Taal B G, ten Bokkel Huinink W W, Rodenhuis S
Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam.
Ann Oncol. 1993 Jan;4(1):81-2. doi: 10.1093/oxfordjournals.annonc.a058369.
In preparation for a phase II trial we performed a dose-finding study involving tauromustine (TCNU), fluorouracil (5-FU) and leucovorin (LV), applied in patients with colon cancer. To prevent TCNU/5-FU antagonism, a phenomenon recently demonstrated in vitro, special attention was paid to the sequencing of these agents.
In 25 patients with advanced colorectal carcinoma (13 M, 12 F, median age 51 yrs), four dose levels of TCNU (25, 30, 35 or 40 mg/m2) were investigated. The agent was administered orally once per week in weeks 1 through 4, in combination with fixed i.v. doses of 400 mg/m2 5-FU and 80 mg/m2 LV, once a week, weeks 1 through 8. Unless progression occurred, two 8-week cycles were applied. TCNU was administered at least 24 hours prior to 5-FU, because recent in vitro studies suggested that such an interval is required to obtain additive cytotoxicity.
All 25 patients were evaluable for toxicity; 23 patients received at least one full 8-week course, and 13 were eligible for second cycles. Significant haematologic toxicity, predominantly thrombocytopenia WHO grade 3 or 4, was mainly encountered at the 35 and 40 mg/m2 dose levels. Although occasionally severe, myelosuppression did not result in toxic deaths; spontaneous haemorrhage was never observed, and platelet transfusions were not required. Additional toxicity, also related to the two higher dose levels, consisted of diarrhea (WHO grade 3) and the 'hand and foot syndrome', both occurring in a single patient; two patients developed fever of undetermined origin, but only one of them required hospitalization and antibiotic treatment. The overall response rate was 20% (7 partial responses in 25 evaluable patients).
For phase II studies, we recommend a weekly oral dose of 40 mg/m2 TCNU, weeks 1 through 4, in combination with 400 mg/m2 5-FU and 80 mg/m2 LV (IV), once a week, weeks 1 through 8.
为准备一项II期试验，我们开展了一项剂量探索研究，涉及在结肠癌患者中应用瘤氮芥（TCNU）、氟尿嘧啶（5-FU）和亚叶酸钙（LV）。为防止TCNU/5-FU拮抗作用（这是最近在体外证实的一种现象），对这些药物的给药顺序给予了特别关注。
在25例晚期结直肠癌患者（13例男性，12例女性，中位年龄51岁）中，研究了TCNU的四个剂量水平（25、30、35或40mg/m²）。在第1至4周每周口服给药一次，联合固定静脉注射剂量的400mg/m² 5-FU和80mg/m² LV，第1至8周每周一次。除非病情进展，给予两个8周周期的治疗。TCNU在5-FU之前至少24小时给药，因为最近的体外研究表明需要这样的间隔时间以获得相加的细胞毒性作用。
所有25例患者均可评估毒性；23例患者接受了至少一个完整的8周疗程，13例符合第二个周期的条件。显著的血液学毒性，主要是WHO 3级或4级血小板减少，主要出现在35和40mg/m²剂量水平。虽然偶尔严重，但骨髓抑制未导致毒性死亡；从未观察到自发性出血，也不需要输注血小板。与两个较高剂量水平相关的其他毒性包括腹泻（WHO 3级）和“手足综合征”，均仅发生在1例患者中；2例患者出现不明原因发热，但其中仅1例需要住院和抗生素治疗。总缓解率为20%（25例可评估患者中有7例部分缓解）。
对于II期研究，我们推荐在第1至4周每周口服40mg/m² TCNU，联合400mg/m² 5-FU和80mg/m² LV（静脉注射），第1至8周每周一次。
