唑来膦酸联合化疗治疗肺癌骨转移的疗效分析及骨代谢标记物的研究

Efficacy of zoledronic acid combined with chemotherapy in treatment of skeletal metastases of non-small cell lung cancer and the bone metabolic markers

目的观察唑来膦酸联合化疗治疗肺癌骨转移的临床疗效,以及骨代谢标记物尿I型胶原交联氨基末端肽（uNTX）及血清骨碱性磷酸酶（sBALP）变化,评价其在肺癌骨转移的临床价值。方法选择2007年2月~2009年1月广州医学院附属肿瘤医院内二科肺癌骨转移患者32例。唑来磷酸4 mg,每3周1次,含铂方案化疗,每3周1疗程。在治疗前后分别以ELISA、小麦菌凝集素沉淀法测定uNTX、sBALP。随访骨相关事件（SREs）及生存状况。结果治疗后疼痛程度减轻,镇痛药用量减少,与治疗前相比差异显著（P=0.01）;治疗期间无骨相关事件发生;治疗前后血钙、血肌酐水平无明显变化;11例患者发生了14人次可能与唑来膦酸相关的不良事件。基线uNTX/Cr及sBALP水平明显高于正常,其浓度与骨转移负荷成正相关,与疼痛强度无显著相关。治疗3个月时uNTX/Cr及sBALP水平明显降低,而放射性核素全身骨显像（ECT）尚无明显改变;32例患者中,24例基线uNTX/Cr水平高于正常,治疗后15例降至正常,9例仍维持在较高水平,两者骨相关事件发生率为53%比89%（P=0.039）;26例基线sBALP水平高于正常,治疗后16例降至正常,10例仍维持在较高水平,两者骨相关事件发生率为50%比90%（P=0.038）。uNTX/Cr,sBALP水平对生存率的影响无统计学意义。结论唑来膦酸联合化疗是肺癌骨转移的有效治疗方式,安全性和耐受性良好。尿NTX、血清BALP在肺癌骨转移的诊断及对治疗反应的监测及骨相关事件的预测方面有一定价值。

Objective To evaluate the clinical efficacy of zoledronic acid combined with chemotherapy in the management of skeletal metastasis of non-small cell lung cancer（NSCLC） and investigate the value in urine amino-terminal telopeptide of type I collagen（uNTX） and serum bone specific alkaline phosphatase（sBALP） in monitoring skeletal metastasis of NSCLC.Methods From February,2007 to January,2009,32 NSCLC patients with bone metastases received treatment with zoledronic acid at the dose of 4 mg given every 3 weeks and platinum-based chemotherapy（each cycle lasting for 3 weeks）.Before and during the treatments,uNTX and sBALP were measured in these patients using ELISA and precipitation with wheat germ lectin,respectively.The patients were followed up for skeletal-related events（SREs） and status of survival.Results A significant decrease occurred in the pain scores and analgesic use in the patients after the therapy.SREs were not observed during the treatment.Serum creatinine and calcium levels underwent no significant variation during the treatment.Eleven patients reported 14 possible zoledronic acid-related adverse events.The concentration of uNTX and sBALP in patients with bone metastases was above the upper limit of the normal range.A positive correlation was observed between the levels of the markers and the extent of bone metastases.At the third month,uNTX and sBALP were significantly lowered,but radionuclide whole-body bone imaging showed no obvious changes.Of the 32 patients,24 had elevated uNTX values,which became normal after the treatment in 15 patients and remained elevated in the other 9 patients.SREs occurred in these two subgroups at the rates of 53% and 89%（P=0.039）,respectively.Twenty-six patients had elevated sBALP level,and 16 of them exhibited normal sBALP level after the treatment.The incidences of SREs in the patients with elevated and normal sBALP level were 50% and 90%（P=0.038）,respectively.The levels of uNTX/Cr and sBALP were not correlated to the survival of the patients.Conclusion Zoledronic acid combined with chemotherapy is an effective treatment for NSCLC with bone metastases.Zoledronic acid is safe and well tolerated.Urinary NTX and serum BALP have a high value in the diagnosis,therapeutic effect monitoring and SRE prediction of NSCLC with bone metastases.