特罗凯脉冲一些资料

      最初知道特罗凯脉冲，是从安安的帖子里，后来特地找安安咨询了具体用法，实际就是：第一天吃4粒特罗凯，停三天，然后继续吃4粒，停三天，这样反复下去 ，一般肯定不建议这么用，只是在危急的时候尝试尝试吧，在多发脑转，又无法再次全脑放疗的情况下，或者存在脑膜转移的情况下，还是值得一试的，今年，我就知道身边有三个病友用了这个方法，稳定下了形势。这里也附上yezi给的特罗凯脉冲的一些英文资料，供大家参考。

An Effective Treatment for (some patients with) Leptomeningeal Carcinomatosis in Lung Cancer?
January 31, 2010 - 2:34 pm
Dr. West
Leptomeningeal carcinomatosis, also referred to as carcinomatous meningitis, is an uncommon but certainly not rare complication in lung cancer that I consider to be among the most dreaded.  This occurs when cancer cells are in the cerebrospinal fluid (CSF) that bathe and cushion the brain and spinal cord, and cancer cells deposit on the meninges, the lining around the brain and spinal cord.


Meningeal carcinomatosis is a diagnosis that I need to consciously remind myself to think about when I see a patient with lung cancer experience a rapid clinical decline that isn’t associated with radiographic evidence of significant progression in the extracranial cancer we’ve been following, or when I see a patient with a constellation of neurologic signs and symptoms that just don’t fit together for an anatomically-based lesion like a brain metastasis, stroke, or peripheral neuropathy.
One central reason that leptomeningeal carcinomatosis is also especially dreaded because we really tend to do so poorly in treating it.  Craniospinal radiation therapy (RT) has been tried, and there is the option of giving chemotherapy directly into the CSF through a series of lumbar puncture (spinal tap) procedures or through an Ommaya reservoir that is implanted into the skull to deliver chemo right into the fluid collections inside the center of the brain.  Unfortunately, none of these options has been effective (particularly in lung cancer, though results in breast cancer treatment have been more favorable), and most thoracic oncology experts and general oncologists have favored a focus on comfort care as the primary intervention.
I was intrigued at a meeting about a year ago to have heard in a conversation with Dr. Mark Socinski, renowned thoracic oncologist at UNC Chapel Hill, about a case (sebsequently described in a case history in the Journal of Clinical Oncology) of a never-smoking woman who had initially responded on Tarceva (erlotinib), then progressed and switched to chemo with Avastin (bevacizumab), and then developed worsening double vision and was ultimately diagnosed with meningeal carcinomatosis after a lumbar puncture (LP, or “spinal tap”) confirmed cancer cells in her CSF (positive “cytology”).
On the basis of a trial they were doing at University of North Carolina at Chapel Hill, giving “pulsed” Tarceva at 600 mg by mouth given one day every 4 days (so the same total amount as the normal daily administration, but four pills one one of every four days only), he started her on this, and she had symptomatic clearance and resolution/normalization of her cytology on a repeat LP.   She tolerated this well and continued to feel better for many months.
I filed this information away but unfortunately had occasion to consider it again very recently. A patient of mine, a 41 year old Caucasian woman with a remote prior smoking history, had initially presented with brain metastases as well as chest and bone disease, biopsy-proven as lung adenocarcinoma, and after initial whole brain RT and palliative RT to her painful hip lesion, I started her on chemo-based first line treatment.  She had a very nice partial response, but she eventually became weary of it (I started here on cisplatin-based chemo), and I switched her to maintenance Alimta (pemetrexed). She did very well on that for about 14 months, barely noticing side effects, and doing things like asking if she can go to the gym on the same day as her chemo (so clearly feeling well).
She showed modest but convincing progression several weeks ago, and we talked about further options. At that point, a leading consideration was Tarceva-based treatment, and we were actually planning to have her pursue a trial of Tarceva/Avastin (which now allows patients with treated, asymptomatic brain mets), when the screening head MRI showed diffuse meningeal enhancement highly consistent with meningeal carcinomatosis.   Because she had a history of Lyme disease and had undergone several LPs in that work-up, she didn’t want another if it wasn’t likely to change management. At right around that time, I had sent off her tumor for EGFR mutation testing, and she has an exon 19 deletion, a known activating mutation very often associated with good responses.
She started on tarceva, initially at the standard 150 mg daily dosing, since I knew that some patients with brain metastases had had very good responses of brain metastases to EGFR inhibitors.  Over the next week, she had two transient episode of difficulty getting words out (known as an expressive aphasia) that resolved spontaneously after several minutes.   At that point, I had her switch to the 600 mg every four day dosing schedule.   It’s now been another couple of weeks, and she hasn’t


