Brain metastases are a very common manifestation of cancer that have historically been approached as a single disease entity given the uniform association with poor clinical outcomes. Fortunately, ...our understanding of the biology and molecular underpinnings of brain metastases has greatly improved, resulting in more sophisticated prognostic models and multiple patient-related and disease-specific treatment paradigms. In addition, the therapeutic armamentarium has expanded from whole-brain radiotherapy and surgery to include stereotactic radiosurgery, targeted therapies and immunotherapies, which are often used sequentially or in combination. Advances in neuroimaging have provided additional opportunities to accurately screen for intracranial disease at initial cancer diagnosis, target intracranial lesions with precision during treatment and help differentiate the effects of treatment from disease progression by incorporating functional imaging. Given the numerous available treatment options for patients with brain metastases, a multidisciplinary approach is strongly recommended to personalize the treatment of each patient in an effort to improve the therapeutic ratio. Given the ongoing controversies regarding the optimal sequencing of the available and expanding treatment options for patients with brain metastases, enrolment in clinical trials is essential to advance our understanding of this complex and common disease. In this Review, we describe the key features of diagnosis, risk stratification and modern paradigms in the treatment and management of patients with brain metastases and provide speculation on future research directions.
An estimated 20% of patients with cancer will develop brain metastases. Approximately 200,000 individuals in the United States alone receive whole-brain radiotherapy (WBRT) each year to treat brain ...metastases. Historically, the prognosis of patients with brain metastases has been poor; however, with new therapies, this is changing. Because patients are living longer following the diagnosis and treatment of brain metastases, there has been rising concern about treatment-related toxicities associated with WBRT, including neurocognitive toxicity. In addition, recent clinical trials have raised questions about the use of WBRT. To better understand this rapidly changing landscape, this review outlines the treatment roles and toxicities of WBRT and alternative therapies for the management of brain metastases.
Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to ...the tumor.
To investigate whether TTFields improves progression-free and overall survival of patients with glioblastoma, a fatal disease that commonly recurs at the initial tumor site or in the central nervous system.
In this randomized, open-label trial, 695 patients with glioblastoma whose tumor was resected or biopsied and had completed concomitant radiochemotherapy (median time from diagnosis to randomization, 3.8 months) were enrolled at 83 centers (July 2009-2014) and followed up through December 2016. A preliminary report from this trial was published in 2015; this report describes the final analysis.
Patients were randomized 2:1 to TTFields plus maintenance temozolomide chemotherapy (n = 466) or temozolomide alone (n = 229). The TTFields, consisting of low-intensity, 200 kHz frequency, alternating electric fields, was delivered (≥ 18 hours/d) via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both groups (150-200 mg/m2) for 5 days per 28-day cycle (6-12 cycles).
Progression-free survival (tested at α = .046). The secondary end point was overall survival (tested hierarchically at α = .048). Analyses were performed for the intent-to-treat population. Adverse events were compared by group.
Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men 68%), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Systemic adverse event frequency was 48% in the TTFields-temozolomide group and 44% in the temozolomide-alone group. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTFields-temozolomide vs no patients who received temozolomide alone.
In the final analysis of this randomized clinical trial of patients with glioblastoma who had received standard radiochemotherapy, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the previous interim analysis.
clinicaltrials.gov Identifier: NCT00916409.
Summary The SPine response assessment In Neuro-Oncology (SPINO) group is a committee of the Response Assessment in Neuro-Oncology working group and comprises a panel of international experts in spine ...stereotactic body radiotherapy (SBRT). Here, we present the group's first report on the challenges in standardising imaging-based assessment of local control and pain for spinal metastases. We review current imaging modalities used in SBRT treatment planning and tumour assessment and review the criteria for pain and local control in registered clinical trials specific to spine SBRT. We summarise the results of an international survey of the panel to establish the range of current practices in assessing tumour response to spine SBRT. The ultimate goal of the SPINO group is to report consensus criteria for tumour imaging, clinical assessment, and symptom-based response criteria to help standardise future clinical trials.
Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are treatment options for brain metastases in ...patients with EGFR-mutant non-small-cell lung cancer (NSCLC). This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI. Materials and Methods A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study. Exclusion criteria included prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after WBRT/SRS, or insufficient follow-up. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. Overall survival (OS) and intracranial progression-free survival were measured from the date of brain metastases. Results The median OS for the SRS (n = 100), WBRT (n = 120), and EGFR-TKI (n = 131) cohorts was 46, 30, and 25 months, respectively ( P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. Although the SRS and EGFR-TKI cohorts shared similar prognostic features, the WBRT cohort was more likely to have a less favorable prognosis ( P = .001). Conclusion This multi-institutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed.
Central nervous system (CNS) metastases are a common complication in patients with epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer (NSCLC), resulting in a poor prognosis ...and limited treatment options. Treatment of CNS metastases requires a multidisciplinary approach, and the optimal treatment options and sequence of therapies are yet to be established. Many systemic therapies have poor efficacy in the CNS due to the challenges of crossing the blood‐brain barrier (BBB), creating a major unmet need for the development of agents with good BBB‐penetrating biopharmaceutical properties. Although the CNS penetration of first‐ and second‐generation EGFR tyrosine kinase inhibitors (TKIs) is generally low, EGFR‐TKI treatment has been shown to delay time to CNS progression in patients with CNS metastases from EGFR‐mutated disease. However, a major challenge with EGFR‐TKI treatment for patients with NSCLC is the development of acquired resistance, which occurs in most patients treated with a first‐line EGFR‐TKI. Novel EGFR‐TKIs, such as osimertinib, have been specifically designed to address the challenges of acquired resistance and poor BBB permeability and have demonstrated efficacy in the CNS. A rational, iterative drug development process to design agents that could penetrate the BBB could prevent morbidity and mortality associated with CNS disease progression. To ensure a consistent approach to evaluating CNS efficacy, special consideration also needs to be given to clinical trial endpoints.
Implications for Practice
Historically, treatment options for patients who develop central nervous system (CNS) metastases have been limited and associated with poor outcomes. The development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has improved outcomes for patients with EGFR‐mutated disease, and emerging data have demonstrated the ability of these drugs to cross the blood‐brain barrier and elicit significant intracranial responses. Recent studies have indicated a role for next‐generation EGFR‐TKIs, such as osimertinib, in the treatment of CNS metastases. In the context of an evolving treatment paradigm, treatment should be individualized to the patient and requires a multidisciplinary approach.
摘要
在患有表皮生长因子受体(EGFR)突变的非小细胞肺癌(NSCLC)患者中,中枢神经系统(CNS)转移是常见的并发症,可致预后不良并且治疗方案有限。CNS转移的治疗需要多学科方法,而最佳的治疗方案和治疗顺序还有待确定。由于存在穿越血脑屏障(BBB)的挑战,许多全身性治疗在CNS中疗效不佳,导致具有良好BBB穿透性生物制药的开发工作,远远未能满足人们的需求。虽然第一代和第二代EGFR酪氨酸激酶抑制剂(TKIs)的CNS渗透率普遍较低,但EGFR‐TKI治疗已显示延缓了EGFR突变的CNS转移患者的CNS进展。然而,获得性耐药是EGFR‐TKI治疗NSCLC患者的一个主要挑战,大多数接受一线EGFR‐TKI治疗的患者都存在这个问题。新的EGFR‐TKI(如Osimertinib)是专门用来解决获得性抗药性和BBB通透性差的难题,并在CNS中显示了疗效。一个可以穿透BBB的合理迭代的药物开发过程,可以防止CNS疾病进展相关的病损率和死亡率。为了确保评估CNS疗效的一致性,还需要特别考虑临床试验终点。
实践意义
一直以来,向出现中枢神经系统(CNS)转移的患者提供的治疗方案很有限,并且与不良预后相关。表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKIs)的发展改善了EGFR突变患者的预后。已经开始有数据显示,这些药物能够跨越血脑屏障,并引起明显的颅内缓解。最近研究表明,新一代EGFR‐TKI(如osimertinib)在治疗CNS转移中起着重要作用。在不断发展的治疗模式中,治疗应针对患者实现个体化,并需要采取多学科方法。
This review article discusses preclinical and clinical evidence for EGFR tyrosine kinase inhibitors in the treatment of central nervous system metastases, within the context of current treatment options.
