Management of brain metastases

Brain metastases represent a common and devastating complication of cancer. With advances in surgery, radiology, and medical and radiation oncology, the number of treatment options have greatly increased. In addition, the prognosis for patients can vary widely depending on factors such as the number of lesions, extent of extracranial disease, age, and functional status. Recently, the possible impairment of whole brain radiation therapy on neurocognitive function has been a subject of concern and debate. Thus, the use of whole brain radiation therapy in conjunction with other treatment modalities should be optimized to ensure the best outcomes with regard to tumor control and functional status. As a result, patient management has become controversial, with strong opinions often dictating “optimal” therapy. This review of the management of brain metastases focuses on whole brain radiation therapy, surgery, stereotactic radiosurgery, radiation sensitizers, and clinical trials.     

Management of brain metastases

Brain metastases occur in 20–40 % of patients with cancer and their frequency has increased over time. Lung, breast and skin (melanoma) are the commonest sources of brain metastases, and in up to 15 % of patients the primary site remains unknown. After the introduction of MRI, multiple lesions have outnumbered single lesions. Contrast-enhanced MRI is the gold standard for the diagnosis. There are no pathognomonic features on CT or MRI that distinguish brain metastases from primary malignant brain tumors or nonneoplastic conditions: therefore a tissue diagnosis by biopsy should be always obtained in patients with unknown primary tumor before undergoing radiotherapy and/or chemotherapy. Some factors are prognostically important: a high Performance Status, a solitary brain metastasis, an absence of systemic metastases, a controlled primary tumor and a younger age. Based on these factors, subgroups of patients with different prognosis have been identified (RPA class I, II, III). Symptomatic therapy includes corticosteroids to reduce vasogenic cerebral edema and anticonvulsants to control seizures. In patients with newly diagnosed brain metastases prophylactic anticonvulsants should not be used routinely. The combination of surgery and whole-brain radiotherapy (WBRT) is superior to WBRT alone for the treatment of single brain metastasis in patients with limited or absent systemic disease and good neurological condition. Complete surgical resection allows a relief of intracranial hypertension, seizures and focal neurological deficits. Radiosurgery, alone or in conjunction with WBRT, yields results which are comparable to those reported after surgery followed by WBRT, provided that lesion's diameter does not exceed 3–3.5 cm. Radiosurgery offers the potential of treating patients with surgically inaccessible metastases. Still controversial is the need for WBRT after surgery or radiosurgery: local control seems better with the combined approach, but overall survival does not improve. Late neurotoxicity in long surviving patients after WBRT is not negligeable; to avoid this complication patients with favorable prognostic factors must be treated with conventional schedules of RT, and monitoring of cognitive functions is important. WBRT alone is the treatment of choice in patients with single brain metastasis not amenable to surgery or radiosurgery, and with an active systemic disease, and in patients with multiple brain metastases. A small subgroup of these latter may benefit from surgery. The response rate of brain metastases to chemotherapy is similar to the response rate of the primary tumor and extracranial metastases, some tumor types being more chemosensitive (small cell lung carcinoma, breast carcinoma, germ cell tumors). New radiosensitizers and cytotoxic or cytostatic agents, and innovative technique of drug delivery are being investigated. Received: 20 May 2002, Accepted: 23 May 2002 Correspondence to Riccardo Soffietti, MD     

Management of brain metastases.

