Lebwohl D E, Canetta R
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, USA.
Ann Oncol. 1999;10 Suppl 6:139-46.
Anthracyclines and taxanes are the two most active classes of chemotherapy for the treatment of advanced breast cancer. Recent studies have investigated combination therapy including doxorubicin (Dox) and paclitaxel. The efficacy of this combination has been established in a phase III study conducted by ECOG, comparing Dox/paclitaxel versus Dox versus paclitaxel. The combination is superior to Dox or paclitaxel with respect to response rate and time to disease progression, indicating that the combination provides a new standard for the first line treatment of metastatic breast cancer [1]. Phase II studies using higher doses of Dox and using shorter infusions of paclitaxel have suggested the combination can be further optimized; Gianni reported a 94% objective response rate using Dox 60 mg/m2 followed by paclitaxel 175 mg/m2 given over three hours [2]. The more active regimens are associated with enhanced cardiotoxicity; this toxicity can be avoided, however, by limiting the exposure to doxorubicin. The newer regimens have now been moved into phase III studies. Future progress for this disease will depend on the introduction of new agents. Two novel drugs are currently being investigated in randomised phase III trials as potentiators of Dox and/or paclitaxel. One is a monoclonal antibody from Genentech (Herceptin, trastuzumab) directed at the HER-2/neu oncogene, which is overexpressed in > 25% of breast cancers [3]. Recent results indicate that Herceptin in combination with paclitaxel (or with a Dox plus cyclophosphamide regimen) induces a higher response rate (RR) and prolongs the time to disease progression when compared to chemotherapy alone. The second agent N,N-diethyl-2[4-(phenylmethyl)-phenoxy] ethanamine.HCl (DPPE, BMS-217380-01), when combined with Dox, was associated with a higher RR than previously observed with Dox alone [4]. A randomized trial of Dox versus Dox plus DPPE is ongoing. The possible mechanisms underlying chemo-potentiation by these agents are discussed. As new anthracycline/taxane combinations establish themselves in earlier stages of the disease, the need for effective, non-cross resistant salvage regimens will emerge.
蒽环类药物和紫杉烷类药物是治疗晚期乳腺癌最有效的两类化疗药物。最近的研究探讨了包括阿霉素（Dox）和紫杉醇在内的联合治疗。这种联合治疗的疗效已在东部肿瘤协作组（ECOG）进行的一项III期研究中得到证实，该研究比较了阿霉素/紫杉醇与阿霉素与紫杉醇单用的疗效。在缓解率和疾病进展时间方面，联合治疗优于阿霉素或紫杉醇，这表明该联合治疗为转移性乳腺癌的一线治疗提供了新的标准[1]。使用更高剂量阿霉素和更短时间输注紫杉醇的II期研究表明，该联合治疗可以进一步优化；詹尼报告称，使用60mg/m²阿霉素，随后在三小时内输注175mg/m²紫杉醇，客观缓解率达94%[2]。活性更强的治疗方案与心脏毒性增加有关；然而，通过限制阿霉素的暴露量，可以避免这种毒性。目前，这些更新的治疗方案已进入III期研究。该疾病未来的进展将取决于新药物的引入。目前，两种新型药物正在随机III期试验中作为阿霉素和/或紫杉醇的增效剂进行研究。一种是基因泰克公司的单克隆抗体（赫赛汀，曲妥珠单抗），它针对HER-2/neu癌基因，该基因在超过25%的乳腺癌中过度表达[3]。最近的结果表明，与单纯化疗相比，赫赛汀联合紫杉醇（或与阿霉素加环磷酰胺方案联合）可诱导更高的缓解率（RR），并延长疾病进展时间。第二种药物N,N-二乙基-2-[4-(苯甲基)-苯氧基]乙胺·盐酸盐（DPPE，BMS-217380-01）与阿霉素联合使用时，缓解率高于之前单独使用阿霉素时的观察结果[4]。一项关于阿霉素与阿霉素加DPPE的随机试验正在进行。讨论了这些药物化疗增效的可能机制。随着新的蒽环类/紫杉烷类联合治疗方案在疾病早期确立其地位，将出现对有效、无交叉耐药的挽救方案的需求。
