Follow-up neurological evaluation in patients with small cell lung carcinoma treated with prophylactic cranial irradiation and chemotherapy

The safety of prophylactic cranial irradiation (PCI) has recently been questioned, based on reports of computerized tomographic abnormalities mainly seen in children, who received PCI and chemotherapy, primarily for acute lympbocytic leukemia. In order to clarify the significance of these findings, we examined a series of adult patients who were long term survivors (18–48 months, median 26 months, after all treatment). These patients were treated with combination radiotherapy and chemotherapy for small cell lung carcinoma and received cranial irradiation in the absence of known brain involvement by tumor. Patients were divided into three groups: three patients who received PCI + intrathecal metbotrexate (MTX) (Group 1), and ten who received only PCI (Group 2). An additional three patients (Group 3) were identified as long term survivors (41–70 months after all treatments) of a similar treatment program without any central nervous system (CNS) prophylaxis. All patients received an extensive evaluation of a variety of clinical parameters, EEG, and computer tomography (CT). Although CT abnormalities were detectable (mild cerebral atrophy in eight patients, encephaiomalacia in one of the 13 patients with CNS prophylaxis, and wild atrophy in two of the three patients without CNS prophylaxis~ so significant clinical abnormalities or EEG changes were detectable. While this group of patients is small, it is a unique cohort: adults who have received cranial irradiation in the absence of known brain tumor with long term follow-up. The precise role of CNS prophylaxis in the etiology of CT abnormalities is unclear, and the lack of clinically significant changes would suggest no contraindication to PCI when indicated.     

局限期小细胞肺癌预防性脑照射后脑转移相关危险因素分析

小细胞肺癌具有易复发和转移的生物学特点,脑是小细胞肺癌肺外转移的好发部位。局限期小细胞肺癌患者行预防性脑照射(PCI)能够有效降低脑转移的发生率,延长总生存期。但是在PCI后仍有近1/3的患者发生脑转移。本文对PCI后脑转移的危险因素进行综述,目的在于判断何种局限期小细胞肺癌亚组患者能够从PCI中获益,从而为PCI的临...     

550例局限期小细胞肺癌放化疗达缓解者预防性脑照射后脑转移风险评估

目的:评价影响放化疗后达完全缓解、部分缓解(CR/PR)的局限期小细胞肺癌(SCLC)患者预防性脑照射(PCI)后脑转移(BM)风险、预后因素。方法:收集2002—2017年间在浙江省肿瘤医院治疗疗效达CR/PR且经PCI治疗的550例局限期SCLC患者的基本资料,回顾分析PCI后BM风险因素及预后。采用 ...     

局部晚期非小细胞肺癌术后脑转移高危因素分析

背景与目的 脑转移已经成为局部晚期非小细胞肺癌（NSCLC）治疗失败的最主要因素之一。预防性脑放射是否用于NSCLC目前仍没有定论。本研究的目的是评估局部晚期NSCLC术后发生脑转移的高危因素，以便确定预防性脑放射的指征。方法 回顾性分析223例在我院行外科手术的Ⅲ期NSCLC患者，分析其脑转移的高危因素，建立数学模型。结果 全组病例中位生存期28个月，1、2、3年生存率分别为84．3％、56．9％、44．8％。全组病例脑转移发生率为38．1％（85／223）。多个区域纵隔淋巴结转移、多个纵隔淋巴结转移以及非鳞癌患者的脑转移发生率显著高于单区域纵隔淋巴结转移、纵隔淋巴结转移数目较少以及鳞癌患者（P=0．000，P=0．000，P=0．013）。脑转移的高危数学模型：logit（P）=8．215-0．903×纵隔淋巴结阳性数-0．872×手术性质-0．714×病理类型-1．893×纵隔淋巴结转移程度-0．948×病理分期-1．034×术后化疗。P≥0．44为脑转移高危人群。结论 局部晚期NSCLC术后脑转移高危因素有：非鳞癌、纵隔多区域淋巴结转移、纵隔多个淋巴结转移。P≥0．44可能作为局部晚期NSCLC患者在临床研究中行预防性脑放射的参考指征。     

