Introduction: Denosumab, a fully human anti-RANKL monoclonal antibody, reduces the incidence of skeletal-related events in patients with bone metastases from solid tumors. We present survival data for the subset of patients with lung cancer, participating in the phase
3 trial of denosumab versus zoledronic acid (ZA) in the treatment of bone metastases from solid tumors (except breast or prostate) or multiple myeloma.
Methods: Patients were randomized 1:1 to receive monthly subcu-taneous denosumab 120 mg or intravenous ZA 4 mg. An exploratory analysis, using Kaplan–Meier estimates and proportional hazards models, was performed for overall survival among patients with non–small-cell lung cancer (NSCLC) and SCLC.
Results: Denosumab was associated with improved median overall survival versus ZA in 811 patients with any lung cancer (8.9 versus 7.7 months; hazard ratio [HR] 0.80) and in 702 patients with NSCLC (9.5 versus 8.0 months; HR 0.78) (p = 0.01, each comparison). Further analysis of NSCLC by histological type showed a median survival of 8.6 months for denosumab versus 6.4 months for ZA in patients with squamous cell carcinoma (HR 0.68; p = 0.035). Incidence of overall adverse events was balanced between treatment groups; serious adverse events occurred in 66.0% of denosumab-treated patients and 72.9% of ZA-treated patients. Cumulative incidence of osteonecrosis of the jaw was similar between groups (0.7% denosumab versus 0.8% ZA). Hypocalcemia rates were 8.6% with denosumab and 3.8% with ZA. Conclusion: In this exploratory analysis, denosumab was associated with improved overall survival compared with ZA, in patients with metastatic lung cancer.
Key Words: Lung cancer, Bone metastases, Survival, Clinical study. (J Thorac Oncol. 2012;7: 1823–1829)
L
ung cancer, characterized as non–small-cell lung cancer (NSCLC) or small-cell lung cancer (SCLC), is the lead-ing cause of cancer mortality worldwide.1 Advanced NSCLCaccounts for more than 80% of newly diagnosed cases, and stage IV disease is associated with 5-year survival rates of less than 5%.2 Primary tumors invade the vascular and lymphatic
chan-nels, causing metastatic dissemination to distant sites. Common metastatic sites include bone, liver, lung, adrenals, and brain.3
Copyright © 2012 by the International Association for the Study of Lung Cancer
ISSN: 1556-0864/12/0712-1823
Overall Survival Improvement in Patients with
Lung Cancer and Bone Metastases Treated with
Denosumab Versus Zoledronic Acid
Subgroup Analysis from a Randomized Phase 3 Study
Giorgio Vittorio Scagliotti, MD,* Vera Hirsh, MD,† Salvatore Siena, MD,‡ David H. Henry, MD,§
Penella J. Woll, FRCP, PhD,|| Christian Manegold, MD,¶ Philippe Solal-Celigny, MD,#
Gladys Rodriguez, MD** Maciej Krzakowski, MD, PhD,†† Nilesh D. Mehta, MD,‡‡ Lara Lipton, PhD,§§
José Angel García-Sáenz, MD, PhD,|||| José Rodrigues Pereira, MD,¶¶ Kumar Prabhash, MD,##
Tudor-Eliade Ciuleanu, MD, PhD,*** Vladimir Kanarev, MD,†† Huei Wang, PhD,‡‡‡,
Arun Balakumaran, MD, PhD,§§§ and Ira Jacobs, MD, MBA§§§
*Department of Clinical and Biological Sciences, University of Turino, Orbassano, Italy; †Department of Oncology, McGill University Health Centre, Montreal, Canada; ‡The Falck Division of Medical Oncology, Department of Oncology, Ospedale Niguarda Ca’ Granada, Milan, Italy; §Joan Karnell Cancer Center, Pennsylvania Hospital, Philadelphia, Pennsylvania; ||Department of Oncology, Weston Park Hospital, University of Sheffield, Sheffield, United Kingdom; ¶Department of Surgery, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany; #Centre Jean Bernard, Clinique Victor Hugo, Le Mans, France; **South Texas Oncology and Hematology, San Antonio, Texas; ††The Maria Sklodowska-Curie Institute of Oncology, Warsaw, Poland; ‡‡Oncology Hematology Associates of Northern Illinois, Gurnee, Illinois; §§Department of Medical Oncology, Western Hospital, Footscray, Victoria, Australia; ||||Department of Medical Oncology, Hospital Clínico San Carlos, Madrid, Spain; ¶¶Instituto do Cancer Arnaldo Vieira de Carvalho, University of São Paulo Medical School, Sao Paolo, Brazil; ##Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India; ***Institutul Oncologic I. Chiricuta, Cluj-Napoca, Romania; †††Regional Oncology Dispensary with Inpatient Sector, Plovdiv, Bulgaria; ‡‡‡Global Biostatistical Sciences, and §§§Clinical Development, Amgen Inc., Thousand Oaks, California. Funding for this study was provided by Amgen Inc.
