【3年】爸爸，很爱很爱你，你的爱永远陪伴我。。

与爱同行

安安，不知道咋安慰你。

爱的力量

正在写着考虑回家的事情，很纠结很恍惚的部分，接到妈妈的电话，匆匆忙忙的说爸爸尿路感染，她去医院开消炎药，医生不给，要求必须住院，说明了严重性，一旦在家处理不好，发烧就不行了。我问怎么知道尿路感染，说尿很浑浊，我问没有带点化验么。妈妈说没有。。我很怕白折腾。不过估计蛋白肯定超标。。跟我商量一下就先在我们家附近一家小医院住着，比较近，家人也方便来回照应。妈妈跟我说她觉得力比泰不行了，周六打了才7天不到，现在又开始疼痛加剧，止疼药也要加量吃。我早预计到了，所以这次根本没抱希望，虽然也很震惊重返才撑了这么几天。。语气急促，说完匆匆忙忙挂了，还一边嘀咕要找谁谁。。。上次接爸爸出院的时候，用了2辆车还有救护车，10多个人前前后后的抬着还把他弄的非常辛苦，虽然知道去住院这一天始终会到来，没想到这么快。。我不忍心想还有没有机会再回去家里。
一旦入院，照顾的人手也成问题，三姑跟妈妈闹翻了，赌气回家，二姑带着小侄女在我们家已经呆了1，2周了，这份心意我真的很感激，她之前也跟我说如果需要她把孙女送到外公那边过来我家，这次紧急的让她来就只好带着，妈妈偶尔还嫌孩子很吵。。 。一旦入院几头跑，没办法把孩子也固着。家里该多一团乱。。。
每一天都非常不放心，非常想回去，但是实际的困难也只有我知道。。我甚至隐约模糊的觉得我一旦回家就是“认输”了，默认静待这个结果到来。。虽然知道自己不理智，还是很难说服自己面对这个“最后”，家里每一个人都告诉我乖乖呆在深圳，等着“最后”再回去陪陪就是了。我这几年都可以回忆起来我知道我爸爸病的那一秒钟，我马上说我回家，小姨说等着“最后”再回去陪陪就是了。我痛恨死这个“最后”。我不想认输。。。。。
一定要回去了，今晚拿回特罗凯。。明天找经理谈，尽量缩短离职的时间，一般是1个月。。1个月。。。从来不觉得生活的急迫到这个地步，1个月可能就改变很多问题了。。如果继续长假可能还更简单，至少我马上就可以回去。。