局限期小细胞肺癌预防性脑照射后脑转移相关危险因素分析

目的:明确局限期小细胞肺癌患者行预防性脑照射（prophylactic cranial irradiation,PCI）后发生脑转移的危险因素,并对相关因素进行分析。以筛选出不能从PCI中获益的人群,为PCI的临床应用提供参考。方法:回顾性分析2011年08月至2019年12月在我院接受过PCI的167例局限期小细胞肺癌患者的病历资料。采用SPSS 26.0统计软件对病历资料进行统计分析。用Kaplan-Meier法计算脑转移发生率及总生存率,并用Log-rank法进行检验。采用Cox回归对影响脑转移及总生存的危险因素进行单因素及多因素分析。结果:局限期小细胞肺癌患者PCI后1、2、3年脑转移率分别为3.8%、12.7%、18.9%。单因素及多因素分析结果显示原发肿瘤为T4期(P=0.004,HR=7.06,95%CI:1.86~26.82)是影响患者PCI后脑转移的危险因素,T2期（P=0.008,HR=2.48,95%CI:1.26~4.89）、T3期(P=0.003,HR=3.38,95%CI:1.49~7.47)、T4期(P=0.001,HR=3.87,95%CI:1.79~8.35)是影响患者总生存的危险因素。结论:较高的T分期是局限期小细胞肺癌患者PCI后脑转移及总生存的独立危险因素。即使T4期患者PCI后脑转移发生率高于其他期别,但仍能够从PCI中获益。     

乳腺癌发生脑转移的相关因素分析

目的探讨转移性乳腺癌发生脑转移的危险因素.方法采用临床分析的方法对199例转移性乳腺癌病例归纳总结,并采用COX模型单变量和多变量分析法对临床特征进行统计分析.结果肺转移的存在(比值比=4.26,95%,CI:1.9%～9.3%,P=0.0003)和激素受体阴性状态:(比值比=4.15,95%,CI:1.6%～10%,P=0.002),CerbB-2阳性(比值比=4.22,95%,CI:1.5%～11%,P=0.0006)是脑转移发生的预测因素.结论在转移性乳腺癌患者中,肺转移是首发转移位置,激素受体阴性CerbB-2阳性是发生脑转移的危险因素,应在这些患者中进行预防性治疗.     

Systematic analysis of early phase clinical studies for patients with breast cancer: Inclusion of patients with brain metastasis

PurposeThis systematic review aims to better define the limitations and patterns with which patients with MBC and CNS metastasis are enrolled into early phase developmental therapeutics trials.MethodsIn June 2016, PubMed search was conducted using the following keywords: “Breast cancer”. Drug-development phase 1, phase 2 or phase 1/2 trials for patients with MBC were included. Multiple-histology trials and trials without an efficacy endpoint were excluded.ResultsIn total, 1474 studies were included; Inclusion criteria for 423 (29%) allowed for CNS metastasis, 770 (52%) either excluded or did not document eligibility of patients with CNS disease. Trials accruing patients with HER2-positive MBC and including targeted therapies had higher odds of allowing for patients with CNS disease (adjusted OR 1.56, 95% CI 1.08–2.2.6; p = 0.019 and 1.49, 95% 1.08–2.06; p = 0.014, respectively). There were also higher odds of accrual of patients with CNS involvement into clinical trials over time (odds ratio = 1.10, 95% CI 1.07–1.12; p < 0.0001).ConclusionMost published early phase clinical trials either did not clearly document or did not allow for accrual of patients with CNS disease. Early phase trials with targeted agents or enrolling HER2+ MBC had higher odds of permitting CNS metastases.     