Disclosure: Giorgio Vittorio Scagliotti has received payment for lectures from Astra Zeneca, Eli Lilly, Pfizer, and Roche. Vera Hirsh has received hono-rarium for serving on advisory boards from Amgen Inc. Penella J. Woll has received consulting fees from Amgen Inc. David H. Henry has received grants and honoraria from Amgen Inc. for serving on advisory boards and speakers’ bureaus. Philippe Solal-Celigny has received research grants from Amgen Inc. Nilesh D. Mehta has received honoraria from Amgen Inc. for serving on a speakers’ bureau. Tudor-Eliade Ciuleanu has received payment for lectures given on behalf of Amgen Inc. and Novartis. Huei Wang, Arun Balakumaran, and Ira Jacobs are employees and stockholders of Amgen Inc., Thousand Oaks, California.The remaining authors declare no potential conflicts. Address for correspondence: Giorgio Vittorio Scagliotti, MD, Department of
Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Regione Gonzole 10, Orbassano, Torino, Italy 10043. E-mail: giorgio. [email protected]
One of the most frequent sites of metastasis is the bone. An estimated 30% to 40% of patients with NSCLC develop bone metastases and associated osteoclast-mediated bone destruction during the clinical course of the disease.4 Ensuing
complications, collectively known as skeletal-related events (SREs), include pathologic fracture, need for radiation or sur-gery to the bone, or spinal cord compression.5,6 Hypercalcemia
of malignancy is also seen more frequently in patients with metastatic bone disease. SREs cause pain and decreased qual-ity of life, with declines in physical, functional, and emotional well being.7 Health care costs are also substantial, reported to
be $28,000 higher over a 24-month period for patients with SREs compared with a propensity-matched sample of patients without SREs.8
Prevention or delay of SREs may preserve quality of life and reduce health care costs. Antiresorptive agents are fre-quently used for the prevention of SREs in patients with bone metastases. The intravenous bisphosphonate zoledronic acid (ZA) has been shown to reduce SREs in patients with solid tumors, including lung cancer.9–12
An alternative and more recently developed treatment strategy is to specifically target RANKL, which is an essential mediator of osteoclast function, formation, and survival.13–15
It is hypothesized that tumor cells in the bone cause increased expression of RANKL on osteoclasts and their precursors. Excessive RANKL-induced osteoclast activity results in resorption and local bone destruction, leading to SREs.16,17
Denosumab, a fully human anti-RANKL monoclonal antibody, is approved for the prevention of SREs in patients with solid tumors and bone metastases. In a previously reported pivotal phase 3 trial in patients with bone metastases from solid tumors (other than breast or prostate) or multiple myeloma,18 denosumab was shown to be noninferior to ZA
in delaying time to first SRE. Overall survival was similar between the two treatment groups.
Here we present an exploratory analysis of survival among a large subset of patients with lung cancer, who par-ticipated in the previously reported phase 3 trial.18 The
objec-tive of the analysis was to investigate survival in a lung cancer population treated with denosumab versus ZA.
