, we critically discuss the emerging evidence for direct anti-tumor activity of bone-targeting agents, the utility of bone turnover markers for treatment decision and efficacy prediction, as well as the safety and financial aspects of bisphosphonates and denosumab. Furthermore, we provide a possible therapeutic algorithm, and present new pharmacologic agents which are being investigated for the treatment of metastatic bone disease.
Collapse
Affiliation(s)
- Simon P Gampenrieder
- III Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute (SCRI) with Laboratory of Immunological and Molecular Cancer Research (LIMCR) and Center for Clinical Cancer and Immunology Trials (CCCIT), Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Gabriel Rinnerthaler
- III Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute (SCRI) with Laboratory of Immunological and Molecular Cancer Research (LIMCR) and Center for Clinical Cancer and Immunology Trials (CCCIT), Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Richard Greil
- III Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute (SCRI) with Laboratory of Immunological and Molecular Cancer Research (LIMCR) and Center for Clinical Cancer and Immunology Trials (CCCIT), Paracelsus Medical University Salzburg, Salzburg, Austria
| |
Collapse
|
|
36
|
Zoledronic Acid may reduce intraoperative bleeding in spinal tumors: a prospective cohort study. BIOMED RESEARCH INTERNATIONAL 2015; 2015:936307. [PMID: 25685817 PMCID: PMC4317594 DOI: 10.1155/2015/936307] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 10/11/2014] [Indexed: 11/17/2022]
Abstract
Between June 2010 and June 2011, 176 patients were divided into 2 groups: a group with spinal metastasis of solid tumors (n = 157) and a group with multiple myeloma (n = 19). Both groups were further divided into 2 subgroups: a group receiving zoledronic acid before surgery and a control group. The zoledronic acid subgroup of the solid tumors group was group A (n = 81), the control subgroup of the solid tumors group was group B (n = 76), the zoledronic acid subgroup of the multiple myeloma group was group C (n = 10), and the control subgroup of the multiple myeloma group was group D (n = 9). The average intraoperative blood loss during spinal surgery was as follows: 1311 ± 691 mL in group A and 1752 ± 740 mL in group B (P = 0.000) and 1994 ± 810 mL in group C and 3134 ± 795 mL in group D (P = 0.000). Patients receiving zoledronic acid before surgery had significantly less intraoperative bleeding than those who did not receive it. Preoperative use of zoledronic acid can effectively reduce intraoperative bleeding during surgery for the treatment of spinal tumors.
Collapse
|
|
37
|
|
|
38
|
Tamura T, Kurishima K, Nakazawa K, Kagohashi K, Ishikawa H, Satoh H, Hizawa N. Specific organ metastases and survival in metastatic non-small-cell lung cancer. Mol Clin Oncol 2014; 3:217-221. [PMID: 25469298 DOI: 10.3892/mco.2014.410] [Citation(s) in RCA: 230] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 08/27/2014] [Indexed: 12/15/2022] Open
Abstract
The present retrospective study was performed to evaluate the clinicopathological characteristics associated with distant metastasis from non-small-cell lung cancer (NSCLC). The records of NSCLC patients with metastasis at the time of diagnosis between 1999 and 2012 were reviewed. Of the consecutive 1,542 NSCLC patients diagnosed during the study period, 729 (47.3%) patients presented with distant metastasis. Among those 729 metastatic NSCLC patients, 250 (34.3%), 234 (32.1%), 207 (28.4%), 122 (16.7%), 98 (13.4%) and 69 (9.5%) had bone, lung, brain, adrenal gland, liver and extrathoracic lymph node metastasis, respectively. In a multivariate analysis using the Cox proportional hazards model, liver and adrenal gland metastases were unfavorable prognostic factors. However, brain and bone metastases were not statistically significant prognostic factors. Using a logistic regression analysis, metastasis to the adrenal glands and the presence of pleural and/or pericardial fluid effusion were correlated with a poor performance status. Therefore, when planning the treatment of NSCLC patients, particularly those with liver and adrenal gland metastases, we should take into consideration information regarding these unfavorable organ metastases.
