贝伐珠单抗联合阿来替尼治疗ALK阳性肺腺癌脑转移1例

肺癌是全球高发病率、高死亡率的恶性肿瘤,非小细胞肺癌( NSCLC )约占肺癌的 85％.其中间变性淋巴瘤激酶( ALK)融合基因阳性肺癌是NSCLC的独特分子亚型,约占3％～7％[1],棘皮动物微管相关蛋白样 4(EMLL4)-ALK 是NSCLC中的主要融合体,代表大多数ALK阳性病例[2].脑部是最常见的肺癌远处...     

贝伐珠单抗联合奥希替尼治疗晚期肺腺癌致心力衰竭1例

<正>患者女性,67岁,2014年7月因咳嗽咳痰伴发热就诊。胸部CT检查显示右肺尖结节灶,伴右肺门、纵隔多发淋巴结转移。经肺穿刺病理检查显示非小细胞肺癌(腺癌)。2014年8月起行3个周期吉西他滨+顺铂(GP)新辅助化疗方案,化疗后出现Ⅲ度谷丙转氨酶和谷草转移氨酶升高(上限的8倍),疗效评估为部分缓解。2014年11月行肺癌根治术,术后病理     

贝伐珠单抗治疗非小细胞肺癌脑转移的研究进展

脑部是肺癌最常见的远处器官转移部位之一,肺癌脑转移的发生率高,是脑转移性肿瘤中最常见的类型,同时也是肺癌死亡率居高不下的原因之一。抗肿瘤血管生成治疗已成为肺癌治疗的重要手段之一,抗血管生成药物贝伐珠单抗也成为继全脑放疗、立体定位放疗和化疗之后肺癌脑转移患者新的治疗选择。目前,对脑转移的非小细胞肺癌患者应用贝伐珠单抗治疗的临床研究也越来越多,其安全性和有效性是研究重点。本文就贝伐珠单抗治疗非小细胞肺癌脑转移的研究进展做一综述。     

信迪利单抗联合贝伐珠单抗治疗驱动基因阴性晚期肺腺癌护理观察

目的 探讨信迪利单抗联合贝伐珠单抗治疗驱动基因阴性晚期肺腺癌过程中个性化护理效果。方法 纳入郑州大学第一附属医院2020年1月至2022年1月收治的73例接受信迪利单抗联合贝伐珠单抗二线或三线治疗的驱动基因阴性晚期肺腺癌患者,根据护理干预方式的不同分为观察组和对照组,其中对照组33例给予治疗的同时进行常规护理,观察组40例在对照组处理的基础上给予个性化护理。比较观察2组患者近期疗效、生活质量、不良反应、护理满意度等。结果 观察组总有效率为60.00%,高于对照组的51.52%,但比较差异无统计学意义(χ²=0.529,P=0.467)。治疗后,观察组KPS评分为(88.10±5.32)分,高于对照组的(81.42±4.96)分,差异有统计学意义(t=5.500,P<0.001)。2组主要不良反应均为恶心呕吐、腹泻、肝功能异常、甲状腺功能异常、心肌炎、脱发、皮疹、口腔黏膜炎、呼吸困难等,多为轻度,均未影响治疗的正常进行。观察组护理满意度为95.00%,高于对照组的75.76%,差异有统计学意义(χ²=4.153,P=0.042)。结论 信...     

