编者按：脑转移累及许多癌症患者。由于大多数全身疗法的颅内渗透有限，诊断时脑转移的大小和数量，决定了对于体积大或病灶多的脑转移，需要分别采用创伤性或毒性较大的疗法，例如神经外科手术切除或全脑放疗（WBRT）。因此，美国国家综合癌症网络共识指南推荐对所有脑转移发生率较高的癌症（例如II～IV期非小细胞肺癌、任何分期小细胞肺癌、IIIC～IV期黑素瘤）患者进行脑部磁共振筛查。脑转移也常见于某些乳腺癌患者，例如新发转移性人表皮生长因子受体2（ERBB2/HER2）阳性或三阴性乳腺癌患者已有脑转移占8%～11%，并且此类患者在临床过程中的脑转移发生率高达53%。不过，美国国家综合癌症网络并不推荐对所有乳腺癌患者进行脑部筛查，由于缺乏关于该问题的明确或前瞻研究，推荐意见仅仅根据专家共识。
2018年5月17日，《美国医学会杂志》肿瘤学分册在线发表哈佛大学医学院、达纳法伯癌症研究院、达纳法伯布列根女子癌症中心、哈佛大学陈曾熙公共卫生学院、梅奥医院的研究报告，比较了乳腺癌脑转移患者（大部分未经脑磁共振筛查）与非小细胞肺癌脑转移患者（诊断时大部分经脑部磁共振筛查）的表现、处理和结局，分析了脑部磁共振对于癌症脑转移发生率较高患者的意义，确定了针对脑部进行磁共振筛查选择乳腺癌患者的潜在价值。
该研究首先从达纳法伯布列根女子癌症中心找出2000年1月1日～2015年12月31日新诊断为脑转移接受治疗的乳腺癌患者349例和非小细胞肺癌患者659例，对两者的颅内病变、颅内处理、颅内结局进行比较。通过双侧非配对t检验或威尔科克森符号秩和检验、费希尔精确检验，对连续结局指标与分类结局指标进行比较；通过多因素比例风险回归，对时间相关事件结局进行分析；通过竞争风险回归，对脑转移所致死亡进行评定。将双侧P<0.05定义为有统计学意义。对不同比例的风险因素进行验证。由于为回顾分析，该研究获得达纳法伯哈佛癌症中心伦理审查委员会批准，不需书面或口头的患者知情同意。
结果发现，乳腺癌患者与非小细胞肺癌患者的脑转移相比：
病灶直径较大（中位17比14，四分位距10～29比8～23，单位mm，P<0.001）
病灶数量较多（中位3比2，四分位距1～8比1-4，P<0.001）
出现症状较多（265例比399例，75.9%比60.5%，P<0.001）
发生癫痫较多（59例比75例，16.9%比11.4%，P<0.01）
累及脑干较多（28例比28例，8.0%比4.2%，P=0.02）
累及脑膜较多（40例比14例，11.5%比2.1%，P=0.001）
全脑放疗较多（209例比283例，59.9%比42.9%，P<0.001）
生存时间相似（中位：1.45比1.09年，95%置信区间：1.29～1.65比0.98～1.20，P=0.06）
脑病死亡较多（103例比98例，37.3%比19.9%，P<0.001；死亡风险比，1.54，95%置信区间：1.10～2.17，P=0.01）
因此，乳腺癌患者与非小细胞肺癌患者相比，颅内病变较重，并且较多需要全脑放疗作为初始处理。不过，初始针对脑部治疗后，两组的复发或补救治疗结局相似。该结果表明，乳腺癌患者与非小细胞肺癌患者相比，虽然颅内病变的恶性程度、治疗效果相似，但是确诊时间太迟。由于脑部病变严重影响生活质量，故脑部磁共振筛查对于颅内可能受累的恶性肿瘤患者至关重要。此外，早期发现颅内病变有利于创伤性较小或毒性较低的治疗方法，例如立体定向放射外科手术或谨慎使用新型全身药物，而非全脑放疗或神经外科手术切除。当然，该研究的局限包括回顾研究的通病，即存在选择偏倚、潜在临床混杂因素。此外，84例乳腺癌患者（24.0%）筛查了脑转移（例如，根据患者或医疗服务提供者的偏好、临床研究的需要），比例高于既往筛查率较低的研究，而一些非小细胞肺癌患者并未筛查脑转移，包括那些由于出现脑转移症状而被诊断为非小细胞肺癌的患者。因此，该研究结果的统计学意义趋于零。虽然存在这些局限，但是该研究强烈支持对转移性乳腺癌患者有选择地进行脑部磁共振筛查开展进一步研究。
JAMA Oncol. 2018 May 17. [Epub ahead of print]
Implications of Screening for Brain Metastases in Patients With Breast Cancer and Non-Small Cell Lung Cancer.
Daniel N. Cagney; Allison M. Martin; Paul J. Catalano; Paul D. Brown; Brian M. Alexander; Nancy U. Lin; Ayal A. Aizer.
Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, Massachusetts; Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Dana-Farber Cancer Institute, Boston, Massachusetts; Mayo Clinic, Rochester, Minnesota; Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
This study analyzes the value of magnetic resonance imaging of the brain for patients with cancers that frequently metastasize to the brain.
Brain metastases affect many patients with cancer. Given the limited intracranial penetration of most systemic therapies, the size and number of brain metastases at diagnosis determines management, with more invasive or toxic therapies such as neurosurgical resection and whole brain radiation therapy (WBRT) used for bulky and multifocal disease, respectively. Consequently, consensus guidelines from the National Comprehensive Cancer Network recommend screening magnetic resonance imaging (MRI) of the brain for patients with stage II to IV non-small cell lung cancer (NSCLC), small cell lung cancer of any stage, and stage IIIC to IV melanoma—all cancers that frequently metastasize to the brain.
Brain metastases are common in select patients with breast cancer as well: 8% to 11% of patients with de novo metastatic human epidermal growth factor receptor 2 (ERBB2/HER2)-positive or triple negative breast cancer harbor brain metastases, and 46% to 53% of such patients develop brain metastases during their clinical course. Yet, the National Comprehensive Cancer Network does not recommend brain-directed screening for any patients with breast cancer, a recommendation that is based only on expert consensus given the lack of definitive or prospective studies on this issue. To identify the potential value of brain-directed MRI screening to select patients with breast cancer, we compared the presentation, management, and outcome of patients with breast cancer and brain metastases (which are largely unscreened with brain MRI) with those of patients with NSCLC and brain metastases (which are largely screened with brain MRI at diagnosis of systemic malignant neoplasm).
METHODS
We identified patients treated for newly diagnosed brain metastases between January 1, 2000, and December 31, 2015, at Dana-Farber/Brigham and Women's Cancer Center. We then compared intracranial disease burden at presentation, intracranial management, and intracranial outcomes between patients with breast cancer and patients with NSCLC. Using SAS, version 9.4 (SAS Institute Inc), we compared continuous outcome measures using the 2-tailed unpaired t test or Wilcoxon rank sum test with categorical outcome measures using Fisher exact test; we performed a multivariable Cox regression analysis for time-to-event outcomes, except for neurologic death, which was assessed using the Fine and Gray competing risks regression. A 2-sided P<.05 defined statistical significance. Proportional hazards were verified. This study was approved by the Dana-Farber/Harvard Cancer Center institutional review board, which waived the need for written or oral patient informed consent.
RESULTS
Table 1 compares the baseline characteristics between 349 patients with breast cancer and 659 patients with NSCLC. Patients with breast cancer, compared with patients with NSCLC, presented with larger (median [interquartile range (IQR)] diameter, 17 [10-29] mm vs 14 [8-23] mm; P<.001) and more numerous (median [IQR], 3 [1-8] vs 2 [1-4]; P<.001) brain metastases. Patients with breast cancer were also more likely than patients with NSCLC to be symptomatic at presentation (265 [75.9%] vs 399 [60.5%]; P<.001), present with seizures (59 [16.9%] vs 75 [11.4%]; P=.01), harbor brainstem involvement (28 [8.0%] vs 28 [4.2%]; P=.02), have leptomeningeal disease at diagnosis (40 [11.5%] vs 14 [2.1%]; P<.001), and receive WBRT as initial management (209 [59.9%] vs 283 [42.9%]; P<.001;Table 1). After initial brain-directed therapy, no significant differences in recurrence or treatment-based intracranial outcomes were found between the 2 groups. However, neurological death was more common in patients with breast cancer than patients with NSCLC, both as a percentage of total deaths (103 [37.3%] vs 98 [19.9%]; P<.001; Table 1) and as a time-to-event based outcome (hazard ratio, 1.54; 95% CI, 1.10-2.17; P=.01; Table 2).
DISCUSSION
Patients with breast cancer presented with more advanced intracranial disease than did patients with NSCLC and more frequently required WBRT as initial management. However, after initial brain-directed therapy, no differences in recurrence or salvage therapy-based outcomes between the 2 cohorts were noted. This finding suggests that intracranial disease in patients with breast cancer was not more aggressive or resistant to treatment but rather was diagnosed at a later stage.
Brain-directed MRI screening for patients who harbor malignant neoplasms with potential for intracranial involvement is important given the impact of neurological compromise on quality of life. In addition, early identification of intracranial disease facilitates less invasive or less toxic approaches, such as stereotactic radiosurgery or careful use of promising systemic agents rather than WBRT or neurosurgical resection.
The limitations of our study include its retrospective nature, inherent selection bias, and potential clinical confounders. In addition, 84 patients with breast cancer (24.0%) were screened for brain metastases (eg, patient/provider preference, clinical trial)—representing a higher percentage than in previous studies, which screened less frequently—whereas some patients with NSCLC were not, including patients diagnosed with NSCLC due to symptomatic brain metastases. Our results are, therefore, biased toward the null. Despite these limitations, this study strongly supports further investigation into MRI screening of the brain among select patients with metastatic breast cancer.
DOI: 10.1001/jamaoncol.2018.0813
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