爱的力量

暂时没有入院，下午妈妈风风火火的打来电话，等我晃过神来，开始安排手头的事情考虑马上交接回去的时候，又看到她QQ来说，在卫生所找了个护士上门挂水，问了半天，还是这小地方的半熟人都知道我爸爸的病，不敢随意的给他用药，我妈又是个稳不住的性格，马上就开始慌乱。
晚上打电话回去，爸爸接的，妈妈带着小侄女溜达去了。跟爸爸聊了很久，平时跟他说话不敢超过5分钟，怕他会累，今天也听到后面有点累，但是还好。。吃饭好了一些，爸爸想坐起来吃，说坐起来就吃的多很多，我又趁机跟他商量摇床的问题，他说那样受不了，还是得腿放下来，之前2天，胃一直不舒服，吃不下饭，妈妈给我说一口饭嚼2分钟也不吞下去，我很担心是出现什么脑部问题，我让妈妈用胃药，她说爸爸吞不下去。。今天问爸爸，爸爸很激动的说，她每次把药一大把一次性的塞进去，他喝一口水进去就满嘴钻，很恼火。。听语气估计之前也为这个跟我妈争过。我也恼火我妈妈的表述方式，之前我扎实的担心了很久。
我很认真的告诉爸爸，无论有任何的不舒服还是直接告诉我，只有告诉我了才能想办法，爸爸答应了，说腿部肌肉萎缩的好厉害，除了按摩没有其他办法了，我在家里还能保证，我走之前打算去请一个按摩师，一个月1600，又被家人阻止了。。都争相说不如把钱给她们。 跟爸爸说愿意再吃保康素么，可以促进肌肉的，爸爸答应了，下次去邵医生诊所多买一些回来。
跟爸爸再过了一遍止疼药的量，我真是郁闷为什么要给减量，我又不能直接跟我妈妈对峙说不要省钱，这1,2周老在为这个事情纠缠。她总能找出各种理由说止疼药的副作用多大。。我当然明白，所以才尽量配方用，减少阿片类，但是无论如何也不能让爸爸在疼痛中。只能交待爸爸要按量吃，不要一疼就加吗啡，万恶的止疼药又不是我可以简简单单买到的。。。之前一个深圳的病友来找我，拿着好多多瑞吉帖都是宁养院给的，看的我眼花缭乱的羡慕。。自费150一张，为了这个去年还跟我妈闹了一次。。我回去就好了吧。。隐约也感觉到了后面门诊的费用将是相当庞大的，以前有一些公务员补贴等，自费的部分这几年每次都是1,2K而已，其他的我开销也不在我妈眼皮子底下，阻力小点。。发了半天牢骚。。
这周打算开始吃特罗凯了，之前止疼药的量乱用，单用疼痛程度也很难衡量判断什么了，不过还是得转方案了，我不能时时刻刻的观察判断，评估变得这么艰难，跟我妈妈的沟通有闹脾气的水分，跟爸爸的沟通又有怕我担心的水分。。

hjjeff

安安，
看了你一路叙述下来，
我真害怕以后我也一步一步的经历你走过的路，
但是至少我还能从你这里找到方向，
让我不是如此迷茫。

又千万次的想起上天不公平，
我知道这样没用，
也只是给自己平白无故添烦恼罢了。

希望这个“最后”不要来，
永远都别来。

hjjeff

安安，今天我爸爸检查CA199指标是47.60，标准时37，
不知道是怎么个情况，
医生说没关系。
我不放心啊，
期待你的回复。

jomn111

太不容易了

爱的力量

原帖由 hjjeff 于 2010-4-28 21:50 发表
安安，今天我爸爸检查CA199指标是47.60，标准时37，
不知道是怎么个情况，
医生说没关系。
我不放心啊，
期待你的回复。

hjjeff, 癌胚抗原在初期观察如果与病情进展吻合，属于敏感的类型，尤其是看哪个值是最敏感的，CA199或者CEA等，以后都可以拿这个来对比，但是要以你父亲的历史数据来对比，已经得CA就不需要再看标准值了没有什么太大意义了。。并且癌胚抗原的波动与很多因素都有关联，不能过度神话癌胚抗原的指标意义，对于有实体瘤的病人，还是以监控实体瘤为准。

爱的力量

留点资料，关于大剂量脉冲使用特罗凯的，针对脑膜转移和脊髓转移等中枢神经性转移的。暂时放着，如果很多人都关注的话，我抽时间翻译一下。。。
大概意思是说，普通口服计量的特罗凯/易瑞沙在脑膜以及中枢神经部分的浓度达不到，只有血浆水平的1%，所以不能得到抑制，但也在这个案例中推测，脑膜以及中枢神经部分的肿瘤没有耐药的变异T790M，所以对于曾经响应了易瑞沙和特罗凯的人（就算耐药），也可能通过大剂量的脉冲使用来受益控制住脑膜以及中枢神经部分的转移灶。

