洛铂与草酸铂在联合化疗方案中毒副作用的比较

摘要

目的: 比较洛铂、草酸铂在氟尿嘧啶、四氢叶酸钙联合化疗方案中的毒副作用. 

方法:  将2006-2007年52例结、直肠癌术后患者随机分为两组, 洛铂联合化疗组26例, 共85个疗程, 草酸铂联合化疗组26例, 共73个疗程. 化疗方案为洛铂50 mg/m²或草酸铂85 mg/m², 静脉滴注2 h以上, 第1天; 四氢叶酸钙200 mg/m²静脉滴注2 h以上, 第1天和第2天; 氟尿嘧啶400 mg/m²静脉推注, 然后600 mg/m²持续静脉输注22 h以上, 第1天和第2天; 每2周重复. 

结果: 毒副作用以骨髓抑制及胃肠道反应为主. 洛铂组和草酸铂组患者白细胞减少Ⅰ-Ⅱ级分别占60.0%, 50.7%; 血小板减少Ⅰ-Ⅱ级占66.7%, 21.3%; 胃肠道反应恶心占16.7%, 37.3%; 发生呕吐占3.3%, 6.7%; 洛铂组患者白细胞和血小板减少Ⅲ级分别占6.7%, 10.0%, 周围神经症状Ⅰ级占5.9%; 草酸铂组白细胞减少Ⅲ-Ⅳ级占41.3%, 周围神经症状Ⅰ-Ⅱ级占42.7%, Ⅲ-Ⅳ级占9.3%.

结论:  洛铂、草酸铂分别与氟尿嘧啶和四氢叶酸钙联合使用均为安全的化疗方案. 洛铂组对骨髓的抑制主要表现在血小板减少, 而草酸铂组主要表现在白细胞减少. 洛铂组的胃肠道反应及神经毒性较草酸铂组轻.

关键词: 毒副作用; 联合化疗; 洛铂; 草酸铂; 氟尿嘧啶; 四氢叶酸钙

Comparison of adverse reactions of combination chemotherapy: lobaplatin versus oxaliplatin

Hong-Feng Zhou, Yu-Xin Zhang, Liang-Ping Wu, Jian-Wen Deng, Hong-Liang Ding, Hui-Xin Kang

Hong-Feng Zhou, Yu-Xin Zhang, Liang-Ping Wu, Jian-Wen Deng, Hong-Liang Ding, Hui-Xin Kang, Department of General Surgery, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou 510010, Guangdong Province, China

Correspondence to: Hong-Feng Zhou, Department of General Surgery, Guangzhou General Hospital of Guangzhou Military Command, 111 Liuhua Road, Liwan District, Guangzhou 510010, Guangdong Province, China. zhouhf69@hotmail.com

Received: July 29, 2007
Revised: November 25, 2007
Accepted: December 15, 2007
Published online: January 18, 2008

Abstract

AIM: To compare the adverse effects of lobaplatin with that of oxaliplatin in combination chemotherapy.

METHODS: From 2006 to 2007, 52 colorectal cancer patients after surgery were randomly separated into two groups. A total of 85 courses were completed for 26 patients in the lobaplatin combination chemotherapy group. A total of 73 courses were completed for 26 patients in the oxaliplatin combination chemotherapy group. The drug regimens were: lobaplatin 50 mg/m² (or oxaliplatin, 80 mg/m²), iv in 500 mL D5W over 2 h on day 1; calcium leucovorin 200 mg/m², iv in D5W over 2 h on day 1 and day 2; fluorouracil 400 mg/m², iv bolus, after calcium leucovorin, then 600 mg/m², iv over 22 h on day 1 and day 2.