贝伐珠单抗治疗肺腺癌脑转移瘤伴难治性脑水肿效果观察

目的探讨贝伐珠单抗治疗肺腺癌脑转移瘤伴难治性脑水肿的效果及对血清血管内皮生长因子(VEGF)的影响。方法回顾性分析2015年7月至2018年12月青岛市中心医院收治的25例肺腺癌脑转移伴难治性脑水肿患者的临床资料,既往经甘露醇联合糖皮质激素脱水降颅压治疗无效。患者分为单用贝伐珠单抗组和联用贝伐珠单抗组。给予贝伐珠单抗(5 mg/kg)治疗后评估患者临床症状、功能状态评分(KPS)、瘤周水肿程度以及血清VEGF水平的变化。结果治疗后19例患者症状明显减轻,6例患者症状改善不明显;所有患者KPS评分高于治疗前,瘤周水肿指数较治疗前下降,差异均具有统计学意义(均P<0.05)。治疗后血清VEGF水平较治疗前降低,且联用贝伐珠单抗组血清VEGF水平低于单用贝伐珠单抗组,差异均有统计学意义(均P<0.05)。治疗中出现高血压3例,便血及咯血各1例,经对症处理后好转,无严重不良反应发生。结论贝伐珠单抗治疗肺腺癌脑转移伴难治性瘤周水肿具有一定疗效,可以改善患者生命质量,且可有效降低患者血清VEGF水平,提示VEGF有可能成为判断疗效及疾病进展的重要指标之一。     

奥希替尼联合抗血管生成靶向药对人肺腺癌细胞抑制作用的实验研究

目的:通过体外细胞学实验初步探究奥希替尼联合两种不同机制的抗血管靶向治疗药物（贝伐珠单抗或阿帕替尼）治疗表皮生长因子受体（EGFR）敏感突变和T790M耐药突变肺腺癌细胞的抗肿瘤活性及其作用机制。方法:培养人肺腺癌细胞PC-9（E19 del）和H1975（E21 L858R/E20 T790M）,CCK-8法检测奥希替尼及抗血管靶向治疗药物（贝伐珠单抗或阿帕替尼）单药或联合处理肺腺癌细胞48 h后的抑瘤率;蛋白质印迹法检测EGFR及其下游AKT和ERK信号通路蛋白表达情况。结果:PC-9和H1975肺腺癌细胞对奥希替尼敏感且呈剂量依赖性。奥希替尼联合抗血管生成靶向药物（贝伐珠单抗,阿帕替尼）较同等浓度的单药奥希替尼可增加对PC-9和H1975细胞株的抑瘤率（P<0.05）。低浓度奥希替尼联合高浓度阿帕替尼（1 000 nmol/L）的抑制作用与高浓度奥希替尼相当（P>0.05）。随着联合的阿帕替尼浓度的升高,对PC-9和H1975细胞抑瘤率也有一定程度的提高（P<0.05）。不同处理因素对PC-9细胞的抑制率均高于对H1975细胞（P<0.01）。随着奥希替尼浓度的上升,p-EGFR、p-AKT、p-ERK磷酸化蛋白表达逐渐降低。结论:奥希替尼联合贝伐珠单抗或阿帕替尼会进一步增强对EGFR敏感突变或T790M突变肺腺癌细胞的杀伤作用。奥希替尼与阿帕替尼联合使用具有很强的抑瘤活性,具有很好的应用前景。奥希替尼单药或与抗血管形成药联合作用可能是进一步下调EGFR及其下游AKT和ERK信号通路的活化。     

贝伐珠单抗联合厄洛替尼治疗NSCLC疗效及安全性Meta分析

目的 贝伐珠单抗(bevacizumab,B)及厄洛替尼(erlotinib,E)作用于不同的靶点,在抗肿瘤机制中有相互补充的作用,本研究通过Meta分析比较贝伐珠单抗联合厄洛替尼(B+E)与贝伐珠单抗单药治疗(Bevacizumab,B)或联合化疗(B+chem)对非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的疗效及安全性.方法 计算机检索Medline、web of science、Cochrane library和EMbase等数据库,结合手工检索,检索时间至2016-12-18,收集比较B+E与B或B+chem治疗NSCLC的临床试验,按照Cochrane系统评价方法,采用 RevMan 5.3软件进行 Meta 分析,分析了无进展生存期(progression-free-survival,PFS)、总生存期(overall survival,OS)和不良事件(adverse event)等结局指标.结果 共纳入6项临床试验.B+E与B单药治疗相比,能够提高患者的PFS,HR=0.65,95%CI为0.57~0.74;两组OS差异无统计学意义,HR=0.96,95%CI为0.83~1.11.对于EGFR突变的患者,B+E与B单药治疗相比,能够提高患者的PFS,HR=0.43,95%CI为0.30~0.61;而在EGFR野生型患者中,B+E与B单药治疗PFS差异无统计学意义,HR=0.85,95%CI为0.70~1.04.而B+E与B+chem治疗相比,B+E组PFS(HR=1.88,95%CI为1.45~2.44)及OS(HR=1.36,95%CI为1.03~1.79)均显著低于B+chem组.EGFR突变的患者,B+E与B+chem相比,PFS差异无统计学意义,HR=0.58,95%CI为0.22~1.55).而在EGFR野生型患者中,B+E与B+chem相比,PFS更短,HR=1.96,95%CI为1.37~2.82.B+E方案可能会增加患者发生3~4级皮疹及腹泻的可能.结论 在NSCLC患者中,B+E治疗方案与B单药治疗相比具有更好的疗效,然而与B+chem方案相比,B+E方案仅在EGFR突变患者中具有更好的疗效.结果仍需大样本量研究证实.     

