Chau W K, Lin C K, Chow M P, Wang S Y, Liu J M, Ho C H, Chiu C F, Hsu H C, Tan T D, Chan W K
Department of Medicine, Veterans General Hospital-Taipei, Taiwan, R.O.C.
Zhonghua Yi Xue Za Zhi (Taipei). 1994 Nov;54(5):312-20.
Sequential cycles of combination chemotherapy with high-dose cyclophosphamide, etoposide and cisplatin (sHDCEP) can largely increase the total dose (TD) of drug delivered. If granulocyte colony-stimulating factor (G-CSF) and/or autologous peripheral blood stem cell (PBSC) rescue can shorten the duration of cytopenia between cycles of sHDCEP, the dose intensity (DI) can be increased as well. In order to explore the feasibility of delivering maximal TD and DI by administration of sHDCEP with G-CSF and/or PBSC rescue, this trial is undertaken to investigate the hematologic and nonhematologic toxicity observed with sHDCEP by G-CSF and/or PBSC rescue.
Patients with refractory malignancy and well preserved physiologic function for whom no available therapy is likely to cure or prolong the survival were eligible for the study. Each cycle of high-dose chemotherapy consisted of: cyclophosphamide 5,000 mg/m2, etoposide 1,500 mg/m2 and cisplatin 150 mg/m2. G-CSF and/or PBSC were administered alternatively after each cycle as rescue for myelosuppression. The next cycle was given to patient who showed response to the previous cycle after recovery from toxicity for a maximal of 4 cycles.
Two cases of refractory malignancy with progressive disease were treated by sHDCEP for 7 cycles, including 4 cycles with G-CSF rescue, 2 cycle with PBSC rescue, and 1 cycle with G-CSF + PBSC rescue. In the 4 cycles rescued by G-CSF alone, we observed a slightly slower granulocyte and markedly prolonged platelet recovery in the subsequent cycle. By comparing the effect of G-CSF and/or PBSC rescue on hematologic recovery with the preceding cycle in the same patient, we found that G-CSF rescue provided faster granulocyte recovery than PBSC, but PBSC rescue provided faster platelet recovery than G-CSF. Rescue by larger number of PBSCs provided only faster platelet but not granulocyte recovery than rescue by adding G-CSF to a very small number of PBSCs. However, G-CSF plus the very small number of PBSCs provided shorter duration of both granulocytopenia and thrombocytopenia than rescue by G-CSF alone. The most common nonhematologic toxicity from sHDCEP included transient nausea, vomiting, diarrhea and mild impairment of liver function but we observed no significant or irreversible major organ damage. The side effect from PBSC collection was mild and toxicity from reinfusion of the thawed PBSCs was not obvious. Using G-CSF and/or PBSC rescue, sHDCEP was delivered repeatedly in no more than 4 weeks for the next-cycles except for patient 1 who had cycle 4 delayed because of prolonged platelet recovery by only G-CSF rescue in cycle 3.
Our initial experience has shown that the nonhematologic toxicity from sHDCEP, G-CSF and PBSC rescue was well tolerated. Prolonged platelet recovery after sequential cycles of HDCEP by only G-CSF rescue delayed the next cycle of chemotherapy. Although the next cycle was delivered within 4 weeks by only PBSC rescue, concurrent infusion of G-CSF and larger number of PBSCs should provide the most rapid hematologic recovery. Sequential high-dose chemotherapy administered by this model is likely to provide the maximal delivery of TD and DI, and is worthy of further clinical trials.
高剂量环磷酰胺、依托泊苷和顺铂联合化疗（sHDCEP）的序贯周期可大幅增加给药的总剂量（TD）。如果粒细胞集落刺激因子（G-CSF）和/或自体外周血干细胞（PBSC）救援能缩短sHDCEP周期之间的血细胞减少持续时间，剂量强度（DI）也可提高。为了探索通过G-CSF和/或PBSC救援给予最大TD和DI的可行性，本试验旨在研究G-CSF和/或PBSC救援下sHDCEP观察到的血液学和非血液学毒性。
难治性恶性肿瘤且生理功能保存良好、现有治疗方法不太可能治愈或延长生存期的患者符合研究条件。每个高剂量化疗周期包括：环磷酰胺5000mg/m²、依托泊苷1500mg/m²和顺铂150mg/m²。每个周期后交替给予G-CSF和/或PBSC以救援骨髓抑制。对前一周期毒性恢复后显示有反应的患者给予下一周期，最多4个周期。
2例难治性恶性肿瘤伴疾病进展患者接受sHDCEP治疗7个周期，其中4个周期采用G-CSF救援，2个周期采用PBSC救援，1个周期采用G-CSF+PBSC救援。在仅由G-CSF救援的4个周期中，我们观察到随后周期中粒细胞恢复稍慢，血小板恢复明显延长。通过比较同一患者中G-CSF和/或PBSC救援对血液学恢复与前一周期的效果，我们发现G-CSF救援比PBSC能更快地使粒细胞恢复，但PBSC救援比G-CSF能更快地使血小板恢复。与在极少量PBSC中添加G-CSF进行救援相比，大量PBSC进行救援仅能使血小板恢复更快，而不能使粒细胞恢复更快。然而，G-CSF加极少量PBSC比仅用G-CSF救援能使粒细胞减少和血小板减少的持续时间更短。sHDCEP最常见的非血液学毒性包括短暂性恶心、呕吐、腹泻和轻度肝功能损害，但我们未观察到明显或不可逆的主要器官损伤。PBSC采集的副作用轻微，解冻的PBSC回输的毒性不明显。除患者1因第3周期仅G-CSF救援导致血小板恢复延长而使第4周期延迟外，使用G-CSF和/或PBSC救援，后续周期的sHDCEP在不超过4周内重复给药。
我们的初步经验表明，sHDCEP、G-CSF和PBSC救援的非血液学毒性耐受性良好。仅G-CSF救援在HDCEP序贯周期后血小板恢复延长会延迟下一周期化疗。虽然仅PBSC救援能在4周内给予下一周期，但同时输注G-CSF和大量PBSC应能实现最快的血液学恢复。通过该模型进行的序贯高剂量化疗可能实现最大的TD和DI给药，值得进一步进行临床试验。
