厄洛替尼联合全脑放疗治疗非小细胞肺癌脑转移的临床观察

背景与目的 非小细胞肺癌腩转移灶的治疗包括手术及放化疗,但脑转移灶的控制率均不佳,患者中位生存期4-6个月.小分子酪氨酸激酶抑制剂厄洛替尼容易进入血脑屏障,单药使用时可控制脑转移灶的生长.本次临床观察的目的是评价厄洛替尼联合全脑放疗对非小细胞肺癌脑转移患者的疗效及毒副反应.方法 回顾性研究肿瘤科2006年-2009年间12例非小细胞肺癌脑转移患者.均采用厄洛替尼口服联合全脑放疗,其中厄洛替尼剂量为150 mg/d;全脑放疗的剂量为(3 000-3 600)cGy/(10-12)F.放疗完成后2月内评价近期疗效.结果 脑转移灶控制率为91.7%,其中PR 66.7%,SD 25%.副反应主要是皮疹(75%)和乏力(91.7%).结论 厄洛替尼联合全脑放疗对非小细胞肺癌脑转移灶的疗效高于单纯全脑放疗,且毒副反应可以耐受.     

厄洛替尼同步全脑放疗二线治疗无症状的多发性肺腺癌脑转移患者的临床疗效观察

摘 要：［目的］ 比较厄洛替尼单药和厄洛替尼同步全脑放疗二线治疗无症状的多发性肺腺癌脑转移患者的效果及安全性。［方法］ 选择全身化疗后进展的、无症状的多发性肺腺癌脑转移患者39例,通过随机数字法分为厄洛替尼单药治疗组和厄洛替尼同步全脑放疗治疗组。厄洛替尼单药组（19例）给予口服厄洛替尼150mg/d直到病情进展或出现不能耐受的副作用;厄洛替尼同步全脑放疗组给予全脑放疗（37.5Gy/15次,3周）,厄洛替尼150mg/d,从放疗的第一天开始口服直到病情进展或出现不能耐受的副作用。主要观察指标是比较两组患者的客观有效率（ORR）、神经系统无进展生存期（nPFS）、无进展生存期（PFS）、生存期（OS）及不良反应的发生情况。［结果］ 厄洛替尼单药组与厄洛替尼同步全脑放疗组的ORR分别为52.6%和85.0%（P=0.041）;中位nPFS分别9.4个月和13.7个月（P=0.001）;中位PFS分别为6.9个月和8.5个月（P=0.228）,中位OS为15.1个月和18.8个月（P=0.046）。无4度及以上不良反应发生。［结论］ 与厄洛替尼单药相比,厄洛替尼同步全脑放疗二线治疗无症状的多发性肺腺癌脑转移患者,能够明显提高客观有效率、局部神经系统无进展生存期、延长患者的生存期,同时没有明显增加患者的不良反应。     

厄洛替尼联合全脑放疗治疗NSCLC脑转移的疗效及患者生存分析

目的研究厄洛替尼联合全脑放疗治疗非小细胞肺癌脑转移的疗效以及患者生存效果。方法随机选取非小细胞肺癌患者98例,根据治疗途径分为对照组和实验组,每组49例患者。对照组患者接受全脑放疗;实验组患者接受厄洛替尼联合全脑放疗,即患者在放疗开始应用厄洛替尼片,应用到放疗完成后2个月为止。对全部入组患者定期进行住院或者门诊随访。结果 2组患者经治疗后,实验组患者完全缓解率为12.2%,部分缓解率为28.6%,病灶稳定率为42.9%,病灶进展率为16.3%,而对照组患者完全缓解仅有1例,差异具有统计学意义(χ~2=3.950,P<0.05)。2组对比,对照组患者的疾病控制率远远低于实验组,差异具有统计学意义(χ~2=1.376,P<0.05);此外,实验组患者的生存时间明显长于对照组,差异具有统计学意义(P<0.05)。实验组患者主要的不良反应为皮疹和恶心呕吐。结论厄洛替尼联合全脑放疗治疗非小细胞肺癌脑转移,疗效显著,能够有效地控制脑转移病灶,提高患者客观有效率和生存率。     

非小细胞肺癌脑转移厄洛替尼结合全脑放疗治疗的理论基础和研究进展

非小细胞肺癌（NSCLC）脑转移患者预后极差,全脑放疗（WBRT）不能同时控制颅外病灶。酪氨酸激酶抑制剂（TKI）对肺腺癌脑转移瘤患者的研究结果是令人鼓舞的,表皮生长因子受体（EGFR）突变状态与疗效相关。厄洛替尼配合全脑放疗治疗肺癌脑转移患者增敏的理论基础存在。目前,小型临床试验资料显示厄洛替尼联合全脑放疗较单纯厄洛替尼疗效更佳,且不良反应可耐受。     