MATERIALS AND METHODS
This exploratory analysis was conducted in the sub-group of patients with lung cancer who participated in the international, double-blind, phase 3 trial comparing deno-sumab versus ZA for the treatment of bone metastases in patients with advanced cancer (excluding breast or pros-tate cancer) or multiple myeloma.18 Key efficacy endpoints
included the time to first onstudy SRE and time to first and subsequent onstudy SREs. Details of the study design and results for the primary and key secondary endpoints have been previously reported.18
In brief, the trial had an event-driven design: the primary analysis was conducted when approximately 745 patients experienced an onstudy SRE. Eligible patients were at least 18 years old, had histologically or cytologically confirmed solid tumors (except prostate or breast cancer) or myeloma, and radiographic evidence of at least one bone metastasis or
osteolytic lesion. Key exclusion criteria were prior treatment with intravenous bisphosphonates, planned radiation or sur-gery to bone, and unhealed dental or oral sursur-gery. Patients were randomized 1:1 to receive either monthly subcutaneous injection of denosumab 120 mg (plus intravenous infusion of placebo) or monthly intravenous infusion of ZA 4 mg (plus subcutaneous injection of placebo). The ZA dose was adjusted for renal impairment. Daily calcium and vitamin D supple-mentation was strongly recommended for all patients.
For this exploratory analysis, a total of 811 lung cancer patients (411 for denosumab and 400 for ZA) were evaluated. Baseline characteristics and patient disposition were summa-rized with descriptive statistics. Overall survival analyses were performed separately for all lung cancer patients, patients with versus those without visceral metastases, NSCLC patients, NSCLC patients by histological type, and SCLC patients. Kaplan–Meier (KM) estimates of the survival function were graphically displayed, and KM estimates for the median time of survival (months) for each treatment group were summa-rized. Hazard ratios (HR) of denosumab compared with ZA for overall survival and corresponding 95% confidence inter-vals (CI) were estimated using proportional hazards models. Adverse events were coded using the Medical Dictionary for Regulatory Activities version 12.0 and were summarized with patient incidences. Hypocalcemia and osteonecrosis of the jaw (ONJ) were identified as adverse events of interest as they are associated with inhibition of bone resorption.
RESULTS Baseline Characteristics
The denosumab and ZA treatment groups were similar with respect to baseline characteristics including sex, age, ethnicity, and Eastern Cooperative Oncology Group (ECOG) status (Table 1). Most patients were men, older than 60 years, and white; 80% or more in each group had a baseline ECOG status of 0 or 1. In each group, the median time from diagnosis of cancer to the first bone metastasis was approximately 1 month, and the median time from the diagnosis of bone metastasis to randomization in the study was approximately 1.5 months. Approximately 50% in each group had an SRE before randomization. Among the patients who experienced an SRE before enrollment, radiotherapy to bone was the most common type, followed by pathological fracture, surgery to bone, and spinal cord compression. The proportion of patients with each type of SRE was balanced between treatment groups. The majority of patients (89%) had undergone prior systemic anticancer therapy. More than 80% of the patients in each group had NSCLC, and more than half of the NSCLC patients had an adenocarcinoma histological type (Table 2). Onstudy cancer chemotherapy is summarized in Table 3. Across both lung cancer subtypes and in both treatment groups, the majority of patients were treated with one or two agents for up to 6 months.
Patient Disposition
The treatment groups were generally similar with respect to disposition categories at the time of the primary
analysis (Fig. 1). Approximately 87% of patients in the deno-sumab group compared with 92% in the ZA group discon-tinued from the study before the primary analysis data cutoff date. The most common reasons for discontinuation were death, consent withdrawal, and disease progression. Adverse events were recorded as the reason for discontinuation in 4% of denosumab patients and 6% of ZA patients.
