The impact of zoledronic acid therapy in survival of lung cancer patients with bone metastasis

Abstract

Bone metastases occur in 20-40% of patients with lung cancer. Recent studies demonstrate a direct antiproliferative effect of 3rd generation bisphosphonates (BPs) on lung tumors, which may influence the survival. Therefore, we examined the clinical impact of zoledronic acid (ZOL; Zometa 1 ), a 3rd generation BP, with a focus on the survival, time to progression and pain effect in lung cancer patients with bone metastases. Lung cancer patients (n 5 144, Stage IV) with evidence of metastasis bone scan were included. Eighty-seven of 144 experienced bone pain and received ZOL, 4 mg i.v. every 21 days (Group A), whereas the other 57 patients received no ZOL (Group B). All patients were treated with a combination chemotherapy consisted of docetaxel 100 mg/ m 2 and carboplatin AUC 5 6. It was found that Group A had a statistically significant longer survival (p < 0.01) when compared to Group B. A statistically significant positive correlation was found between the number of cycles of therapy with ZOL and total patient survival (p < 0.01, Pearson correlation) and time to progression (p < 0.01). Pain effect of ZOL had no significant difference between the 2 groups of patients (p > 0.05). Urine N-telopeptide of type I collagen (NTx) levels decreased in patients with NTx 29 nM BCE/mM creatinine at baseline after treatment with ZOL. The results of our study suggest that the addition of ZOL increases overall survival in lung cancer patients with bone metastases. The longer period of receiving ZOL, the better effect on survival and time to progression. ' 2009 UICC Key words: lung cancer; bone metastasis; bisphosphonates; zoledronic acid; N-telopeptide; type I collagen Lung cancer is the leading cause of death from cancer worldwide. Approximately 80% of lung cancers can be histologically classified as non-small-cell lung cancer (NSCLC). The majority of patients present with locally advanced (37%) or metastatic (38%) disease at the time of diagnosis. 1 It has been estimated that 30-65% of patients with metastatic lung cancer will develop bone metastases. 2,3 Bone metastases cause considerable skeletal morbidity, including bone pain, pathologic fractures, spinal cord compression and hypercalcemia of malignancy. 2 These skeletal-related events (SREs) are the result of the resorption of mineralized bone by osteoclasts. The management of skeletal complications is typically a multimodal endeavor involving surgery, radiation therapy, analgesics and more recently the administration of bisphosphonates (BPs). 4 BPs have been extensively used in the treatment and prevention or palliation of skeletal complications associated with osteolytic lesions in patients with breast cancer, 5 multiple myeloma 6 and more recently in other solid tumors, such as lung cancer.BPs act on bone cells such as osteoclasts and are generally used to treat lytic bone lesions caused by malignancies or bone resorption disorders such as osteoporosis. All BPs are characterized by a phosphorus-carbon-phosphorus (P-C-P)-containing central structure, which promotes the...

Specific organ metastases and survival in metastatic non-small-cell lung cancer

“…Zoledronic acid may also explain the improved survival in patients with bone metastases (16). Second, liver metastasis was an unfavorable prognostic factor in our study, which was consistent with previously reported results (3,5).…”

Zoledronic acid negatively affects the expansion of in vitro activated human NK cells and their cytolytic interactions with Ewing sarcoma cells

“…Based on the rationale that ZA may interfere with stimulatory interactions between the bone microenvironment and tumor cells and on observations of direct antiproliferative effects against tumor cells (3)(4)(5), the drug was also evaluated for the treatment of primary and metastatic bone tumors. As expected, ZA demonstrated clinical antitumor activity in multiple myeloma (6) and osteosarcoma (7) and against (micro)metastatic bone and/or bone marrow disease in solid tumors (8,9). In preclinical studies in Ewing sarcoma, ZA was found to inhibit in vivo tumor growth both alone and in synergism with chemotherapies (4,5), and initial clinical reports suggest that ZA combined with chemotherapy may be effective in refractory disease (10).…”

“…ZA has attracted recent interest as a non-cytotoxic anticancer drug and is under clinical investigation for use in various diseases, including primary bone tumors (3,4,(7)(8)(9). Promising features of ZA include the observed anticancer synergies between bisphosphonates and cytotoxic chemotherapies (4,30), the favorable toxicity profile, and the proposed effect on the tumor-promoting bone/bone marrow microenvironment to prevent dissemination.…”

Zoledronic acid use in cancer patients

“…64 In addition, patients with bone metastases from LC (N ¼ 144) who received standard chemotherapy and ZOL (4 mg iv every 21 to 28 days for 1 year) for bone pain had longer median survival compared with patients who received standard chemotherapy but not ZOL (578 days vs 384 days, respectively; P < .001). 65 Additional therapies may improve survival further. For example, among patients with metastatic HRPC who received androgen blockade (N ¼ 38), combining ZOL (4 mg iv every 4 weeks) with dexamethasone (4 mg daily for up to 1 month, then gradually reduced to 1 mg daily by the fourth month) and octreotide (20 mg intramuscularly every 28 days) significantly improved median progressionfree survival (P < .0001) and OS (P ¼ .0027) compared with ZOL alone.…”