Sinnige H A, Buter J, de Vries E G, Uges D R, Roenhorst H W, Verschueren R C, Sleijfer D T, Willemse P H, Mulder N H
Department of Internal Medicine, University Hospital, Groningen, The Netherlands.
Eur J Cancer. 1993;29A(12):1715-20. doi: 10.1016/0959-8049(93)90111-r.
5-Fluorouracil (5-FU) activity has been improved by the use of leucovorin (LV) or alpha-2a interferon (alpha-IF). We investigated the feasibility and activity of addition of alpha-IF to a 5-FU/LV regimen. A phase I study with 26 patients (14 previously untreated, 12 previously treated) with disseminated cancer was conducted. 15 patients were treated with 5-FU/LV and 11 with 5-FU/LV/alpha-IF. The 5-FU/LV regimen consisted of escalating doses of 5-FU bolus intravenously on days 2 and 3, combined with repeated oral LV on days 1, 2 and 3. Treatment was every 2 weeks. In the 5-FU/LV/alpha-IF schedule, 18 x 10(6) U alpha-IF subcutaneously daily was added on days 1, 2 and 3. The phase I study was followed by a phase II study of 5-FU/LV/alpha-IF at the established 5-FU dose in 29 previously untreated patients with disseminated colorectal cancer. The optimal 5-FU dose in both parts of the phase I study was 750 mg/m2/day. Mucositis, diarrhea and leucopenia were dose limiting. Although alpha-IF added its own toxicity (fever, flu-like symptoms, fatigue), it did not decrease the optimal dose of 5-FU. In the phase II study 28 patients were evaluable for response: three complete responses and 12 partial responses were observed (response rate 54%, 95% confidence interval, 34 to 72%). Pharmacokinetics of oral LV was performed in patients treated with and without alpha-IF: significantly higher serum levels of LV and 5-methyltetrahydrofolate were found after alpha-IF addition. Influence of alpha-IF on gastrointestinal absorption or renal clearance could be excluded. In conclusion, this 5-FU/LV/alpha-IF combination seems active in metastatic colorectal cancer. The pharmacokinetic interaction between alpha-IF and LV may play a role in the activity of this regimen. Controlled studies are necessary to establish the value of addition of alpha-IF to 5-FU/LV regimens.
使用亚叶酸（LV）或α-2a干扰素（α-IF）可提高5-氟尿嘧啶（5-FU）的活性。我们研究了在5-FU/LV方案中加入α-IF的可行性和活性。对26例播散性癌症患者（14例既往未接受过治疗，12例既往接受过治疗）进行了I期研究。15例患者接受5-FU/LV治疗，11例接受5-FU/LV/α-IF治疗。5-FU/LV方案包括在第2天和第3天静脉推注递增剂量的5-FU，并在第1、2和3天重复口服LV。每2周进行一次治疗。在5-FU/LV/α-IF方案中，在第1、2和3天每天皮下注射18×10⁶Uα-IF。I期研究之后，对29例既往未接受过治疗的播散性结直肠癌患者，按照已确定的5-FU剂量进行了5-FU/LV/α-IF的II期研究。I期研究两部分中的最佳5-FU剂量均为750mg/m²/天。黏膜炎、腹泻和白细胞减少是剂量限制性毒性反应。虽然α-IF增加了自身的毒性（发热、流感样症状、疲劳），但并未降低5-FU的最佳剂量。在II期研究中，28例患者可评估疗效：观察到3例完全缓解和12例部分缓解（缓解率54%，95%置信区间，34%至72%）。对接受和未接受α-IF治疗的患者进行了口服LV的药代动力学研究：加入α-IF后，LV和5-甲基四氢叶酸的血清水平显著升高。可以排除α-IF对胃肠道吸收或肾脏清除的影响。总之，这种5-FU/LV/α-IF联合方案似乎对转移性结直肠癌有活性。α-IF与LV之间的药代动力学相互作用可能在该方案的活性中起作用。需要进行对照研究以确定在5-FU/LV方案中加入α-IF的价值。