            

had any recurrences of neurologic symptoms. I’ll be following her closely and repeating scans soon.
I’m optimistic that this is a truly valuable treatment for at least some patients with meningeal carcinomatosis. Dr. Socinski tells me that he has had a second patient who responded well in a similar situation.  I’m not sure if this is a beneficial effect we’re likely to only see in patients who have an EGFR mutation, but it’s certainly an option I’m inclined to consider again for a situation in which it’s hard to find any treatments to be very hopeful about.  I wanted to highlight this in case anyone else out there sees a similar case and might see if this approach of pulsed erlotinib can provide a benefit.

Dr. West January 31, 2010 - 8:55 pm
There’s a very small amount of evidence on “pulsed” tarceva out there. One advantage would be that higher doses may achieve therapeutic concentrations in the CSF, but I don’t know of any oncologist advocating this relatively untested approach as an off-protocol alternative to standard daily dosing. I might consider it in patients who have already received whole brain radiation and now have progressing metastases. However, while I’m pretty optimistic about this approach for patients with an EGFR mutation (very limited numbers thus far, but encouraging), I’m more guarded about whether it will offer much to patients who don’t have an EGFR mutation.



Dr. West, April 27, 2010 - 9:00 pm
One benefit of the pulsed schedule that I related from the published experience from Dr. Socinski is that the total dose of Tarceva is the same as the normal schedule of 150 mg by mouth daily. I think it could well add another wrinkle to have a schedule of 1500 mg every 7 days, effectively requiring a far greater than standard dose that could leave many insurers unenthusiastic or completely unwilling to cover the added cost of a treatment plan that doesn’t have any established place yet. However, if there were to be evidence that the higher dose was more effective, it would change the situation and make me far more inclined to pursue that challenge. Right now, however, I don’t think there’s reason to conclude that the 1500 mg every 7 day schedule is superior to 600 mg every 4 days.

瓶子 发表于 2011-6-14 14:40

                               
登录/注册后可看大图

had any recurrences of neurologic symptoms. I’ll be following her closely and repeating scans soon. ...

Regardless, I wish you both good luck on the upcoming MRI scan.