Brain metastases are common and often occur in patients whose systemic cancer is quiescent. When brain metastases occur, they considerably decrease the quality of life in patients who otherwise might be functional. An early diagnosis and vigorous treatment of the brain metastasis, while only rarely curative, may lead to a useful remission of the brain symptoms and may both enhance the quality of the patient's life and prolong survival. Patients with known cancer and neurological symptoms should all undergo appropriate diagnostic tests which include either CT scan or magnetic resonance imaging and, if a lesion is found and a definitive diagnosis can not be established, biopsy. Single or solitary brain metastases in patients with good systemic performance status should be strongly considered for surgical extirpation which will both make the diagnosis and deliver definitive treatment to the lesion. Patients with poor systemic performance status and/or multiple brain metastases are candidates for whole brain radiation therapy. Whole brain radiation therapy is also indicated in patients after successful surgical extirpation of a single metastasis. The role of focal radiation therapy and chemotherapy in the treatment of brain metastases is still being evaluated. Preliminary evidence suggests that focal radiation therapy is probably useful for the treatment of relapsed metastases and that chemotherapy may be useful in the primary treatment of small or asymptomatic brain metastases. Appropriate use of therapeutic modalities directed at brain tumors will ameliorate symptoms in most patients and usually increase survival and enhance the quality of the patient's life.     

Current management of brain metastases

INTRODUCTION: Cerebral metastases occur in 15 to 20% of cancers and their incidence is increasing. The majority occur at an advanced stage of the disease, but metastasis may be the inaugural sign of cancer. The aim of treatments, which are often palliative, is to preserve the neurological status of the patient with the best quality of life. STATE OF ART: Corticosteroids are widely used for symptomatic palliation, requiring close monitoring and regular dose adaptation. Antiepileptic drugs should be given only for patients who have had a seizure. In case of multiple cerebral metastases occurring at an advanced stage of the disease, whole brain radiation is the most effective therapy for rapid symptom control. However, radiotherapy moderately improves overall survival, which often depends on the progression of disseminated systemic disease. On the contrary, surgery is indicated in case of a solitary metastasis, particularly when the patient is young (less than 65 years), with good general status (Karnofsky greater than 70), and when the systemic disease is under control. Radiosurgery offers an attractive alternative for these patients with good prognostic factors and a small number of cerebral metastases (< or = 4). PERSPECTIVES: Chemotherapy, considered in the past as not effective, is taking on a more important place in patients with multiple nonthreatening metastases from chemosensitive cancers (breast, testes...). Radiosurgery and whole brain radiotherapy are complementary techniques. Their respective role in the management of multiple metastases (< 4) remains to be further investigated. CONCLUSIONS: Therapeutic options are increasingly effective to improve the functional prognosis of patients with cerebral metastases. Ideally, a multidisciplinary assessment offers the best choice of therapeutic modalities.     

脑转移瘤切除的“超边缘”理念

脑转移瘤（BM）是一些恶性肿瘤的常见并发症,手术作为神经外科治疗颅脑肿瘤最传统的方式依然发挥着不可替代的作用。BM的传统全切手术后往往复发率较高,越来越多的临床与病理证据支持该类肿瘤与正常脑组织并非界限分明,致使脑转移瘤的“超边缘切除”应运而生。鉴于脑功能的保护,应用之初仅限于非功能区,现如今已携手电生理检测、导航系统、术中唤醒等精密手段走进功能区,并基于微创理念在手术入路、瘤体切除等方面不断尝试,努力在最大范围切除肿瘤与保护脑功能之间做到最优化。通过回顾大量BM的超边缘切除相关研究,该文系统阐述了该手术理念的发生与发展。国际神经病学神经外科学杂志, 2023, 50(2): 77-81]     

脑转移瘤的现代治疗

脑转移瘤(brain metastases)系继发于癌症的颅内最常见的肿瘤.Amold等(2001年)报告脑转移瘤比颅内原发肿瘤高出10倍,是造成癌症患者死亡的主要原因之一.由于脑转移瘤患者其原发癌症多非晚期,且脑转移瘤大多为实质性,因此,如获早期诊断和适当地治疗可取得改善症状、延长生存时间和提高生存期生活质量等较满意的临床疗效,值得神经外科医师重视.     