Risk factors for neurocognitive decline in lung cancer patients treated with prophylactic cranial irradiation: A systematic review

BackgroundProphylactic cranial irradiation (PCI) reduces brain metastasis incidence in lung cancer, however with risk of neurocognitive decline. Nevertheless, risk factors for neurocognitive decline after PCI remain unclear.MethodsWe systematically reviewed the PubMed database according to the PRISMA guideline. Inclusion criteria were: randomized clinical trials (RCTs) and observational/single arm trials evaluating PCI, including ≥20 patients, reporting neurocognitive test results for lung cancer. Primary aim: evaluate risk factors associated with neurocognitive decline after PCI.ResultsTwenty records were eligible (8 different RCTs, 8 observational studies), including 3553 patients in total (858 NSCLC, 2695 SCLC) of which 73.6% received PCI. Incidence of mild/moderate cognitive decline after PCI varied from 8 to 89% (grading not always provided); for those without PCI, this was 3.4–42%. Interestingly, 23–95% had baseline cognitive impairment. Risk factors were often not reported. In one trial, both age (>60 years) and higher PCI dose (36 Gy) including twice-daily PCI were associated with a higher risk of cognitive decline. In one trial, white matter abnormalities were more frequent in the concurrent or sandwiched PCI arm, but without significant neuropsychological differences. One trial identified hippocampal sparing PCI to limit the neurocognitive toxicities of PCI and another reported an association between hippocampal dose volume effects and memory decline. As neurocognition was a secondary endpoint in most RCTs, and was assessed by various instruments with often poor/moderate compliance, high-quality data is lacking.ConclusionsAge, PCI dose, regimen and timing might be associated with cognitive impairment after PCI in lung cancer patients, but high-quality data is lacking. Future PCI trials should collect and evaluate possible risk factors systematically.     

现代诊疗技术下脑预防照射在局限期小细胞肺癌中的疗效分析

目的:探讨现代综合治疗模式及诊断技术下,局限期小细胞肺癌(SCLC)放化疗有效者行脑预防照射(PCI)的疗效及复发失败模式。方法:回顾性分析2006—2014年间共201例于中国医学科学院肿瘤医院接受放化疗综合治疗且达有效[完全缓解(CR)/部分缓解(PR)]的局限期SCLC患者的临床资料。综合治疗采用以调强放疗和≥4...     

局限期SCLC预防性脑照射后脑转移的危险因素分析

目的 评价预防性脑照射后高危脑转移因素,为个体化治疗提供依据。方法 回顾分析2005—2010年间本院诊治的接受PCI的局限期SCLC患者188例。Kaplan-Meier法计算累计脑转移率,采用Logrank法单因素分析和Cox模型多因素分析与累计脑转移发生可能的因素。结果 188例患者中31例出现脑转移(16.5%),其中1、2、3年累计脑转移发生率分别为4%、15%、20%。单因素分析显示治疗前Ⅲ期、肿瘤标记物升高、化放疗后未达CR、局部区域复发患者具有较高的脑转移率(P=0.044、0.037、0.005、0.007),多因素分析显示化放疗结束时未达CR、化放疗后局部区域复发患者PCI后脑转移率高(P=0.003、0.040)。结论 化放疗后未达CR或化放疗后局部区域复发者PCI后具有较高的脑转移率。对这部分患者密切的中枢神经系统随访加挽救性脑放疗可能是较好的替代PCI的方法。     

Research progress on prophylactic cranial irradiation in non-small cell lung cancer

Brain metastasis has become a major failure pattern with the prolonged survival of patients with non-small cell lung cancer (NSCLC). Prophylactic cranial irradiation (PCI) has been proven to play a significant role in small cell lung cancer, whereas its value in NSCLC is still controversial. Therefore, this article reviewed the role of PCI in NSCLC, high-risk factors of brain metastasis, timing, dose fraction and toxicity of PCI, etc.     

Estimation of intracranial failure risk following hippocampal-sparing whole brain radiotherapy

Purpose

To estimate the risk of undertreatment in hippocampal-sparing whole brain radiotherapy (HS-WBRT).

Methods

Eight hundred and fifty six metastases were contoured together with the hippocampi in cranial MRIs of 100 patients. For each metastasis, the distance to the closest hippocampus was calculated. Treatment plans for 10 patients were calculated and linear dose profiles were established. For SCLC and NSCLC, dose–response curves were created based on data from studies on prophylactic cranial irradiation, allowing estimating the risk for intracranial failure.

