中国普外基础与临床杂志

中国普外基础与临床杂志

潜在可切除性胃癌的新辅助化疗

查看全文

目的 总结潜在可切除胃癌的新辅助化疗(neoadjuvant chemotherapy,NAC)的现状。
方法 通过PubMed,以胃肿瘤、胃癌/癌、新辅助治疗/化疗及术前治疗/化疗为关键词,检索近5年的相关文献。并检索2007及2008年ASCO年会的相关进展。总结NAC在胃癌中的研究现状,评价其必要性和可行性,分析病例选择依据、缓解预测因子及存在的问题和发展方向。
结果 共检索随机对照试验7个,其中3个为Ⅲ期试验。已进行的多数研究显示,NAC在胃癌的治疗中是安全、有效和可行的。但生存取得显著改善的NAC随机研究尚少,缺乏严格NAC与单独手术或围手术期化疗与辅助化疗对比的NAC随机研究。如何选择适当的病例、有效的NAC方案和治疗缓解的预测,尚需要解决。
结论 NAC在胃癌的治疗中是安全、有效和可行的,但仍需进一步严格的前瞻性随机Ⅲ期试验证实。新的细胞毒性药物和分子靶向治疗可能是将来进展的实质基础。

Objective To summarize the current value of neoadjuvant chemotherapy (NAC) for potentially resectable gastric cancer.
Methods The recent 5-year literatures searched through the PubMed with the key words: stomach neoplasm, gastric cancer/carcinoma, neoadjuvant therapy/chemotherapy and preoperative therapy/chemotherapy as well as the relevant reports presented in the ASCO Annual Meeting in 2007 and 2008 were analyzed. The present status of NAC for advanced gastric cancer was summarized, the necessity and feasibility were evaluated, and the patients features for selecting, the predictors for response, the mainly existing problems and development trend of NAC were analyzed.
Results At present, there were 7 randomized control trails (RCT) published, and among them 3 were phase Ⅲ. It was safe, effective and feasible to most of trails in NAC for gastric cancer. However, it was still little to obtain survival benefit for NAC RCT, and short of randomized trial comparing strict preoperative chemotherapy to surgery alone or perioperative chemotherapy to surgery plus adjuvant chemotherapy. It remained lots of problems such as how to select the appropriate patients, the effective induced regimes and the predicted factors, the evaluated indices for response.
Conclusion NAC is a safe, feasible and efficient method to potentially resectable gastric cancer, but strict phase Ⅲ randomized trials are needed. In the future, substantial improvements of treatment outcome will likely depend on the novel drugs and molecular biological targeted therapies.

关键词: 胃肿瘤; 新辅助治疗; 新辅助化疗; 术前化疗

Key words: Stomach neoplasm; Neoadjuvant therapy; Neoadjuvant chemotherapy; Preoperative chemotherapy

