| 肝癌治疗首选手术切除,目前似已成为共识。但在看来是“根治”的手术切除后,多达 25% 的病人术后不久便在肝内出现复发 (1 、 2) 。这一现象提示在手术切除时,肝内已有转移灶存在,只是当时未发现而已。动物实验研究发现,部分肝切除可刺激肝内残存肿瘤生长 (3 、 4) 。 近年来,冷消融已成为治疗肝肿瘤的重要手段 (5) 。肝冷冻是否也能促进肝内残存肿瘤生长呢?有文献报告冷冻治疗后并发症少,生存期也较长,发现大鼠孤立性肝肿瘤冷消融治疗后生存率较之切除后为高 (6 、 7) 。 美国纽约 Memorial Sloan-Kettering 癌症中心 Allen 等 (8) 作了以下实验:方法:共分二组:每组用成年雄性 Buffalo 大鼠 10 只。将化学诱发的肝癌细胞株 (Mca-RH7777) 注射到大鼠侧腹部,使之形成肿瘤块,再将此肿瘤块 1mm 3 移植于肝左叶,以形成实验性肝癌。 2 周后,或者作部分肝切除 ( 切除 30%) ,或者将冷冻导管直接插入肿瘤内进行冷消融 ( 导管顶端温度降至 -198 ℃ ) ,对照组未移植肿瘤,但作剖腹或肝冷冻处理。再 2 周后,脾内注入肝癌细胞悬液。 3 周后处死动物,检查肝内肿瘤数目。
结果: 1.冷冻治疗组肝内肿瘤数115±38个,对照组65±136个,两组无差异(P=0.17),而肝部分切除组为278±74个,明显高于对照组(P<0.02)和冷冻组(P=0.04)。 2.肝组织学检查显示肝切除组肝内40%被肿块占据,而冷冻组和对照组无一只动物有肝被肿块完全占据的现象。在冷冻组周围,有明显炎症反应,主要是淋巴细胞,冷冻区炎症浸润轻微,但有出血性坏死,未见活存的癌细胞。 3.肝部分切除组切除后48小时血清碱性纤维生长因子(FGF-basic)明显升高(达30±14pg/ml),而对照组和冷冻组FGF-basic仍保持正常范围内。 这份实验提示,与肝部分切除不同,肝肿瘤冷消融不会促进肝内残存肿瘤生长。 这一设计严谨的实验提出了一个问题,肝癌时,手术切除到底有无实际益处,冷消融是否不但可代替肝切除,似乎比之肝切除更优? 多年来,人们一直为肝癌手术后复发所困扰。手术切除后肝癌复发的机制可能包括手术操作本身的不良影响,切除激发的全身性免疫抑制和部分肝切除后 Kupffer 细胞功能受损等 (9-11) 。近年来发现,在部分肝切除后,肝生成一系列生长因子,尤其是 FGG - basic 增多,这些因子促进了残存肝肿瘤生长 (12-14) 。前述 Allen 等所进行的实践就证明了这点:肝切除后手术后 48 小时血清 FGF - basic 显著上升。 多年来研究者推测,冷消融后留下的冷冻肿瘤组织可作为抗原,刺激肿瘤免疫产生 (6,15) 。曾有研究发现,双侧侧腹部肿瘤鼠在一侧肿瘤冷冻治疗后对侧肿瘤发生坏死 (16,17) 。冷冻治疗后血清 FGF - basic 不升高,提示有某种机制抑制了促进肿瘤生长的因子,此可能是冷冻治疗和部分肝切除所引起的后果不一致的原因 (8) 。 目前,对于可以切除的肝肿瘤,是否可用冷冻治疗替代手术切除,尚难说。但至少可以得出这样的看法,对于“不能切除或估计切除效果不好”的肝肿瘤,勉强切除可能是无益的,冷冻疗法对这些病例应作为首选治疗。 参考文献 1.Fortner JG.Percutaneous of colorectal cancer after hepatic resection.Am J Surg1988;155:378: 2.Bozzetti, F, Bignami, P, Morabito, A, Doci, R, and Gennari, L. Patterns of failure following surgical resection of colorectal cancer liver metastases. Ann. Surg. 1987 ; 205:264 3.Fisher, B, and Fisher, ER. Experimental studies of factors influencing hepatic metastases: II. Effect of partial hepatictomy. Cancer1959 ; 12:929 4.Paschkis, KE, Cantarow, A, Stasney, J, and Hobbs , JH. Tumor growth in partially hepatectomized rats. Cancer Res. 1955 ; 15:579 5.Seifert JK,JungingerT.Cryotherapy for liver tumors:current status,perspectives,clinical results,and review of literature.Technol Cancer Res Treat 2004;3:151-64. 6.Cooper, I. S. A new method of destruction or extirpation of benign or malignant tissues. N. Engl. J. Med. 1963 ; 268:743 7.Tanaka, S. Immunological aspects of cryosurgery in general surgery. Cryobiology 1982 ; 19:247 8.Allen PJ, D'Angelica M, Hodyl C, Lee J, You YJ, and Fong Y, The effects of hepatic cryosurgery on Tumor growth in the liver J Surg Res 1998;77:132-136. 9.Fisher, B, and Fisher, ER. Experimental studies of factors influencing hepatic metastases. III: Effect of surgical trauma with special reference to liver injury. Ann. Surg. 1959 ; 150:731 10.Panis Y, Nordlinger, B, Uliveri, JM, Herve, JP, Delelo, R, and Ballet, F. An experimental model of colon cancer in the rat. Effects of surgical trauma and immunosuppression on colonic carcinogenesis and spontaneous liver metastases. Surg. Res. Commun. 1991 ; 11:99 11.Pearson, HJ, Anderson , J, Chamberlain, J, and Bell , PR. The effect of Kupffer cell stimulation or depression on the development of liver metastases in the rat. Cancer Immun. Immunother. 1986 ; 23:214 12. Kan , M, Huang, JS, Mansson , PE , Yasumitsu, H, Carr, B, and McKeehan, WL. Heparin-binding growth factor type 1(acidic fibroblast growth factor): a potential biphasic autocrine and paracrine regulator of hepatocyte regeneration. Proc. Natl. Acad. Sci. USA1989 ; 86:7432 13.Michalopoulos, G.K. Liver regeneration: molecular mechanisms of growth control. FASEB J. 1990 ; 4:176 14.Jiang, WG., Lloyds, K.C, Nakamura, T., and Hallet , MB . Regulation of spreading and growth of colon cancer cells by hepatocyte growth factor. Clin. Exp. Metastasis 1993 ; 11:235 15.Jacob, G., AK, and Hobbs , K. E. A comparison of cryodestruction with excision or infarction of an implanted tumor in rat liver. Cryobiology 1984 ; 21:148 16.Bayjoo. P, Rees, RC, Goepel, JR, and Jacob, G. Natural killer cell activity following cryosurgery of normal and tumour bearing liver in an animal model. J. Clin. Lab. Immunol. 1991 ; 35:129, 17.Wing, MG, Goepel. JR, Jacob, G., Rees. RC, and Rogers, K. Comparison of excision versus cryosurgery of an HSV-2 induced fibrosarcoma. Survival, extent of metastatic disease and host immunocompetence following surgery. Cancer Immunol. Immunother. 1988 ; 26:169 |