直肠癌术后应用奥沙利铂联合5-氟尿嘧啶、亚叶酸钙进行同步放疗的剂量研究

A study on the maximal tolerated dose of oxaliplatin in a concurrent radiotherapy and chemotherapy protocol for postoperative rectal cancer patients

目的探讨Ⅱ、Ⅲ期直肠癌术后，应用奥沙利铂（oxaliplatin，L—OHP）、5-氟尿嘧啶（5-Fu）、亚叶酸钙（LV）进行同步放疗的剂量限制性毒性（dose limiting toxicity，DLT）和最大耐受剂量（maximal tolerated dose，MTD），并观察其毒副作用。方法将Ⅱ、Ⅲ期直肠癌术后、经病理证实为直肠腺癌的21例患者分为5组（每组3例3组，每组6例2组），行全程常规分割放疗，总剂量50Gy／25f；同期进行化疗，5-Fu固定在恒定的剂量（300mg／m^2 2h内静脉滴注，然后500mg／m^2 22h内静脉滴注，d1，d2）。LV剂量为200mg／m^2静脉滴注2h，d1，d2。L-OHP的用药剂量则逐渐增加，起始剂量组（3例）为45mg／m^2，静脉滴注，d1；组递增剂量为10mg／m^2，如无DLT出现，进入下一剂量组，直至出现DLT；DLT的次一剂量组为MTD。结果DLT为3度放射性直肠炎和3度血液毒性，发生于L-OHP 85mg／m^2组剂量水平；次一剂量L-OHP 75mg／m^2为MTD。主要毒性反应为放射性直肠炎、白细胞减少、厌食和放射性皮炎。结论直肠癌同步放化疗L-OHP联合5-Fu、LV方案中L—OHP的最大耐受剂量为75mg／m^2。

Objectives To determine maximal tolerated dose （MTD） and dose-limiting toxicity （ DLT ） of oxaliplatin （ L-OHP ） when combined with constant dosing of 5-Fu, LV and concurrent radiotherapy in postoperative patients with rectal cancer. Methods A total of 21 patients with stage Ⅱ or Ⅲ rectal adenocareinoma after curative surgery were treated with radiotherapy to a total dose of 50 Gy in 5 weeks. L-OHP was administered at a dosage of 45 mg/m^2 （n = 3） , 55 mg/m^2 （n =3） ,65 mg/m^2 （n = 3） , 75 mg/m^2 （ n = 6） , and 85 mg/m^2 （ n = 6） once a week for 2 weeks （ first cycle） followed by a second cycle after a 14-day break. 5-Fu and LV at a fixed dose of 5-Fu 300 mg/m^2 ivdrip for 2 h, then 500 mg/m^2 ivdrip within 22 h,d1 ,d2 LV 200 mg/m^2 ivdrip 2 h d1 ,d2. DLT was defined as grade Ⅲ or Ⅳ hematologic and nonhematologic toxicity. Results Grade Ⅰ -Ⅲ leukopenia, diarrhea, and nausea/vomiting were the most common toxic side effects, and most were of grade 1-2. DLT was first observed in 2 of 3 patients at 75 mg/ m^2 （ 1 of grade Ⅲ diarrhea and 1 of grade Ⅲ leukopenia）. L-OHP at dosage of 85 mg/m2 caused DLT in 4 of 6 patients （2 of grade Ⅲ leukopenia and 1 of grade Ⅲ diarrhea and 1 of grade Ⅲ diarrhea）. Conclusions Diarrhea was the most common dose-limiting toxicity （DLT）. The maximal tolerated dose （MTD）of L-OHP in this setting was 75 mg/m^2 which was comparable to the maximal tolerated dose of L-OHP seen in the neoadjuvant setting.