RESULTS: The adverse reactions that occurred frequently were myelosuppression and gastrointestinal tract reaction. In the lobaplatin group, white cell count was decreased to grade Ⅰ or Ⅱ in 60.0% of courses, and grade Ⅲ in 6.7% of courses (P < 0.01). Platelet count was decreased to grade Ⅰ or Ⅱ in 66.7% of courses, and grade Ⅲ in 10.0% of courses (P < 0.01). Nausea was seen in 16.7% and vomiting in 3.3% of courses (P < 0.01). Peripheral neuropathy was seen in 5.9% of courses (P < 0.01). In the oxaliplatin group, white cell count was decreased to grade Ⅰ or Ⅱ in 50.7% of courses, grade Ⅲ or IV in 41.3% of courses. Platelet count was decreased to grade Ⅰ or Ⅱ in 21.3% of courses. Nausea was 37.3% and vomiting was seen in 6.7% of courses (P < 0.01). Peripheral neuropathy of grade I or II was seen in 42.7% of courses, and grade Ⅲ or Ⅳ in 9.3% of courses. Hemoglobin, GPT, diarrhea, urea nitrogen and alopecia did not differ significantly between the two groups.

CONCLUSION: Chemotherapy in combination with lobaplatin and oxaliplatin or in combination with fluorouracil or calcium leucovorin is safe. Platelet count is significantly decreased during myelosuppression in patients treated with lobaplatin combination therapy. Leukocyte count is significantly decreased with oxaliplatin chemotherapy. Gastrointestinal tract reactions and neurotoxicity are less frequent in patients treated with lobaplatin rather than oxaliplatin chemotherapy.

Key Words: Adverse reaction; Combination chemotherapy; Lobaplatin; Oxaliplatin; Fluorouracil; Calcium leucovorin

0 引言

FOLFOX4方案是国际公认的结肠癌辅助化疗的标准方案[1], 洛铂(lobaplatin)是第三代的铂类抗癌药, 是SFDA2005去年批准上市的一类抗肿瘤新药. 对于洛铂的疗效及毒副作用国内外已有文献报道[2-7]. 我科自2006-2007年以来将洛铂替换FOLFOX4方案中的草酸铂作为结肠癌辅助化疗的新方案, 共治疗了85个疗程, 对两种方案的毒副作用进行了观察和比较, 现报道于下.

1 材料和方法

1.1 材料

全组患者52例, 男33例, 女19例, 年龄32-78(平均53.6±15.2)岁, 均为结、直肠癌术后患者, 近1 mo未进行化疗或放疗. 随机分为两组, 一组接受含洛铂的联合化疗方案治疗, 另一组接受FOLFOX4方案治疗. 洛铂联合化疗组26例, 共85个疗程, 草酸铂联合化疗组26例, 共73个疗程.

1.2 方法

洛铂的联合化疗方案: 洛铂50 mg/m²静脉滴注2 h以上, 第1天; 四氢叶酸钙200 mg/m²静脉滴注2 h以上, 第1天和第2天; 氟尿嘧啶400 mg/m²静脉推注, 然后600 mg/m²持续静脉输注22 h以上, 第1天和第2天; 共约48 h为一个疗程, 每2周重复, 连续治疗6个疗程. FOLFOX4方案[8]: 草酸铂85 mg/m²静脉滴注2 h以上, 第1天; 四氢叶酸钙200 mg/m²静脉滴注2 h以上, 第1天和第2天; 氟尿嘧啶400 mg/m²静脉推注, 然后600 mg/m²持续静脉输注22 h以上, 第1天和第2天; 共约48 h为一个疗程, 每2周重复, 连续治疗6个疗程. 治疗毒副反应判断标准按WHO标准评定.

统计学处理 应用SPSS10.0软件包进行χ²检验.

2 结果

毒副作用以骨髓抑制及胃肠道反应为主, 见表1, 洛铂组患者白细胞减少Ⅰ-Ⅱ级占60.0%, Ⅲ级占6.7%(P<0.01). 血小板减少Ⅰ-Ⅱ级占66.7%, Ⅲ级占10.0%(P<0.01). 胃肠道反应恶心占16.7%, 发生呕吐占3.3%(P<0.01). 周围神经症状Ⅰ级占5.9%(P<0.01). 草酸铂组患者白细胞减少Ⅰ-Ⅱ级占50.7%, Ⅲ-Ⅳ级占41.3%. 血小板减少Ⅰ-Ⅱ级占21.3%. 胃肠道反应恶心占37.3%, 发生呕吐者占6.7%. 周围神经症状Ⅰ-Ⅱ级占42.7%, Ⅲ-Ⅳ级占9.3%. 血红蛋白、谷丙转氨酶、腹泻、尿素氮、脱发在两组中无显著性差异.