厄洛替尼联合放疗治疗晚期非小细胞肺癌脑转移疗效的Meta分析

目的:通过Meta分析观察厄洛替尼联合放疗治疗晚期非小细胞肺癌脑转移的疗效。方法:计算机检索PubMed、Medline、CNKI、VIP和万方医学网等数据库,检索时间截至2018年10月,纳入厄洛替尼联合放疗治疗晚期非小细胞肺癌脑转移的临床随机对照试验。对所检索文献进行筛选、资料提取和Cochrane系统评价方法学质量评价后,采用RevMan 5.3软件进行Meta分析。结果:共纳入6个临床试验研究,合计460例患者。研究结果显示:厄洛替尼联合放疗治疗晚期非小细胞肺癌脑转移疗效的有效率差异具有统计学意义（OR=2.72,P＜0.000 01,95%CI=1.84~4.01）,且能有效提高患者1年生存率,降低不良反应发生率。结论:厄洛替尼联合放疗治疗晚期非小细胞肺癌脑转移的疗效显著,临床值得推广。     

非小细胞肺癌脑转移厄洛替尼和吉非替尼治疗临床比较

目的比较和评价厄洛替尼和吉非替尼靶向治疗非小细胞肺癌脑转移的疗效。方法回顾性分析2009-01-01-2012-11-25广州医科大学附属第一医院81例晚期NSCLC初诊有脑转移患者和111例晚期NSCLC初诊无脑转移患者,192例患者均为肺腺癌合并EGFR基因突变,分为吉非替尼和厄洛替尼治疗组,生存分析采用Kaplan-Meier法统计,组间生存率比较采用Log-rank检验。结果初诊有脑转移患者颅内病灶,客观有效率为45.68%(37/81),疾病控制率为90.12%(73/81)。吉非替尼、厄洛替尼治疗的无进展生存期(progression-free survival,PFS)分别为9.5和9.0个月,P=0.344;不同EGFR突变类型(19外显子序列缺失突变、21外显子突变)PFS比较分别为10.4和8.6个月,P=0.408。初诊无脑转移患者PFS分别为14.0和15.0个月,P=0.369;不同EGFR突变类型的PFS分别为14.0和15.0个月,P=0.408。结论厄洛替尼和吉非替尼一线治疗肺癌EGFR突变脑转移效果无显著性差异。     

厄洛替尼治疗非小细胞肺癌脑转移初步分析

背景与目的 非小细胞肺癌(Non-small-cell lung cancer,NSCLC)脑转移较常见,预后不佳.厄洛替尼是一种表皮生长因子受体酪氨酸激酶抑制剂,多应用于治疗晚期NSCLC.本研究拟了解厄洛替尼治疗NSCLC脑转移的疗效、预后及其相关因素.方法 回顾性分析30例NSCLC脑转移患者的临床资料,所有患者均口服厄洛替尼150mg/d.直到疾病进展、死亡或发生不可耐受的副反应.结果 厄洛替尼对颅内病灶的疗效为部分缓解2例(6.7%).疾病稳定17例(56.7%).疾病控制率为63.4%,对全身病变的总体疗效为部分缓解2例(6.7%),疾病稳定5例(16.7%),疾病控制率为23.4%.年龄、性别、吸烟状况、病理类型、PS评分、脑转移数目、脑转移时间、化疗及脑部放疗与否、副反应等各亚组之间的疗效对比均未见有统计学差异.中位疾病进展时间2.4个月,中位生存期7.7个月,1年、2年生存率分别为38.4%和15.2%.单因素分析显示生存期与患者的PS评分、吸烟状况、是否进行过脑部放疗及化疔具有相关性,多因素分析则显示生存期仅与患者是否进行过脑部放疗具有相关性,与患者的吸烟状况接近有统计学意义.结论 厄洛替尼对NSCLC脑转移具有一定的疗效,接受过脑部放疗的患者具有较好的生存获益,非吸烟者的生存时间有好于吸烟者的趋势.厄洛替尼可以作为NSCLC脑转移的一种治疗选择.     

