Systemic treatments for mesothelioma: standard and novel.
Systemic treatments for mesothelioma: standard and novel.
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DOI：
10.1007/s11864-008-0071-3
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发表时间：
2008-06
影响因子：
4.3
通讯作者：
Kindler, Hedy Lee
中科院分区：
文献类型：
--
作者：
Kindler, Hedy Lee
全身治疗是大多数间皮瘤患者的唯一治疗选择，对于他们来说，年龄，共病医学疾病，非上皮组织学和局部晚期疾病通常排除手术。多年来，化疗对这种癌症的自然史影响甚微，产生了相当大的虚无主义。无数的药物进行了评估，其中大多数达到反应率低于20%，中位生存期<1年。有几个因素阻碍了间皮瘤患者的全身治疗方案的评价。这种疾病并不常见，每年仅影响约2500名美国人。因此，大多数临床试验规模较小，随机研究具有挑战性。由于几个原因，这些小型试验的患者人群中存在显著的异质性。由于所有的间皮瘤分期系统是基于手术，这是几乎不可能准确地确定谁没有被切除的病人的阶段。在同一项研究中，极早期疾病患者可能与更晚期的患者集中在一起。这种疾病本身是异质性的，有许多不同的预后因素，最明显的是三种病理亚型上皮型、肉瘤样型和双相型，它们有不同的自然病程，对治疗的反应也各不相同。最后，反应评估是有问题的，因为胸膜病变难以准确和可重复地测量。评估标准在不同试验之间往往不同，使得一些交叉试验比较难以解释。尽管有这些局限性，近年来，对这种疾病的系统治疗的乐观情绪激增。几种细胞毒性药物已被证明可以产生可重复的反应，改善生活质量，或延长间皮瘤的生存期。具有单药活性的药物包括培美曲塞、雷替曲塞、长春瑞滨和长春氟宁。顺铂联合培美曲塞或雷替曲塞治疗可延长生存期。在培美曲塞、雷替曲塞、吉西他滨、伊立替康或长春瑞滨基础上加用顺铂可提高缓解率。培美曲塞联合顺铂被认为是该疾病的基准一线治疗方案，基于在456例患者中进行的III期试验，该试验的缓解率为41%，中位生存期为12.1个月。维生素补充叶酸是必不可少的，以减少毒性，虽然最近的数据表明，可能有一个最佳剂量的叶酸，应管理;更高的剂量可能会降低培美曲塞的有效性。关于培美曲塞治疗的持续时间和时间，还有几个尚未解决的问题，这些问题是计划进行的临床试验的主题。必须认识到，培美曲塞/顺铂联合治疗观察到的改善虽然是真实的，但仍然是适度的。其他活性药物或药物组合可能更适合特定个体，仍需要进一步研究以改善这些结果。由于美国的大多数间皮瘤发生在老年人中，因此不含顺铂的培美曲塞组合可能更适合某些患者。现在已经开发出有效的药物用于初始治疗，一些经典的细胞毒性药物和许多新的药物正在二线环境中进行评估。这些包括靶向表皮生长因子、血小板衍生生长因子、血管内皮生长因子、src激酶、组蛋白脱乙酰酶、蛋白酶体和间皮素的药物。鉴于近年来取得的进展，有理由相信将继续开发更有效的治疗方法。
Systemic therapy is the only treatment option for the majority of mesothelioma patients, for whom age, co-morbid medical illnesses, non-epithelial histology, and locally advanced disease often preclude surgery. For many years, chemotherapy had a minimal impact on the natural history of this cancer, engendering considerable nihilism. Countless drugs were evaluated, most of which achieved response rates below 20% and median survival of <1 year. Several factors have hampered the evaluation of systemic regimens in patients with mesothelioma. The disease is uncommon, affecting only about 2500 Americans annually. Thus, most clinical trials are small, and randomized studies are challenging to accrue. There is significant heterogeneity within the patient populations of these small trials, for several reasons. Since all of the staging systems for mesothelioma are surgically based, it is almost impossible to accurately determine the stage of a patient who has not been resected. Patients with very early stage disease may be lumped together with far more advanced patients in the same study. The disease itself is heterogenous, with many different prognostic factors, most notably three pathologic subtypes—epithelial, sarcomatoid, and biphasic—that have different natural histories, and varying responses to treatment. Finally, response assessment is problematic, since pleural-based lesions are difficult to measure accurately and reproducibly. Assessment criteria often vary between trials, making some cross-trial comparisons difficult to interpret. Despite these limitations, in recent years, there has been a surge of optimism regarding systemic treatment of this disease. Several cytotoxic agents have been shown to generate reproducible responses, improve quality of life, or prolong survival in mesothelioma. Drugs with single-agent activity include pemetrexed, raltitrexed, vinorelbine, and vinflunine. The addition of pemetrexed or raltitrexed to cisplatin prolongs survival. The addition of cisplatin to pemetrexed, raltitrexed, gemcitabine, irinotecan, or vinorelbine improves response rate. The combination of pemetrexed plus cisplatin is considered the benchmark front-line regimen for this disease, based on a phase III trial in 456 patients that yielded a response rate of 41% and a median survival of 12.1 months. Vitamin supplementation with folic acid is essential to decrease toxicity, though recent data suggests that there may be an optimum dose of folic acid that should be administered; higher doses may diminish the effectiveness of pemetrexed. There are also several unresolved questions about the duration and timing of treatment with pemetrexed that are the subject of planned clinical trials. It is essential to recognize that the improvements observed with the pemetrexed/cisplatin combination, though real, are still modest. Other active drugs or drug combinations may be more appropriate for specific individuals, and further research is still needed to improve upon these results. Since the majority of mesotheliomas in the United States occur in the elderly, non-cisplatin-containing pemetrexed combinations may be more appropriate for some patients. Now that effective agents have been developed for initial treatment, several classical cytotoxic drugs and many novel agents are being evaluated in the second-line setting. These include drugs targeted against the epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor, src kinase, histone deacetylase, the proteasome, and mesothelin. Given the progress made in recent years, there is reason to believe that more effective treatments will continue to be developed.
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影响因子：
50.5
作者：
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通讯作者：
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影响因子：
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作者：
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作者：
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通讯作者：
Edwards, Brenda K.
影响因子：
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作者：
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通讯作者：
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