Blanke C D, Messenger M, Taplin S C
Department of Medicine, The Vanderbilt Cancer Center, Nashville, TN, USA.
Semin Oncol. 1997 Oct;24(5 Suppl 18):S18-57-S18-63.
Unresectable metastatic colorectal cancer remains a significant cause of morbidity and mortality in both the United States and Europe. To date, no chemotherapeutic regimen for this disease has demonstrated a definitive survival advantage compared with 5-fluorouracil (5-FU) plus leucovorin (LV). However, recent trials have raised the possibility that the combination of trimetrexate (TMTX) plus 5-FU/LV may improve response rates and survival in patients with metastatic colorectal cancer. Trimetrexate is a nonclassical antifolate that has demonstrated antitumor activity against a number of malignancies, including those resistant to the classical antifolate methotrexate. While the single-agent activity of TMTX remains modest in metastatic colorectal cancer, the combination of TMTX/5-FU/LV has shown significant activity in several phase II trials. Reported studies include a phase II trial in chemotherapy failures that demonstrated a 20% response rate, and two multicenter phase II trials in previously untreated patients that demonstrated 50% and 38% overall response rates, respectively. Diarrhea was the dose-limiting toxicity in all trials, although a regimen of scheduled loperamide was quite effective in mitigating this complication. These studies are being followed up with two confirmatory phase II studies in chemorefractory patients and two randomized phase III trials comparing TMTX/5-FU/LV with standard 5-FU/LV.
无法切除的转移性结直肠癌在美国和欧洲仍然是发病和死亡的重要原因。迄今为止，与5-氟尿嘧啶（5-FU）加亚叶酸（LV）相比，针对这种疾病的化疗方案尚未显示出明确的生存优势。然而，最近的试验提出了三甲曲沙（TMTX）加5-FU/LV联合用药可能提高转移性结直肠癌患者缓解率和生存率的可能性。三甲曲沙是一种非经典抗叶酸剂，已显示出对多种恶性肿瘤具有抗肿瘤活性，包括对经典抗叶酸剂甲氨蝶呤耐药的肿瘤。虽然TMTX在转移性结直肠癌中的单药活性仍然有限，但TMTX/5-FU/LV联合用药在多项II期试验中已显示出显著活性。已报道的研究包括一项针对化疗失败患者的II期试验，其缓解率为20%，以及两项针对既往未接受治疗患者的多中心II期试验，其总缓解率分别为50%和38%。腹泻是所有试验中的剂量限制性毒性，尽管使用洛哌丁胺的方案在减轻这种并发症方面相当有效。这些研究之后将开展两项针对化疗难治性患者的验证性II期研究，以及两项将TMTX/5-FU/LV与标准5-FU/LV进行比较的随机III期试验。
