Atkins Michael B, Gollob Jared A, Sosman Jeffrey A, McDermott David F, Tutin Linda, Sorokin Patricia, Parker Robert A, Mier James W
Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Clin Cancer Res. 2002 Oct;8(10):3075-81.
In an effort to reduce the frequency of central nervous system (CNS) progression in patients with metastatic melanoma with ongoing systemic response to biochemotherapy, we modified our standard concurrent biochemotherapy regimen by replacing dacarbazine (DTIC) with oral temozolomide.
Patients received cisplatin, vinblastine, and temozolomide (20 mg/m(2) cisplatin and 1.2 mg/m(2) vinblastine i.v., days 1-4; 150 mg/m(2) p.o. temozolomide, days 1-4) concurrent with interleukin 2 (9 MIU/m(2)/day) by continuous i.v. infusion on days 1-4 and IFN-alpha (5 MU/m(2)/day) on days 1-5, 8, 10, and 12. Prophylactic antibiotics and a maximum of four cycles were administered. Routine granulocyte-colony stimulating factor and aggressive antiemetics were also provided. Tumor staging included torso computed tomography scans and brain magnetic resonance imaging pretreatment, after cycle 4 and then every 3 months for 2 years. Torso computed tomography scans were also performed after cycle 2.
A total of 147 treatment cycles were administered to 48 patients. No patients had received prior chemotherapy or interleukin 2; however, 19 (40%) had received prior adjuvant IFN-alpha. Significant toxicities included 2 deaths from cardiac events (pericarditis al tamponade and posttreatment myocardial infarction with associated ventricular arrhythmia) and 3 gastrointestinal serious adverse events (pancreatitis, appendicitis, and upper GI bleed). No other nonhematological grade 4 toxicities were observed. Tumor responses were seen in 22 of 47 evaluable patients (relative risk, 47%) with 7 complete responses (15%). Response durations ranged from 1 to 29+ months with 1 currently ongoing. Median survival was 7.5 months. The CNS was the initial site of progression in 2 responding patients. An additional 6 responding patients developed CNS progression within 3 months of systemic progression. Initial CNS progression was significantly less frequent what was seen with the prior DTIC-based biochemotherapy regimen (2 of 22 versus 12 of 19; P = 0.001).
This regimen appears to be active and reasonably well tolerated in patients with metastatic melanoma. Although the substitution of temozolomide for DTIC reduced the incidence of initial CNS progression, this effect did not appear to result in an improved overall outcome.
为降低转移性黑色素瘤患者在对生物化疗有持续全身反应时中枢神经系统（CNS）进展的频率，我们通过用口服替莫唑胺替代达卡巴嗪（DTIC）来修改我们的标准同步生物化疗方案。
患者接受顺铂、长春碱和替莫唑胺（顺铂20mg/m²和长春碱1.2mg/m²静脉注射，第1 - 4天；替莫唑胺150mg/m²口服，第1 - 4天），同时在第1 - 4天通过持续静脉输注给予白细胞介素2（9MIU/m²/天），并在第1 - 5天、8天、10天和12天给予干扰素-α（5MU/m²/天）。给予预防性抗生素，最多进行四个周期。还提供常规的粒细胞集落刺激因子和积极的止吐药。肿瘤分期包括治疗前、第4周期后以及随后2年每3个月进行一次的躯干计算机断层扫描和脑部磁共振成像。在第2周期后也进行躯干计算机断层扫描。
共对48例患者进行了147个治疗周期。没有患者接受过先前的化疗或白细胞介素2；然而，19例（40%）接受过先前的辅助干扰素-α治疗。显著的毒性反应包括2例因心脏事件死亡（心包炎伴心包填塞和治疗后心肌梗死伴相关室性心律失常）和3例胃肠道严重不良事件（胰腺炎、阑尾炎和上消化道出血）。未观察到其他非血液学4级毒性反应。47例可评估患者中有22例出现肿瘤反应（相对风险，47%），其中7例完全缓解（15%）。反应持续时间为1至29 +个月，1例目前仍在进行中。中位生存期为7.5个月。2例有反应的患者中枢神经系统是初始进展部位。另外6例有反应的患者在全身进展后3个月内出现中枢神经系统进展。初始中枢神经系统进展的频率明显低于先前基于DTIC的生物化疗方案（22例中的2例与19例中的12例；P = 0.001）。
该方案在转移性黑色素瘤患者中似乎有活性且耐受性较好。虽然用替莫唑胺替代DTIC降低了初始中枢神经系统进展的发生率，但这种效果似乎并未导致总体结果得到改善。
