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转移性非精原细胞瘤性睾丸生殖细胞肿瘤化疗的当前趋势

Current trends in chemotherapy for metastatic nonseminomatous testicular germ cell tumors.

作者信息

Bokemeyer C

机构信息

Eberhard-Karls-Universität Tübingen, Medizinische Klinik und Poliklinik, Deutschland.

出版信息

Oncology. 1998 May-Jun;55(3):177-88. doi: 10.1159/000011854.

Abstract

With the introduction of cisplatin-based chemotherapy, metastatic testicular cancer represents a model for a highly curable malignant disease. Approximately 70-80% of patients achieve a durable remission following chemotherapy +/- secondary surgery of residual tumors. With the development of prognostic classifications based on clinically available parameters, the aims of chemotherapy have been twofold: on the one hand, the reduction of toxicity in patients with 'low-risk' metastatic disease without a concomitant reduction in treatment efficacy and, on the other hand, the improvement of treatment results in patients with 'poor-prognosis' criteria who achieve a long-term cure rate of less than 50% with standard chemotherapy regimens. Despite a number of large randomized studies attempting either to avoid the toxicity of bleomycin or to reduce cisplatin-associated side-effects through the substitution with carboplatin, the combination of cisplatin, etoposide and bleomycin (PEB) given at 3-week intervals still remains the standard treatment for metastatic disease. The role of high-dose chemotherapy with autologous stem cell support is currently being investigated in order to improve the outcome of patients with relapse after previous chemotherapy and of patients initially exhibiting advanced metastatic disease. For patients with relapsed disease receiving high-dose chemotherapy, a prognostic score has recently been developed: cisplatin-refractory disease, beta human gonadotropin values > 1,000 U/l or primary mediastinal germ cell tumors are factors characterizing patients which will profit less from high-dose chemotherapy treatment than patients with chemosensitive disease at relapse. Standard dose salvage regimens only result in a 20% long-term survival rate. In contrast, high-dose salvage chemotherapy may yield a cure rate of approximately 40%. However, the only randomized study comparing high-dose versus conventional-dose therapy in patients with relapsed disease is still ongoing. The investigation of dose-intensive approaches as first-line treatment is currently being studied by several institutions. Despite preliminary favorable results, this approach still cannot be considered standard treatment. A randomized study comparing high-dose chemotherapy with 4 cycles of standard PEB was initiated in the USA in 1996. The evaluation of new drugs in testicular cancer patients with absolute cisplatin-refractory disease has demonstrated that paclitaxel is one of the few agents with antitumor activity in these patients. Paclitaxel has therefore been included in combination regimens--such as cisplatin, ifosfamide and paclitaxel--for the treatment of patients with first and second relapse of testicular cancer. These combinations are used as induction therapy prior to high-dose salvage treatment. Due to the large group of patients with metastatic disease being cured nowadays, the long-term side effects of treatment have become even more important. One of the major risk factors for the development of late toxicities such as oto-, neuro-, nephro-, gonadal and cardiovascular toxicity is the cumulative dose of cisplatin applied during therapy. The development of new treatment strategies, such as the use of adjuvant chemotherapy for stage I disease, the widespread application of high-dose chemotherapy with peripheral stem cell rescue and the use of new cytotoxic agents, makes the evaluation of the late effects of treatment for testicular cancer within controlled clinical trials mandatory.

摘要

随着基于顺铂的化疗方法的引入,转移性睾丸癌成为一种可高度治愈的恶性疾病的典范。大约70 - 80%的患者在化疗及对残留肿瘤进行辅助手术后可实现持久缓解。随着基于临床可用参数的预后分类的发展,化疗的目标有两个:一方面,在不降低治疗效果的情况下降低“低风险”转移性疾病患者的毒性;另一方面,改善符合“预后不良”标准的患者的治疗结果,这些患者采用标准化疗方案的长期治愈率低于50%。尽管有多项大型随机研究试图避免博来霉素的毒性或通过用卡铂替代来减少顺铂相关的副作用,但每3周给药一次的顺铂、依托泊苷和博来霉素(PEB)联合方案仍然是转移性疾病的标准治疗方法。目前正在研究高剂量化疗联合自体干细胞支持的作用,以改善先前化疗后复发的患者以及最初表现为晚期转移性疾病的患者的治疗结果。对于接受高剂量化疗的复发疾病患者,最近制定了一个预后评分:顺铂难治性疾病、β人绒毛膜促性腺激素值>1000 U/l或原发性纵隔生殖细胞肿瘤是患者的特征因素,与复发时对化疗敏感的患者相比,这些患者从高剂量化疗治疗中获益较少。标准剂量挽救方案的长期生存率仅为20%。相比之下,高剂量挽救化疗的治愈率可能约为40%。然而,唯一一项比较复发疾病患者高剂量与传统剂量治疗的随机研究仍在进行中。几个机构目前正在研究将剂量密集方法作为一线治疗。尽管有初步的良好结果,但这种方法仍不能被视为标准治疗。1996年在美国启动了一项比较高剂量化疗与4个周期标准PEB的随机研究。对绝对顺铂难治性疾病的睾丸癌患者使用新药的评估表明,紫杉醇是少数对这些患者具有抗肿瘤活性的药物之一。因此,紫杉醇已被纳入联合方案——如顺铂、异环磷酰胺和紫杉醇——用于治疗睾丸癌首次和第二次复发的患者。这些联合方案在高剂量挽救治疗前用作诱导治疗。由于如今大量转移性疾病患者被治愈,治疗的长期副作用变得更加重要。发生耳毒性、神经毒性、肾毒性、性腺毒性和心血管毒性等晚期毒性的主要危险因素之一是治疗期间应用的顺铂累积剂量。新治疗策略的发展,如对I期疾病使用辅助化疗、广泛应用高剂量化疗联合外周干细胞救援以及使用新的细胞毒性药物使得在对照临床试验中评估睾丸癌治疗的晚期影响成为必要。

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