非小细胞肺癌脑转治疗方法荟萃（更新于2011年11月9日）

老马 · 发表于 2013-11-1 12:11:41

本帖最后由老马于 2013-11-1 12:13 编辑

中国急性缺血性脑卒中诊治指南2010.pdf (241.75 KB, 下载次数: 53)

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老马 · 发表于 2013-11-1 12:14:37

依达拉奉是一种脑保护剂（自由基清除剂）。临床研究提示N-乙酰门冬氨酸（NAA）是特异性的存活神经细胞的标志，脑梗塞发病初期含量急剧减少。脑梗塞急性期患者给予依达拉奉，可抑制梗塞周围局部脑血流量的减少，使发病后第28天脑中NAA含量较甘油对照组明显升高。临床前研究提示，大鼠在缺血/缺血再灌注后静脉给予依达拉奉，可阻止脑水肿和脑梗塞的进展，并缓解所伴随的神经症状，抑制迟发性神经元死亡。机理研究提示，依达拉奉可清除自由基，抑制脂质过氧化，从而抑制脑细胞、血管内皮细胞、神经细胞的氧化损伤。
依达拉奉.jpg

老马 · 发表于 2013-11-2 01:31:22

【中文品名】甘磷酸胆碱
　　【通用药名】CHOLINE ALFOSCERATE
　　【别名】Brezal, Choline alphoscerate, Delecit, Gliatilin, L-α-Glycerophosphorylcholine
　　【化学名称】Ethanaminium 2-[[[(2R)-2,3-dihydroxypropoxy]hydroxyphosphinyl]oxy]-N,N,N-trimethyl-, innersalt
　　【CA登记号】28319-77-9
　　【结构式】
　　【分子式】C8H20NO6P
　　【分子量】257.22
　　【首次上市】1990年，意大利
　　1.2上市剂型及规格
　　针剂、胶囊、口服液
　　1.3类别：保肝药，镇吐药，益智药
　　1.4适应症
　　脑内神经组织退化综合症或者继发性大脑供血不足，具体表现为原生性认知障碍或者老年继发性特性的记忆缺损、定向力混乱和消失、主动性和积极性下降以及注意力无法集中，也包括老年情绪和行为反常，譬如：情绪不稳定，易怒，对周围环境变化反应冷淡，老年假性抑郁症。还可用于保肝、镇吐。
　　用法用量
　　肌肉注射和静脉滴注均为每天一支。医生建议应缓慢注射。
　　甘油磷酰胆碱可称得上是胆碱中的“运输者”以及磷酸盐胆碱中的“急先锋”。它具有对于各种生化病变进行预防和治疗的潜在能力。人们从引发神经组织衰退综合症的各种因素中发现它具有减少身体紧张性和改变神经元膜中磷酸盐类脂化合物结构的奇特作用。阿尔佛雪拉特胆碱的化学结构(含有40,5%胆碱)以及相互联系的物理化学特性，保证了它成为一种对脑组织非常有益的、能随时保护脑组织新陈代谢的物质。临床前的药理学试验的结果和临床研究都已经证实了阿尔佛雪拉特胆碱对大脑的认知和记忆功能不无裨益，尤其是对于因大脑衰退疾病引起的情感和行为障碍大有帮助。
　　国内外上市情况：
　　该品种1990年在意大利上市,由LPBIstitutoFarmaceutico公司开发，并随后在波兰、韩国、俄罗斯、希腊上市：
　　LPB公司(Novartis/Italfarmaco)开发成为一种促智能药(Company communication，Italfarmaco，Jun 1993)。该药物对衰老性记忆力减退有效。它是作为大脑皮层神经元中乙酰胆碱和神经元膜中磷脂的前体物质而起作用的(Company communication，Italfarmaco，Mar 1992)。该药品在意大利(1990年)由LPB公司上市，商品名为Delecit。在意大利，同时还由Novartis公司和Italfarmaco公司经销，商品名分别为Brezal和Gliatilin。在波兰该药品由Italfarmaco公司上市(1993年)，商品名为Gliatilin；在阿根廷由Montpellier公司上市(1995年)，商品名为Gliatilin；在韩国由Dong Wha公司上市(1996年，商品名为Gliatilin)；在俄罗斯的上市公司则是Italfarmaco公司(1997年)(Company communications，Italfarmaco，Jun 1993＆Mar 1997＆Dong Wha，Feb 1997)。在智利和巴西该产品的许可权分别转让给了Silesia公司和Eurofarma公司(Company communication，Italfarmaco，Mar 1997)。在德国该产品已经获得注册，在捷克共和国、斯洛伐克、墨西哥和其他一些国家还在等待注册(Company communications，Halfarmaco，Feb 1993＆Jan 1997＆Dong Wha，Jan 1997)。在比利时和荷兰处于临床前阶段。
　　抗痴呆药物的研究和开发已引起世界各国医药界的高度重视，近年来，随着对老年神经生理、生化、药理等方面研究的不断深入，导致相关药物的开发研究不断取得进展。现在对老年性痴呆症尚无有效的治疗方法，目前就中国市场上最常见的抗痴呆症药物主要有：吡拉西坦(脑复康)、长春西汀(卡兰)、甲氯酚酯(遗尿丁)、艾地苯酮、茴拉西坦、奥拉西坦等数十个品种,奥拉西坦为吡拉西坦的更新换代品种。
　　在一项对55-65岁男性老年器质性脑综合征患者进行的为期12周的随机的同剂量甘油磷酰胆碱和奥拉西坦疗效的比较研究中，表明两者都有很好的耐受性，无病人因不良反应而出现停止治疗的现象。奥拉西坦在维持治疗中疗效起效快，但随着治疗的停止药效快速的衰退；甘油磷酰胆碱起效慢，但疗效更持久，停止治疗8周后与8周治疗期间的临床疗效一致。从国外多年的临床疗效来看，甘油磷酰胆碱在治疗颅脑损伤及老年痴呆方面都有很好的疗效，且副作用小。

