Advances in Clinical Medicine
Vol.07 No.02(2017), Article ID:21008,6 pages
10.12677/ACM.2017.72013

The Development of Treatment of Gastric Cancer with Liver Metastasis

Wangxun Jin

Dept. of Abdominal Tumor Surgery, Zhejiang Cancer Hospital, Hangzhou Zhejiang

Received: May 18th, 2017; accepted: Jun. 16th, 2017; published: Jun. 19th, 2017

ABSTRACT

The prognosis of patients of gastric cancer with liver metastasis (GCLM) is very poor. The appropriate management of the liver lesion, including surgical resection, radiofrequency ablation, transarterial therapy and radiotherapy could improve the outcome of GCLM.

Keywords:Gastric Cancer, Liver Metastasis, Local Treatment

胃癌肝转移局部治疗的进展

金望迅

浙江省肿瘤医院腹部肿瘤外科,浙江 杭州

收稿日期:2017年5月18日;录用日期:2017年6月16日;发布日期:2017年6月19日

摘 要

胃癌一旦发生肝转移(gastric cancer with liver metastasis, GCLM),其预后极差。对病人恰当地进行肝脏病灶的局部处理,包括手术、射频、经动脉插管化疗、放疗等,能够改善患者预后。

关键词 :胃癌,肝转移,局部治疗

Copyright © 2017 by author and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

1. 引言

胃癌伴肝转移预后极差;在全身治疗的基础上,谨慎选择合适的患者进行局部病灶的处理,患者可能会得到生存获益;对病人进行多学科综合讨论,并制定相应治疗策略,给患者进行全身和多种方法的局部治疗,包括手术切除、射频、经肝动脉插管化疗、放疗等,可以改善患者的预后。

2. 手术切除肝脏病灶

虽然GCLM患者预后要差于结直肠癌肝转移患者,然而从发表的文献看,对合适的病人进行手术切除,能够改善患者预后。Markar SR [1] 对1990至2015年期间病例数超过10例以上的文献共39篇进行了复习,发现接受原发灶和肝转移病灶切除的GCLM患者其平均1,3,5年生存率为68%,31%,27%,肝脏病灶的切除提高了总体生存时间(overall survival, OS)。GCLM肝转移灶的手术治疗需要遵循肝脏外科安全原则以及肿瘤外科根治原则,即残肝余量足够,肝脏病灶的R0切除。以下是影响GCLM患者手术疗效的主要因素。

单发以及较小的肝脏转移瘤手术切除后预后较好。Aizawa M [2] 等对74例接受外科治疗的同时性GCLM患者进行了回顾性分析,发现单发转移患者和多发转移患者相比,中位生存期分别为24.2月和12.6月,5年OS分别为27.2%和5.5%。其他学者 [3] [4] 也有同样的研究结果。至于肿瘤大小,研究发现直径小于4~5 cm且局限于单叶是肝转移瘤切除的良好适应症 [5] [6] 。

异时性转移患者手术效果较好。Tatsubayashi T [7] 等对15例同时性转移以及13例异时转移的患者进行对比,发现同时性转移的患者其生存时间更短;异时性转移患者预后较好,其5年OS为59%;同样,中山大学癌症中心的回顾性分析发现同时性肝转移肝切除术后,5年OS为29.4%,明显低于异时性转移患者。虽然同时性肝转移并非肝切除术的禁忌症,但是同时性肝转移预示着肿瘤生物学行为较差,或初诊时即处于较晚期状态。

原发病灶较局限患者,肝切除术后效果较好。Koga R [8] 等回顾性分析了42例接受根治性切除的GCLM患者,结果显示原发灶是否伴有浆膜侵出(T分期)是独立的预后因素,所有存活超过5年的8名患者中有6名其病灶未侵出浆膜。其他一些文章分析了患者组织学分型,T分期,N分期,肝转移数目以及肿瘤大小,结果发现原发灶局限,淋巴结转移少均是预后良好的指标 [5] [9] 。原发灶的姑息性切除,对控制肝转移灶有益 [10] 。