厄洛替尼联合全脑放射治疗非小细胞肺癌多发脑转移的初步观察

背景与目的:非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的多发脑转移预后极差。全脑放射治疗(whole brain radiotherapy,WBRT)是标准治疗方法。大多数临床研究结果显示化疗对肺癌多发脑转移的疗效不佳。厄洛替尼(Erlotinib,TARCEVA)是表皮生长因子受体的酪氨酸激酶抑制剂,用于NSCLC的治疗,本研究目的在于探讨WBRT同期联合厄洛替尼治疗NSCLC患者多发脑转移的疗效与耐受性。方法:12例NSCLC患者伴有多发脑转移接受WBRT(40Gy/20次/4周)并同期口服厄洛替尼150mg,每日1次,共计28天。治疗结束后和每3个月一次进行临床疗效评价直至疾病进展。结果:总有效率100%,其中完全缓解率66.7%,部分缓解率33.3%。中位总生存时间10个月,中位疾病进展时间8个月。临床症状缓解率100%。3例(25%)出现1级皮疹,1例(8.3%)发生轻度腹泻。结论:厄洛替尼同期联合WBRT治疗NSCLC多发脑转移有良好的近期治疗效果和耐受性。     

厄洛替尼与吉非替尼治疗非小细胞肺癌脑转移患者的疗效比较研究

目的：观察并比较厄洛替尼和吉非替尼靶向治疗非小细胞肺癌脑转移的疗效和不良反应发生情况。方法将100例非小细胞肺癌脑转移患者按随机数字表法分为两组各50例,分别给予吉非替尼和厄洛替尼治疗,比较两组不良反应及治疗效果。结果吉非替尼组和厄洛替尼组的疾病控制率分别为96.0%、92.0%,总有效率分别为76.0%、76.0%,两组比较,差异无统计学意义（P﹥0.05）;在不良反应方面,两组患者治疗后均出现不良反应,厄洛替尼组皮疹、恶心呕吐不良反应的发生率高于吉非替尼组（P﹤0.05）,但在腹泻和肝功能损害发生率方面,两组比较差异无统计学意义（P﹥0.05）,吉非替尼组总不良反应发生率低于厄洛替尼组（P﹤0.05）。结论非小细胞肺癌脑转移患者应用厄洛替尼和吉非替尼靶向治疗效果相当,但吉非替尼导致的总不良反应发生率低于厄洛替尼,值得在非小细胞肺癌脑转移患者治疗中临床推广。     

对比厄洛替尼和吉非替尼靶向治疗非小细胞肺癌脑转移的临床效果

目的 探讨非小细胞肺癌脑转移患者采用厄洛替尼和吉非替尼靶向治疗的临床效果及安全性.方法 64例非小细胞肺癌脑转移患者中34例患者采用吉非替尼口服治疗,30例患者采用厄洛替尼治疗.对比2组患者近、远期疗效,生活质量以及不良反应的发生情况.结果 2组患者治疗2个月后,吉非替尼组疾病控制率稍高于厄洛替尼组,有效率稍低于厄洛替尼组,但差异无统计学意义(P＞0.05);2组患者2年生存率无明显差异(P＞0.05).厄洛替尼组各项不良反应发生率较吉非替尼组明显增高,差异具有统计学意义(P＜0.05).2组患者治疗2个月后,吉非替尼组Karofsky生活质量评分有效率明显高于厄洛替尼组,差异具有统计学意义(P＜0.05).结论 吉非替尼和厄洛替尼对NSCLC脑转移患者均有较好的治疗效果,但吉非替尼不良反应发生率较低,生活质量较高.     

The management of brain edema in brain tumors

This review focuses on pathophysiology, clinical signs, and imaging of brain edema associated with intracranial tumors and its treatment. Brain edema in brain tumors is the result of leakage of plasma into the parenchyma through dysfunctional cerebral capillaries. The latter type of edema (ie, vasogenic edema) and the role of other types in brain tumors is discussed. Vascular endothelial growth factor-induced dysfunction of tight junction proteins probably plays an important role in the formation of edema. Corticosteroids are the mainstay of treatment of brain edema. When possible, corticosteroids should be used in a low dose (eg, 4 mg dexamethasone daily) to avoid serious side effects such as myopathy or diabetes. Higher doses of dexamethasone (16 mg/day or more), sometimes together with osmotherapy (mannitol, glycerol) or surgery, may be used in emergency situations. On tapering, one should be aware of the possible development of corticosteroid dependency or withdrawal effects.Novel therapies include vascular endothelial growth factor receptor inhibitors and corticotropin releasing factor, which should undergo further clinical testing before they can be recommended in practice.     

