Safety and efficacy of outpatient gamma knife radiosurgery for multiple cerebral metastases

This review highlights the experience of a single institution using the Leksell gamma knife for 8 years. More than 500 patients with multiple cerebral metastases received outpatient radiosurgery. The results prove that there is a high efficacy and attractively low morbidity of modern outpatient radiosurgery. When compared with whole brain radiation therapy, radiosurgery improved survival in patients with cerebral metastases. Most importantly, the number of brain metastases had no prognostic impact in patients with non-small cell lung cancer, renal cell cancer, malignant melanoma and gastrointestinal cancer.     

Therapeutic management of brain metastasis

This review focuses on the management of brain metastases. The four main modes of therapy are discussed: whole brain radiation therapy (WBRT), surgery, radiosurgery, and chemotherapy. Young patients with limited extracranial disease may benefit from surgical resection of a single brain metastasis, and from radiosurgery (or stereotactic radiotherapy) if two to four brain metastases are present. Whether WBRT after surgery or radiosurgery is beneficial is uncertain. Therefore, two approaches can be justified in patients with a good prognosis: WBRT after surgery or radiosurgery, or alternatively, observation with MRI follow-up after surgery or radiosurgery. A hyperfractionated radiation scheme is then to be preferred to limit late toxicity of WBRT. Patients with extensive extracranial tumour activity or impaired quality of life may benefit from radiosurgery (one to four brain metastases), or from shorter WBRT schedules. We propose a decision tree on the various ways to treat brain metastasis.     

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.     

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.     

伽玛刀治疗脑转移瘤的临床研究(附112例临床分析)

目的 探讨伽玛刀治疗脑转移瘤的临床疗效及相关因素.方法 采用伽玛刀治疗为主,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83例患者,随访期6～32个月,肿瘤控制率94%,中位生存期10.8个月,1年生存率55.9%,2年生存率15.8%.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.     

Influence of postoperative radiation therapy of cerebral metastases on survival time and disease related to living condition

Cerebral metastases are frequently observed in patients with systemic carcinoma as indication for new progress of the disease. Neurological deficits or seizures indicating cerebral metastases reduce the disease-related living conditions of the patients. Improving quality of life and survival time is the overriding goal of an early treatment after the diagnosis of cerebral metastases. Contemporary treatment include surgical removal of the cerebral metastases followed by whole brain irradiation and in some cases additional systemic chemotherapy for the primary tumor. This study was conducted to test the hypothesis that whole brain radiation following surgical removal improves the quality of life and the survival time in patients with cerebral metastasis. From January 1, 1994 to December 31, 2000, a total of 139 patients (mean age 59 +/- 2.3 years, m : f = 84 : 55) with cerebral metastases were investigated. Disease-related living conditions were assessed by Karnofsky score, the median time of follow-up was 11 months. For the analysis, patients were divided into groups with and without radiation therapy. Additionally, groups of patients with singular and two brain metastases were defined. In patients with singular brain metastases neither the survival time nor disease-related living conditions during the remaining life time was increased by postoperative whole brain irradiation. Almost all patients died due to the progression of the primary tumor. Patients with more than one metastases seemed to have a slight but not significant benefit from irradiation therapy after surgical removal of all metastases. In conclusion, these results indicate that an uncritical irradiation therapy of neurocranium after surgical removal of cerebral metastases is not beneficial in terms of survival time or disease-related living conditions.     

EFNS Guidelines on diagnosis and treatment of brain metastases: report of an EFNS Task Force

The objectives have been to establish evidence-based guidelines and identify controversies regarding the management of patients with brain metastases. The collection of scientific data was obtained by consulting the Cochrane Library, bibliographic databases, overview papers and previous guidelines from scientific societies and organizations. A tissue diagnosis is necessary when the primary tumor is unknown or the aspect on computed tomography/magnetic resonance imaging is atypical. Dexamethasone is the corticosteroid of choice for cerebral edema. Anticonvulsants should not be prescribed prophylactically. Surgery should be considered in patients with up to three brain metastases, being effective in prolonging survival when the systemic disease is absent/controlled and the performance status is high. Stereotactic radiosurgery should be considered in patients with metastases of 3–3.5 cm of maximum diameter. Whole-brain radiotherapy (WBRT) after surgery or radiosurgery is debated: in case of absent/controlled systemic cancer and Karnofsky Performance score of 70 or more, one can either withhold initial WBRT or deliver early WBRT with conventional fractionation to avoid late neurotoxicity. WBRT alone is the treatment of choice for patients with single or multiple brain metastases not amenable to surgery or radiosurgery. Chemotherapy may be the initial treatment for patients with brain metastases from chemosensitive tumors.     