3. 肝转移病灶的射频治疗

射频消融(radiofrequency ablation, RFA)治疗直径小于3 cm的原发性肝癌其临床疗效接近手术切除 [11] [12] [13] ,但仍逊于手术治疗 [14] 。射频消融可以经皮穿刺进行,无需开腹,创伤小;对于位置深在的病灶,可以避免肝切除术中病灶难于定位以及肝脏手术时大量出血的难题;对于病灶较多或复发的患者,RFA可以逐个、反复毁损病灶,保护肝脏实质。有研究表明,消融时产生的可溶性肿瘤抗原进入循环后,可以刺激机体抗肿瘤免疫;同时,由于避免了开放手术的应激导致的免疫抑制,可以协同提高机体的抗肿瘤免疫作用 [15] [16] 。

射频消融最佳适应症是病灶数目小于3个,最大直径 < 3 cm;肿瘤位置与重要解剖部位有一定距离;当然射频的适应症也受术者操作水平影响,随着临床经验的积累,其适应症也在不断扩大。凝血功能障碍以及肿瘤数目过多,位置紧贴血管以及重要脉管结构是限制其临床应用的主要原因 [17] 。直径小于2.5 cm的病灶被完全消融的几率大于90%,直径大于5 cm的病灶被完全消融的几率则小于50%,因此,肿瘤大小是影响射频消融效果的因素之一。

从已有文献看,选择合适的GCLM患者进行RFA治疗取得了不错的疗效 [18] [19] 。Chen J报告疗效结果是:并发症发生率为5% (1/21),无死亡发生;中位生存期是14月,1,2,3,5年生存率分别为70%,11%,5%,3%;消融部位复发概率为19% (4/21);肿瘤单发和多发者比较,生存期显著延长(22 vs 10月)。陈开波 [20] 等发现GCLM患者接受全身化疗其平均生存期为14.4月;在全身化疗的基础上再进行肝脏射频消融,平均生存期从第一次RFA算起为16.7月,<60岁组的平均生存期为22.5月;≥60岁组的平均生存期为11.3月。其治疗结果显示60岁以下且没有肝外脏器转移的GCLM患者接受RFA治疗可延长总体生存期,异时性和肝脏多发转移的患者复发相对较快。目前尚无前瞻性、多中心的临床试验,多数文献报告的是一些反复进行肝切除,化疗;复发后又接受RFA治疗的GCLM病例 [21] [22] [23] [24] [25] 。然而,RFA治疗胃癌肝转移疗效仍远远低于结肠癌肝转移患者,说明胃癌的生物学行为仍较结肠癌要差 [26] 。此外,对于较大的肿瘤使用消融方法进行治疗,由于消融的不完全,可能会增加肿瘤的侵袭性 [27] [28] 。

4. HAI以及TACE

经肝动脉灌注化疗(hepatic artery infusion, HAI)以及经肝动脉化疗栓塞(transarterial chemoembolization, TACE)是肝转移瘤治疗的重要方法之一。由于肝转移瘤血供以肝动脉为主,因此,胃癌肝转移可行经肝动脉化疗或者化疗栓塞术进行治疗。导管可经股动脉插管至肝动脉(Seldingrer技术)或术中置管。在灌注过程中,如何使足量的化疗药物进入肿瘤组织,是提高局部疗效的关键举措,例如注意堵塞胃十二指肠动脉,以免药物流失 [29] ;操作过程中需要寻找肿瘤侧支供血动脉,并加以全部栓塞,以确保注入的化疗药物聚集于肿瘤区域。病灶血供各有不同,其灌注或栓塞的策略也有所不同:姚玮 [30] 等分析52例GCLM患者肝脏病灶,发现7例(13.5%)为富血供,染色均匀,31例(59.6%)为边缘环形染色,14例(26.9%)为乏血供或不染色;如果病灶有明显的肿瘤染色,则表明供血血管确切,可将导管超选择进入肝叶或肝段的肿瘤靶血管,选择合适的栓塞剂进行栓塞治疗;如病灶没有明显染色或已行栓塞治疗后,将导管留置于病灶相关供血动脉,由体外化疗泵经动脉导管持续灌注化疗药物 [31] [32] 。进行药物灌注的时候,注意需要避免并发症的发生:例如在术中灌注的时候暂时夹闭胆囊动脉、胃右动脉以避免胆囊坏死;注意堵塞动静脉瘘,既能够使药物集中在靶区,又避免药物进入肺循环引起肺栓塞。