贝伐珠单抗治疗脑转移瘤难治性瘤周水肿的疗效分析

目的 观察贝伐珠单抗治疗恶性肿瘤脑转移瘤难治性瘤周水肿的疗效及不良反应。方法 回顾性分析于本院接受贝伐珠单抗治疗的14例伴难治性瘤周水肿的恶性肿瘤脑转移瘤患者的临床资料,包括乳腺癌脑转移7例、肺癌5例、食管癌1例、右上颌窦腺样囊性癌1例。所有患者均为甘露醇、地塞米松等常规治疗无效的难治性脑水肿病例。评估患者在贝伐珠单抗治疗前后的临床症状、生活质量评分及MRI显示的水肿体积,并详细记录治疗相关不良反应。结果 全组患者接受贝伐珠单抗治疗的中位剂量为4.76 mg/kg。全组14例患者中,11例患者在贝伐珠单抗给药后头晕、头痛症状明显减轻,3例患者症状改善不明显。全组14例患者贝伐珠单抗治疗后瘤周水肿体积较治疗前明显减少［（38 804±14 859）mm3 vs.（80 100±28 338）mm3,P=0.02］,水肿指数较治疗前有降低的趋势（15.38±7.12 vs. 26.40±16.52,P＞0.05）,但差异无统计学意义。14例患者中有1例于第2次贝伐珠单抗治疗后出现上颌窦创面大量出血死亡,3例患者出现可控制的高血压,未出现蛋白尿、贫血、口腔炎等其他并发症。结论 贝伐珠单抗可控制恶性肿瘤脑转移的难治性瘤周水肿,为严重脑水肿患者争取放疗机会,但应谨慎掌握适应证,警惕严重不良反应。     

不同EGFR突变肺腺癌脑转移患者WBRT分析

目的 探讨肺腺癌脑转移患者不同EGFR突变状态WBRT疗效差别。方法 回顾分析2010—2015年在本院诊治的89例肺腺癌脑转移患者,所有患者均行EGFR检测。脑转移一线6 MV X线外照射:WBRT30 Gy分10次或40 Gy分20次(≤3个脑转移灶IMRT同步加量40~45 Gy分10次或50~60 Gy分20次)。比较EGFR突变和野生型患者的有效率、IPFS、OS。Kaplan-Meier法计算IPFS、OS并Logrank检验和单因素分析,Cox模型多因素分析。结果 89例患者总有效率为62%,中位IPFS为7.0个月(95%CI为6.060~7.940),中位OS为12.0个月(95%CI为9.539~14.465)。单因素和多因素分析结果显示脑转移患者有效率与KPS评分、EGFR突变状态相关(P=0.009、0.035),KPS评分、EGFR突变状态是IPFS的影响因素(P=0.048、0.000),KPS评分、原发灶控制是OS的影响因素(P=0.000、0.031)。结论 肺腺癌脑转移患者WBRT后,EGFR突变较野生型有效率高,IPFS时间长,OS无差别。     