Choriocarcinoma presenting with brain metastases

Abstract

Although choriocarcinoma is a gynaecologic malignancy, it may well present with nongynaecologic symptoms. We present such a case with metastases to the lungs and brain. The malignancy had arisen in a full-term pregnancy ending nine months prior to admission. In female patients presenting with cerebral metastases, a pregnancy test will either confirm or dismiss the possibility of choriocarcinoma. [Neurol Res 1994; 16: 403-404]     

Radation therapy for brain metastases

We treated 183 patients who had brain metastases with whole-brain radiation therapy (RT) and adrenocortico- steroids utilizing a new high-dose radiation protocol. Treatment produced neurological improvement in 135 patients (74%); there was no change in 37 (20%), and deterioration occurred i n l l (6%). Of those patients who improved, two-thirds maintained neurological improvement for the remainder of their lives or for at least nine months, and one-third relapsed. One-third of those who relapsed improved again with steroids or further RT. Clinical improvement paralleled tumor regression on CT scan. Despite the clinical response, median survival was only twelve weeks; 24% lived six months and 8% lived one year. Death resulted from progressive brain disease in 16% of the patients. Two-thirds of the patients died of advancing systemic disease in the setting of stable, improved neurological function. These data suggest that the majority of patients with brain metastases benefit from RT and that systemic cancer, not central nervous system disease, limits the length of life.     

Adjuvant whole brain radiation following resection of brain metastases

Brain metastasis is a common complication of systemic cancer and significant cause of suffering in oncology patients. Despite a plethora of available treatment modalities, the prognosis is poor with a median survival time of approximately one year. For patients with controlled systemic disease, good performance status, and a limited number of metastases, treatment typically entails surgical resection or radiosurgery, followed by whole brain radiotherapy (WBRT) to control microscopic disease. WBRT is known to control the progression of cancer in the brain, but it can also have toxic effects, particularly with regard to neurocognition. There is no consensus as to whether the benefit of WBRT outweighs the potential harm. We review the evidence related to the question of whether patients undergoing surgical resection of brain metastases should receive adjuvant WBRT.     

Meningiomas associated with brain metastases

The authors report a series of 6 patients with simultaneous occurrence of meningioma and single brain metastasis, who underwent surgical removal with histological verification of both lesions. The site of the primary tumor was the breast in 3 cases, the ovary in one, the lung in one, and was unknown in one. Among the six patients, two had a carcinomatous metastasis accidentally found into a meningioma after histological examination of the meningiomatous mass. Two others had a brain metastasis in the cerebral parenchyma surrounding the meningioma; both lesions were removed in an one-stage operation. Finally, two patients, whose lesions were distant, first underwent removal of the brain metastasis, whereas the meningioma was excised 10 and 13 months later. The pathogenetic relationships between meningiomas and tumors of the female reproductive system are discussed. The occurrence of a metastasis into a meningioma is a rather unusual event, which has been described in 50 previously reported cases. The correct differential diagnosis between meningioma and metastasis is very important in these patients. An intracranial mass lesion occurring in patients with known malignant tumors elsewhere in the body (mainly females with breast cancers) has a small but real chance of being a meningioma.     

伽玛刀治疗脑转移瘤的疗效观察

目的 观察伽玛刀治疗脑转移瘤的临床治疗效果.方法 采用国产OUR-XGD型头部伽玛刀,结合手术、放疗、化疗等综合治疗手段治疗112例脑转移瘤患者.结果 随访85例患者,随访期36-72个月,肿瘤控制率95%.生存期1-48个月,平均生存期14.3个月,中位生存期12个月,0.5年生存率86%,1年生存率59%,2年生存率21%.结论 伽玛刀治疗脑转移瘤是一种安全有效的治疗手段,配合科学合理的综合治疗措施可进一步提高疗效.

Abstract：

Objective To explore the efficacy of gamma knife radiosurgery for brain metastases.Method 112 cases with brain metastases were treated by gamma knife.Among them, most cases were combined surgery with whole brain radiation therapy and chemotherapy.Results 85 cases were followed up for 36-72 months,the total local control rate was 95%, the mean survival time of all patients was 12 months,0.5 year survival rate was 86%, 1 year survival rate was 59%, 2 year survival rate was 21%.Conclusions The treatment of gamma knife radiosurgery for brain metastases is an effective and safe method.     