Collapse
Affiliation(s)
- Tomohiro Tamura
- Division of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba; Mito Medical Center, University of Tsukuba, Mito, Ibaraki, Japan
| | - Koichi Kurishima
- Division of Respiratory Medicine, Tsukuba Medical Center Hospital; Mito Medical Center, University of Tsukuba, Mito, Ibaraki, Japan
| | - Kensuke Nakazawa
- Division of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba; Mito Medical Center, University of Tsukuba, Mito, Ibaraki, Japan
| | - Katsunori Kagohashi
- Division of Respiratory Medicine, Mito Medical Center, University of Tsukuba, Mito, Ibaraki, Japan Mito Medical Center, University of Tsukuba, Mito, Ibaraki, Japan
| | - Hiroichi Ishikawa
- Division of Respiratory Medicine, Tsukuba Medical Center Hospital; Mito Medical Center, University of Tsukuba, Mito, Ibaraki, Japan
| | - Hiroaki Satoh
- Division of Respiratory Medicine, Mito Medical Center, University of Tsukuba, Mito, Ibaraki, Japan Mito Medical Center, University of Tsukuba, Mito, Ibaraki, Japan
| | - Nobuyuki Hizawa
- Division of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba; Mito Medical Center, University of Tsukuba, Mito, Ibaraki, Japan
| |
Collapse
|
|
39
|
Roza T, Hakim L, van Poppel H, Joniau S. Bone-targeted therapies for elderly patients with renal cell carcinoma: current and future directions. Drugs Aging 2014; 30:877-86. [PMID: 24072355 DOI: 10.1007/s40266-013-0117-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Bone metastases are very common in advanced renal cell carcinoma (RCC) and can have a huge impact on quality of life by leading to skeletal-related events (SREs), including pain, pathologic fractures and spinal cord compression with need for surgery or radiotherapy. Because of their osteolytic aspect and biologic behaviour, these SREs are more common in patients with bone metastases from RCC than from other malignancies. As overall survival is increased by new anti-angiogenic drugs like tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors, the incidence of SREs is rising, making the clinical management of bone metastases in RCC ever more important, especially in the more vulnerable elderly patient. In this review we discuss the current advances and future directions in bone-targeted therapies in patients with RCC with a special focus on the elderly population. Recently, two bone-targeted agents have been approved in the prevention of SREs in advanced RCC: zoledronic acid and denosumab. To date, there is no specific data on the use of bisphosphonates or denosumab in the elderly and specific studies in this setting are warranted. We compare the available evidence for the use and implications of both agents in the elderly patient and give general information on safety concerns that could be more important in these patients.
Collapse
Affiliation(s)
- Thomas Roza
- Department of Urology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium,
| | | | | | | |
Collapse
|
|
40
|
Murakami H, Yamanaka T, Seto T, Sugio K, Okamoto I, Sawa T, Hirashima T, Takeda K, Atagi S, Fukuoka M, Nakanishi Y, Nakagawa K, Yamamoto N. Phase II study of zoledronic acid combined with docetaxel for non-small-cell lung cancer: West Japan Oncology Group. Cancer Sci 2014; 105:989-95. [PMID: 24837137 PMCID: PMC4317856 DOI: 10.1111/cas.12448] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Revised: 05/12/2014] [Accepted: 05/14/2014] [Indexed: 01/11/2023] Open
Abstract
The aim of this open-label, multicenter, randomized phase II trial was to evaluate the efficacy and safety of zoledronic acid in combination with docetaxel in previously treated patients with non-small-cell lung cancer (NSCLC) and bone metastases. In this study, patients randomly received docetaxel (60 mg/m2) with (group DZ) or without (group D) zoledronic acid every 21 days. There were 50 patients in each group, and the primary endpoint was progression-free survival. In an efficacy analysis of 94 patients (DZ, 48; D, 46), the median progression-free survival was 2.7 months (95% confidence interval [CI], 1.5–3.5 months) for the DZ group and 2.6 months (95% CI, 1.5–3.4 months) for the D group (stratified log-rank test, P = 0.89). The median overall survival was 10.4 months (95% CI, 7.0–15.8 months) for the DZ group and 9.7 months (95% CI, 6.1–12.5 months) for the D group (stratified log-rank test, P = 0.62). There were no clinically relevant differences in the frequencies of grade 3 or 4 adverse events between the two groups. No treatment-related deaths occurred in the DZ group. Zoledronic acid combined with docetaxel was well tolerated but did not meet the primary endpoint of demonstrating a longer progression-free survival in advanced NSCLC patients with bone metastases compared with docetaxel alone. This trial was registered with the University Hospital Medical Information Network (UMIN000001098).