Results

Only 0.4% of metastases were located inside a hippocampus in 3% of all patients. SCLC showed a relatively high rate of hippocampal metastasis (18.2% of all SCLC patients) and HS-WBRT in a commonly applied fractionation scheme would increase the risk for brain relapse by ∼4% compared to conventional WBRT. NSCLC showed a lower rate of brain metastasis in the hippocampi (2.8%) and HS-WBRT would account for a slightly increased absolute risk of 0.2%.

Conclusions

Prophylactic or therapeutic HS-WBRT is expected to be associated with a low risk of undertreatment. For SCLC, it bears a minimally elevated risk of failure compared to standard WBRT. In NSCLC, HS-WBRT is most likely not associated with a clinically relevant increase in risk of failure.     

术后局限期小细胞肺癌预防性脑照射疗效分析

目的 探讨局限期小细胞肺癌(SCLC)术后行预防性脑照射(PCI)的疗效。方法 回顾分析2003-2015年浙江省肿瘤医院收治的接受根治性手术治疗的52例局限期SCLC患者资料。根据术后是否行PCI治疗分为PCI组(19例,Ⅰ、Ⅱ、Ⅲ期分别为5、5、9例)和非PCI组(33例,Ⅰ、Ⅱ、Ⅲ期分别为12、5、16例)。采用Kaplan-Meier法生存分析,Cox模型多因素预后分析。结果 PCI组和非PCI组中位总生存时间分别为32.9、20.4个月,2年总生存率高于非PCI组(72%∶38%,P=0.023);中位颅内无进展生存时间分别为32.5、17.1个月,PCI组2年颅内无进展生存率优于非PCI组(89%∶53%,P=0.026)。亚组分析结果显示PCI治疗可使Ⅲ期患者总生存获益(P=0.031),而Ⅰ、Ⅱ期患者生存获益不显著(P=0.924、0.094)。多因素Cox回归分析结果显示PCI是总生存的影响因素(HR=0.330,P=0.041)。结论 SCLC术后行PCI治疗可降低术后脑转移的发生率,并使SCLC患者总OS获益。     

影像组学在局限期小细胞肺癌脑预防照射优化中的价值

目的探讨治疗前胸部增强CT影像组学模型对局限期小细胞肺癌(LS-SCLC)脑转移的预测能力以及指导个体化预防性脑照射(PCI)的价值。方法回顾性分析2012年1月至2018年12月在山西省肿瘤医院经病理确诊为小细胞肺癌及影像学检查确定为局限期患者资料97例。基于最小绝对值收缩和选择算子(LASSO)Cox与相关性检验筛选与LS-SCLC脑转移显著相关的影像组学特征构建模型, 使用校正曲线、受试者操作特征曲线下面积(AUC)、内部5折交叉验证、决策曲线分析(DCA)与整合布莱尔评分(IBS)评估影像组学模型的预测效能与临床获益, 使用Kaplan-Merier曲线和log-rank检验绘制生存曲线和评估组间差异。结果提取出影像组学特征1272个, 使用LASSO Cox回归和相关性检验筛选特征, 最后通过8个与LS-SCLC患者脑转移发生相关的影像组学特征构建影像组学模型。影像组学模型预测LS-SCLC患者1年与2年脑转移的AUC分别为0.845(95%CI为0.746～0.943)和0.878(95%CI为0.774～0.983)。5折内部交叉验证、校正曲线、DCA以及IBS显示模型有...     

Analysis of gene expression involved in brain metastasis from breast cancer using cDNA microarray

BACKGROUND: Brain metastases occur in 15% to 30% of breast cancer patients, usually as a late event. The patterns of metastases to different organs are determined by the tumor cell phenotype and interactions between the tumor cells and the organ environment. METHODS: We investigated the gene expression profile occurring in brain metastases from a breast cancer cell line. We used cDNA microarrays to compare patterns of gene expression between the mouse breast cancer cell line Jyg MC (A) and a subline that often metastasis to brain, (B). RESULTS: By Microarray analysis about 350 of 21,000 genes were significantly up-regulated in Jyg MC (B). Many candidate genes that may be associated with the establishment of brain metastasis from breast cancer were included. Interestingly, we found that the expression of astrocyte derived cytokine receptors (IL-6 receptor, TGF-beta receptor and IGF receptor) were significantly increased in Jyg MC (B) cells. These results were confirmed by RT-PCR. CONCLUSIONS: These results suggest that cytokines produced by glial cells in vivo may contribute, in a paracrine manner, to the development of brain metastases from breast cancer cells.     