立体定向放射外科治疗脑转移瘤

目的：探讨脑转移瘤的立体定向放射治疗的方法,临床结果。方法：采用单纯ＳＲＳ治疗颅内转移瘤３３例,ＳＲＳ＋ＷＢＲＴ治疗４２例,３１例行单纯全脑放疗。单纯ＳＲＳ治疗的剂量为１４～２２Ｇｙ／单次,ＳＲＳ＋ＷＢＲＴ则在单次ＳＲＳ后在行全脑放疗３０～４０（ｙ）３～４周,单纯ＷＢＲＴ治疗剂量４０～５０Ｇｙ／４～５周。结果：经２～３年随访,ＳＲＳ组３３例ＰＲ＋ＣＲ局部控制率８７．８％,一年生存率７５．８％,两年生存率４５．５％;ＳＲＳ＋ＷＢＲＴ组４１例,ＣＲ＋ＰＲ９２．９％,一年生存率８８．１％,两年生存率４７．６％;两组对照无显著差异（Ｐ〉０．１０）,但无对照有显著差异（Ｐ〈０．０５）,ＷＢＲＴ组３１例,ＣＲ＋ＰＲ８７．１％,两年生存率２５．８％,与ＳＲＳ＋ＷＢＲＴ组对照无显著差异（Ｐ〉０．１０）,瘤生存率分别为４８．４％     

Extraneural metastases of paediatric brain tumours

A survey of published cases of extraneural metastases of primary brain tumours in children under the age of 18 years revealed 245 cases; 60.7% occurred in boys and 27.3% were directly related to the placing of a shunt. The most common entities leading to extraneural metastases were medulloblastomas (56.3%), germinomas (9.8%), glioblastomas (6.9%), ependymomas (3.7%) and pilocytic astrocytomas (2.9%). While medulloblastomas were frequent among non-shunt-related metastases (69.4%), germ cell tumours were most common among shunt-related metastases (33.3%). Metastases were encountered equally often in bone (56.3%) and visceral organs (55.5%) but were markedly rarer in lymph nodes (25.3%). Medulloblastomas showed a preference for bones (88.3% of cases), germinomas for bones (77.8%) and visceral organs (66.7%), whereas ependymomas and ependymoblastomas were more frequently found in lymph nodes and visceral organs (71.5-100%). The most frequent sites of bone metastases were the pelvis (59.3% of cases with osseous lesions), femur (54%) and vertebrae (46%). Medulloblastomas preferentially spread into pelvis, femur and vertebrae, whereas germ cell tumours mainly involved pelvis, femur and ribs and glioblastomas vertebrae and pelvis. Most frequent sites of lymph node metastases were cervical (45.8% of cases with nodular lesions) and thoracic (31.3%) with 54% of children suffering from medulloblastomas and 7.9% from germ cell tumours. The most frequent organ involved in non-shunt-related metastases were the lungs (56.5% of children with visceral lesions) followed by muscle/soft tissue (26.9%), pleura (16.4%), skin (14.9%) and liver (13.4%). Among shunt-related cases, the peritoneum was the most frequent site (86.6% of children). The mean interval between primary brain tumour and occurrence of metastasis was 22.1 months with particularly grave outcomes among medulloblastomas, non-germinomatous germ cell tumours and glioblastomas (85.5-100% deceased children), whereas 60% of children suffering from germinomas were still alive at the time of reporting.     

X-刀治疗脑转移瘤

从1995年3月到1996年3月,我院采用德国Brain Scan X-刀治疗系统,共治疗180例颅内疾病病人,其中脑转移瘤43例,经过6～12个月随访,结果表明,X-刀治疗脑转移瘤效果理想,肿瘤生长局部控制率达95.34%,81.40%肿瘤于3～6个月内消失或明显缩小,6个月以上生存率达77.14%,无明显并发症.本文总结了适应证的选择、影像学要求、治疗计划设计和优化、疗效判断标准以及并发症防治等方面的经验和体会.     