Update of stereotactic radiosurgery for brain tumors

PURPOSE OF REVIEW: This paper will review the recent publications of stereotactic radiosurgery for brain tumors. RECENT ADVANCES: Despite its controversial beginning, stereotactic radiosurgery has rapidly gained acceptance among neurosurgeons, radiation oncologists, and neuro-oncologists as a valuable treatment option for patients with certain benign and malignant brain tumors. Over the past year, a number of publications have confirmed the efficacy and safety of this treatment modality as the sole treatment modality or as part of the multimodality management of brain tumor patients. These publications ranged from the first multi-institutional phase III trial of radiosurgery for patients with brain metastases to numerous retrospective papers about treatment outcomes. Also, a number of these publications have explored the use of newer imaging modalities to improve treatment outcomes while others reported on the rare complication of radiation-associated second tumors. SUMMARY: Recent publications of stereotactic radiosurgery have increased our understanding of the use of this technology. Future studies are needed to further improve outcomes, minimize toxicities and increase our understanding of this treatment modality.     

Metastases to the brain: current management perspectives

Brain metastases are ten-times more common than primary brain tumors and are a common complication in patients with systemic cancer. The most common sources of brain metastases are lung and breast cancers, although in 15% of patients, the primary site is unknown. Optimal treatment is dependant upon tumor location, size, number of tumors and status of the systemic disease. Currently, management of brain metastases with surgery, radiotherapy and stereotactic radiosurgery is known to improve the quality of life and even life expectancy for selected patients. Techniques under investigation include focal radiation techniques, magnetic resonance imaging guided thermal ablation of metastases, drug delivery modes that bypass the blood-brain barrier and novel drug and molecular therapeutics. Efforts are ongoing to understand the molecular biology of brain metastases.     

Chemotherapy and targeted molecular therapies for brain metastases

As therapy for systemic cancers improves, an increasing number of patients are developing brain metastases. Although conventional therapy with surgery, radiation therapy and radiosurgery has improved the outcome of a significant number of patients, many develop multiple lesions that are not amenable to standard treatments. In this review, the current role of chemotherapy and targeted molecular agents for brain metastases is summarized and future directions are discussed.     

Management of Brain Metastases in the New Era of Checkpoint Inhibition

Purpose of the Review

Brain metastasis is a common complication of advanced malignancies, especially, lung cancer, breast cancer, renal cell carcinoma, and melanoma. Traditionally surgery, when indicated, and radiation therapy, either as whole-brain radiation therapy or stereotactic radiosurgery, constituted the major treatment options for brain metastases. Until recently, most of the systemic chemotherapy agents had limited activity for brain metastases. However, with the advent of small molecule tyrosine kinase inhibitors and immunotherapy agents, there has been renewed interest in using these agents in the management of brain metastases.

Recent Findings

Immune checkpoint inhibitors have revolutionized the treatment of metastatic melanoma, lung cancer, kidney cancer, and bladder cancer among others. They modulate the immune system to recognize tumor antigens as “non-self” antigens and mount an immune response against them.

Summary

Initial studies of using immune checkpoint inhibitors in brain metastases have shown promising activity, and several clinical trials are currently underway. Studies are also assessing the combination of radiation therapy and immunotherapy in brain metastases. The results of these ongoing clinical trials have the potential to change the therapeutic paradigm in patients with brain metastases.

     

Stereotactic radiotherapy for cerebral metastases using CyberKnife

During recent decade development of frameless techniques of fixation enabled introduction of stereotactic radiation therapy in metastatic brain lesions and made possible irradiation of large foci involving or proximal to eloquent and critical brain areas. This paper focuses on comparative analysis of effectiveness of hypofractionation (HRST) and radiosurgery (SRS) using CyberKnife system in cerebral metastases. Since November 2009 till June 2011 54 patients with cerebral metastases were treated using CyberKnife system. Age of patients ranged between 25 and 77 years (mean 54 years). 16 patients received radiosurgical treatment (mean total dose was 22.5-35 Gy, number of fractions varied from 2 to 7, mean volume of irradiation was 22.69 cm3) and 8 patients were treated by HRST with RS of selected foci (mean total dose reached 23 and 30 Gy, mean volume of irradiation was 1.02 cm3 and 11.19 cm3, respectively). Indices of overall regression and stabilization of disease for HRST and SRS groups were 81% and 79%, respectively. With mean follow-up period of 12.3 (1-16.1) months median survival for SRS and HRST reached 6.38 (1-15.8) and 6.2 (0.2-16.1) months and median recurrence-free survival was 3.6 (1-13.6) and 5.5 (2-14.2) months, respectively. Obtained results confirmed biological advantages of fractionated stereotactic radiotherapy of large cerebral tumors in comparison with radiosurgery. Prospective studies with rigid criteria of inclusion are required to determine optimal dose/volume/fractionation interrelations in stereotactic radiation treatment of cerebral metastases.     