Carcinomatous Meningitis in Non–Small-Cell Lung Cancer: Response to High-Dose Erlotinib
1.        Nirav Dhruva and
2.        Mark A. Socinski
+ Author Affiliations
1.        Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC
A 56-year-old woman who never smoked presented with cough and progressive dyspnea. Chest x-ray and computed tomography (CT) scan revealed right pleural effusion and innumerable small pulmonary nodules (Fig 1A). CT scan of the abdomen, bone scan, and magnetic resonance imaging (MRI) of the brain were negative for distant disease. Poorly differentiated adenocarcinoma was established by transbronchial biopsy. Given her never smoker status and stage IV disease, she entered into a clinical trial and received erlotinib (150 mg daily) alone. She had a dramatic response of her pulmonary disease (Fig 1B) with complete resolution of her cough and dyspnea. She remained on erlotinib for 7 months, at which point her cough returned, and her chest CT scan revealed an increase in the size and number of pulmonary nodules. Erlotinib was discontinued, and she received treatment with carboplatin, paclitaxel, and bevacizumab for six cycles followed by an additional two cycles of bevacizumab alone with minimal response radiographically, but her cough resolved. The patient then developed diplopia, and left cranial nerve IV palsy was demonstrated. Subsequent brain MRI revealed diffuse leptomeningeal disease most prominent near the cerebellum. She received a course of whole-brain radiotherapy to a dose of 30 Gy. As her systemic disease was still in a minor response without evidence of disease progression, bevacizumab was continued every 3 weeks. Four months later, her chest CT and brain MRI (Fig 2A) were stable; however, her diplopia worsened, and she developed mild ataxia. A lumbar puncture (LP) was performed revealing findings consistent with carcinomatous meningitis (Table 1, LP 1). Given the stability of her systemic disease, bevacizumab was continued. Erlotinib was added at a dose of 600 mg orally every 4 days based on an ongoing phase I trial at the Lineberger Comprehensive Cancer Center (Chapel Hill, NC).1 Her CNS symptoms improved along with her performance status. Subsequent LPs done 3 and 6 months later revealed improvements in her biochemical parameters as well as clearing of her malignant cells (Table 1; LP 2, 3). A repeat brain MRI at 6 months after erlotinib initiation displayed resolution of the leptomeningeal findings, which were most notable on the coronal T1–weighted images (Fig 2B). The patient remained on erlotinib at 600 mg orally every 4 days for a total duration of 10 months with minimal skin and gastrointestinal toxicity. She continued to have minimal diplopia and ataxia with relatively good performance status. During this time, her cough worsened coincident with disease progression on her chest CT despite changes in treatment with addition of pemetrexed and then gemcitabine. She was placed on hospice and passed away shortly thereafter, 28 months from initial diagnosis of stage IV disease.

瓶子 发表于 2011-6-14 14:42

                               
登录/注册后可看大图

Regardless, I wish you both good luck on the upcoming MRI scan.

View larger version:
•        In this page
•        In a new window
•        PowerPoint Slide for Teaching
Fig 1.

View larger version:
•        In this page
•        In a new window
•        PowerPoint Slide for Teaching
Fig 2.
View this table:
•        In this window
•        In a new window
Table 1.
Summary of Cerebrospinal Fluid Findings
The treatment of carcinomatous meningitis in advanced non–small-cell lung cancer (NSCLC) is less than satisfying; without treatment, median survival ranges from 4 to 6 weeks.2 Palliation of symptoms represents an important but challenging treatment goal in this condition.3 Recent reports describe responses in selected patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).4–8 This case exemplifies the unique biology of advanced NSCLC in selected patients. Scant data exists on the pharmacokinetics of EGFR TKIs with regard to penetration into the CSF; however, this patient clinically responded to pulse dose erlotinib. She was not known to have an EGFR mutation, but her baseline demographic (nonsmoking female with adenocarcinoma) and clinical course suggest that the presence of a mutation was likely. Previously reported in the literature is a case in which the presence of an EGFR sensitivity mutation (exon 19) persisted in the disease which relapsed in the CNS, while the systemic disease was characterized by a resistance mutation (T790M).5 Increasing the dose of orally administered gefitinib increased the CSF concentration,5 which was the rationale for the strategy employed in our patient. The difference between the existing reports in the literature and this case is that our patient had a prior exposure to erlotinib and exhibited progression of systemic disease while on first-line erlotinib. She then received bevacizumab-based therapy and progressed within the meninges while her systemic disease was stable. The notable features are the clinical improvement as well as improvement in CSF parameters as a result of high intermittent doses of erlotinib, along with a radiographic response. This response suggests that the CSF disease remained sensitive to erlotinib, and the higher doses led to higher CSF penetration. Although this remains speculative as we did not measure levels of erlotinib in the CSF, preliminary data from the ongoing phase I trial at our institution has shown this to be true,1 which mirrors the experience of others with gefitinib.5 The most compelling facet of this case is the prospect that higher doses of EGFR TKIs such as erlotinib might offer prolonged survival and palliation in a notably dismal condition desperate for improved therapy.