经肝动脉灌注治疗的主要的化疗药物和全身化疗的药物相仿,包括铂类和氟脲嘧定类等;既可单药也可多药联合;栓塞剂多用可降解淀粉或者明胶海绵 [29] [30] [33] 。灌注所使用的药物可能对疗效也会产生不同的影响。姚玮等 [30] 对比了雷替曲塞和氟尿嘧啶效果;发现雷替曲塞组和氟脲嘧定组的反应率(RR)分别为50.0%、19.2% (P < 0.05);疾病控制率(DCR)分别为84.6%、53.8% (P < 0.05),表明雷替曲塞效果要明显优于氟尿嘧啶。

HAI和/或TACE能够延长GCLM患者生存期。经肝动脉给药化疗既可以增加局部疗效,也可以减轻全身毒副反应,且可以根据患者全身状况,给予剂量和疗程的调整。HAI或者TACE客观有效率介于50%~91%之间 [34] ;TACE不但对亚临床转移灶有效,还可以使60%的肝转移灶缩小,这将有利于后续治疗如切除或消融治疗的开展。陈俊强 [35] 等报道,HAI治疗GCLM疗效要优于姑息胃切除,HAI组(n = 10)中位生存期为(476 ± 118) d,姑息胃切除组(n = 14)为(202 ± 25) d,(P = 0.0198),HAI组和姑息切除组患者1年生存率分别为56.2%和14.6%。可见,HAI/TACE用于胃癌继发肝转移取得了不错的效果;中止HAI治疗的主要原因是疾病进展以及导管问题。

5. TACE联合手术或射频消融

虽然HAI以及TACE治疗GCLM疗效不错,但仍然是一种非根治性方法;患者接受HAI/TACE治疗的过程,也是对病情反复评估的过程,即:如果经HAI/TACE治疗后病灶短期内进展,说明肿瘤的生物学行为较差,局部治疗效果有限;而如果治疗过程中,全身情况较好,肝脏病灶稳定或者缩小,则说明疾病进展缓慢,仍可抓住时机,对肝脏病灶进行局部切除或者毁损,以求“根治” [36] 。介入治疗后,行RFA治疗有以下有利之处 [37] [38] :TACE所用碘化油栓塞剂在CT扫描时呈高密度影,为RFA穿刺提供更为明确的标记;碘化油本身导热性比水溶液强,能够促使热量传导,扩大RFA凝固性坏死灶的体积;TACE可以通过减少或消除病灶周围血流使消融区域增大;病灶供血动脉的栓塞能够有效地降低RFA术后出血等并发症;TACE治疗可以进一步减少RFA治疗时针道播种转移的风险。

6. 放疗

放疗可谓“光学切除”,用于GCLM的局部治疗,其并发症和风险要远低于手术治疗;放疗要求肝脏病灶局限于一侧肝脏,残余肝脏足够,以免进行放疗后肝功能不全。放疗往往与介入治疗联合,其优势是:化疗药物增敏作用;碘油沉积在病灶有助于放疗定位。研究发现 [39] 经肝动脉栓塞化疗联合放疗治疗GCLM患者,可显著提高患者的近期有效率及1年生存率,上调免疫调节因子IL-2及TNF-a、IFN-r的水平。牟建国等将胃癌伴肝转移的患者分成卡培他滨化疗组(n = 20)以及联合放疗组(n = 26),发现放疗组有效率为76.9%,化疗组有效率为53.8% (P < 0.05);中位疾病进展时间、1年生存率,中位生存期均要优于单纯口服化疗组 [40] 。