Clinical outcomes for glioblastoma remain poor. Treatment with immune checkpoint blockade has shown benefits in many cancer types. To our knowledge, data from a randomized phase 3 clinical trial ...evaluating a programmed death-1 (PD-1) inhibitor therapy for glioblastoma have not been reported.
To determine whether single-agent PD-1 blockade with nivolumab improves survival in patients with recurrent glioblastoma compared with bevacizumab.
In this open-label, randomized, phase 3 clinical trial, 439 patients with glioblastoma at first recurrence following standard radiation and temozolomide therapy were enrolled, and 369 were randomized. Patients were enrolled between September 2014 and May 2015. The median follow-up was 9.5 months at data cutoff of January 20, 2017. The study included 57 multicenter, multinational clinical sites.
Patients were randomized 1:1 to nivolumab 3 mg/kg or bevacizumab 10 mg/kg every 2 weeks until confirmed disease progression, unacceptable toxic effects, or death.
The primary end point was overall survival (OS).
A total of 369 patients were randomized to nivolumab (n = 184) or bevacizumab (n = 185). The MGMT promoter was methylated in 23.4% (43/184; nivolumab) and 22.7% (42/185; bevacizumab), unmethylated in 32.1% (59/184; nivolumab) and 36.2% (67/185; bevacizumab), and not reported in remaining patients. At median follow-up of 9.5 months, median OS (mOS) was comparable between groups: nivolumab, 9.8 months (95% CI, 8.2-11.8); bevacizumab, 10.0 months (95% CI, 9.0-11.8); HR, 1.04 (95% CI, 0.83-1.30); P = .76. The 12-month OS was 42% in both groups. The objective response rate was higher with bevacizumab (23.1%; 95% CI, 16.7%-30.5%) vs nivolumab (7.8%; 95% CI, 4.1%-13.3%). Grade 3/4 treatment-related adverse events (TRAEs) were similar between groups (nivolumab, 33/182 18.1%; bevacizumab, 25/165 15.2%), with no unexpected neurological TRAEs or deaths due to TRAEs.
Although the primary end point was not met in this randomized clinical trial, mOS was comparable between nivolumab and bevacizumab in the overall patient population with recurrent glioblastoma. The safety profile of nivolumab in patients with glioblastoma was consistent with that in other tumor types.
ClinicalTrials.gov Identifier: NCT02017717.
During brain neoplasia, malignant cells subjugate the immune system to provide an environment that favors tumor growth. These mechanisms capitalize on tumor-promoting functions of various immune cell ...types and typically result in suppression of tumor immune rejection. Immunotherapy efforts are underway to disrupt these mechanisms and turn the immune system against developing tumors. While many of these therapies are already in early-stage clinical trials, understanding how these therapies impact various tumor cell populations, including self-renewing cancer stem cells, may help to predict their efficacy and clarify their mechanisms of action. Moreover, interrogating the biology of glioma cell, cancer stem cell, and immune cell interactions may provide additional therapeutic targets to leverage against disease progression. In this review, we begin by highlighting a series of investigations into immune cell-mediated tumor promotion that do not parse the tumor into stem and non-stem components. We then take a closer look at the immune-suppressive mechanisms derived specifically from cancer stem cell interactions with the immune system and end with an update on immunotherapy and cancer stem cell-directed clinical trials in glioblastoma.
Glioblastoma is the most common primary malignant brain tumor diagnosed in the USA and is associated with a poor prognosis. The outcomes in elderly patients (more than 65 years of age) are worse when ...compared to those younger than age 65 at the time of diagnosis. Older patients are not always offered treatments that would otherwise be considered standard of care due to comorbidities and concerns about toxicity and tolerability. The initial European Organization for Research and Treatment of Cancer study that led to approval of temozolomide in glioblastoma excluded patients more than 70 years of age. This review outlines challenges that arise in the treatment of glioblastoma in the elderly population and discusses results of recent studies that established the role of adjuvant chemotherapy in addition to radiation and surgery. There is evidence that these patients can benefit from a more aggressive and safe resection, from hypofractionated radiation treatments, and from adjuvant temozolomide.
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