Garufi C, Dogliotti L, D'Attino R M, Tampellini M, Aschelter A M, Pugliese P, Perrone M, Nisticó C, Comis S, Terzoli E
Oncologia Medica Complementare, Istituto Regina Elena Roma, Viale Regina Elena 291, 00161 Rome, Italy.
Cancer. 2001 Feb 15;91(4):712-20.
Irinotecan (CPT-11) is an active drug in the treatment of patients with advanced colorectal carcinoma. The infusion of 5-fluorouracil (5-FU) according to circadian rhythms was used previously to decrease toxicity and to increase its therapeutic efficacy. The objective of this study was to establish the maximum tolerated dose (MTD) of CPT-11 together with a chronomodulated infusion of 5-FU and the l-form of folinic acid (FA). Secondary end points were the assessment of activity and quality of life (QoL).
Twenty-six patients with advanced colorectal carcinoma who had received previous treatment with 5-FU were entered on this Phase I study. At least three patients were recruited at each dose level. The CPT-11 starting dose was 175 mg/m(2) on Day 1 with an increase of 50 mg/m2 per dose level. A daily administration of chronomodulated 5-FU (900 mg/m2; peak delivery rate at 04:00) and FA (175 mg/m2; peak delivery rate at 04:00) for 5 days every 3 weeks was given with CPT-11. After the first three patients, the 5-FU dose was reduced to 700 mg/m2 per day due to toxicity. No intrapatient dose escalation was allowed.
One hundred sixty-one courses were delivered. Dose-limiting toxicity was observed during the first course in seven patients (27%). Four patients developed neutropenia, with one patient reporting febrile neutropenia, two patients reporting severe stomatitis, and six patients reporting severe diarrhea. CPT-11 MTD was reached at 350 mg/m2 when a toxic death was observed with a recommended dose of 325 mg/m2. Six partial responses were observed (23%). The median duration of response and the progression free and overall survival rates were 199 days, 175 days, and 359 days, respectively. QoL was not affected by the treatment.
The recommended dose for Phase II trials is 325 mg/m2 CPT-11 on Day 1, which is similar to the dose given as a single agent, together with a 5-day chronomodulated infusion of 700 mg/m2 5-FU and 175 mg/m2 FA. Intensification of this schedule every 2 weeks should be achievable.
伊立替康（CPT - 11）是治疗晚期结直肠癌患者的一种有效药物。先前曾采用根据昼夜节律输注5 - 氟尿嘧啶（5 - FU）的方法来降低毒性并提高其治疗效果。本研究的目的是确定CPT - 11与5 - FU及左旋亚叶酸钙（FA）的时辰调节输注联合使用时的最大耐受剂量（MTD）。次要终点是评估活性和生活质量（QoL）。
26例先前接受过5 - FU治疗的晚期结直肠癌患者进入了这项I期研究。每个剂量水平至少招募3名患者。CPT - 11起始剂量为第1天175 mg/m²，每剂量水平增加50 mg/m²。每3周给予5天的时辰调节的5 - FU（900 mg/m²；04:00时达到峰值给药速率）和FA（175 mg/m²；04:00时达到峰值给药速率），与CPT - 11同时使用。在前3例患者之后，由于毒性，5 - FU剂量降至每天700 mg/m²。不允许在患者内进行剂量递增。
共进行了161个疗程。7例患者（27%）在第一个疗程期间出现剂量限制性毒性。4例患者发生中性粒细胞减少，1例患者报告发热性中性粒细胞减少，2例患者报告严重口腔炎，6例患者报告严重腹泻。当观察到1例毒性死亡且推荐剂量为325 mg/m²时，CPT - 11达到了MTD 350 mg/m²。观察到6例部分缓解（23%）。缓解的中位持续时间、无进展生存期和总生存率分别为199天、175天和359天。治疗未影响生活质量。
II期试验的推荐剂量为第1天325 mg/m²的CPT - 11，这与单药给药剂量相似，同时给予5天的时辰调节输注，700 mg/m²的5 - FU和175 mg/m²的FA。每2周强化此方案应该是可行的。