文章引用

金望迅. 胃癌肝转移局部治疗的进展
The Development of Treatment of Gastric Cancer with Liver Metastasis[J]. 临床医学进展, 2017, 07(02): 78-83. http://dx.doi.org/10.12677/ACM.2017.72013

参考文献 (References)

  1. 1. Markar, S.R., Mikhail, S., Malietzis, G., et al. (2016) Influence of Surgical Resection of Hepatic Metastases from Gastric Adenocarcinoma on Long-Term Survival: Systematic Review and Pooled Analysis. Annals of Surgery, 263, 1092- 1101. https://doi.org/10.1097/SLA.0000000000001542

  2. 2. Aizawa, M., Nashimoto, A., Yabusaki, H., et al. (2014) Clinical Benefit of Surgical Management for Gastric Cancer with Synchronous Liver Metastasis. Hepato-Gastroenterology, 61, 1439-1445.

  3. 3. Makino, H., Kunisaki, C., Izumisawa, Y., et al. (2010) Indication for Hepatic Resection in the Treatment of Liver Metastasis from Gastric Cancer. Anticancer Research, 30, 2367-2376.

  4. 4. Qiu, J.L., Deng, M.G., Li, W., et al. (2013) Hepatic Resection for Synchronous Hepatic Metastasis from Gastric Cancer. European Journal of Surgical Oncology, 39, 694-700. https://doi.org/10.1016/j.ejso.2013.03.006

  5. 5. Takemura, N., Saiura, A., Koga, R., et al. (2012) Long-Term Outcomes after Surgical Resection for Gastric Cancer Liver Metastasis: An Analysis of 64 Macroscopically Complete Resections. Langenbeck’s Archives of Surgery, 97, 951-957. https://doi.org/10.1007/s00423-012-0959-z

  6. 6. Sakamoto, Y., Sano, T., Shimada, K., et al. (2007) Favorable Indications for Hepatectomy in Patients with Liver Metastasis from Gastric Cancer. Journal of Surgical Oncology, 95, 534-539. https://doi.org/10.1002/jso.20739

  7. 7. Tatsubayashi, T., Tanizawa, Y., Miki, Y., et al. (2017) Treatment Outcomes of Hepatectomy for Liver Metastases of Gastric Cancer Diagnosed Using Contrast-Enhanced Magnetic Resonance Imaging. Gastric Cancer, 20, 387-393. https://doi.org/10.1007/s10120-016-0611-7

  8. 8. Koga, R., Yamamoto, J., Ohyama, S., et al. (2007) Liver Resection for Metastatic Gastric Cancer: Experience with 42 Patients Including Eight Long-Term Survivors. Japanese Journal of Clinical Oncology, 37, 836-842. https://doi.org/10.1093/jjco/hym113

  9. 9. Manba, N., Nashimoto, A., Yabusaki, H., et al. (2009) Evaluation of Hepatic Resection for Synchronous Liver Metastasis from Gastric Cancer. Japanese Journal of Cancer and Chemotherapy, 36, 2016-2018.

  10. 10. Li, Z., Fan, B., Shan, F., et al. (2015) Gastrectomy in Comprehensive Treatment of Advanced Gastric Cancer with Synchronous Liver Metastasis: A Prospectively Comparative Study. World Journal of Surgical Oncology, 13, 212. https://doi.org/10.1186/s12957-015-0627-1

  11. 11. El-Fattah, M.A., Aboelmagd, M., Elhamouly, M., et al. (2017) Prognostic Factors of Hepatocellular Carcinoma Survival after Radiofrequency Ablation: A US Population-Based Study. United European Gastroenterology Journal, 5, 227-235. https://doi.org/10.1177/2050640616659024

  12. 12. Facciorusso, A., Serviddio, G., Muscatiello, N., et al. (2014) Local Ablative Treatments for Hepatocellular Carcinoma: An Updated Review. Medicine (Baltimore), 93, 271.