引用本文: 肖仕明,吴宸,姜淮芜. 潜在可切除性胃癌的新辅助化疗. 中国普外基础与临床杂志, 2009, 16(8): 680-685. doi: 复制

登录后 ,请手动点击刷新查看全文内容。 没有账号,
1. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002 [J]. CA Cancer J Clin, 2005; 55(2): 74-108.
2. 肖仕明, 姜淮芜, 吴宸, 等. 根治性近端胃切除术后的两种重建术式评价 [J]. 中国普外基础与临床杂志, 2008; 15(9): 682-685.
3. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer[J]. N Engl J Med, 2008; 358(1): 36-46.
4. Foukakis T, Lundell L, Gubanski M, et al. Advances in the treatment of patients with gastric adenocarcinoma[J]. Acta Oncol, 2007; 46(3): 277-285.
5. Sakamoto J, Paoletti X. Meta-analyses of randomized trials assessing the interest of postoperative adjuvant chemotherapy in gastric cancer[J]. J Clin Oncol (Meeting Abstracts), 2008; 26(15S): 4543.
6. De Vita F, Giuliani F, Galizia G, et al. Neo-adjuvant and adjuvant chemotherapy of gastric cancer[J]. Ann Oncol, 2007; 18(Suppl 6): vi120-vi123.
7. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer[J]. N Engl J Med, 2006; 355(1): 11-20.
8. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27[J]. J Clin Oncol, 2008; 26(5): 778-785.
9. Medical Research Council Oesophageal Cancer Working Gro-up. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial [J]. Lancet, 2002; 359(9319): 1727-1733.
10. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer[J]. N Engl J Med, 2004; 351(17): 1731-1740.
11. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction[J]. N Engl J Med, 2001; 345(10): 725-730.
12. Sasako M, Sano T, Yamamoto S, et al. D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer[J]. N Engl J Med, 2008; 359(5): 453-462.
13. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine[J]. N Engl J Med, 2007; 357(18): 1810-1820.
14. 季加孚. 胃癌外科的现状与发展趋势 [J]. 中国普外基础与临床杂志, 2006; 13(1): 1-3.
15. 陈志新, 张波. 胃癌综合治疗现状及展望 [J]. 中国普外基础与临床杂志, 2008; 15(1): 71-73.
16. Frei E 3rd. Clinical cancer research: an embattled species[J]. Cancer, 1982; 50(10): 1979-1992.
17. Wilke H, Preusser P, Fink U, et al. Preoperative chemotherapy in locally advanced and nonresectable gastric cancer: a phase Ⅱ study with etoposide, doxorubicin, and cisplatin[J]. J Clin Oncol, 1989; 7(9): 1318-1326.
18. Songun I, Keizer HJ, Hermans J, et al. Chemotherapy for operable gastric cancer: results of the Dutch randomised FAMTX trial. The Dutch Gastric Cancer Group (DGCG)[J]. Eur J Cancer, 1999; 35(4): 558-562.
19. Fujii M, Kosaki G, Tsuchiya S, et al. Randomized trial of preoperative adjuvant chemotherapy using oral 5-FU in operable gastric cancer [A]. Proc Am Soc Clin Oncol, 1999; 18: Abstract 1045.
20. Kang YK, Choi DW, Im YH, et al. A phase Ⅲ randomized comparison of neoadjuvant chemotherapy followed by surgery versus surgery for locally advanced stomach cancer [A]. Proc Am Soc Clin Oncol, 1996; 15: Abstract 503.
21. Allum W, Cunningham D, Weeden S, et al. Perioperative chemotherapy in operable gastric and lower oesophageal cancer: A randomised, controlled trial (the MAGIC trial, ISRCTN 93793971) [A]. Proc Am Soc Clin Oncol, 2003; 22: Abstract 998.
22. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy in operable gastric and lower oesophageal cancer: final results of a randomised, controlled trial (the MAGIC trial, ISRCTN 93793971) [J]. J Clin Oncol (Meeting Abstracts), 2005; 23(16S): 4001.
23. Boige V, Pignon J, Saint-Aubert B, et al. Final results of a randomized trial comparing preoperative 5-fluorouracil (F)/cisplatin (P) to surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC ACCORD07-FFCD 9703 trial[J]. J Clin Oncol (Meeting Abstracts), 2007; 25(18S): 4510.
24. Zhang ZX, Gu XZ, Yin WB, et al. Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of adenocarcinoma of gastric cardia (AGC)—report on 370 patients [J]. Int J Radiat Oncol Biol Phys, 1998; 42(5): 929-934.