Planning for brain surgery in brain tumors

A precise knowledge of the localization of an intracerebral mass is a basic requirement for the planning of neurosurgical operations. Stereotactic atlases offer the possibility to adapt pre-operative imaging data onto normal anatomical conditions in the CNS. These atlases, however, reflect the standard variants of the CNS and do not allow to draw conclusions on local and secondary changes of the anatomy caused by the presence of pathological processes. The physical model proposed in this paper provides an estimate of the displacement of brain areas by an intracerebral mass. The modeling of brain parenchyma deformation is based on the mechanics of deformed media. The implementation of the model is successful in the group of primary brain tumors and meningiomas, and uses empirically-obtained data of a prospectively-selected patient population. The aim of the proposed model is, as further step, the integration and adaptation in apposite software solutions for the stereotactic orientation in the CNS.     

Histopathological changes in the brain after radiotherapy of brain metastasis

This is the histopathological analysis of 18 post-irradiated brains with metastases of breast cancers. There was no evidence of radiation necrosis, except for one with demyelinization and one with degeneration of nerve cells. There was no radiation damage in re-irradiated group. Whole brain irradiation of about 40 Gy may be safe, but that of 60 Gy or more may be not so safe. It may be more useful for preventing of radiation damage to take split-course-method or shrinking-technique at doses of 40 Gy or more. The combination of chemotherapy and radiation therapy seems to aggravate the course of radiation damage.     

Whole brain radiotherapy for the treatment of multiple brain metastases

BACKGROUND： Brain radiotherapy is used to treat cancer patients who have brain metastases resulting from various primary malignancies. OBJECTIVES： To assess the effectiveness and adverse effects of whole brain radiotherapy （WBRT） in adult patients with multiple metastases to the brain. SEARCH STRATEGY： CENTRAL （The Cochrane Library）, MEDLINE, EMBASE, CANCERLIT, and CINAHL were searched. SELECTION CRITERIA： Randomized controlled trials （RCTs） in which adult patients with multiple metastases to the brain from any primary cancer and treated with WBRT were included. Trials of prophylactic WBRT were excluded as well as trials that dealt with surgery or WBRT, or both, for the treatment of a single brain metastasis. DATA COLLECTION AND ANALYSIS：     

Value of whole brain re-irradiation for brain metastases--single centre experience

AimsThere is controversy in published studies regarding the role of repeat whole brain radiation (WBRT) for previously irradiated brain metastases. The aim of our retrospective study was to document the practice at Princess Margaret Hospital with respect to the re-irradiation of patients with progressive or recurrent brain metastatic disease after initial WBRT.Materials and methodsA comprehensive computerised database was used to identify patients treated for brain metastases with more than one course of WBRT between 1997 and 2003. Seventy-two patients were treated with WBRT for brain metastases and retreated with WBRT at a later date. The records of these patients were reviewed.ResultsThe median age was 56.5 years. The most common primary sites were lung (51 patients) and breast (17 patients). The most frequent dose used for the initial radiotherapy was 20 Gy/5 fractions (62 patients). The most common doses of re-irradiation were 25 Gy/10 fractions (22 patients), 20 Gy/10 fractions (12 patients), 15 Gy/5 fractions (11 patients) and 20 Gy/8 fractions (10 patients). Thirty-one per cent of patients experienced a partial clinical response after re-irradiation, as judged by follow-up clinical notes; 27% remained stable; 32% deteriorated after re-irradiation. Patients who had Eastern Cooperative Oncology Group performance status 0–1 at the time of retreatment lived longer. In responders, the mean duration of response was 5.1 months. The median survival after re-irradiation was 4.1 months. One patient was reported as having memory impairment and pituitary insufficiency after 5 months of progression-free survival.ConclusionRepeat radiotherapy may be a useful treatment in carefully selected patients. With increased survival and better systemic options for patients with metastatic disease, more patients may be candidates for consideration of repeat WBRT for recurrent brain metastases, but prospective studies are needed to more clearly document their outcomes.     

MR characterization of brain and brain tumor response to radiotherapy

This paper describes our experience in using the T1 and T2 relaxation times for quantitative evaluation of brain and brain tumor response to radiation therapy. Twenty-two computed T1 and 22 computed T2 images were obtained from 66 routine inversion-recovery and spin-echo magnetic resonance (MR) brain scans. The relaxation times of the brain tissues, determined from the computed images, were examined as a function of the absorbed dose. Statistical evaluation of the results showed no significant difference between the relaxation times of irradiated and not irradiated tissues, including tumor and normal white matter. Influence of the magnetic field strength and imaging techniques on the computed T1 and T2 values was confirmed. We conclude that the relaxation time values, as obtained today using conventional MR scanner and standard software, are not specific enough to warrant a correct assessment of the acute radiation effect on the brain tissues.     