  13. 13. Lei, J.Y., Wang, W.T., Yan, L.N., et al. (2016) Radiofrequency Ablation versus Surgical Resection for Small Unifocal Hepatocellular Carcinomas. World Journal of Gastrointestinal Pharmacology and Therapeutics, 7, 477-489.

  14. 14. Gravante, G., Overton, J., Sorge, R., et al. (2011) Radiofrequency Ablation versus Resection for Liver Tumours: An Evidence-Based Approach to Retrospective Comparative Studies. Journal of Gastrointestinal Surgery, 15, 378-387. https://doi.org/10.1007/s11605-010-1377-6

  15. 15. Li, G., Staveley-O’Carroll, K.F., Kimchi, E.T., et al. (2016) Potential of Radiofrequency Ablation in Combination with Immunotherapy in the Treatment of Hepatocellular Carcinoma. Journal of Clinical Trials, 6, 257. https://doi.org/10.4172/2167-0870.1000257

  16. 16. Napoletano, C., Taurino, F., Biffoni, M., et al. (2008) RFA Strongly Modulates the Immune System and Anti-Tumor Immune Responses in Metastatic Liver Patients. International Journal of Oncology, 32, 481-490. https://doi.org/10.3892/ijo.32.2.481

  17. 17. Wakamatsu, T., Ogasawara, S., Chiba, T., et al. (2017) Impact of Radiofrequency Ablation-Induced Glisson’s Capsule-Associated Complications in Patients with Hepatocellular Carcinoma. PLoS ONE, 12, e0170153. https://doi.org/10.1371/journal.pone.0170153

  18. 18. Sucandy, I., Cheek, S., Golas, B.J., et al. (2016) Longterm Survival Outcomes of Patients Undergoing Treatment with Radiofrequency Ablation for Hepatocellular Carcinoma and Metastatic Colorectal Cancer Liver Tumors. HPB (Oxford), 18, 756-763. https://doi.org/10.1016/j.hpb.2016.06.010

  19. 19. Chen, J., Tang, Z., Dong, X., et al. (2013) Radiofrequency Ablation for Liver Metastasis from Gastric Cancer. European Journal of Surgical Oncology, 39, 701-706. https://doi.org/10.1016/j.ejso.2013.03.023

  20. 20. 陈开波. 胃癌肝转移的治疗策略探讨——化疗和射频消融的疗效评估[D]: [博士学位论文]. 杭州: 浙江大学, 2014.

  21. 21. Nakada, S., Kawamoto, J., Yoichi, T., et al. (2015) A Case Report—A Synchronous Liver Metastasis from Gastric Cancer Treated with Chemotherapy, Surgical Resection of the Gastric Cancer, and RFA of the Liver Metastasis. Japanese Journal of Cancer and Chemotherapy, 42, 1992-1994.

  22. 22. Katsuyama, S., Murata, M., Tanaka, N., et al. (2015) A Case of Gastric Cancer with Multiple Liver Metastases Treated with XP Chemotherapy and RFA Resulting in a Complete Response for a Long Time. Japanese Journal of Cancer and Chemotherapy, 42, 1614-1616.

  23. 23. Takagi, T., Nakase, Y., Fukumoto, K., et al. (2010) Long-Term Disease-Free Survival Following Multimodal Treatment in a Patient with Curatively Unresectable Advanced Gastric Cancer with Metachronous Liver Metastasis. Japanese Journal of Cancer and Chemotherapy, 37, 2421-2423.

  24. 24. Harada, H., Nishimura, A., Nishimura, T., et al. (2010) Experience with Surgical Resections of Metachronous Liver and Bilateral Pulmonary Metastases from Gastric Cancer. The Japanese Journal of Thoracic Surgery, 63, 1094-1097.

  25. 25. Hashimoto, K. and Suzuki, M. (2009) A Case of Metachronous Liver Metastasis from Gastric Cancer Treated with Multidisciplinary Therapy Including Hepatectomy. Japanese Journal of Cancer and Chemotherapy, 36, 2324-2325.