表1 洛铂、草酸铂在联合化疗中毒副作用比较.

毒副反应	洛铂组					草酸铂组					χ2	P
	0	Ⅰ	Ⅱ	Ⅲ	Ⅳ	0	Ⅰ	Ⅱ	Ⅲ	Ⅳ
血红蛋白降低	60	17	6	2	0	57	11	7	0	0	2.826	>0.05
白细胞减少	28	37	14	6	0	10	15	23	27	4	37.217	<0.01
血小板减少	20	28	28	9	0	59	13	3	0	0	53.482	<0.01
出血	85	0	0	0	0	75	0	0	0	0
谷丙转氨酶升高	79	6	0	0	0	73	2	0	0	0	1.618	>0.05
恶心呕吐	68	14	3	0	0	32	28	5	0	0	15.740	<0.01
腹泻	85	0	0	0	0	71	4	0	0	0	2.719	>0.05
尿素氮升高	78	7	0	0	0	71	3	1	0	0	2.313	>0.05
头发	82	3	0	0	0	70	5	0	0	0	0.297	>0.05
周围神经	80	5	0	0	0	37	21	11	6	1	43.282	<0.01

3 讨论

洛铂是第三代的铂类抗癌药, 国外文献报道其与顺铂的抗癌活性相似, 但肾毒性和胃肠道反应较轻, 且可能与顺铂有部分非交叉性耐药[9-10].

本临床观察发现, 洛铂、草酸铂分别与氟尿嘧啶和四氢叶酸钙联合化疗的毒副作用以骨髓抑制及胃肠道反应为主. 其中以白细胞和血小板减少尤为明显, 是主要的剂量限制性因素, 与文献报道一致[2-3,11]. 因白细胞、血小板以化疗结束后2 wk降到最低, 而此时患者都已出院, 因此2 wk后一定要求患者复查血象, 根据结果采取措施, 防止感染和出血. 洛铂组对骨髓的抑制主要表现在血小板减少, 而草酸铂组主要表现在白细胞减少. 这种对骨髓抑制选择性有待进一步研究. 洛铂组的胃肠道反应及神经毒性较草酸铂组轻, 这也是影响患者主观感受的主要因素, 在本研究的预实验期, 我们发现同时接受两种化疗方案的患者明显感觉接受洛铂治疗较草酸铂治疗舒适.

本化疗方案因治疗病例较少, 随访时间较短, 国内外尚无大宗病例报道, 疗效有待进一步观察[12-13].

评论

背景资料

目前, 结直肠癌以FOLFOX作为一线化疗方案, FOLFOX4是国际公认的标准方案, 但毒副反应较大. 洛铂是第三代的铂类抗癌药, 临床前研究结果表明, 他与顺铂的抗癌活性相似, 但肾毒性和胃肠道反应较轻, 且可能对部分顺铂耐药的肿瘤有效. 国内曾进行了Ⅰ、Ⅱ临床研究, 当时中文名叫乐铂. 2005年被SFDA批准为一类抗肿瘤新药上市. 将洛铂替换FOLFOX4方案中草酸铂以降低化疗的毒副作用成为符合逻辑的推理, 国内几家大医院已开始对新方案进行初步的临床研究.

同行评议者

周国雄, 主任医师, 南通大学附属医院消化内科

创新盘点

本化疗方案的安全性笔者曾做过报道. 与草酸铂的毒副作用比较亦为首次报道. 因病例较少, 随访时间较短, 对其疗效和安全性还有待进一步观察.

同行评价

本文比较了洛铂与草酸铂在联合化疗方案中毒副作用, 可读性强, 文笔流畅, 统计准确, 有一定的临床指导价值.