Subacute brain atrophy induced by radiation therapy of malignant brain tumors

In order to analyze brain atrophy after radiation therapy to the brain tumors, we calculated a CSF-cranial volume ratio on CT scan as an index of brain atrophy, and estimated dementia-score by Hasegawa's method in 91 post-irradiated patients with malignant brain tumors. Radiation-induced brain atrophy was observed in 51 out of 91 patients (56%) and dementia in 23 out of 47 patients (49%). These two conditions were closely related, and observed significantly more often in aged and whole-brain-irradiated patients. As radiation-induced brain atrophy accompanied by dementia appeared 2-3 months after the completion of radiation therapy, it should be regarded as a subacute brain injury caused by radiation therapy.     

Isolation and characterization of microvessels from normal brain and brain tumors

We describe a new technique for isolating microvessels from both brain and brain tumors. This method is relatively quick and provides a microvessel preparation free of contamination by other brain tissue. Using this method, structurally intact microvessels from normal rat brain and from a malignant rat astrocytoma were isolated and characterized with light microscopy, scanning electron microrscopy and transmission electron microscopy. In contrast to microvessels derived from normal rat brain, rat astrocytoma microvessels had endothelial cells with multilayered basement membranes, extensive microvilli on the cell surfaces, and a significant increase in the number of pinocytes in the cytoplasm. Furthermore, astrocytoma microvessel endothelial cells had pleomorphic electron dense nuclei with pale perichromatin, whereas the nuclei of endothelial cells of microvessels derived from normal brain tissue were finely granular and homogeneous with characteristically electron dense perichromatin. The morphologic characteristics of the astrocytoma microvessels are similar to the histologic changes seen in astrocytoma tissue in situ, and correlate well with the known altered functions of brain tumor neovasculature.     

Astroglial growth factors in normal human brain and brain tumors: comparison with embryonic brain

Summary Aqueous extracts of 18-day embryonic chicken brains, 15-day embryonic and adult rat brains and human brain tumors, as well as control histologically-normal adult human brain taken from around brain tumors or around arteriovenous malformations each stimulated the growth of cultured chick astrocytes. Eight mitogenic fractions were separated reproducibly by Bio-Gel P-10 molecular seive chromatography. They had apparent molecular weights (M.W.) of 24, 17, 12, 9, 5, 2.8, 1.4 and 1.2 kD. The activity of each fraction was concentration dependent. The fractions did not appear to be artifactually derived by proteolysis from a larger mitogen since (i) protease inhibitors were added at the time of homogenization to prevent degradation, (ii) protease treatment did not produce large quantities of the lower molecular weight fractions, (iii) incubation of brain extracts for up to four hours at 30° C did not alter the activity of the various mitogenic fractions and (iv) addition of albumin to inhibit protease activity similarly did not change the profile of the factors. In contrast, treatment with protease reduced the activity of all the factors although those with M.W. of 5 and 1.2 kD were inactivated more slowly than the others. The various fractions were stable when rechromatographed. This suggested they were not chance aggregates derived artifactually during extraction but rather might have physiological and pathological roles. The activities of each mitogenic fraction were significantly higher in brain extracts from embryonic rats than in those from adult rats. In brain extracts of rat and chicken embryos the fractions of lower M.W. 5 kD to 1.2 kD were relatively abundent. In contrast in brain extracts from adult rats the predominant mitogenic fractions had apparent M.W. of 24,17 and 12 kD. In histologically normal adult human brain taken from around the tumors or around arteriovenous malformations the 5 kD fraction was present in small amounts and the fractions of lower molecular weight were present in very small amounts. In human glial brain tumors there was a preponderance of the 5 kD activity and more of the 2.8 and 1.4 kD activity fractions than in histologically normal adult human brain. But there was relatively less activity in the 24 and 17 kD fractions. The growth factor profile of human meningiomas was quite different from that of histologically normal human brain or human glial brain tumors. The fraction from meningiomas that was most mitogenic for astrocytes had a molecular weight of 12 kD. Although the higher molecular weight factors may represent already described growth factors derived from brain, the lower molecular weight factors have not been reported previously.