酪氨酸激酶抑制剂新辅助治疗高危肾癌的临床研究

Clinical study of neoadjuvant therapy of tyrosine kinase inhibitor in high-risk renal cell carcinoma

目的 探讨对高危肾癌患者采用酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）靶向药物术前新辅助治疗的临床价值和安全性. 方法 2010年6月至2013年12月对33例高危肾癌患者行TKI靶向药物治疗,其中8例TKI靶向药物治疗后接受手术治疗.男6例,女2例.年龄42 - 56岁,平均50岁.7例伴有副肿瘤综合征,1例为双肾癌.肿瘤分期：T3aN1M1期和T3bN0M0期各3例,T3aN0M0期和T3bN0M1期各1例,其中淋巴结和肺转移各3例,骨转移1例.4例合并下腔静脉瘤栓,其中3例MayoⅢ级,1例MayoⅣ级.术前美国东部肿瘤协作组评分：3分3例,2分4例,0分1例.8例均先口服TKI靶向药物,之后接受手术治疗.4例口服舒尼替尼,50 mg,1次/d,服药4周停2周;4例口服索拉非尼,400 mg,2次/d,持续用药.TKI靶向药物应用8-12周,术前停药6-16 d,平均12d. 结果 8例均耐受TKI靶向药物治疗.7例伴有副肿瘤综合征患者一般状况明显改善,其中3例行根治性肾切除术＋下腔静脉瘤栓取出术,2例行腹腔镜下根治性肾切除术,1例行深低温停循环根治性肾切除术＋下腔静脉瘤栓取出术,1例行根治性肾切除术.1例双侧肾癌患者双侧肿瘤明显缩小,行双侧保留肾单位手术.8例术中可见肿瘤与周围组织有轻、中度粘连.术中出血量120-500 ml,平均280 ml.围手术期无严重并发症发生,手术切口均愈合良好.病理诊断均为肾透明细胞癌.术后4例继续服用TKI药物.随访4-42个月,8例均存活,未见肿瘤复发;4例术前有转移患者疗效评价为疾病稳定. 结论 TKI靶向药物新辅助治疗高危肾癌患者是安全的,不增加手术风险.对于不耐受手术患者,该方法可改善患者一般状况,提高手术耐受性,创造手术机会;对于孤立肾肾癌、双肾癌患者,增加了行保留肾单位手术的可能性.

Objective To investigate the safety and clinical significance in presurgical application of tyrosine kinase inhibitor （TKI） targeted therapy in high-risk renal-cell-carcinoma patients.Methods TKI targeted therapy was applied to 33 high-risk renal-cell-carcinoma patients from Jun.2010 to Dec.2013,7 cases with paraneoplastic symdromes and 1 with bilateral lesions received surgical treatments.There were 6 males and 2 females in this group with average age of 50 （42-56） years.They were high-risk patients because of renal tumor and vena caval tumor thrombus in 3 cases,renal tumor and vena caval tumor thrombus and hypercalcinemia in 1 case,renal tumors with metastasis to lung and lymph nodes in 2 cases,renal tumor with metastasis to lung and bones in 1 cases,and bilateral kidney cancer in 1 case.The clinical stages included 3 cases of T3aN1M1 and T3bN0M0 respectively,and 1 case of T3bN0M1 and T3aN0M0,respectively.The primary metastasis sites were lymph nodes and lung （3 cases respectively）,and another 1 in bone.4 cases suffered from vena cava tumor thrombi with 3 staged Mayo Ⅲ and 1 Mayo Ⅳ.7 cases with paraneoplastic syndromes were contra-indicated for surgery due to poor ECOG performance score （with score 3 in 3 cases and 2 in 4 cases）.4 cases received Sorafinib 400mg po bid and the other 4 Sunitinib 50 mg po qd,4 weeks on and 2 weeks off,with duration of 8-12 weeks.Medical therapy ceased 6 to 16 days （median 12 days） before operation.Results Patients with neoadjuvant therapy experienced good toleration.The 7 cases with poor ECOGs improved during medical therapy.The tumor sizes in the bilateral lesions shrunk remarkably.All 7 patients received surgery：3 radical nephrectomies,4 nephrectomies and resections of Vena Caval tumor thrombus,and 1 bilateral lesions underwent nephron sparing surgery.Operations were successful though with mild to moderate adhesion,and the blood loss ranged from 120 to 500 ml,with averaged of 280 ml.Pathologic results were clear-cell renal carcinomas.All incisions were well-healed.4 patients with metastasis continued TKI therapy.All patients were alive without recurrence during the follow-up of 4 to 42 mon.Conclusions Presurgical application of targeted therapy is safe and may increase the opportunity of surgery for some patients with poor general situation,also patients with bilateral lesions may benefit from it for its possibility of nephron sparing.