Borden E C, Amato D A, Rosenbaum C, Enterline H T, Shiraki M J, Creech R H, Lerner H J, Carbone P P
J Clin Oncol. 1987 Jun;5(6):840-50. doi: 10.1200/JCO.1987.5.6.840.
This study addressed two major questions regarding therapeutic use of Adriamycin ([Adr] Adria Laboratories, Columbus, OH) in adult soft tissue sarcomas: the influence of dosing schedule and the value of adding imidazole carboxamide (DTIC) to Adr. Patients with objectively measurable metastatic soft tissue sarcomas were randomized to Adr 70 mg/m2 intravenously (IV) day 1 and every 3 weeks (94 patients); Adr 20 mg/m2 IV day 1, 2, and 3, and 15 mg/m2 IV day 8 and weekly thereafter (89 patients); and Adr 60 mg/m2 IV day 1 and DTIC 250 mg/m2 days 1 to 5, repeated every 3 weeks (92 patients). The regimens using Adr as a single agent resulted in an equivalent response frequency (18% and 16%) and survival (median, 8.0 and 8.4 months). DTIC significantly increased (P less than .02) the overall response frequency of Adr to 30%. However, DTIC did not influence survival (median, 8.0 months) or increase the number of complete responses. The toxicities of the two single-agent regimens differed: Adr weekly resulted in more stomatitis (P = .09) and less hematologic toxicity (P less than .05). DTIC resulted in substantially increased toxicity, primarily gastrointestinal (P less than .002); overall, 98% of patients receiving Adr-DTIC experienced moderate or worse toxicity. To decrease the potential for error in interpretation of treatment results, histopathological confirmation of diagnosis was undertaken by a panel of reference pathologists; pathology slides were submitted on 97% of entered patients. The on-study clinical diagnosis was affirmed in 199 of 316 patients (63%) with a final review. In 23% of patients, the panel agreed with the diagnosis of soft tissue sarcoma, but not with the type. In 14%, the panel concluded that a diagnosis of mesenchymal malignancy could not be affirmed. Final treatment results were based on the 275 pathologically confirmed, eligible patients. The most common histological subtype entered was leiomyosarcoma (99 patients). The response to Adr-DTIC of this subtype was higher (44%) than that of any other subtype. However, this difference alone was not responsible for the overall superiority of the combination. This confirmed that the combination of DTIC plus Adr adds to the response rate of Adr alone in soft tissue sarcomas. Whether the increased response frequency, without an impact on survival, is worth the significantly greater toxicity remains a subjective judgement that must be made within the context of the individual patient.
本研究针对阿霉素（[Adr]，阿德里亚实验室，俄亥俄州哥伦布市）在成人软组织肉瘤治疗中的应用提出了两个主要问题：给药方案的影响以及在阿霉素中添加咪唑羧酰胺（DTIC）的价值。将具有客观可测量转移性软组织肉瘤的患者随机分为三组：第1天静脉注射（IV）阿霉素70mg/m²，每3周一次（94例患者）；第1、2、3天静脉注射阿霉素20mg/m²，第8天静脉注射15mg/m²，此后每周一次（89例患者）；第1天静脉注射阿霉素60mg/m²，第1至5天静脉注射DTIC 250mg/m²，每3周重复一次（92例患者）。使用阿霉素单药治疗的方案产生了相当的缓解频率（18%和16%）和生存率（中位数分别为8.0个月和8.4个月）。DTIC显著提高（P<0.02）了阿霉素的总体缓解频率至30%。然而，DTIC并未影响生存率（中位数8.0个月）或增加完全缓解的数量。两种单药治疗方案的毒性不同：每周使用阿霉素导致更多的口腔炎（P = 0.09）和更少的血液学毒性（P<0.05）。DTIC导致毒性大幅增加，主要是胃肠道毒性（P<0.002）；总体而言，接受阿霉素-DTIC治疗的患者中有98%经历了中度或更严重的毒性。为降低治疗结果解释中潜在的误差，由一组参考病理学家进行组织病理学诊断确认；97%的入组患者提交了病理切片。在316例患者中的199例（63%）经过最终复查后，研究中的临床诊断得到确认。在23%的患者中，专家组同意软组织肉瘤的诊断，但不同意其类型。在14%的患者中，专家组得出结论，无法肯定间叶性恶性肿瘤的诊断。最终治疗结果基于275例经病理证实的合格患者。入组的最常见组织学亚型是平滑肌肉瘤（99例患者）。该亚型对阿霉素-DTIC的缓解率（44%）高于任何其他亚型。然而，仅这一差异并不能解释联合治疗的总体优势。这证实了DTIC加阿霉素的联合治疗增加了软组织肉瘤中阿霉素单药的缓解率。增加的缓解频率但未影响生存率，是否值得显著更高的毒性，这仍然是一个必须在个体患者背景下做出的主观判断。