Sustained response to standard dose osimertinib in a patient with plasma T790M‐positive leptomeningeal metastases from primary lung adenocarcinoma

A 44‐year‐old male, never smoker, suffers from stage IV adenocarcinoma of the right lung with epidermal growth factor receptor (EGFR) exon‐21 L858R point mutation on initial presentation. After 23 months of treatment with gefitinib, intercalated with multiple courses of radiotherapy, leptomeningeal metastases (LMs) developed. Acquired T790M mutation was confirmed by the droplet digital polymerase chain reaction plasma EGFR test. After switching to osimertinib at the standard dose, his neurocognitive function improved clinically, coupled with sustained radiological improvement. As this clinical entity is underrepresented in clinical trials, the practicability of plasma EGFR testing and the optimal dose–response relationship of osimertinib in T790M‐positive lung cancer complicated with LM deserves further exploration.     

Efficacy of third-line pemetrexed monotherapy versus pemetrexed combination with bevacizumab in patients with advanced EGFR mutation-positive lung adenocarcinoma

Objective

The purposes of this study were to observe the effects of different treatment strategies, including third-line pemetrexed alone versus its combination with bevacizumab, in patients with advanced epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma, and to analyze the effects of the different medication orders of first- and second-line drugs on third-line efficacy.

Patients and methods

One hundred and sixteen cases of patients with EGFR-positive lung adenocarcinoma who had received third-line pemetrexed alone or in combination with bevacizumab between March 2010 and March 2014 at Guangzhou Institute of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University were analyzed retrospectively. Additionally, all the patients were treated with first-line gemcitabine and cisplatin (GP) chemotherapy and second-line EGFR tyrosine kinase inhibitor (TKI) or with first-line EGFR-TKI and second-line GP chemotherapy.

Results

The median survival of 61 cases with third-line pemetrexed monotherapy was 36.22 months, the median survival time of 55 cases with third-line pemetrexed plus bevacizumab was 38.76 months, and there was a significant difference in survival time between the two groups (P=0.04). Subgroup analysis revealed that among the 55 cases with third-line bevacizumab plus pemetrexed treatment, the median survival of 29 patients with first-line GP and second-line EGFR-TKI was 42.80 months, while the median survival of 26 patients with first-line EGFR-TKI and second-line GP was only 34.46 months; additionally, there was a significant difference in the survival time between the two subgroups (P=0.001). Among 61 cases with third-line pemetrexed treatment, the median survival of 34 patients with first-line GP and second-line EGFR-TKI was 38.72 months, while the median survival of 27 patients with first-line EGFR-TKI and second-line GP was only 32.94 months; the survival time of the two subgroups was significantly different (P=0.001).

Conclusions

Regardless of the order of the first- and second-line chemotherapy and TKI therapy, the pemetrexed plus bevacizumab regimen was superior to the pemetrexed monotherapy as the third-line therapy in patients with advanced EGFR-positive lung adenocarcinoma. However, this strategy is worth further investigation in prospective studies.     

Brain metastases in lung adenocarcinoma: impact of EGFR mutation status on incidence and survival

Background

The brain represents a frequent progression site in lung adenocarcinoma. This study was designed to analyse the association between the epidermal growth factor receptor (EGFR) mutation status and the frequency of brain metastases (BM) and survival in routine clinical practice.

Patients and methods

We retrospectively analysed the medical records of 629 patients with adenocarcinoma in Slovenia who were tested for EGFR mutations in order to analyse the cumulative incidence of BM, the time from the diagnosis to the development of BM (TDBM), the time from BM to death (TTD) and the median survival.

Results

Out of 629 patients, 168 (27%) had BM, 90 patients already at the time of diagnosis. Additional 78 patients developed BM after a median interval of 14.3 months; 25.8 months in EGFR positive and 11.8 months in EGFR negative patients, respectively (p = 0.002). EGFR mutations were present in 47 (28%) patients with BM. The curves for cumulative incidence of BM in EGFR positive and negative patients demonstrate a trend for a higher incidence of BM in EGFR mutant patients at diagnosis (19% vs. 13%, p = 0.078), but no difference later during the course of the disease. The patients with BM at diagnosis had a statistically longer TTD (7.3 months) than patients who developed BM later (3.1 months). The TTD in EGFR positive patients with BM at diagnosis was longer than in EGFR negative patients (12.6 vs. 6.8, p = 0.005), while there was no impact of EGFR status on the TTD of patients who developed BM later.

