Retrospective study on the efficacy of bisphosphonates in tyrosine kinase inhibitor‑treated patients with non‑small cell lung cancer exhibiting bone metastasis

Abstract

Bisphosphonates (Bps) inhibit the maturation of osteoclasts and suppress the adhesion of cancer cells to the bone matrix. They are recommended as the standard treatment for tumors exhibiting bone metastasis (BM). However, whether Bps can improve the prognosis of patients with tyrosine kinase inhibitor (TKI)-treated non-small cell lung cancer (NSCLC) exhibiting BM remains unclear. A total of 129 patients with NSCLC initially diagnosed with BM at The First Affiliated Hospital of Sun Yat-Sen University (Guangzhou, China) between January 2005 and December 2017 were analyzed in the present retrospective study. Median progression free survival (mPFS) time, median bone metastasis overall survival (mBM-OS) time and bone-associated progression-free survival were analyzed. Among the 129 patients, patients treated with Bps experienced significantly prolonged PFS time [mPFS: 7.1 vs. 5.1 months; hazard ratio (HR), 0.51; confidence interval (CI), 0.30–0.87; P=0.0114] in comparison with patients not treated with Bps. Of the 49 patients treated with frontline TKIs (EGFR TKIs or ALK TKI), 32 received Bps at the same time, while 17 patients received TKIs alone. The results revealed that mPFS time was significantly greater in the TKIs plus Bps group than in the TKIs alone group (mPFS: 11.2 vs. 6.9 months; HR, 0.13; CI, 0.05–0.35; P<0.0001). Significantly prolonged BM-OS time was also observed in the combination group in comparison with the TKIs alone group (mBM-OS: 31 vs. 22 months; HR, 0.31; CI, 0.10–0.96; P=0.0413). The present study demonstrated that among the patients who received TKIs (EGFR TKIs or ALK TKIs), those who also received Bps experienced significantly longer PFS time and tended to exhibit significantly improved BM-OS time, which indicated that Bps should be added to the treatment regimen of patients with NSCLC exhibiting genetic mutations and bone metastasis who have been prescribed TKIs (EGFR TKIs or ALK TKIs).

High Prevalence and Early Occurrence of Skeletal Complications in EGFR Mutated NSCLC Patients With Bone Metastases

“…Interestingly, the administration of these drugs was associated with better prognosis, that just failed to attain the statistical significance in multivariate analysis. A positive effect of bisphosphonate administration on survival of EGFR mutated lung cancer patients submitted to TKIs was previously observed in 3 published series ( 13 , 14 , 22 ) ( Table 4 ).…”

“…Also, the proportion of major SREs (28%), observed in the present study, is similar to that reported in the mentioned series as well as in other published bone metastatic patient series with different primary histologies ( 19 – 21 ). The outcome of patients with EGFR mutated lung cancer with bone metastases have been evaluated in six published papers in which the SRE frequency was 0% in only one paper ( 22 ), while ranged between 20 and 51% in the remaining five papers ( 13 – 17 ) ( Table 4 ). On the bases of these results, TKIs seem to be not effective in preventing SREs, despite their great efficacy in controlling the disease.…”

Analysis of the Mechanism and Safety of Bisphosphonates in Patients with Lung Cancer and Bone Metastases

“…Quality of survival [ 6 ]: the FACT-G-V score was applied to evaluate the quality of survival, containing indicators of functional status, physical status, emotional status, and family/social status.…”

Incidence of Bone Metastases and Skeletal-Related Events in Patients With EGFR-Mutated NSCLC Treated With Osimertinib

“…42 , 43 Other arguments for the use of BTA are small, hypothesis generating, in vivo (N = 62–129) and in vitro series that reveal synergy between bisphosphonates and EGFR TKIs with effects on tumor suppression, PFS, and OS post-bone metastases. 44 , 45 , 46 This synergistic effect should be evaluated prospectively. Currently, one trial (NCT03958565) is enrolling patients with bone metastasized NSCLC to evaluate the percentage reduction of bone markers in urine or serum while treated with zoledronic acid or denosumab.…”