Overall Survival
In 811 patients with any lung cancer, denosumab was associated with significantly improved overall median survival compared with ZA, with a difference of 1.2 months (KM median = 8.9 months versus 7.7 months; HR = 0.80; 95% CI = 0.67–0.95; p = 0.01) (Fig. 2). Denosumab continued to show a significant survival advantage over ZA when overall survival was adjusted for relevant baseline covariates (age, sex, time from diagnosis of primary cancer to first evidence of metastasis, time from diagnosis of primary cancer to first bone metastasis, visceral metastasis, and ECOG status) and stratified by the randomization stratification factors (previous SRE and systematic anticancer therapy) (HR = 0.81; 95% CI = 0.68–0.96; p = 0.01). In patients with visceral metastases (231 in the denosumab group and 223 in the ZA group), denosumab was also associated with improved overall median survival, with a difference of 1.2 months (KM
median = 7.7 months versus 6.4 months; HR = 0.79; 95% CI = 0.63–0.98; p = 0.03) (Fig. 3).
Denosumab was associated with significantly improved survival in patients with NSCLC, with a difference of 1.5 months (KM median = 9.5 months versus 8.0 months; HR = 0.78; 95% CI = 0.65–0.94; p = 0.01) (Fig. 4A). Overall sur-vival in patients with SCLC was 7.6 months for the deno-sumab group and 5.1 months for the ZA group, a difference of 2.5 months (HR = 0.81; 95% CI = 0.52–1.26; p = 0.36) (Fig. 4B). Denosumab-treated patients with squamous cell carcinoma also showed improved survival compared with the
TABLE 1. Baseline Characteristics of Study Population
Characteristic n (%) or Median (Q1, Q3) Denosumab
N = 411 Zoledronic Acid N = 400
Sex—male 303 (74) 272 (68)
Age (yrs) 60 (54, 68) 61 (54, 69)
Ethnicity—white 364 (89) 353 (88)
ECOG performance status of 0–1 350 (85) 321 (80)
Time from diagnosis of cancer to first bone metastasis (mos)a 0.8 (−0.1, 6.9) 1.0 (0.0, 7.8)
Time from diagnosis of bone metastasis to randomization (mos) 1.5 (0.8, 3.4) 1.6 (0.8, 3.0)
Prior SRE 191 (46) 197 (49)
Prior systemic anticancer therapy 367 (89) 356 (89)
Bone turnover marker: BSAP (µg/L) n 368; 15.5 (11.5, 25.5) 355; 15.6 (11.1, 24.1)
Bone turnover marker: uNTX/creatinine (nmol/mmol) n 340; 37.4 (21.4, 68.3) 339; 35.8 (21.6, 65.1)
aThe lower limit of the interquartile range was a negative number. Some patients complained of bone pain at the initial physician visit; upon investigation, the physician diagnosed cancer.
N, number of patients randomized by actual stratum; ECOG, Eastern Cooperative Oncology Group; BSAP, bone-specific alkaline phosphatase; uNTx, urinary N-telopeptide.
TABLE 2. Distribution of Patients by Lung Cancer Type Lung Cancer Type
n (%) Denosumab N = 411 Zoledronic Acid N = 400
NSCLC 350 (85) 352 (88)
Adenocarcinoma 189 (54) 211 (60)
Squamous Cell 88 (25) 75 (21)
Other 73 (21) 66 (19)
SCLC 61 (15) 48 (12)
Percentages of patients with an NSCLC subtype are based on the number of NSCLC patients.
N, number of randomized patients; NSCLC, non–small-cell lung cancer; SCLC, small-cell lung cancer.
TABLE 3. Onstudy Cancer Chemotherapy in Patients with NSCLC or SCLC
NSCLC (N = 702)
Denosumab n = 350 Zoledronic Acid n = 352 Total number of agents
0 1–2 3–6 > 6 68 (19.4) 237 (67.7) 44 (12.6) 1 (0.3) 79 (22.4) 233 (66.2) 40 (11.4) 0 (0.0) Duration of onstudy
cancer therapy, mos 0-<6 6-<12 ≥ 12 225 (64.3) 70 (20.0) 55 (15.7) 241 (68.5) 65 (18.5) 46 (13.1) SCLC (N = 109)
Denosumab N = 61 Zoledronic Acid N = 48 Total number of agents
0 1–2 3–6 > 6 7 (11.5) 47 (77.0) 7 (11.5) 0 (0.0) 6 (12.5) 37 (77.1) 5 (10.4) 0 (0.0) Duration of onstudy
cancer therapy, mos 0-<6 6-<12 ≥ 12 40 (65.6) 13 (21.3) 8 (13.1) 27 (56.3) 17 (35.4) 4 (8.3)
Total number of agents and duration of therapy.