备注

编辑:程剑侠 电编:何基才

参考文献

1.	Fuse N, Doi T, Ohtsu A, Takeuchi S, Kojima T, Taku K, Tahara M, Muto M, Asaka M, Yoshida S. Feasibility of oxaliplatin and infusional fluorouracil/leucovorin (FOLFOX4) for Japanese patients with unresectable metastatic colorectal cancer. Jpn J Clin Oncol. 2007;37:434-439.  [PubMed]  [DOI]

2.	姜 文奇, 林 桐榆, 徐 瑞华, 管 忠震. 乐铂单药治疗肺癌的临床研究. 浙江肿瘤. 1998;4:241-242.  [PubMed]  [DOI]

3.	冯 光丽, 廖 美琳, 赵 家美, 张 心敏, 陈 智伟, 白 皓, 钟 华. 乐铂单药治疗42例原发性支气管肺癌. 中国癌症杂志. 2000;10:306-309.  [PubMed]  [DOI]

4.	Gietema JA, Veldhuis GJ, Guchelaar HJ, Willemse PH, Uges DR, Cats A, Boonstra H, van der Graaf WT, Sleijfer DT, de Vries EG. Phase II and pharmacokinetic study of lobaplatin in patients with relapsed ovarian cancer. Br J Cancer. 1995;71:1302-1307.  [PubMed]  [DOI]

5.	Gietema JA, de Vries EG, Sleijfer DT, Willemse PH, Guchelaar HJ, Uges DR, Aulenbacher P, Voegeli R, Mulder NH. A phase I study of 1,2-diamminomethyl-cyclobutane-platinum (II)-lactate (D-19466; lobaplatin) administered daily for 5 days. Br J Cancer. 1993;67:396-401.  [PubMed]  [DOI]

6.	姜 文奇, 林 桐榆, 徐 瑞华, 管 忠震. 乐铂单药治疗乳腺癌的Ⅱ期临床研究. 实用癌症杂志. 1998;13:294-295.  [PubMed]  [DOI]

7.	周 宏锋, 张 玉新, 程 黎阳, 丁 洪亮. 洛铂、氟尿嘧啶与亚叶酸钙联合化疗的临床毒副作用. 世界华人消化杂志. 2007;15:86-87.  [PubMed]  [DOI]

8.	Xu N, Fang WJ, Zhang XC, Yu LF, Bao HY, Shi GM, Huang S, Shen P. A Phase II Trial of Oxaliplatin, Folinic Acid, and 5-Fluorouracil (FOLFOX4) as First-Line Chemotherapy in Advanced Colorectal Cancer: A China Single-Center Experience. Cancer Invest. 2007;1-7.  [PubMed]  [DOI]

9.	Harstrick A, Bokemeyer C, Scharnofkse M, Hapke G, Reile D, Schmoll HJ. Preclinical activity of a new platinum analogue, lobaplatin, in cisplatin-sensitive and -resistant human testicular, ovarian, and gastric carcinoma cell lines. Cancer Chemother Pharmacol. 1993;33:43-47.  [PubMed]  [DOI]

10.	刘 秀峰, 秦 叔逵. 洛铂的临床研究进展. 临床肿瘤学杂志. 2006;11:549-552.  [PubMed]  [DOI]

11.	魏 嘉, 王 立峰, 刘 宝瑞. 5-FU相关的药物疗效及毒性预测分子研究进展. 世界华人消化杂志. 2005;13:1889-1893.  [PubMed]  [DOI]

12.	Galanski M, Jakupec MA, Keppler BK. Update of the preclinical situation of anticancer platinum complexes: novel design strategies and innovative analytical approaches. Curr Med Chem. 2005;12:2075-2094.  [PubMed]  [DOI]

13.	林 丽珠, 周 岱翰, 郑 心婷. 洛铂联合氟尿嘧啶和甲酰四氢叶酸治疗晚期耐药胃癌、结直肠癌疗效观察. 中国肿瘤临床. 2007;34:286-288.  [PubMed]  [DOI]