25. Stahl M, Walz MK, Stuschke M, et al. Preoperative chemotherapy (CTX) versus preoperative chemoradiotherapy (CRTX) in locally advanced esophagogastric adenocarcinomas: First results of a randomized phase Ⅲ trial[J]. J Clin Oncol (Meeting Abstracts), 2007; 25(18S): 4511.
26. Nio Y, Koike M, Omori H, et al. A randomized consent design trial of neoadjuvant chemotherapy with tegafur plus uracil (UFT) for gastric cancer—a single institute study[J]. Anticancer Res, 2004; 24(3b): 1879-1887.
27. Hartgrink HH, van de Velde CJ, Putter H, et al. Neo-adjuvant chemotherapy for operable gastric cancer: long term results of the Dutch randomised FAMTX trial[J]. Eur J Surg Oncol, 2004; 30(6): 643-649.
28. Forshaw MJ, Gossage JA, Chrystal K, et al. Neoadjuvant chemotherapy for locally advanced carcinoma of the lower oesophagus and oesophago-gastric junction[J]. Eur J Surg Oncol, 2006; 32(10): 1114-1118.
29. Cascinu S, Scartozzi M, Labianca R, et al. High curative resection rate with weekly cisplatin, 5-fluorouracil, epidoxorubicin, 6S-leucovorin, glutathione, and filgastrim in patients with locally advanced, unresectable gastric cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD) [J]. Br J Cancer, 2004; 90(8): 1521-1525.
30. Yabusaki H, Nashimoto A, Tanaka O. Evaluation of TS-1 combined with cisplatin for neoadjuvant chemotherapy in patients with advanced gastric cancer[J]. Gan To Kagaku Ryoho, 2003; 30(12): 1933-1940.
31. Sym S, Chang H, Ryu M, et al. A phase Ⅱ study of neoadjuvant chemotherapy with docetaxel, capecitabine and cisplatin (DXP) in patients with advanced unresectable or intra-abdominal metastatic gastric cancer[J]. J Clin Oncol(Meeting Abstracts), 2007; 25(18S): 4640.
32. Moon H, Ji JF, Wu AW, et al. Oxaliplatin + 5-fluorouracil/leucovorin (FOLFOX7) as neoadjuvant plus adjuvant treatment versus adjuvant alone in locally advanced resectable gastric cancer: BJSA-01 study design and interim results [A/OL]. 2007 Gastrointestinal Cancers Symposium: Abstract 39.
33. Hfler H, Langer R, Ott K, et al. Prediction of response to neoadjuvant chemotherapy in carcinomas of the upper gastrointestinal tract[J]. Recent Results Cancer Res, 2007; 176: 33-36.
34. Im S, Kim S, Kim J, et al. A phase Ⅱ trial of perioperative chemotherapy with folinic acid, 5-fluorouracil, and oxaliplatin in potentially resectable gastric cancer with regional lymph node metastasis [J]. J Clin Oncol (Meeting Abstracts), 2007; 25(18S): 4602.
35. Ajani JA, Mansfield PF, Crane CH, et al. Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome[J]. J Clin Oncol, 2005; 23(6): 1237-1244.
36. Newman E, Potmesil M, Ryan T, et al. Neoadjuvant chemotherapy, surgery, and adjuvant intraperitoneal chemotherapy in patients with locally advanced gastric or gastroesophageal junction carcinoma: a phase Ⅱ study[J]. Semin Oncol, 2005; 32(6 Suppl 9): S97-S100.
37. Fujitani K, Sasako M, Iwasaki Y, et al. A phase Ⅱ study of preoperative chemotherapy (CX) with S-1 and cisplatin followed by gastrectomy for clinically resectable type 4 and large type 3 gastric cancer: JCOG 0210[J]. J Clin Oncol (Meeting Abstracts), 2007; 25(18S): 4609.
38. Imamura H, IIishi H, Tsuburaya A, et al. Randomized ph-ase Ⅲ study of irinotecan plus S-1 (IRIS) versus S-1 alone as first-line treatment for advanced gastric cancer (GC0301/TOP-002)[A/OL]. 2008 Gastrointestinal Cancers Symposium: Abstract 5.
39. Boku N, Yamamoto S, Shirao K. Randomized phase Ⅲ study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG9912) [J]. J Clin Oncol (Meeting Abstracts), 2007; 25(18S): LBA4513.