Next Section
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Mark A. Socinski, Eli Lilly, Genentech Research Funding: Mark A. Socinski, Eli Lilly, Genentech, Pfizer, Abraxis, Celgene Expert Testimony: None Other Remuneration: None
Previous Section

瓶子 发表于 2011-6-14 14:43

                               
登录/注册后可看大图

View larger version:
•        In this page
•        In a new window

REFERENCES
1.        ↵
1.        Buie LW,
2.        Lindley C,
3.        Shih T,
4.        et al.
(2007) Plasma pharmacokinetics and cerebrospinal fluid concentrations of erlotinib in high-grade gliomas: A novel, phase I, dose escalation study. J Clin Oncol 25(suppl):88s, abstr 2054.
2.        ↵
1.        Grossman SA,
2.        Krabak MJ
(1999) Leptomeningeal carcinomatosis. Cancer Treat Rev 25:103–119.
CrossRefMedline
3.        ↵
1.        Pentheroudakis G,
2.        Pavlidis N
(2005) Management of leptomeningeal malignancy. Expert Opin Pharmacother 6:1115–1125.
CrossRefMedline
4.        ↵
1.        Sakai M,
2.        Ishikawa S,
3.        Ito H,
4.        et al.
(2006) Carcinomatous meningitis from non–small-cell lung cancer responding to gefitinib. Int J Clin Oncol 11:243–245.
CrossRefMedline
5.        ↵
1.        Jackman DM,
2.        Holmes AJ,
3.        Lindeman N,
4.        et al.
(2006) 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 24:4517–4520.
FREE Full Text
6.       
1.        Choong NW,
2.        Dietrich S,
3.        Seiwert TY,
4.        et al.
(2006) Gefitinib response of erlotinib-refractory lung cancer involving meninges: Role of EGFR mutation. Nat Clin Pract Oncol 3:50–57.
CrossRefMedline
7.       
1.        Fukuhara T,
2.        Saijo Y,
3.        Sakakibara T,
4.        et al.
(2008) Successful treatment of carcinomatous meningitis with gefitinib in a patient with lung adenocarcinoma harboring a mutated EGF receptor gene. Tohoku J Exp Med 214:359–363.
CrossRefMedline
8.        ↵
1.        Wagner M,
2.        Besse B,
3.        Balleyguier C,
4.        et al.
(2008) Leptomeningeal and medullary response to second-line erlotinib in lung adenocarcinoma. J Thorac Oncol 3:677–679.
CrossRefMedline

顶一下，可是英文看不懂啊。

新奇呀，真是什么招都有，那是更好了，即达到效果又省了钱。真好！

可能适合爸爸现在的状况呢。。。

一个有效的治疗（有些患者）脑膜癌病肺癌？

2010年1月31日下午2 : 34

威斯特医生

脑膜癌病，也被称为癌性脑膜炎，是一种罕见的，但肯定不是罕见的并发症肺癌，我认为是其中最可怕的。这发生在癌细胞在脑脊液（细胞集落刺激因子），洗澡和减轻脑和脊髓，和癌细胞上的脑膜，李宁围绕脑和脊髓。

脑膜癌病是一个诊断，我需要有意识地提醒我自己想当我看到一个肺癌患者的经验临床快速下降，不相关的影像学证据的显着进展在颅外肿瘤我们已经以下，或当我看到一个病人，一个星座的神经系统症状和体征，只是不不适合在一起的解剖学为基础的病变，如脑转移，中风，或周围神经病变。

一个核心原因，脑膜癌病还特别害怕因为我们真的这样做往往不佳治疗它。全脑全脊髓放射治疗（逆转录）已尝试，并有权给予化疗直接进入脑脊液通过一系列的腰椎穿刺（脊椎）程序或通过储液囊，植入颅骨提供化疗在流体收藏中心内的大脑。不幸的是，没有这些选项是有效的（特别是在肺癌，但结果在乳腺癌的治疗已被更有利），和大多数胸部肿瘤学专家和一般肿瘤有利于注重舒适护理作为主要干预。

