Kaye Stanley B, Vasey Paul A
Cancer Research Campaign Department of Medical Oncology, The Royal Marsden Hospital, Surrey, UK.
Semin Oncol. 2002 Jun;29(3 Suppl 12):22-7. doi: 10.1053/sonc.2002.34261.
In the mid 1990s, the incorporation of paclitaxel into platinum-based therapy for ovarian cancer marked a significant advance in treatment. Future progress will probably involve reductions in toxicity, which may be achieved by combining the less neurotoxic agent docetaxel with carboplatin. In an international phase III study, 1,077 chemotherapy-naive patients with stage Ic-IV ovarian cancer were randomized to receive carboplatin targeted to an AUC of 5 plus either docetaxel 75 mg/m(2) or paclitaxel 75 mg/m(2) for six cycles. Patients treated with paclitaxel plus carboplatin experienced significantly greater neurotoxicity than those treated with docetaxel plus carboplatin. Docetaxel/carboplatin and paclitaxel/carboplatin produced similar rates of objective response (66% and 62%, respectively), and initial data on progression-free survival indicate that the two treatments appear very similar in efficacy. Thus, docetaxel may prove to be a valid alternative to paclitaxel as part of first-line therapy in ovarian cancer. Nevertheless, there remains considerable scope for improvements in treatment. There is the possibility of using existing drugs more effectively, perhaps by the use of sequential rather than concurrent regimens. This would allow the most active drugs to be used at full dose, increase tolerability, and avoid the possibility of negative drug interaction. The integration of molecularly targeted agents, such as those directed at epidermal growth factor receptors, into existing regimens is highly promising but will need to be explored in randomized trials of first-line therapy. Because the prime obstacle to successful treatment is the acquisition of drug resistance, understanding the underlying mechanisms is an important future priority. One candidate is mismatch repair deficiency; the interest here is that experimental resistance reversal is achievable with hypomethylating agents, raising the possibility of future clinical trials if the clinical relevance of this mechanism can be confirmed.
20世纪90年代中期，将紫杉醇纳入铂类为基础的卵巢癌治疗方案标志着治疗取得了重大进展。未来的进展可能涉及降低毒性，这或许可通过将神经毒性较小的多西他赛与卡铂联合使用来实现。在一项国际III期研究中，1077例未经化疗的Ic-IV期卵巢癌患者被随机分为两组，一组接受目标曲线下面积（AUC）为5的卡铂联合75mg/m²多西他赛，另一组接受75mg/m²紫杉醇，均进行6个周期的治疗。接受紫杉醇联合卡铂治疗的患者比接受多西他赛联合卡铂治疗的患者神经毒性明显更大。多西他赛/卡铂组和紫杉醇/卡铂组的客观缓解率相似（分别为66%和62%），无进展生存期的初步数据表明，两种治疗方法的疗效非常相似。因此，多西他赛可能被证明是卵巢癌一线治疗中紫杉醇的有效替代药物。然而，治疗仍有很大的改进空间。有可能更有效地使用现有药物，或许通过采用序贯而非联合方案。这将使最有效的药物能以全剂量使用，提高耐受性，并避免药物相互作用产生负面影响的可能性。将分子靶向药物，如针对表皮生长因子受体的药物，纳入现有治疗方案很有前景，但需要在一线治疗的随机试验中进行探索。由于成功治疗的主要障碍是获得耐药性，了解其潜在机制是未来的一个重要优先事项。一个候选因素是错配修复缺陷；有意思的是，用去甲基化剂可实现实验性耐药逆转，如果能证实该机制的临床相关性，未来就有可能进行临床试验。
