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 2013-3-28 09:08

                               
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1.1        入脑条件
    血脑屏障（blood brain barrier）由介于血循环与脑实质间的软脑膜、脉络丛的脑毛细血管壁 ...

谢谢老马，YEZI和大家的热心分享，学习很多。妈妈全脑放疗后用易11个月，今天复查脑部病灶复发，中度水肿，压迫第四脑室。准备入院看看是否能做第二次全脑放疗加立体局部放疗，如果可以计划配合替莫唑胺和鸦胆子油。再不行就只能试试YEZI提到的特罗凯脉冲+替莫唑胺。刚刚从骨转移骨折的手术中熬过来，脑部有复发了，祈祷妈妈能熬过去！

这个贴子超级好呀，今天才看到。

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ALK gene translocations and amplifications in brain metastases of non-small cell lung cancer.
http://www.ncbi.nlm.nih.gov/pubmed/23453647
BACKGROUND: Increased incidence of brain metastases (BM) in non-small cell lung cancer (NSCLC) with ALK translocations was postulated, however, ALK gene aberrations in NSCLC-BM have not been investigated so far.

METHODS: We investigated ALK and EML4 gene aberrations (amplifications, translocations, inversions) by fluorescent in situ hybridization (FISH) (n=175) and ALK and EML4 protein expression by immunohistochemistry (n=221) in NSCLC BM and corresponding primary tumors.

RESULTS: ALK translocations were found in 4/151 (2.6%; 3 of them involving EML4) of BM of adenocarcinomas (AC), 1/9 (11.1%) of adenosquamous carcinomas (ASC), 0/5 of squamous cell carcinomas (SCC) and 0/10 of large cell carcinomas (LCC). Rearrangement of ALK without involvement of EML4 was seen in 1 AC-BM and rearrangement of EML4 without involvement of ALK in 3 AC-BM, 1 ASC-BM and 1 LCC. ALK amplifications without gene rearrangements were found in BM of 16/151 (10.6%) AC, 2/5 (40%) SCC, 0/9 ASC and one LCC. ALK translocation status was constant between BM and primary tumors in 16 evaluable cases including two cases with ALK-EML4 translocations Among these 16 cases ALK amplification was seen in two BM and none of the primary tumors. All cases with translocations but not with amplifications of ALK showed protein expression. We found no association of ALK gene status with patient age, gender or overall survival time.

CONCLUSIONS: ALK translocations and amplifications are found in approximately 3% and 11% of NSCLC-BM, respectively. While ALK translocations appear to be constant between primary tumors and BM, amplifications seem to be more prevalent in BM. ALK translocation, but not ALK amplification is associated with ALK protein overexpression. Further studies are needed to determine whether NSCLC-BM patients with ALK gene aberrations may benefit from specific inhibitor therapy.

EGFR and HER-2 status of non-small cell lung cancer brain metastasis and corresponding primary tumor.
http://www.ncbi.nlm.nih.gov/pubmed/21067263
We investigated EGFR and HER-2 status in brain metastatic non-small cell lung cancer (NSCLC) and compared them to EGFR and HER-2 status of primary NSCLC. Evaluated were 66 cases of brain metastatic NSCLC, including 20 cases of corresponding primary NSCLC. HER-2 status was investigated by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH), and EGFR status was evaluated by IHC. HER-2 overexpression and/or amplification was/were observed in three cases (4.5 %) of 66 cases of brain metastatic NSCLC, and 23 cases (34.8%) demonstrated EGFR overexpression. Among 20 cases of primary and corresponding metastatic NSCLC, one case showed HER-2 overexpression and amplification in both primary and metastatic tumor. On the other hand, EGFR overexpression was noted in four cases of primary NSCLC and nine cases of metastatic NSCLC. Five cases showed EGFR gain in metastatic NSCLC. Brain metastatic NSCLC demonstrated different expression patterns of the abovementioned biomarkers, particularly EGFR when compared to primary NSCLC. Therefore, HER-2 and EGFR status are suggested to be evaluated in brain metastatic NSCLC for targeted monotherapy.

Effect of gefitinib ('Iressa', ZD1839) on brain metastases in patients with advanced non-small-cell lung cancer.
http://www.ncbi.nlm.nih.gov/pubmed/15474674
BACKGROUND: Gefitinib ('Iressa', ZD1839), an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI), has shown antitumor activity in refractory patients with non-small-cell lung cancer (NSCLC) in clinical trials. We have retrospectively analyzed the efficacy and tolerability of gefitinib in patients with advanced NSCLC treated at Okayama University Hospital.

METHODS: We reviewed the clinical records of 57 patients with advanced NSCLC who had received 250 mg/day gefitinib at our hospital between November 2000 and May 2003. Correlations between the sensitivity of brain metastases and extracranial disease following treatment with gefitinib were also investigated.

