Issels R D, Mittermüller J, Gerl A, Simon W, Ortmaier A, Denzlinger C, Sauer H, Wilmanns W
Institut für Klinische Hämatologie, University of Munich, Federal Republic of Germany.
J Cancer Res Clin Oncol. 1991;117 Suppl 4:S141-7. doi: 10.1007/BF01613220.
From July 1986 to 1990, 65 patients with deep-seated, advanced sarcomas (43 soft-tissue sarcomas, 12 Ewing's sarcomas, 7 chondrosarcomas and 3 osteosarcomas) were entered in a protocol involving regional hyperthermia (RHT) combined with systemic ifosfamide and etoposide. RHT was produced by an electromagnetic deep regional heating device (BSD Medical Corporation, Salt Lake City, Utah). Of these patients, 62% (40 patients) had received ifosfamide-containing drug regimens before entering the RHT study, 26% (17 patients) were pretreated by surgery and/or radiation and 12% (8 patients) were treated primarily. A total of 426 RHT treatments (mean 6.6 RHT/patient) were applied predominantly within the pelvic region (82%) bearing relative large tumours (mean volume 500 cm3). For systemic chemotherapy, all patients received ifosfamide (1.5 g/m2, days 1-5), etoposide (100 mg/m2, days 1, 3, 5) and 2-mercaptoethanesulphonic acid (mesna; 300 mg/m2 x 4, days 1-5) with RHT only given on days 1 and 5 in repeated cycles every 4 weeks. Detailed thermal mapping by invasive thermometry was performed in all patients. In 61 patients evaluable for tumour control the overall objective response rate including 9 complete responders (CR), 4 partial responders (PR) and 8 patients with favourable histological response (FHR) was 34% (95% confidence limits, 23%-46%). Following CR, the patients are alive and remain disease-free (mean disease-free survival 15.6 months). Of the patients with PR and FHR, 3 died from metastatic and/or local disease after 4, 17, and 39 months, and 1 patient died from other disease (acute myelocytic leukemia) after 27 months. The other 8 patients remain stable at 29, 25, 17, 11, 10, 8, 7, and 6 months. Twenty-two patients revealed no change and 18 patients showed local tumour progression (PD). Side-effects of RHT were tolerable and there was no indication of enhanced bone marrow toxicity due to the addition of RHT to the systemic chemotherapy. By analysis of temperature parameters, the time-averaged temperatures of all RHT treatments calculated for 20% (T20), 50% (T50) or 90% (T90) of measured tumour sites differed significantly between responders (CR + PR + FHR) and non-responders (PD), respectively (T20, P = 0.001; T50, P = 0.0005; T90, P = 0.0001). the data further support a strong potential for ifosfamide plus etoposide combined with RHT in pretreated patients with advanced sarcomas.
1986年7月至1990年，65例深部晚期肉瘤患者（43例软组织肉瘤、12例尤因肉瘤、7例软骨肉瘤和3例骨肉瘤）进入一项涉及区域热疗（RHT）联合全身应用异环磷酰胺和依托泊苷的方案。RHT由电磁深部区域加热装置（犹他州盐湖城BSD医疗公司）产生。这些患者中，62%（40例）在进入RHT研究前接受过含异环磷酰胺的药物方案治疗，26%（17例）接受过手术和/或放疗预处理，12%（8例）为初治患者。共进行了426次RHT治疗（平均每位患者6.6次RHT），主要应用于盆腔区域（82%），这些区域存在相对较大的肿瘤（平均体积500 cm³）。对于全身化疗，所有患者均接受异环磷酰胺（1.5 g/m²，第1 - 5天）、依托泊苷（100 mg/m²，第1、3、5天）和2 - 巯基乙烷磺酸（美司钠；300 mg/m²×4，第1 - 5天），RHT仅在第1天和第5天给予，每4周重复一个周期。对所有患者进行了有创温度测量的详细热图绘制。在61例可评估肿瘤控制情况的患者中，总体客观缓解率包括9例完全缓解者（CR）、4例部分缓解者（PR）和8例组织学反应良好者（FHR），为34%（95%置信区间，23% - 46%）。CR后，患者存活且无疾病复发（平均无病生存期15.6个月）。在PR和FHR患者中，3例分别在4、17和39个月后死于转移和/或局部疾病，1例在27个月后死于其他疾病（急性髓细胞白血病）。其他8例患者在29、25、17、11、10、8、7和6个月时病情保持稳定。22例患者病情无变化，18例患者出现局部肿瘤进展（PD）。RHT的副作用可耐受，且没有迹象表明在全身化疗基础上加用RHT会增强骨髓毒性。通过对温度参数的分析，分别计算所有RHT治疗中测量肿瘤部位的20%（T20）、50%（T50）或90%（T90）的时间平均温度，缓解者（CR + PR + FHR）和未缓解者（PD）之间存在显著差异（T20，P = 0.001；T50，P = 0.0005；T90，P = 0.0001）。这些数据进一步支持了异环磷酰胺加依托泊苷联合RHT在预处理的晚期肉瘤患者中具有强大的潜力。