  26. 26. 蔡磊, 李晓武, 夏锋, 等. 射频消融治疗转移性肝癌的临床疗效[J]. 中华消化外科杂志, 2014, 13(3): 190-193.

  27. 27. Zhang, N., Wang, L., Chai, Z.T., et al. (2014) Incomplete Radiofrequency Ablation Enhances Invasiveness and Metastasis of Residual Cancer of Hepatocellular Carcinoma Cell HCCLM3 via Activating β-Catenin Signaling. Journal of Translational Medicine, 9, e115949.

  28. 28. Kong, J., Kong, L., Kong, J., et al. (2012) After Insufficient Radiofrequency Ablation, Tumor-Associated Endothelial Cells Exhibit Enhanced Angiogenesis and Promote Invasiveness of Residual Hepatocellular Carcinoma. Journal of Translational Medicine, 10, 230. https://doi.org/10.1186/1479-5876-10-230

  29. 29. Ota, T., Shuto, K., Ohira, G., et al. (2009) Evaluation of Hepatic Arterial Infusion Chemotherapy for Liver Metastasis from Gastric Cancer. Japanese Journal of Cancer and Chemotherapy, 36, 2019-2021.

  30. 30. 姚玮, 张君儒, 陈连锁, 等. 雷替曲塞TACE治疗胃癌术后肝转移的近期疗效观察[J]. 介入放射学杂志, 2016, 25(2): 125-128.

  31. 31. 陆若飞, 施海辉, 黄桃辉. 经肝动脉灌注化疗栓塞术与单纯肝动脉灌注术对胃癌肝转移瘤的疗效对比[J]. 实用癌症杂志, 2015, 30(1): 63-65.

  32. 32. Tarazov, P.G. (2000) Transcatheter Therapy of Gastric Cancer Metastatic to the Liver: Preliminary Results. Journal of Gastroenterology, 35, 907-911. https://doi.org/10.1007/s005350070004

  33. 33. 刘鹏, 朱旭, 杨仁杰, 等. 72例胃癌肝转移化疗后进展的介入治疗的回顾性分析[J]. 介入放射学杂志, 2013, 22(9): 742-746.

  34. 34. Vogl, T.J., Gruber-Rouh, T., Eichler, K., et al. (2013) Repetitive Transarterial Chemoembolization (TACE) of Liver Metastases from Gastric Cancer: Local Control and Survival Results. European Journal of Radiology, 82, 258-263. https://doi.org/10.1016/j.ejrad.2012.10.006

  35. 35. 陈俊强, 詹文华, 何裕隆, 等. 肝动脉灌注化疗和姑息性胃切除治疗胃癌多发性肝转移患者的疗效比较[J]. 中华胃肠外科杂志, 2003, 6(6): 372-374.

  36. 36. Hasuike, Y., Iwagami, Y., Toyomasu, T., et al. (2013) Efficacy of Combined Local Therapy Especially with Hepatic Arterial Infusion for Liver Metastasis from Gastric Cancer. Japanese Journal of Cancer and Chemotherapy, 40, 1644- 1646.

  37. 37. 赵增富, 任庆莹, 王茹芳, 等. TACE联合RFA治疗胃癌术后肝转移29例[J]. 中国现代普通外科进展, 2014, 17(6): 472-474.

  38. 38. 游建, 何鑫, 王平, 等. 射频消融联合肝动脉栓塞化疗治疗难以手术切除的结肠癌肝转移[J]. 中华实验外科杂志, 2009, 26(9): 1207-1209.

  39. 39. 张强, 方芳, 等. 介入化疗联合放疗对胃癌肝转移患者免疫调控作用及疗效的影响[J]. 世界华人消化杂, 2006, 14(12): 1222-1225.

  40. 40. 牟建国, 刘希光, 马青山. 三维适形放疗联合卡培他滨治疗胃癌肝转移的疗效观察[J]. 中国医药, 2011, 6(2): 143-144.

期刊菜单