Focan C, Levi F, Kreutz F, Focan-Henrard D, Lobelle J P, Adam R, Dallemagne B, Jehaes C, Markiewicz S, Weerts J, Bismuth H, Jasmin C, Misset J L
Les Cliniques Saint-Joseph, Liege, Belgium.
Anticancer Drugs. 1999 Apr;10(4):385-92. doi: 10.1097/00001813-199904000-00006.
High-dose chemotherapy combining regional hepatic artery infusion (HAI) of fluorodeoxyuridine (HAI FUDR) and systemic venous infusion of 5-fluorouracil (i.v. 5-FU) was delivered against liver metastases from colorectal cancer. The hypothesis that chronomodulation of delivery rate along the 24 h time scale would improve the tolerable doses of both drugs was tested. Combined HAI FUDR (80 mg/m2/day) and i.v. 5-FU (1200 mg/m2/day) were administered for five consecutive days every 3 weeks, either as a constant rate infusion (schedule A, 27 patients) or as chronotherapy (schedule B, 29 patients). This latter regimen consisted of a sinusoidal modulation of the delivery rate over the 24 h scale with a maximum at 16:00 for FUDR and 4:00 for 5-FU. Intrapatient dose escalation up to the individual maximum tolerated doses (MTD) was planned for both drugs in the absence of any previous grade 3 or 4 toxicity. All patients had metastatic colorectal cancer, with adjuvant or palliative chemotherapy given to six patients (22%) on schedule A and 12 patients on schedule B (41%). Severe stomatitis occurred in 71% of the patients and was dose limiting. No hepatic toxicity was encountered. Dose reductions of 5-FU and/or FUDR were required for 17 of 27 patients on schedule A (63%) as compared to 11 of 29 patients on schedule B (38%), following reaching the individual MTD (p<0.05). Over the first six cycles, patients on schedule B received higher doses (mg/m2/cycle; FUDR: 522 +/- 85 versus 499 +/- 50, p=0.004 and 5-FU: 5393 +/- 962 versus 5136 +/- 963, p=0.009) and higher dose intensities (mg/m2/week; FUDR: 164 +/- 46 versus 151 +/- 52, p=0.018 and 5-FU: 1652 +/- 478 versus 1553 +/- 535, p<0.041) of both drugs than patients on schedule A. As a result the number of courses with doses of 5-FU above 1200 mg/m2/day and/or FUDR above 110 mg/m2/day was larger in group B than in group A (5-FU, A: 67 of 268, 25% versus B: 133 of 321, 41% and FUDR, A: 86 of 268, 32% versus B: 155 of 321, 48%; p<0.001). Objective responses were observed in 13 patients on schedule A (48%) and 11 patients on schedule B (38%). The results support the need for further exploration of chronotherapy of colorectal cancer liver metastases with combined arterial and venous fluoropyrimidine chemotherapy.
采用高剂量化疗联合氟尿苷区域肝动脉灌注（HAI FUDR）及5-氟尿嘧啶全身静脉输注（静脉注射5-FU）治疗结直肠癌肝转移。检验了在24小时时间尺度上对给药速率进行时辰调制可提高两种药物耐受剂量的假设。联合HAI FUDR（80mg/m²/天）和静脉注射5-FU（1200mg/m²/天），每3周连续给药5天，给药方式为恒速输注（方案A，27例患者）或时辰疗法（方案B，29例患者）。后一种方案包括在24小时尺度上对给药速率进行正弦调制，FUDR在16:00达到最大值，5-FU在4:00达到最大值。计划在两种药物均未出现任何先前3级或4级毒性的情况下，将每位患者的剂量逐步增加至个体最大耐受剂量（MTD）。所有患者均患有转移性结直肠癌，方案A中有6例患者（22%）、方案B中有12例患者（41%）接受了辅助或姑息化疗。71%的患者发生严重口腔炎，且口腔炎为剂量限制性毒性。未出现肝毒性。达到个体MTD后，方案A的27例患者中有17例（63%）需要减少5-FU和/或FUDR的剂量，而方案B的29例患者中有11例（38%）需要减少剂量（p<0.05）。在前六个周期中，方案B的患者接受的两种药物剂量（mg/m²/周期；FUDR：522±85对499±50，p=0.004；5-FU：5393±962对5136±963，p=0.009）和剂量强度（mg/m²/周；FUDR：164±46对151±52，p=0.018；5-FU：1652±478对1553±535，p<0.041）均高于方案A的患者。因此，B组中5-FU剂量高于1200mg/m²/天和/或FUDR剂量高于110mg/m²/天的疗程数多于A组（5-FU，A组：268个疗程中的67个，25%；B组：321个疗程中的133个，41%；FUDR，A组：268个疗程中的86个，32%；B组：321个疗程中的155个，48%；p<0.001）。方案A的13例患者（48%）和方案B的11例患者（38%）观察到客观缓解。结果支持进一步探索联合动脉和静脉氟嘧啶化疗对结直肠癌肝转移进行时辰疗法的必要性。