ZA group, with a difference of 2.2 months (KM median = 8.6 months versus 6.4 months; HR = 0.68; 95% CI = 0.47–0.97;
p = 0.035) (Fig. 5A). The treatments were associated with
simi-lar overall survival in patients with adenocarcinoma (Fig. 5B).
Adverse Events
Similar patient incidences of overall adverse events were reported for patients in both treatment groups (Table 4). Patient incidences of serious adverse events were 66.0% for denosumab versus 72.9% for ZA, and of fatal adverse events were 45.1% versus 47.8%, respectively. The most common serious adverse events were tumor progression (16.7% in the denosumab group and 15.4% in the ZA group), dyspnea (9.6% in each group), respiratory failure (6.9% and 7.8%), metastases to the central nervous system (6.7% and 8.1%), and pneumonia (6.2% and 6.3%). The most common fatal events were tumor progression (15.3% in the denosumab group and 12.7% in the ZA group), respiratory failure (4.7% and 6.1%), metastases to the central nervous system (2.0% and 3.0%), general deterioration of physical health (2.0% and 2.8%), and dyspnea (2.2% and 1.8%). Hypocalcemia was experienced by 8.6% of patients in the denosumab group and by 3.8% in the ZA group; less than 1% of each group experienced ONJ.
DISCUSSION
Lung cancer is a common malignancy and is typi-cally aggressive, with poor survival rates after the disease has metastasized to other sites.2 This post hoc analysis of a
large subgroup of patients with metastatic lung cancer showed denosumab treatment significantly improved overall survival as compared with ZA. These results suggest that denosumab may have an additional effect on this disease other than the previously demonstrated bone-protective effects.18
Explanations for the possibly longer survival with deno-sumab treatment in these lung cancer patients include both indirect and direct effects on tumor cells. An indirect effect may derive from the symbiotic relationship between tumor
FIGURE 1. Patient disposition at the time of the primary analysis. FIGURE 2. Overall survival in patients with any lung cancer. KM, Kaplan–Meier. FIGURE 3. Overall survival in patients with and without visceral metastases. KM, Kaplan–Meier; HR, hazards ratio; CI, confi-dence interval.
cells and the bone marrow microenvironment, in which both bone destruction and tumor growth are promoted. In this rela-tionship, tumor cells secrete various factors that stimulate
pro-duction of RANKL.13 The increased expression of RANKL
in the tumor environment leads to increased formation,
activation, and survival of osteoclasts and results in osteolytic lesions.19 Osteolysis then results in the release of growth
fac-tors derived from bone.13,20 These growth factors increase the
production of parathyroid hormone-related protein or pro-mote tumor growth directly.13 Bone destruction increases local
extracellular calcium concentrations, which have also been shown to promote tumor growth and the production of para-thyroid hormone-related protein.20 Denosumab may indirectly
affect skeletal tumor progression by targeting osteoclasts and disrupting this interaction between tumor cells and the bone microenvironment. RANKL inhibition has been shown to reduce bone lesions/osteolysis and skeletal tumor burden in a model of NSCLC21 and to enhance antitumor efficacy of other
therapies on skeletal tumors.22,23
Another hypothesis is that denosumab may improve survival by directly inhibiting RANKL on RANK-expressing tumor cells, which has been demonstrated for breast cancer cells in vivo24 and for a number of tumor cell lines (including
FIGURE 4. Overall survival in patients with NSCLC or SCLC. NSCLC, non–small-cell lung cancer; SCLC, small-cell lung cancer; KM, Kaplan–Meier; HR, hazards ratio; CI, confidence interval.