Gliatilin soft cap.400mg(Choline alfoscerate) (甘磷酸胆碱)(保肝药、镇吐药、与年龄有关的记忆衰退有关)一日3次,一次1片

利利 · 发表于 2013-11-2 18:35:36

老马大哥，请问替吉奥对非小细胞腺癌作用大不？我爸开始第三个月易瑞沙，但高烧不退有肺炎有积液，转移灶增多，怎么办呢？谢谢您啦。

老马 · 发表于 2013-11-4 14:40:35

Pulsatile High-dose Tarceva (erlotinib)

In a recent, small study on the efficacy of pulsatile high-dose Tarceva (median dose: 1500 mg once weekly) in nine patients with EGFR mutations and disease progression while on standard-dose Tarceva treatment, partial brain metastasis response was obtained in six out of nine patients (67%) with a median time to CNS progression of 2.7 months and an OS of 12 months (1).

The rationale for this study was derived from a previous report in which Clarke et al. demonstrated that a pulsatile Tarceva regimen was effective against leptomeningeal metastases in a patient with EGFR mutation who progressed during standard Tarceva treatment (2).

The Tarceva concentration required to inhibit the growth of EGFR-mutated cells by 50% is 100 nM. The standard dose of 150 mg allows a plasma concentration of 3000 nM of erlotinib, while the concentration reached in the cerebrospinal fluid is less than 1% of the plasma level, which is not sufficient to achieve an anti-tumoral effect against CNS metastases (3).

The administration of a high dose (e.g., 1500 mg) once a week is generally well tolerated and allows a concentration of 130 nM Tarceva to be reached in the cerebrospinal fluid (4). Further prospective studies are therefore required to confirm the efficacy of high-dose pulsatile Tarceva in the treatment of brain metastasis from NSCLC.

1. Grommes C, Oxnard GR, Kris MG et al. 'Pulsatile' high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. 13(12), 1364–1369(2011).

2. Clarke JL, Pao W, Wu N, Miller VA, Lassman AB. High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J. Neurooncol. 99(2), 283–286(2010).

3. Jackman DM, Holmes AJ, Lindeman N et al. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. J. Clin. Oncol. 24(27), 4517–4520(2006).