Abstract  Leptomeningeal metastases (LM) occur in 5–10% of patients with solid tumors and are associated with a dismal prognosis. We describe LM from lung adenocarcinoma harboring a mutation in the epidermal growth factor receptor (EGFR) gene that confers sensitivity to the EGFR tyrosine kinase inhibitors (EGFR-TKIs) erlotinib and gefitinib. The CSF concentration of EGFR-TKIs achieved by standard daily dosing may be insufficient for therapeutic effect. However, intermittent (pulsatile) high dose administration (1000–1500 mg/week) achieves a higher CSF concentration than standard dosing, and successfully controlled LM in this patient.
Introduction
Leptomeningeal metastases (LM) affect 5–10% of patients with solid tumors; untreated, median survival is 1–2 months [1]. We describe a patient with LM from non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) kinase domain mutation that confers exquisite sensitivity to the EGFR tyrosine kinase inhibitors erlotinib and gefitinib [2]. Such mutations occur in 10% (USA) to 25% (Asia) of NSCLCs [2]. However, secondary mutations during therapy lead to acquired resistance [2]. A recent case report highlighted that central nervous system (CNS) metastases do not always harbor resistance mutations [3], suggesting retained erlotinib/gefitinib sensitivity if therapeutic drug concentrations are achieved. We induced sustained control of LM harboring an EGFR tyrosine kinase inhibitor (TKI) sensitizing mutation without an acquired resistance mutation with high-dose weekly erlotinib following progression on standard daily dosing. Such “pulsatile” therapy is tolerable [4] and may achieve therapeutic cerebrospinal fluid (CSF) erlotinib concentrations.

Plasma or CSF samples (obtained from another patient) were analyzed at various time points after dosing of erlotinib. To assess the level of erlotinib in blood or CSF, frozen samples were thawed at ambient temperature and extracted with a solvent mixture of methanol and acetonitrile (1/4, v/v). The sample solutions were placed at −20°C for approximately 1 h and then centrifuged at 1000g for 10 min. The supernatants were transferred to a 96-well plate and loaded into an autosampler (model SILHTC, Shimadzu, Columbia, Maryland) for high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) analysis. HPLC was then used to separate erlotinib from any potential interference and measured by MS/MS detection method. Calibration curves were determined for erlotinib to permit conversion of peak areas to the drug amounts against external reference standards. The tandem MS/MS detector (Model ABI/Sciex API 4000, Applied Biosystem, Foster City, California) permitted verification of peak identity as well as a quantitative assessment of the compounds in the samples.

Case
A 54-year-old woman with stage IV NSCLC was treated with carboplatin and paclitaxel without disease response. Molecular analysis of tumor tissue was unavailable at that time. However, her demographic profile (Asian, minimal smoking history, non-small cell histology) predicted her disease would harbor EGFR TKI sensitive cells [2]. Therefore, she then initiated standard daily dosing of erlotinib (150 mg) and her disease responded. Twenty-eight months later, she acquired resistance to erlotinib with progression of disease systemically. Following further progression through an experimental angiogenesis inhibitor, she initiated pemetrexed and resumed standard dose erlotinib. After initial response, 11 months later, her disease again progressed. DNA was extracted from biopsy of a progressing lung lesion and examined using established techniques for analysis of EGFR mutations [5]. Direct sequencing of exons 18-21 encoding the kinase domain of EGFR revealed the L858R mutation associated with EGFR TKI sensitivity (Fig. 1) [2]. It also demonstrated the T790M mutation associated with acquired EGFR TKI resistance (Fig. 1) [2].
She also developed headaches and there was a high clinical suspicion of CNS metastases despite negative imaging (not shown). She refused a lumbar puncture. She initiated empiric temozolomide plus standard dose erlotinib (150 mg daily) for presumed CNS disease, but after one cycle her headaches worsened, and she developed nausea and vomiting concerning for CNS metastases with associated raised intracranial pressure. Magnetic resonance imaging (MRI) of the brain now demonstrated LM (Fig. 2) confirmed by CSF cytology (not shown). By direct sequencing, DNA from CSF cells harbored L858R predicting EGFR TKI sensitivity (Fig. 3, left panel) but not the T790M resistance mutation (data not shown). Because the result for T790M was negative in this sample, we performed a more sensitive fluorescence detection PCR-based assay that takes advantage of a PCR restriction fragment length polymorphism generated by the specific missense mutation (Fig. 3, right panel, arrow, positive control) [6]. That result was also negative, as only the wild type peak was detected (Fig. 3, right panel, bottom). Therefore, we hypothesized that the LM remained sensitive to an EGFR TKI if sufficiently high concentrations of drug could be achieved in the CSF.
The erlotinib concentration required to inhibit growth of cell lines harboring L858R by 50% (IC50) is 100 nM (nM) [2]. Standard dose erlotinib (150 mg daily) achieves 3000 nM in plasma [7], but CSF concentrations of EGFR TKIs are as low as 1% plasma levels below the IC50 [3, 8]. Increasing the daily dose of gefitinib to enhance CSF penetration has been an effective strategy [3], but gefitinib is no longer available in the United States following failure in phase III NSCLC trials. An analogous increase of the daily erlotinib dose above 150–200 mg daily induces unacceptable toxicity. However, weekly high-dose erlotinib up to 2000 mg is tolerable [4].