Collapse
Affiliation(s)
- Haruyasu Murakami
- Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
D'Antonio C, Passaro A, Gori B, Del Signore E, Migliorino MR, Ricciardi S, Fulvi A, de Marinis F. Bone and brain metastasis in lung cancer: recent advances in therapeutic strategies. Ther Adv Med Oncol 2014; 6:101-14. [PMID: 24790650 DOI: 10.1177/1758834014521110] [Citation(s) in RCA: 164] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Bone and brain metastases are a very common secondary localization of disease in patients with lung cancer. The prognosis of these patients is still poor with a median survival of less than 1 year. Current therapeutic approaches include palliative radiotherapy and systemic therapy with chemotherapy and targeted agents. For bone metastasis, zoledronic acid is the most commonly used bisphosphonate to prevent, reduce the incidence and delay the onset of skeletal-related events (SREs). Recently, denosumab, a fully human monoclonal antibody directed against the receptor activator of nuclear factor κB (RANK) ligand inhibiting the maturation of pre-osteoclasts into osteoclasts, showed increased time to SREs and overall survival compared with zoledronic acid. The treatment of brain metastasis is still controversial. Available standard therapeutic options, such as whole brain radiation therapy and systemic chemotherapy, provide a slight improvement in local control, overall survival and symptom relief. More recently, novel target agents such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib and afatinib have shown activity in patients with brain metastasis. Inter alia, in patients harboring EGFR mutations, the administration of EGFR TKIs is followed by a response rate of 70-80%, and a longer progression-free and overall survival than those obtained with standard chemotherapeutic regimens. This review is focused on the evidence for therapeutic strategies in bone and brain metastases due to lung cancer.
Collapse
Affiliation(s)
- Chiara D'Antonio
- 1st Oncological Pulmonary Unit/Department of Medical and Surgical Sciences and Translational Medicine, 'Sapienza' University of Rome, Sant'Andrea Hospital San Camillo, High Specialization Hospital/University of Rome, Sant'Andrea Hospital, Cir. ne Gianicolense 87, 00151, Rome, Italy
| | - Antonio Passaro
- Division of Thoracic Oncology, European Institute of Oncology, Milan, Italy
| | - Bruno Gori
- 1st Oncological Pulmonary Unit, San Camillo, High Specialization Hospital, Rome, Italy
| | - Ester Del Signore
- Division of Thoracic Oncology, European Institute of Oncology, Milan, Italy
| | - Maria Rita Migliorino
- 1st Oncological Pulmonary Unit, San Camillo, High Specialization Hospital, Rome, Italy
| | - Serena Ricciardi
- 1st Oncological Pulmonary Unit, San Camillo, High Specialization Hospital, Rome, Italy
| | - Alberto Fulvi
- 1st Oncological Pulmonary Unit, San Camillo, High Specialization Hospital, Rome, Italy
| | - Filippo de Marinis
- Division of Thoracic Oncology, European Institute of Oncology, Milan, Italy
| |
Collapse
|
|
42
|
Deberne M, Ropert S, Billemont B, Daniel C, Chapron J, Goldwasser F. Inaugural bone metastases in non-small cell lung cancer: a specific prognostic entity? BMC Cancer 2014; 14:416. [PMID: 24913188 PMCID: PMC4057924 DOI: 10.1186/1471-2407-14-416] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Accepted: 05/22/2014] [Indexed: 11/26/2022] Open
Abstract