4. Milton DT, Azzoli CG, Heelan RT et al. A Phase I/II study of weekly high-dose erlotinib in previously treated patients with nonsmall cell lung cancer. Cancer 107(5), 1034–1041(2006).
http://cancerfocus.net/forum/archive/index.php?t-3066.html

老马 · 发表于 2013-11-4 14:45:18

EGFR mutation status and survival after diagnosis of brain metastasis NSCLC.PDF (104.81 KB, 下载次数: 62)

老马 · 发表于 2013-11-14 02:49:53

Temozolomide (Temodar) for Brain Metastases
http://cancergrace.org/cancer-tr ... dar-for-brain-mets/
Historically, chemotherapy has had a relatively minor role in the management of brain metastases. Although there is a rather low response rate in the brain from some standard lung cancer chemo regimens, we generally conclude that most of our chemo can’t be too effective in the brain because of the blood-brain barrier (BBB) that is relatively impermeable to the majority of our commonly used chemo agents (there is some debate about whether the metastases disrupt that barrier and can allow other chemo agents to get into the brain, but that’s still a murky issue). However, some of the drugs that are routinely used to treat primary brain tumors (cancers that start in the brain tissue) can get through the BBB and reach significant concentrations that can effectively fight cancer. One of the agents that has been shown to be valuable in treating primary brain tumors is temozolomide, or Temodar, an oral chemotherapy drug that is given with radiation to the brain and also on its own off of radiation. Because it’s been shown to improve survival for patients with tumors that start in the brain, and is also helpful for patients with metastatic melanomas, it’s also been an agent that has been the focus of research questioning whether it can improve results when added to radiation, or potentially on its own, in patients with brain metastases from solid tumors like lung cancer.

While there haven’t been enough studies of temodar in the treatment of brain metastases to establish a role for it in this setting, the limited studies that have been done have looked encouraging. On its own, if given without whole brain radiation therapy (WBRT), the studies that have been done (abstracts here and here and here, for example) have included a few dozen patients, most or all on these studies having previously received WBRT, and have shown partial response rates (brain metastasis shrinkage) in the single digits, no complete responses, but sometimes with up to about half the patients with stable disease in the brain for several months (although it’s hard to know what to expect in terms of progression in the brain after WBRT). Importantly, it’s reaching for a pretty high bar to be looking for responses of heavily treated patients who have undergone WBRT for brain metastases and are now progressing. The main side effects of temodar were decreased blood counts, some liver test abnormalities, and sometimes nausea and fatigue.

Temodar has also been studied in combination with WBRT. In a study from Spain, Verger and colleagues (abstract here) randomized 85 patients with brain metastases (51% from lung cancer, by far the leading subgroup) to receive WBRT with or without temodar (75 mg/m2/day) during RT and then 200 mg/m2 on days 1-5 every 28 days for a couple of additional months. While the response rate was not significantly improved with temodar, at 90 days there was a better progression-free survival in the recipients of temodar + WBRT (72% vs. 54%), and a decreased risk of dying from brain metastases (69% vs. 41%). Another trial from Greece, by Antonadou and colleagues (abstract here), randomized 52 patients with brain mets (21 with lung cancer) to receive WBRT with or without concurrent temodar, followed by up to 6 cycles of temodar alone (for the first 5 days of each 28 day cycle). This smaller study showed a very high response rate of 96% in the patients who received the combination of temodar and WBRT, compared with 67% for WBRT alone (highly statistically significant), and also greater neurologic symptom improvement with the combination approach.

There are a range of studies being conducted now that are looking at temodar with radiation (list here), sometimes combined with or compared with other agents, especially EGFR inhibitors, since these have also been associated with responses of brain metastases (the subject of a future post). For now, the relatively small studies that have been done haven’t shown it to be a home run, but it looks like this is an agent on a rather short list of drugs that can have an impact on brain metastases, in combination with or following local approaches such as WBRT. Whether temodar can decrease risk of progression in the brain for patients who undergo stereotactic radiosurgery alone, or whether it is more effective when combined with other agents like tarceva, as is being studied, is still unknown right now.