Pharmacokinetic analysis of CSF from another patient with NSCLC LM (not shown) treated with 1500 mg erlotinib weekly demonstrated a peak plasma concentration of 11,300 nM with a concurrent CSF concentration of 130 nM. Therefore, such high dose weekly administration of erlotinib achieved a CSF concentration exceeding the IC50.

Therefore, to increase CSF penetrance over standard daily erlotinib dosing in this patient, we initiated high-dose weekly erlotinib at 1000 mg then 1200 mg; persistent nausea precluded higher doses. Pharmacokinetic analysis was not undertaken in this patient. After 1 month there was a partial radiographic response of LM on brain MRI (Fig. 2b) and after 2 months in the cauda equina (not shown). However, hydrocephalus and persistent symptoms referable to increased intracranial pressure led to a VP shunt and whole-brain radiation therapy, after which she resumed treatment with 1500 mg weekly erlotinib. One month later, progressive intra-thoracic disease led to initiation of cetixumab and erlotinib was continued but changed to low dose (100 mg) daily. She survived 14 months following the diagnosis of CNS disease.

Patients with EGFR mutant lung cancer taking EGFR TKIs may develop LM because of inadequate drug penetration into the CSF through a relatively intact blood-brain barrier, rather than from secondary resistance mutations, despite the concurrent acquisition of resistance mutations outside the CNS [3]. This phenomenon may reflect EGFR independence. However, another explanation is the lack of selective pressure on EGFR- dependent tumor cells during inadequate CSF drug exposure [3]. High-dose weekly erlotinib administration is tolerable [4]. Moreover, such “pulsatile” kinase inhibition induces cancer cell apoptosis as effectively as chronic inhibition [9].

The EGFR kinase domain mutations that confers sensitivity to the EGFR TKIs erlotinib and gefitinib [2] occur in 10% (USA) to 25% (Asia) of NSCLCs as either multi-nucleotide in-frame deletions in exon 19 or single missense mutations in exon 21 such as L858R [2]. However, secondary mutations during therapy, such as T790M, lead to acquired TKI resistance [2]. LM may not harbor resistance mutations [3], suggesting retained TKI sensitivity if therapeutic drug concentrations are achieved in CSF. Others have reported a case of leptomeningeal NSCLC that responded empirically to erlotinib 600 mg every 4 days, but without mutational or pharmacokinetic analysis [10]. We induced sustained control of LM harboring L858R but not T790M with high-dose weekly erlotinib and whole brain radiotherapy following progression on standard daily dosing. Such “pulsatile” therapy is tolerable [4] and, as we demonstrate here via analysis of CSF from a similarly-dosed patient, achieves therapeutic CSF erlotinib concentrations. Improved outcome for LM from NSCLC may be achieved by strategies that yield higher CSF levels of EGFR TKIs, either through increased daily dosing [3], pulsatile dosing described here and elsewhere [10], or new formulations of existing EGFR TKIs that penetrate the blood-brain barrier more effectively or can be administered intrathecally.