Conclusions

Except for a non-significant increase of frequency of BM at diagnosis in EGFR positive patients, EGFR status had no influence upon the cumulative incidence of BM. EGFR positive patients had a longer time to CNS progression. While EGFR positive patients with BM at diagnosis had a longer survival, EGFR status had no influence on TTD in patients who developed BM later during the course of disease.     

Frequent EGFR mutations in brain metastases of lung adenocarcinoma

Lung adenocarcinomas often metastasize to the brain, and the prognosis of patients with brain metastases is still very poor. The epidermal growth factor receptor (EGFR) gene is mutated in a considerable fraction of primary lung adenocarcinomas, in particular those with drastic response to EGFR tyrosine kinase inhibitors. The present study was designed to elucidate the prevalence of EGFR mutations in brain metastases and the timing of their occurrence during cancer progression. EGFR mutations were detected in 12 of 19 metastatic lung adenocarcinomas to the brain (63%). This frequency was higher than those in previous studies for EGFR mutations at various stages of lung adenocarcinoma in East Asia, including Japan (i.e., 20-55%). In 6 cases with EGFR mutations, the corresponding primary lung tumors were also examined for the mutations, and in all of them, the same types of EGFR mutations were detected also in the primary tumors. In 2 of them, second metastatic brain tumors in addition to the first ones were also available for analysis, and the same types of EGFR mutations were detected in both the first and second ones in both cases. These results indicate that EGFR mutations are present frequently in brain metastases and occur preceding brain metastasis. These findings will be highly informative for treatment of metastatic lung adenocarcinoma to the brain.     

肺腺癌多发脑转移全脑放疗结合化疗的时机与疗效

目的:比较全脑放疗同步化疗与全脑放疗至30Gy时再联合化疗的近期疗效及生存率,以探讨全脑放疗后结合化疗的时机。方法:收集肺腺癌多发脑转移（转移灶>3个）的患者共47例,根据RTOG独立递归分级指数(RPA）先把47例患者分成3层,然后按放化疗的顺序把每层的患者随机分成A、B两组。放射治疗均采取全脑放疗至（40~50）Gy/（20~25）次。化疗方案采用NP方案（培美曲塞二钠+奈达铂）。A组患者全脑放疗并同步给予化疗,B组患者全脑放疗至30Gy再给予化疗。统计学方法用Pearson χ2检验,Fischer's确切概率法检验两组资料入组病例的特征,比较两组的近期疗效、生存率统计及生存曲线绘制采用Kaplain-Meier法,用Log-rank法检测生存率的差异并对各层进行分层分析。结果:A、B两组患者的近期有效率分别为50%与60%(P＞0.05)。A、B两组半年生存率为53.7%与82.2%,1年生存率为10.8%与27.4%,中位生存期分别为7个月与8个月,两组生存率经Log-rank检验, 有统计学差异（P=0.000<0.05）;进一步进行分层分析:第一分层A、B两组的半年生存率为80.2%与100.0%,1年生存率为16.2%与43.6%,中位生存期分别为9个月与11个月,经Log-rank检验,有统计学差异（P=0.000<0.05）;第二分层A、B两组的半年生存率为0与67.3%,1年生存率均为0,中位生存期分别为4个月与7个月,经Log-rank检验,有统计学差异（P=0.000<0.05）;第三分层A、B两组的半年生存率均为0,中位生存期分别为3个月与5个月,经Log-rank检验,有统计学差异（P=0.009<0.05）。结论:全脑放疗至30Gy时再联合化疗较同步放化疗有提高近期疗效的趋势并可延长生存期,对临床治疗具有一定的指导意义。