Zoledronic acid and survival in patients with metastatic bone disease from lung cancer and elevated markers of osteoclast activity.
BACKGROUND
Bone metastases from non-small cell lung cancer (NSCLC) are associated with skeletal-related events (SREs) and elevated levels of N-telopeptide of type I collagen (NTX) in some patients. Zoledronic acid (ZOL) reduces SRE risk and NTX levels.


METHODS
To assess effects of baseline variables, including NTX levels (normal = NTX < 64 nmol/mmol creatinine; high = NTX > or = 64 nmol/mmol creatinine), on treatment effects in NSCLC patients, a retrospective analysis was performed in NSCLC patients with bone metastases (N = 382) treated with ZOL or placebo every 3 weeks in a 21-month randomized clinical trial in patients with NSCLC or other solid tumors. Cox proportional hazards models assessed relative risks (RRs) of SREs, bone lesion progression, and death. Multivariate models analyzed covariate effects on survival.


RESULTS
For both placebo- and ZOL-treated patients, high baseline NTX correlated with increased SRE risk (p = 0.068 and 0.012, respectively). Although high versus normal baseline NTX correlated with more than twofold increased risks of bone lesion progression and death in the placebo group (p = 0.039 and 0.001, respectively), correlations were weaker in the ZOL group (RR = 1.38; p = 0.0186 and RR = 1.27; p = 0.142, respectively), suggesting an interaction effect of ZOL and baseline NTX. Among patients with high baseline NTX, ZOL significantly reduced the RR of death by 35% versus placebo (p = 0.024). Per multivariate analysis, ZOL treatment (p = 0.005), higher lymphocyte count (p = 0.011), performance status 0 to 1 (p = 0.012), and absence of narcotic use (p = 0.016) correlated with improved survival.


CONCLUSIONS
This retrospective analysis revealed statistically significant correlations between ZOL and increased survival versus placebo in NSCLC patients and high baseline NTX levels.
Hirsh
Vera
V
McGill University Health Centre, Montreal, Quebec, Canada. vera.hirsh@muhc.mcgill.ca
Major
Pierre P
PP
Lipton
Allan
A
Cook
Richard J
RJ
Langer
Corey J
CJ
Smith
Matthew R
MR
Brown
Janet E
JE
Coleman
Robert E
RE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000097:blood; D014408:Biomarkers, Tumor / Q000652:urine; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D002170:Canada / Q000453:epidemiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D024042:Collagen Type I / Q000187:drug effects / Q000652:urine*; D004164:Diphosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010010:Osteoclasts / Q000378:metabolism*; D010455:Peptides / Q000187:drug effects / Q000652:urine*; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology; D000077211:Zoledronic Acid
D014408:Biomarkers, Tumor; D050071:Bone Density Conservation Agents; D024042:Collagen Type I; D004164:Diphosphonates; D007093:Imidazoles; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; D000077211:Zoledronic Acid; D000469:Alkaline Phosphatase