TABLE 4. Patient Incidence of Adverse Events Event n (%) Denosumab
N = 406 Zoledronic Acid N = 395 All adverse events 393 (96.8) 377 (95.4) Serious adverse events 268 (66.0) 288 (72.9) Fatal adverse events 183 (45.1) 189 (47.8) Adverse events of interest
Hypocalcemia 35 (8.6) 15 (3.8)
Osteonecrosis of the jaw 3 (0.7) 3 (0.8)
N, number of patients who received ≥ 1 dose of active study medication.
FIGURE 5. Overall survival in patients with non–small-cell lung cancer by histological type. KM, Kaplan-Meier; HR, hazards ratio; CI, confidence interval.
lung cancer cells) in vitro.25 RANKL inhibition may have a
direct antineoplastic effect on lung cancer cells via apoptosis or antimigration activity.26
In our study, denosumab was also associated with improved overall survival in lung cancer patients with visceral metastases, which commonly determine the pace of disease progression and death. This observation may point toward potential effects of denosumab beyond the skeleton. Indeed, preclinical evidence indicates that RANKL inhibition can reduce distant metastasis, and that this effect is potentially independent of osteoclast inhibition. In models using mouse mammary tumor virus neu transgenic mice, RANKL inhibi-tion significantly decreased spontaneous lung metastases.24
Another study27 showed that mouse mammary tumor virus
neu mice crossed with RANK heterozygotes had decreased
incidence of lung metastases; pharmacological blockade of RANKL had a similar effect. Conversely, lung metastases were increased upon systemic RANKL exposure. Preclinical investigations are underway to confirm whether RANKL inhi-bition may exert antitumor activity via indirect (via osteoclast inhibition) and/or direct (e.g., apoptosis, inhibition of cancer migration/invasion) effects on lung cancer cells.
Several baseline variables, including age and ECOG status, did not account for the increase in overall survival observed in denosumab-treated patients. However, other patient characteristics may play a role in survival. For example, bone turnover markers can provide insight into the aggressive-ness of metastases. N-telopeptide of type I collagen (NTX) is a sensitive marker of osteolysis. High baseline NTX lev-els were correlated with increased SRE risk in a retrospective analysis of 382 patients with NSCLC and bone metastases.9
When compared with placebo, ZA reduced the relative risk of death in patients with high baseline NTX in that retrospective analysis.9 As denosumab is a more potent inhibitor of bone
turnover, better outcomes may also be expected.
As observed in the analysis of adverse events in the full study population,18 hypocalcemia occurred more frequently
with denosumab than with ZA. This observation is consis-tent with the more poconsis-tent antiresorptive effect of denosumab. The rate of serious adverse events was similar in both arms (approximately 66% for denosumab versus 73% for ZA). Overall, the treatments had similar safety profiles, including similar rates of ONJ. No additional adverse events or differ-ences in adverse event rates were observed in the lung cancer subgroup compared with the full study population.
Subcutaneous drug administration offers advantages over intravenous administration. It is associated with fewer acute phase reactions and does not require renal monitoring. As observed in the analysis of adverse events in the full study population, approximately 15% of the ZA group had acute phase reactions compared with 7% of the denosumab group. In addition, approximately 11% of patients in the ZA group had renal adverse events, despite dose adjustments and dose withholding for renal impairment, per the ZA label, compared with 8% of patients in the denosumab group.
In summary, in this post hoc exploratory analysis of a large subgroup of patients with lung cancer and bone metas-tases, denosumab treatment was associated with significantly
improved overall survival compared with ZA. The strength of these data lies in the large number of patients evaluated and the consistency of the observation across subsets, whereas the limitation of these data is the retrospective nature of the analysis. These findings warrant further prospective clinical investigation.
ACKNOWLEDGMENTS
Michele Vivirito and Amy Foreman-Wykert, PhD, were supported by Amgen Inc. and assisted the authors with writ-ing, editwrit-ing, and structuring of this article.
We thank William Dougall, PhD (Amgen Inc.) for criti-cal review.
REFERENCES
1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009.