Radiotherapeutic management of brain metastases from breast cancer

We have reviewed the medical records of 28 breast cancer patients with brain metastases who were treated with radiotherapy at our clinic from 1980 through 1994 (4 patients, postoperatively; 24 patients, radiotherapy alone). Radiotherapy was delivered as whole brain irradiation using lateral opposed 10 MV X-rays. Ten patients received an additional boost to a reduced field. One patient was treated with localized stereotactic irradiation alone. The radiation dose for tumors ranged from 32 Gy to 60 Gy (mean, 49 Gy) in 2 or 3 Gy daily fractionated doses. The brain was the first site of metastatic involvement in only two patients. In the 26 evaluable patients, neurologic functional improvement was achieved in 24 patients (92%) with complete response (CR) in 1 2 patients (46%) and partial response (PR) in 1 2 patients (46%). The survival rates from the initial treatment were 39% at 5 years and 16% at 10 years (median survival time, 50 months), and those after treatment of brain metastases were 29% at one year and 18% at 2 years (median survival time, 6 months). Performance status tended to be associated with survival (p=0.10), and the presence of liver metastasis was the most important risk factor concerning survival (p=0.056). Two patients suffered severe chronic complications. One patient developed severe dementia after whole brain irradiation with a total dose of 45 Gy in 3 Gy daily fractionated dose, and another patient developed widespread brain necrosis after combined radiotherapy with intrathecal local infusion of methotrexate. Radiotherapeutic management is useful for breast cancer patients with brain metastasis, and long-term survival may also be possible even if patients have preexisting extracranial metastases, except for hepatic involvement. Radiation-related complications should therefore be avoided in these patients.     

SRT联合拉帕替尼治疗HER2阳性乳腺癌脑转移疗效及预后分析

目的 探讨立体定向放射治疗(Stereotactic radiotherapy,SRT)联合拉帕替尼治疗HER2阳性乳腺癌脑转移的疗效及预后。方法 回顾性分析91例HER2阳性乳腺癌脑转移患者接受拉帕替尼靶向治疗的同时接受全脑放疗或SRT的情况,其中42例患者接受SRT的同时进行拉帕替尼联合卡培他滨治疗(SRT组),另外49例患者采用全脑放疗同时进行拉帕替尼联合卡培他滨治疗(全脑放疗组)。评价其疗效和毒性,定期随访,并行多因素Cox回归分析其预后相关因素。结果 放疗结束后1月SRT组脑部病灶客观缓解率为92.86%(39/42),全脑放疗组客观缓解率为77.55%(38/49),SRT组优于全脑放疗组(χ²=4.070,P=0.044)。SRT组和全脑组12个月受照射肿瘤病灶无进展生存率分别为95.20%及83.10%, SRT组优于全脑放疗组(χ²=10.851,P=0.001)。 SRT组无颅内转移生存率与全脑放疗组无统计学差异(P＞0.05)。SRT组和全脑放疗组1年生存率分别为85.70%和69.40%,2年生存率分别为66.70%和55.10%,两组中位生存期分别为31.56个月和25.00个月,SRT组优于全脑放疗组(P=0.002)。多因素Cox回归分析结果表明无颅外转移(HR=0.527,95% CI:0.290~0.957,P=0.035),颅内病灶≤3个(HR=2.457,95% CI:1.223~4.933,P=0.012),放疗方式SRT(HR=1.746,95% CI:1.055~2.888,P=0.030)是HER2阳性乳腺癌脑转移放疗预后的独立保护因素。结论 SRT联合拉帕替尼在局部控制率以及生存率上优于全脑放疗联合拉帕替尼。颅内病灶个数少、无颅外转移灶和放疗方式是HER2阳性乳腺癌脑转移治疗的良好预后因素。