40. Narahara H, Koizumi W, Hara T, et al. Randomized phase Ⅲ study of S-1 alone versus S-1 + cisplatin in the treatment for advanced gastric cancer (The SPIRITS trial) SPIRITS: S-1 plus cisplatin vs S-1 in RCT in the treatment for stomach cancer[J]. J Clin Oncol (Meeting Abstracts), 2007; 25(18S): 4514.
41. Ajani JA, Moiseyenko VM, Tjulandin S, et al. Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase Ⅲ trial of advanced gastric or gastroesophageal cancer adenocarcinoma: the V-325 Study Group[J]. J Clin Oncol, 2007; 25(22): 3205-3209.
42. Rougier P, Oba K. Meta-analyses of randomized trials assessing the interest chemotherapy in advanced gastric cancer[J]. J Clin Oncol (Meeting Abstracts), 2008; 26(15S): 4563.
43. Kamoshida S, Suzuki M, Shimomura R, et al. Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer[J]. Br J Cancer, 2007; 96(2): 277-283.
44. Rojas Llimpe FL, Di Fabio F, Ceccarelli C, et al. Prognostic significance of ki67, p53, TS and EGFR in advanced gastric and gastroesophageal junction cancer patients treated with cetuximab plus FOLFIRI (FOLCETUX study)[J]. J Clin Oncol (Meeting Abstracts), 2007; 25(18S): 4604.
45. Fukuda H, Takiguchi N, Koda K, et al. Thymidylate synthase and dihydropyrimidine dehydrogenase are related to histological effects of 5-fluorouracil and cisplatin neoadjuvant chemotherapy for primary gastric cancer patients [J]. Cancer Invest, 2006; 24(3): 235-241.
46. Chang H, Azuma M, Goldman B, et al. Gene expression levels of HER2 and IL-8 and polymorphism in IL-8 associated with clinical outcome in advanced or metastatic gastric cancer treated with lapatinib in SWOG 0413 trial[J]. J Clin Oncol(Meeting Abstracts), 2007; 25(18S): 4647.
47. Di Fabio F, Pinto C, Bucca E, et al. Predictive value of circulating VEGF in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma treated with cetuximab in combination with cisplatin and docetaxel (Italian phase Ⅱ DOCETUX Study) [J]. J Clin Oncol (Meeting Abstracts), 2008; 26(15S): 15605.
48. Kim J, Chae Y, Moon J, et al. Prognostic impact of apoptosis-related gene polymorphisms in patients with advanced gastric cancer treated with paclitaxel and cisplatin chemotherapy [J]. J Clin Oncol (Meeting Abstracts), 2008; 26(15S): 4569.
49. Helgason HH, Engwegen JY, Cats A, et al. Serum proteomic profiling of advanced gastric cancer and identification of proteomic changes following response to epirubicin, cisplatin and capecitabine chemotherapy as diagnostic and predictive biomarkers [J]. J Clin Oncol (Meeting Abstracts), 2007; 25(18S): 4537.
50. Ott K, Herrmann K, Lordick F, et al. Early metabolic response evaluation by fluorine-18 fluorodeoxyglucose positron emission tomography allows in vivo testing of chemosensitivity in gastric cancer: long-term results of a prospective study[J]. Clin Cancer Res, 2008; 14(7): 2012-2018.
51. Shah MA, Yeung H, Trocola R, et al. The characteristics and utility of FDG-PET/CT scans in patients with localized gastric cancer (GC) [A/OL]. 2007 Gastrointestinal Cancers Symposium: Abstract 2.
52. Shah MA, Yeung H, Coit D, et al. A phase Ⅱ study of preoperative chemotherapy with irinotecan (CPT) and cisplatin (CIS) for gastric cancer (NCI 5917): FDG-PET/CT predicts patient outcome [J]. J Clin Oncol (Meeting Abstracts), 2007; 25(18S): 4502.
53. Ott K, Herrmann K, Langer R, et al. Is 3-deoxy-3-[18F]fluorothymidine (FLT)-PET in combination with the proliferation index marker MIB1 predictive of response and prognosis in locally advanced neoadjuvant treated gastric cancer?[A/OL]. 2008 Gastrointestinal Cancers Symposium: Abstract 21.