Background In non-small cell lung cancer patients (NSCLC), median survival from the time patients develop bone metastasis is classically described being inferior to 6 months. We investigated the subcategory of patients having an inaugural skeletal-related-event revealing NSCLC. The purpose of this study was to assess the impact of bone involvement on overall survival and to determine biological and tumoral prognosis factors on OS and PFS. An analysis of the subgroup of solitary bone metastasis patients was also performed. Methods In a population of 1208 lung cancer patients, 55 consecutive NSCLC patients revealed by inaugural bone metastasis and treated between 2003 and 2010, were retrospectively analysed. Survival was measured with a Kaplan-Meyer curve. Univariate and multivariate analysis were performed using the Stepwise Cox proportional hazard regression model. A p value of less than 0,05 was considered statistically significant. Results Estimated incidence of revealing bone metastasis is 4,5% among newly diagnosed lung cancer patients. Median duration of skeletal symptoms before diagnosis was 3 months and revealing bone site was located on axial skeleton in 70% of the cases. Histology was adenocarcinoma (78%), with small primary tumors Tx-T1-2 accounting for 71% of patients. Rate of second SRE is 37%. Median overall survival was 8.15 months, IQR [5–16 months], mean survival 13.4 months, and PFS was 3.5 months. In multivariate analysis, variables significantly associated with shortened survival were advanced T stage (HR = 2.8; p = 0.004), weight loss > 10% (HR = 3.1; p = 0.02), inaugural spinal epidural metastasis (HR 2.5; p = 0.0036), elevated C-reactive protein (HR = 4.3; p = 0.002) and TTF-1 status (HR = 2.42; p = 0.004). Inaugural spinal epidural metastasis is a very strong adverse pronostic factor in these cases, with a 3 months median survival. Single bone metastasis patients showed prolonged survival of 14.2 months versus 7.6 months, only in univariate analysis (HR = 0.42; p = 0.0059). Conclusion Prognosis of lung cancer patients with inaugural SRE remains pejorative. Accurately estimating the survival of this population is helpful for bone surgical decision-making at diagnosis. The trend for a higher proportion of adenocarcinoma in NSCLC patients should result with an increasing number of patients with inaugural SRE at diagnosis.
Collapse
Affiliation(s)
- Mélanie Deberne
- Radiation Oncology Department, Institut Curie, 26 rue d'Ulm, Paris 75005, France.
| | | | | | | | | | | |
Collapse
|
|
43
|
Verron E, Schmid-Antomarchi H, Pascal-Mousselard H, Schmid-Alliana A, Scimeca JC, Bouler JM. Therapeutic strategies for treating osteolytic bone metastases. Drug Discov Today 2014; 19:1419-26. [PMID: 24742971 DOI: 10.1016/j.drudis.2014.04.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 03/11/2014] [Accepted: 04/07/2014] [Indexed: 01/15/2023]
Abstract
The recent progress in oncologic management of patients with localized cancer or metastatic disease has permitted a significant improvement in life expectancy. Nevertheless, bone metastases and their consequent skeletal-related events (SREs) are still associated with unfavorable prognosis and greatly affect quality of life. Global management of these bone metastases includes traditional local approaches (surgery, radiotherapy, etc.) and systemic administration of chemotherapeutic agents. This review focuses on treatments specific for bone metastases and, in particular, on inhibitors of bone resorption that are effective for preventing and delaying the development of SREs.