我的兴趣在会议大约一年前已听到对话标志索辛斯基博士，著名的胸部肿瘤在北卡罗来纳大学教堂山，一个案件（sebsequently描述在一个案件的历史在临床肿瘤学杂志）一个从未吸烟的妇女谁最初回应特罗凯（埃罗替尼），然后发展和交换化疗和贝伐单抗（贝伐单抗），和发达国家日益恶化的双重视野和最终被确诊为脑膜癌病后腰椎穿刺（唱片，或“脊椎”）证实肿瘤细胞在脑脊液（积极细胞学”）。

在试验的基础它们在北卡罗来那大学教堂山，给“脉冲”特罗凯在600毫克口服，一天每4天（以相同的总金额为正常的日常管理，但四丸一一每四天），他开始了她的这个，她有症状清除和分辨率/正常化她细胞学对重复唱片。她不能容忍这感觉更好，持续数月。

我提起这个信息，但不幸有机会重新考虑一下，最近。我的病人，一个41岁的白人妇女与远程以前的吸烟史，最初提出的脑转移瘤以及胸部和骨疾病，活检证实为肺腺癌，并在最初的全脑逆转录和姑息逆转录她的痛苦的髋关节病变，我开始了她的chemo-based第一线治疗。她有一个很好的部分反应，但她最终厌倦了（我开始在顺铂为基础的化疗），我给她换维修塞（培美曲塞）。她很好，约14个月，几乎没有注意的副作用，和做的事情一样，问她是否可以去健身房的同一天，化疗（如此清晰的感觉好）。

她不大但令人信服的进展，几个星期前，我们谈到了进一步的选项。在这一点上，主要考虑的是tarceva-based治疗，我们本来计划让她追求审判特罗凯/阿瓦斯丁（现在允许患者的治疗，无症状脑代谢症候群），当检查头部磁共振成像显示弥漫性脑膜增强高度一致的脑膜癌病。因为她有一个历史的莱姆病和经历了几次的内毒素在工作，她不想如果它不可能改变管理。在那段时间，我把她的肿瘤表皮生长因子受体基因突变检测，和她有一个19号外显子缺失，一个已知的激活突变往往与良好的反应。

她开始接受特罗凯治疗，最初在标准的150毫克每日剂量，因为我知道，有些患者的脑转移瘤有很好的反应，脑转移瘤表皮生长因子受体抑制剂。在接下来的一周，她有两只短暂插曲困难的话（也称为表现失语），解决自发地在几分钟。在这一点上，我让她切换到600毫克每四天给药时间表。它现在被其他几个星期，她也没有

任何复发的神经症状。我会紧紧地跟着她，很快的重复扫描。

我很乐观，这是一个真正有价值的治疗至少有部分患者脑膜癌病。索辛斯基博士告诉我，他有一个病人谁反应良好，在类似的情况。我不知道如果这是一个有益的影响可能是我们只看到谁患者有表皮生长因子受体突变，但它肯定是一个选择，我倾向于认为再次在这种情况下很难找到任何治疗是非常乐观。我想强调，这在其他人那里看到类似的情况，看看这种方式脉冲埃罗替尼可以提供一个好处。

2010年1月31日下午8 : 55西博士

有少量证据“脉冲”特罗凯那里。一个好处是，高剂量可达到治疗浓度的脑脊液，但我不知道任何肿瘤倡导这种相对考验的做法作为一种替代标准每日剂量场外协议。我会考虑谁患者已经收到全脑放疗和现在有进展的转移。然而，虽然我很看好这一方法的患者表皮生长因子受体突变（非常有限的数字迄今，但令人鼓舞的），我更谨慎是否将提供给病人谁没有一个表皮生长因子受体突变。

威斯特医生，2010年4月27日-晚上9 : 00

利用脉冲时间表，我从出版的经验，从索辛斯基博士的总剂量的特罗凯是一样的正常时间表150毫克口服每日。我认为这很可能增加一个皱纹有时间表1500毫克每7天有效，需要远远超过标准剂量会留下许多保险公司热情或完全不愿意支付额外的费用，一个治疗计划，没有任何既定的地方。然而，如果要有证据表明，高剂量更有效，这将改变现状，使我更倾向于追求挑战。现在，然而，我不认为有理由得出这样的结论：1500毫克每7天的行程是优于600毫克每4天。