Extraneural metastases in childhood brain tumors

Althogh extraneural metastases are known to occur with primary tumors of the central system, they are considered a rarity. Large autopsy series have place the frequency at 0.4 to 0.5%. At the roswell Park Memorial Institute, 36 children with brain tumors have been treated with a combination of surgery, radiotherapy, and chemotherapy in the past 12 years. We recently reviewed the autopsies obtained on 15 of these children and found that 4 (26%) had extraneural metastases. An additional child, who was not autopsied, had extraneural extension diagnosed during life. This inordinately high incidence of metastases outside the nervous system in children with aggressively trated brain tumors raises questions about their cause. The prolonged survival of these patients may have allowed growth of sufficient generations of extracranial metastatic cells for the extraneural disease to become clinically significant. Another possibility is that chemotherapy may alter the patients' immune system and thus promote extracranial tumor growth. As larger numbers of childhood brain tumors are managed with multimodality therapy, it may be possible to evaluate the extent to which tratment allows intracranial neoplasms to spread outside the nervous system.     

Lack of angiogenesis in experimental brain metastases

Angiogenesis is believed to be essential for the growth of metastatic tumors in the brain. We analyzed the vascularization of tumors formed by 4 epithelial cell lines (C38, ZR75, HT25, and H1650) and a fibrosarcoma (HT1080) cell line injected into the brains of mice. No peritumoral angiogenesis was observed. Tumors apparently acquired their vasculature by incorporation of native vessels. Vessel density was lower, but vessel diameter and vascular cell proliferation were higher within all tumors versus those in the peritumoral tissue. There was an inverse correlation between the number of incorporated vessels and vascular cell proliferation. Epithelial tumors with pushing growth patterns had lower vessel density and elevated vascular cell proliferation compared with invasive tumors. The incorporated vessels retained their normal structure, with the exception of astrocyte foot processes that were replaced by tumor cells. Attachment to the vascular basement membrane led to the differentiation of the ZR75 breast cancer cells. In the HT1080 metastases, there was intussusceptive angiogenesis, that is, the fibrosarcoma cells that were attached to the vessel caused lumen splitting and filled the developing pillars. Branching angiogenesis was not observed either in the tumors or in control cerebral wounds. These data suggest that sprouting angiogenesis is not needed for the incipient growth of cerebral metastases and that tumor growth in this model is a result of incorporation of host vessels.     

脑转移瘤的诊断和外科治疗

目的 总结脑转移瘤的治疗经验.方法 回顾分析76例神经外科收治的临床或病理确诊为脑转移瘤的病例资料.结果 55例接受开颅转移瘤切除术,其中2例死亡;2例行活检术;2例急诊去骨瓣减压术;5例行放化疗;12例对症支持治疗.结论 根据患者病情合理选择外科治疗可以取得较好的疗效.     

伽玛刀治疗脑转移瘤临床分析

目的　回顾分析伽玛刀治疗脑转移瘤的方法及疗效。方法　伽玛刀治疗脑转移瘤 2 6 2例 ,随访 182例共 2 76个病灶。单发 39例 ,单纯伽玛刀治疗 2 1例 ,伽玛刀 +全脑放疗 18例。多发 14 3例 ,伽玛刀治疗前后均辅以全脑放疗。结果　 182例随访 6～ 2 8个月。完全缓解 110例 (6 0 .4 % ) ,部分缓解 6 2例 (34.1% ) ,无变化 7例(3.8% ) ,进展 3例 (1.7% )。生存期 3～ 2 8个月 ,平均 14个月。存活 12个月以上 76例 (41.8% ) ,存活 2 4个月以上 82例 (45 .1% )。 39例单发转移瘤 ,两种治疗方法的治疗结果无显著差异 (P >0 .0 5 )。结论　伽玛刀治疗脑转移瘤 ,安全、见效快、并发症少 ,疗效确切 ,能有效的提高生存质量 ,延长生长时间。单发或 3个以内的转移瘤 ,可以单用伽玛刀单次或分次治疗 ,避免全脑放疗的不良反应。