Collapse
Affiliation(s)
- Elise Verron
- INSERM U791, Université de Nantes, Faculté de Chirurgie Dentaire, 44042 Nantes, France.
| | | | | | - Annie Schmid-Alliana
- Univ Nice Sophia Antipolis, CNRS, iBV, UMR7277, UFR Médecine, 06107 Nice Cedex 2, France
| | - Jean-Claude Scimeca
- Univ Nice Sophia Antipolis, CNRS, iBV, UMR7277, UFR Médecine, 06107 Nice Cedex 2, France
| | - Jean-Michel Bouler
- INSERM U791, Université de Nantes, Faculté de Chirurgie Dentaire, 44042 Nantes, France
| |
Collapse
|
|
44
|
Kosaka T, Yamaki E, Mogi A, Kuwano H. A Case of Lung Adenocarcinoma with Postoperative Recurrence of Multiple Bone Metastases that Showed a Gradual Complete Response to Combined Administration of Erlotinib and Zoledronic Acid. TUMORI JOURNAL 2014; 100:e45-8. [DOI: 10.1177/030089161410000223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
We describe a case of lung adenocarcinoma with multiple postoperative bone metastases that showed a gradual but complete response to combined administration of erlotinib and zoledronic acid. A 76-year-old man with moderately differentiated adenocarcinoma underwent a radical left upper lobectomy and mediastinal lymph node dissection. Three and a half years after the operation, serum carcinoembryonic antigen (CEA) was elevated and 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) revealed multiple bone metastases. Pretreatment evaluation of EGFR mutations in the resected primary adenocarcinoma specimen showed an L858R mutation in exon 21. Gefitinib was started as first-line treatment. However, evaluation 1 month after administration revealed progressive disease. Erlotinib was started as second-line treatment, and evaluation 1 month after administration revealed that the disease was stable. Administration of zoledronic acid was then begun with continuation of erlotinib. After 2 courses of zoledronic acid, the serum CEA level had not changed but the maximum standardized uptake values of each region uniformly decreased. Furthermore, the uptake of 18FDG completely disappeared after 6 courses. Subsequently, the serum CEA level continued to decrease and the disappearance of 18FDG uptake was confirmed after 10 courses (12 months after initiation of erlotinib administration). Our results suggest that the combined administration of both drugs is effective against bone metastases.
Collapse
Affiliation(s)
- Takayuki Kosaka
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan
| | - Ei Yamaki
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan
| | - Akira Mogi
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan
| | - Hiroyuki Kuwano
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan
| |
Collapse
|
|
45
|
Zoledronic acid treatment in advanced non-small cell lung cancer patients with bone metastases. Med Oncol 2014; 31:898. [PMID: 24573639 DOI: 10.1007/s12032-014-0898-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 02/17/2014] [Indexed: 10/25/2022]
Abstract
Bone metastases occur in 30-40% of patients with advanced non-small cell lung cancer (NSCLC). Several studies have demonstrated the direct anticancer effect of zoledronic acid against lung cancer; however, most of these studies are preclinical research. A total of 311 NSCLC patients with bone metastases who were treated with zoledronic acid at Zhejiang Cancer Hospital between 2008 and 2011 were identified. Of these, 109 patients received zoledronic acid (4 mg intravenously every 21-28 days) more than 6 times (Group A), and the other 204 patients received zoledronic acid <6 times (Group B). All patients received standard chemotherapy and other treatments. Survival time was significantly longer in Group A than in Group B (385 vs. 275 days; P = 0.002), and the incidence of malignant pleural effusion was lower in Group A than in Group B (22.0 vs. 33.8%; P = 0.041). In conclusion, our study results suggest that a longer zoledronic acid treatment period had a better effect on survival. Zoledronic acid use might decrease the incidence of malignant pleural effusion.
