Takeda Y, Kobayashi K, Akiyama Y, Soma T, Handa S, Kudoh S, Kudo K
Department of Respiratory Medicine, International Medical Center of Japan, Tokyo, Japan.
Int J Cancer. 2001 Apr 15;92(2):269-75. doi: 10.1002/1097-0215(200102)9999:9999<::aid-ijc1179>3.0.co;2-3.
It has been reported that 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), have absorption characteristics of weakly basic drugs, suggesting that alkalization of the intestinal lumen might reduce reabsorption and its attendant side effects. Furthermore, stasis of stools containing these compounds is thought to induce damage to the intestinal mucosa. The prevention of CPT-11-induced side effects by oral alkalization (OA) combined with control of defecation (CD) was estimated in a case-control study of lung cancer patients. Coinciding with day 1 of CPT-11 infusion and for 4 days thereafter, OA and CD were practiced utilizing orally administered sodium bicarbonate, magnesium oxide, basic water and ursodeoxycholic acid. OA involved the daily use of all four therapeutics, and CD required doses of up to 4.0 g/day of magnesium oxide and 2 L/day of excess basic water. From three ongoing prospective phase I/II studies, we selected 37 consecutive patients who were treated with CPT-11 in combination with cisplatin in the presence of OA and CD (group B). Thirty-two control subjects who were matched to the background characteristics of the case patients were treated with the same regimen in the absence of OA and CD (group A). Toxicities induced by the CPT-11/cisplatin combination were evaluated and analyzed in group A and group B in a case-control format. The use of OA and CD resulted in significantly higher stool pH (p < 0.0001), while reducing the incidence of delayed diarrhea (> or = grade 2: group A 32.3% versus group B 9.4%; p = 0.005), nausea (p = 0.0001), vomiting (p = 0.001) and myelotoxicity, especially granulocytopenia (p = 0.03) and lymphocytopenia (p = 0.034). In addition, dose intensification was well tolerated in patients receiving OA and CD, allowing dose escalation from 35.6 +/- 6.0 to 39.9 +/- 5.6 mg/m(2)/week (p < 0.001). Tumor response rates for non-small cell lung cancer were 59.3% (16/27 patients) in group B compared with 38.5% (10/26 patients) in group A. Multivariate analysis revealed that the risk of CPT-11-induced delayed diarrhea greater than grade 2 was associated with OA and CD (odds ratio for delayed diarrhea, 0.14 with use of OA and CD; 95% confidence interval, 0.05 to 0.4; p = 0.0002) and age (odds ratio, 1.08 per increase in age; 95% confidence interval, 1.02 to 1.15; p = 0.009). OA and CD appear to be useful in preventing the dose-limiting side effects of CPT-11 noted in clinical practice, mainly nausea, vomiting, granulocytopenia and especially delayed diarrhea. Risk factors statistically associated with delayed diarrhea include advanced age and the use of CPT-11 without OA and CD.
据报道，7-乙基-10-[4-(1-哌啶基)-1-哌啶基]羰基氧基喜树碱（CPT-11）及其活性代谢产物7-乙基-10-羟基喜树碱（SN-38）具有弱碱性药物的吸收特性，这表明肠腔碱化可能会减少重吸收及其伴随的副作用。此外，含有这些化合物的粪便淤滞被认为会导致肠黏膜损伤。在一项肺癌患者的病例对照研究中，评估了口服碱化（OA）联合排便控制（CD）对预防CPT-11引起的副作用的效果。在CPT-11输注的第1天及之后的4天，通过口服碳酸氢钠、氧化镁、碱性水和熊去氧胆酸来实施OA和CD。OA包括每日使用所有四种治疗方法，而CD需要每日服用高达4.0 g的氧化镁和2 L的过量碱性水。从三项正在进行的前瞻性I/II期研究中，我们选择了37例连续接受CPT-11联合顺铂治疗且同时进行OA和CD的患者（B组）。32例与病例患者背景特征相匹配的对照受试者在未进行OA和CD的情况下接受相同方案治疗（A组）。以病例对照的形式对A组和B组中CPT-11/顺铂联合治疗引起的毒性进行了评估和分析。OA和CD的使用导致粪便pH值显著升高（p < 0.0001），同时降低了延迟性腹泻（≥2级：A组32.3%，B组9.4%；p = 0.005）、恶心（p = 0.0001）、呕吐（p = 0.001）和骨髓毒性的发生率，尤其是粒细胞减少（p = 0.03）和淋巴细胞减少（p = 0.034）。此外，接受OA和CD的患者对剂量强化耐受性良好，允许剂量从35.6±6.0 mg/m²/周增加到39.9±5.6 mg/m²/周（p < 0.001）。B组非小细胞肺癌的肿瘤缓解率为59.3%（16/27例患者），而A组为38.5%（10/26例患者）。多因素分析显示，CPT-11引起的大于2级延迟性腹泻的风险与OA和CD（延迟性腹泻的优势比，使用OA和CD时为0.14；95%置信区间，0.05至0.4；p = 0.0002）以及年龄（优势比，年龄每增加1岁为1.08；95%置信区间，1.02至1.15；p = 0.009）相关。OA和CD似乎有助于预防临床实践中CPT-11的剂量限制性副作用，主要是恶心、呕吐、粒细胞减少，尤其是延迟性腹泻。与延迟性腹泻有统计学关联的危险因素包括高龄以及在未进行OA和CD的情况下使用CPT-11。
