Pyrhönen S, Hahka-Kemppinen M, Muhonen T
Department of Radiotherapy and Oncology, Helsinki University Central Hospital, Finland.
J Clin Oncol. 1992 Dec;10(12):1919-26. doi: 10.1200/JCO.1992.10.12.1919.
The goal of this study was to determine the therapeutic efficacy and toxicity of a four-drug chemotherapy regimen combined with natural leukocyte interferon alfa (IFN-alpha) for metastatic melanoma.
Between December 1988 and December 1991, 48 consecutive unselected patients with metastatic melanoma were entered onto this phase II study. Forty-five of these patients were assessable for response and 46 for toxicity. The four-drug chemotherapy regimen was as follows: dacarbazine (DTIC) 200 mg/m2 days 1 to 5, vincristine 1 mg/m2 days 1 and 4, bleomycin 15 mg days 2 and 5 intravenously (IV), and lomustine (CCNU) 80 mg day 1 orally. IFN-alpha, initiated day 8, was administered 3 x 10(6) IU/d, subcutaneously (SC) for 6 weeks, followed by 6 x 10(6) IU three times per week. A small protocol modification was adopted from the 21st patient onwards whenever there was more than 2 months' stabilization or progression with the original protocol: IFN therapy was split into 2-week treatment periods interrupted by a 2-week rest period.
Among the 45 assessable patients, the objective response rate was 62% (95% confidence limit, 48 to 77); six patients (13%) achieved a complete response (CR) and 22 (49%) a partial response (PR). Metastases in such sites as liver also responded favorably (one CR, six PR, one stable disease [SD], two progressive disease [PD]). After splitting IFN therapy for nonresponders, in two patients PD and in another two patients SD changed into regression. Three of the six patients with a CR have suffered a relapse, but the other three have been off treatment for 7, 18, and 31 months without recurrence. Most of the symptomatic patients also experienced rapid relief of symptoms. Overall toxicity of this mainly outpatient regimen seemed to be acceptable. One patient died of a septic fever with grade 4 leukopenia and thrombocytopenia. The most frequent side effects were transient fever, nausea/vomiting, fatigue, and grade I/II hematologic toxicity.
Results demonstrate a remarkably high response rate in combining IFN-alpha and four chemotherapeutic agents. The apparent schedule-dependency of responses must be further explored in a controlled phase III study.
本研究的目的是确定一种四联化疗方案联合天然白细胞干扰素α（IFN-α）治疗转移性黑色素瘤的疗效和毒性。
1988年12月至1991年12月，48例未经选择的转移性黑色素瘤患者连续进入该II期研究。其中45例患者可评估疗效，46例可评估毒性。四联化疗方案如下：达卡巴嗪（DTIC）200mg/m²，第1至5天；长春新碱1mg/m²，第1天和第4天；博来霉素15mg，第2天和第5天静脉注射（IV）；洛莫司汀（CCNU）80mg，第1天口服。IFN-α于第8天开始使用，皮下注射（SC）3×10⁶IU/d，持续6周，随后每周3次，每次6×10⁶IU。从第21例患者开始，每当按照原方案病情稳定或进展超过2个月时，采用一项小的方案修改：IFN治疗分为2周治疗期，中间间隔2周休息期。
在45例可评估患者中，客观缓解率为62%（95%置信区间，48%至77%）；6例患者（13%）达到完全缓解（CR），22例（49%）达到部分缓解（PR）。肝脏等部位的转移灶也有良好反应（1例CR，6例PR，1例疾病稳定[SD]，2例疾病进展[PD]）。对无反应者采用IFN治疗分阶段给药后，2例患者的PD和另外2例患者的SD转变为病情缓解。6例CR患者中有3例复发，但另外3例已停止治疗7、18和31个月，无复发。大多数有症状的患者症状也迅速缓解。这种主要在门诊进行的方案的总体毒性似乎可以接受。1例患者死于伴有4级白细胞减少和血小板减少的败血症发热。最常见的副作用是短暂发热、恶心/呕吐、疲劳和I/II级血液学毒性。
结果表明，IFN-α与四种化疗药物联合使用时缓解率非常高。反应明显的方案依赖性必须在一项对照的III期研究中进一步探索。