CA Cancer J Clin 2009;59:225–249.
2. Ries LAG, Melbert D, Krapcho M (Eds.), SEER Cancer Statistics Review, 1975–2004. Available at: http://seer.cancer.gov/csr/1975_2004/. Accessed January 25, 2012.
3. DeVita VT, Lawrence TS, Rosenberg SA. DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology, 9th Edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2011.
4. Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 2001;27:165–176.
5. Coleman RE. Bisphosphonates: clinical experience. Oncologist 2004;9 Suppl 4:14–27.
6. Vogel CL, Yanagihara RH, Wood AJ, et al. Safety and pain palliation of zoledronic acid in patients with breast cancer, prostate cancer, or multiple myeloma who previously received bisphosphonate therapy. Oncologist 2004;9:687–695.
7. Weinfurt KP, Li Y, Castel LD, et al. The significance of skeletal-related events for the health-related quality of life of patients with metastatic prostate cancer. Ann Oncol 2005;16:579–584.
8. Delea TE, McKiernan J, Brandman J, et al. Impact of skeletal complica-tions on total medical care costs among patients with bone metastases of lung cancer. J Thorac Oncol 2006;1:571–576.
9. Hirsh V, Major PP, Lipton A, et al. Zoledronic acid and survival in patients with metastatic bone disease from lung cancer and elevated markers of osteoclast activity. J Thorac Oncol 2008;3:228–236.
10. Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid versus pla-cebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial–the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group.
J Clin Oncol 2003;21:3150–3157.
11. Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer 2004;100:2613–2621.
12. Hirsh V, Tchekmedyian NS, Rosen LS, Zheng M, Hei YJ. Clinical benefit of zoledronic acid in patients with lung cancer and other solid tumors: analysis based on history of skeletal complications. Clin Lung Cancer 2004;6:170–174.
13. Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004;350:1655–1664.
14. Hofbauer LC, Neubauer A, Heufelder AE. Receptor activator of nuclear factor-kappaB ligand and osteoprotegerin: potential implications for the pathogenesis and treatment of malignant bone diseases. Cancer 2001;92:460–470.
15. Selvaggi G, Scagliotti GV. Management of bone metastases in cancer: a review. Crit Rev Oncol Hematol 2005;56:365–378.
16. Coleman RE, Major P, Lipton A, et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 2005;23:4925–4935.
17. Brown JE, Cook RJ, Major P, et al. Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 2005;97:59–69.
18. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011;29:1125–1132.
19. Kitazawa S, Kitazawa R. RANK ligand is a prerequisite for cancer-asso-ciated osteolytic lesions. J Pathol 2002;198:228–236.
20. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2:584–593.
21. Feeley BT, Liu NQ, Conduah AH, et al. Mixed metastatic lung cancer lesions in bone are inhibited by noggin overexpression and Rank:Fc administration. J Bone Miner Res 2006;21:1571–1580.
22. Miller R, Jones J, Roudier M, et al. The RANKL inhibitor OPG-Fc, either alone or in combination with docetaxel, blocks lung cancer-induced osteolytic lesions and reduces skeletal tumor burden in a murine model of non-small cell lung cancer in bone. Presented at the 9th International
Conference on Cancer-Induced Bone Disease, Arlington, VA, October 28–31, 2009.
23. Miller RE, Roudier M, Jones J, Armstrong A, Canon J, Dougall WC. RANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasis. Mol
Cancer Ther 2008;7:2160–2169.
24. Gonzalez-Suarez E, Jacob AP, Jones J, et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis.
Nature 2010;468:103–107.
25. Chen LM, Kuo CH, Lai TY, et al. RANKL increases migration of human lung cancer cells through intercellular adhesion molecule-1 up-regula-tion. J Cell Biochem 2011;112:933–941.
26. Jones DH, Nakashima T, Sanchez OH, et al. Regulation of cancer cell migration and bone metastasis by RANKL. Nature 2006;440: 692–696.
27. Tan W, Zhang W, Strasner A, et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signal-ling. Nature 2011;470:548–553.