Collapse
|
|
46
|
Nagykálnai T, Landherr L. [Management of bone metastases]. Orv Hetil 2014; 155:217-25. [PMID: 24486845 DOI: 10.1556/oh.2014.29781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The skeleton is the most common site to be affected by advanced breast, prostatic, lung, kidney, thyroid and other solid tumors (in addition to myeloma multiplex). Bone metastases cause significant morbidity with nearly always fatal outcome. Over 600 000 new patients diagnosed in the developed countries yearly. On average every 4-6 months patients suffer from series of severe skeletal complications such as pathologic fractures, spinal cord compression, hypercalcemic events, etc., besides the permanent pain. Local external beam radiotherapy, systemic radioisotope-, endocrine-, and chemotherapy, oral and i.v. bisphosphonates and recently s.c. denosumab are the mainstays of treatment, in addition to pain-killers and other usual "classical" interventions. The modern treatments singificantly reduce the probability of skeletal complications and improve the patients' quality of life and, sometimes, they extend the survival as well. The authors briefly summarize the available treatment options.
Collapse
|
|
47
|
Isla D, Afonso R, Bosch-Barrera J, Martínez N. Zoledronic acid in lung cancer with bone metastases: a review. Expert Rev Anticancer Ther 2014; 13:421-6. [DOI: 10.1586/era.13.15] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
|
|
48
|
Beuselinck B, Wolter P, Karadimou A, Elaidi R, Dumez H, Rogiers A, Van Cann T, Willems L, Body JJ, Berkers J, Van Poppel H, Lerut E, Debruyne P, Paridaens R, Schöffski P. Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases. Br J Cancer 2013; 107:1665-71. [PMID: 23132391 PMCID: PMC3493858 DOI: 10.1038/bjc.2012.385] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
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.
Collapse
Affiliation(s)
- B Beuselinck
- Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Herestraat 49, Herestraat 49, B-3000 Leuven, Belgium.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Avilés A, Neri N, Huerta-Guzmán J, Nambo MJ. Randomized clinical trial of zoledronic acid in multiple myeloma patients undergoing high-dose chemotherapy and stem-cell transplantation. ACTA ACUST UNITED AC 2013; 20:e13-20. [PMID: 23443988 DOI: 10.3747/co.20.1055] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND A growing body of evidence is demonstrating that the nitrogen-containing bisphosphonate zoledronic acid (zol) improves clinical outcomes in various cancer settings, including multiple myeloma. Those findings provided the rationale for conducting an open-label randomized controlled phase iii trial to evaluate the effect of zol on overall survival (os) and progression-free survival (pfs) in patients with previously untreated high-risk multiple myeloma. METHODS The trial randomly assigned 308 adult patients less than 65 years of age with previously untreated symptomatic multiple myeloma (1:1) to receive zol 4 mg intravenously once every 28 days for 24 months (n = 151) or no zol (n = 157). Before autologous stem-cell transplantation (asct), all patients received a high-dose noncytotoxic induction regimen of dexamethasone, all-trans-retinoic acid, and interferon alpha 2b. RESULTS After a median follow-up of 69.8 months (range: 36.5-96 months), the 10-year pfs (66% vs. 52%, p < 0.001) and os (67% vs. 48%, p < 0.001) rates were significantly higher in treated patients than in control patients. Overall response (77% zol vs. 75% control), complete response (52% vs. 46%), and very good partial response (25% vs. 29%) rates were similar between the groups. Treatment was generally well tolerated, with no reports of renal impairment or osteonecrosis of the jaw. CONCLUSIONS In symptomatic previously untreated multiple myeloma patients, zol combined with high-dose therapy followed by asct improved os and pfs without appreciable toxicity. These findings provide additional evidence of the meaningful anticancer activity of zol in this patient population.
Collapse
Affiliation(s)
- A Avilés
- Oncology Research Unit, Oncology Hospital, National Medical Center, imss , Mexico DF, Mexico
| | | | | | | |
Collapse
|
|
50
|
Zoledronic acid negatively affects the expansion of in vitro activated human NK cells and their cytolytic interactions with Ewing sarcoma cells. Oncol Rep 2013; 29:2348-54. [DOI: 10.3892/or.2013.2350] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 01/21/2013] [Indexed: 11/05/2022] Open
|