54. Kwon H, Oh S, Kim S, et al. Clinicopathologic significance of hypoxia-inducible factor 1α, p53, and vascular endothelial growth factor expression and preoperative serum vascular endothelial growth factor level in gastric cancer [J]. J Clin Oncol (Meeting Abstracts), 2008; 26(15S): 4576.
55. Cutsem EV, Kang Y, Chung H, et al. Efficacy results from the TOGA trial: A phase Ⅲ study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC) [J]. J Clin Oncol (Meeting Abstracts), 2009; 27(18S): LBA4509.
56. Matsubara J, Moriwaki T, Yamada Y, et al. Impacts of dihydropyrimidine dehydrogenase (DPD), epidermal growth factor receptor (EGFR), and excision repair cross-complementing gene 1 (ERCC1) on outcomes of patients with advanced gastric cancer[A/OL]. 2007 Gastrointestinal Cancers Symposium: Abstract 5.
57. Beyer BC, Heiss MM, Simon EH, et al. Urokinase system expression in gastric carcinoma: prognostic impact in an independent patient series and first evidence of predictive value in preoperative biopsy and intestinal metaplasia specimens[J]. Cancer, 2006; 106(5): 1026-1035.
58. Lurje G, Husain H, Hendifar AE, et al. Use of thrombin-receptor 1 (PAR-1), endostatin (ES), and interleukin-8 (IL-8) gene polymorphisms to predict tumor recurrence in patients with surgically resected gastric cancer [J]. J Clin Oncol (Meeting Abstracts), 2008; 26(15S): 4559.
59. Zhao WH, Wang SF, Ding W, et al. Apoptosis induced by preoperative oral 5′-DFUR administration in gastric adenocarcinoma and its mechanism of action[J]. World J Gastroenterol, 2006; 12(9): 1356-1361.
60. Tabernero J, Macarulla T, Ramos FJ, et al. Novel targeted therapies in the treatment of gastric and esophageal cancer[J]. Ann Oncol, 2005; 16(11): 1740-1748.
61. Bramhall SR, Hallissey MT, Whiting J, et al. Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial[J]. Br J Cancer, 2002; 86(12): 1864-1870.
62. Pinto C, Di Fabio F, Barone C, et al. Cetuximab in combination with cisplatin and docetaxel as first-line treatment in patients with locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma (Italian phase Ⅱ DOCETUX study)[J]. J Clin Oncol (Meeting Abstracts), 2008; 26(15S): 4575.
63. Lordick F, Lorenzen S, Hegewisch-Becker S, et al. Cetuximab plus weekly oxaliplatin/5FU/FA (FUFOX) in 1st line metastatic gastric cancer. Final results from a multicenter phase Ⅱ study of the AIO upper GI study[J]. J Clin Oncol (Meeting Abstracts), 2007; 25(18S): 4526.
64. Moehler MH, Trarbach T, Seufferlein T, et al. Cetuximab with irinotecan/Na-Fa/5-FU as first-line treatment in advanced gastric cancer: Preliminary results of a nonrandomised multi-centre AIO phase Ⅱ study [A/OL]. 2008 Gastrointestinal Cancers Symposium: Abstract 102.
65. Hammad N, Philip PA, Shields AF, et al. A phase Ⅱ study of bevacizumab, docetaxel, and oxaliplatin in gastric and gastroesophageal junction (GEJ) cancer [A/OL]. 2008 Gastrointestinal Cancers Symposium: Abstract 30.
66. Iqbal S, Goldman B, Lenz HJ. A phase Ⅱ SWOG study of GW572016 (lapatinib) as first line therapy in patients (pts) with advanced or metastatic gastric cancer [J]. J Clin Oncol (Meeting Abstracts), 2007; 25(18S): 4621.
67. Sgroi MM, Hanna NH, McCollum AD, et al. Preoperative cetuximab and radiation (XRT) for patients (pts) with surgically resectable esophageal and gastroesophageal (GE) junction carcinomas: A pilot study from the Hoosier Oncology Group and the University of Texas-Southwestern [J]. J Clin Oncol (Meeting Abstracts), 2008; 26(15S): 4564.
68. Wanebo HJ, DiPetrillo T, Kennedy T. Cetuximab-based ne-oadjuvant chemoradiation appears to facilitate surgical resection in patients with locally advanced esophageal and gastric cancer [A/OL]. 2008 Gastrointestinal Cancers Symposium: Abstract 33.