RESULTS: Extracranial objective responses were observed in 15 (27%; 95% confidence interval 15.8-40.3%) patients. Fourteen out of 57 patients had brain metastases; six experienced objective responses (one complete response, CR and five partial responses, PR) and eight had stable disease (SD) in the brain. Seven out of 14 patients with brain metastases experienced objective responses in their extracranial tumors and, interestingly, objective responses in the brain were observed in six (86%) of these patients. Multivariate analysis found that advanced age (> or = 70 years) and the presence of brain metastases were associated with clinical response to gefitinib (P = 0.01 and 0.05, respectively), and that female patients were more likely to respond. Median survival and median duration of response were 9.1 and 7.7 months, respectively. The majority of adverse events (AEs) were mild and reversible skin and gastrointestinal disorders, with grade 3 adverse events observed in six (11%) patients.

CONCLUSIONS: This retrospective analysis has found that gefitinib is effective and well tolerated in patients with refractory NSCLC, confirming previous phase II trial data. Interestingly, gefitinib appeared to be effective for brain metastases as well as extracranial tumors. Further prospective trials are warranted to evaluate the efficacy of gefitinib in elderly patients and in patients with brain metastases.

CNS metastases in non-small-cell lung cancer: Current role of EGFR-TKI therapy and future perspectives
http://www.ncbi.nlm.nih.gov/pubmed/23453646
A considerable proportion of non-small-cell lung cancer (NSCLC) patients will develop central nervous system (CNS) metastases throughout the course of their disease and these manifestations cause significant morbidity and mortality. Accordingly, novel therapies with high efficacy and low toxicity are needed for NSCLC-related CNS metastases. In NSCLC patients with activating epidermal growth factor receptor gene (EGFR) mutations EGFR-specific tyrosine kinase inhibitors (TKI) represent effective and well tolerated modes of therapy, however, it has been unclear whether these drugs are also able to cross the blood-brain-barrier (BBB) and cause remission of CNS metastases. Recent studies suggest that this might indeed be the case and intracerebral response rates of 70-80% in molecularly selected patients are considerably higher compared to what would be expected for standard approaches like systemic chemotherapy and whole brain radiation therapy. Limitations in the application of EGFR-TKI may arise from genetic heterogeneity between the primary tumor and CNS metastases. Accordingly, the acquisition of repeated biopsies from all relevant metastatic sites, including the CNS, may be necessary to guide therapeutic decisions. However, even in EGFR-wildtype patients EGFR-TKI seem to represent a valuable second line therapy with response rates of about 10%. Application of EGFR-TKI in a "pulsative" pattern may help to overcome insufficient delivery of TKI to the cerebro-spinal fluid and may further increase response rates and time until progression. In the future, combination of EGFR-TKI with radiation or chemotherapy and/or incorporation of next-generation TKI should be evaluated regarding their potential for further optimizing therapy of NSCLC patients with CNS metastases.

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Neuro Oncol. 2012 Oct 25. [Epub ahead of print]


A phase I/II trial of vandetanib for patients with recurrent malignant glioma.

Kreisl TN, McNeill KA, Sul J, Iwamoto FM, Shih J, Fine HA.
Source
Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (T.K., K.M., F.I., J.S., H.F.); Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland (J.S.).

Abstract
Vandetanib is a once-daily multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and the rearranged-during-transfection oncogene. A phase I trial was conducted to describe the pharmacokinetics of vandetanib in patients with recurrent glioma on enzyme-inducing anti-epileptic drugs (EIAEDs) and to identify the maximum tolerated dose (MTD) in this population. A phase II trial evaluated the efficacy of vandetanib in patients with recurrent malignant glioma not on EIAEDs as measured by 6-month progression-free survival (PFS6). In the phase I trial, 15 patients were treated with vandetanib at doses of 300, 400, and 500 mg/day, in a standard dose-escalation design. The MTD in patients on EIAEDs was 400 mg/day, and steady-state levels were similar to those measured in patients not on EIAEDs. Dose-limiting toxicities were prolonged QTc and thromboembolism. Thirty-two patients with recurrent glioblastoma multiforme (GBM) and 32 patients with recurrent anaplastic gliomas (AGs) were treated in the phase II trial, at a dosage of 300 mg/day on 28-day cycles. Six patients (4 GBM, 2 AG) had radiographic response. PFS6 was 6.5% in the GBM arm and 7.0% in the AG arm. Median overall survival was 6.3 months in the GBM arm and 7.6 months in the AG arm. Seizures were an unexpected toxicity of therapy. Vandetanib did not have significant activity in unselected patients with recurrent malignant glioma.