Brain metastases

PURPOSE OF REVIEW: Brain metastases occur in 10-30% of cancer patients, and they are associated with a dismal prognosis. Radiation therapy has been the mainstay of treatment for patients without surgically treatable lesions. For patients with good prognostic factors and a single metastasis, surgical resection is recommended. The management of patients with multiple metastases, poor prognostic factors, or unresectable lesions is, however, controversial. Recently published data will be reviewed. RECENT FINDINGS: Radiation therapy has been shown to substantially reduce the risk of local recurrence after surgical resection of brain metastases, although this does not translate into improved survival. Recently, stereotactic radiosurgery has emerged as an increasingly important alternative to surgery that appears to be associated with less morbidity and similar outcomes. Other potentially promising therapies under investigation include interstitial brachytherapy, new chemotherapeutic agents that cross the blood-brain barrier, and targeted molecular agents. SUMMARY: Patients with brain metastases are now eligible for a number of treatment options that are increasingly likely to improve outcomes. Randomized, prospective trials are necessary to better define the utility of radiosurgery versus surgery in the management of patients with brain metastases. Future investigations should address quality of life and neurocognitive outcomes, in addition to traditional outcome measures such as recurrence and survival rates. The potentially substantial role for chemotherapeutics that cross the blood-brain barrier and for novel targeted molecular agents is now being elucidated.     

Clinical features of brain metastasis from salivary gland tumors

Salivary gland tumors comprise a group of 24 tumor subtypes with a wide range of clinical behaviors and propensities for metastasis. Several prognostic factors have been identified that help predict the development of systemic metastases, most commonly to the lung, liver, or bone. Metastases to the brain are rare. To better understand the behavior of salivary gland tumors that metastasise to the brain, we performed a retrospective cohort analysis on a series of patients to highlight features of their medical and surgical management. From 2007 to 2011, a database of 4117 elective craniotomies were queried at a single institution to identify patients surgically treated for salivary gland metastases to the brain. Three patients were identified. Histologic subtypes included salivary duct carcinoma, poorly differentiated carcinoma, and papillary mucinous adenocarcinoma. They had all undergone previous treatment for their primary malignancy. The mean time to intracranial metastasis was 48 months from initial diagnosis (range, 14–91 months). Treatment for intracranial metastases included surgical resection, whole brain radiation, stereotactic radiosurgery, and chemotherapy. Intracranial metastases from salivary gland tumors are rare, present years after diagnosis of the primary tumor, and are treatable with multimodality therapy.     

Treating brain metastases: current approaches and future directions

Brain metastases frequently present with neurologic signs or symptoms in a patient with a history of cancer. The finding of a brain metastasis is usually associated with terminal disease. However, patients with brain metastases are a heterogeneous group. Therefore, the treatment of brain metastases must be tailored to each individual patient. In this article, which patients with brain metastases benefit from surgical resection, radiosurgery and whole-brain radiation therapy are reviewed. Reports of treating patients with brain metastases with chemotherapy are also reviewed and data that supports prophylactic treatment of the brain for select patients is discussed. This review aims to provide a framework for treating patients with different presentations of brain metastases and to highlight important avenues for future research.     

伽玛刀联合洛莫司汀治疗脑多发转移瘤的临床研究

目的伽玛刀联合洛莫司汀治疗脑转移瘤,提高疗效。方法采用病例对照研究的方法,采用本中心2004年1月至2005年9月确诊的脑转移瘤病人178例,病灶数446个,随机分为实验组和对照组,实验组85例病人,220个病灶,在伽玛刀治疗(边缘剂量10~14Gy)后给与洛莫斯汀3.5mg/kg体重顿服化疗,每间隔8周给药一次,共计3次。对照组93例病人,226个病灶单纯采取伽玛刀治疗,每隔3个月复查MRI,统计肿瘤的局控率,病人的生存时间和Karnofsky评分以及并发症情况,样本的生存率,然后进行统计学分析。结果实验组的肿瘤局控率,治疗后KPS评分及生存时间、生存率均高于对照组,而并发症的发生率两组间无差异。结论伽玛刀联合洛莫司汀治疗脑转移瘤是一种有效的措施,效果较单纯伽玛刀佳。     

Clinical management of brain metastasis

Brain metastasis is a common complication ocurring in about 15–20% of all cancer patients. For the initial management, distinguishing between three types of presentation is essential: de novo brain metastasis, simultaneous presentation of both brain metastasis and the primary tumour (usually lung carcinoma), and the presentation of a patient known to have systemic cancer developing a brain metastasis. For de novo brain metastasis, surgery is required, and detecting the primary tumour is of limited value. For simultaneous presentation, both a craniotomy and a thoracotomy may be indicated and may lead to cure in a number of cases. For a sequential presentation, the outcome is determined by a number of independent prognostic factors: age, performance status, and the extent of metastatic disease. In relatively young patients with a single brain metastasis, good performance status and no progression of systemic disease, treatment by either surgery or radiosurgery in combination with whole brain radiation therapy is indicated. Otherwise, as in multiple brain metastases, radiation therapy only is the main treatment. For symptomatic therapy of brain oedema or increased intracranial pressure, dexamethasone is administered. The standard doses of dexamethasone may vary between 4 and 16 mg/day, depending on the severity of symptoms. Received: 10 July 1997 Accepted: 27 October 1997     

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.     

The diagnosis and management of brain metastases.

The median survival after whole-brain irradiation of patients with brain metastases is 4 months. Because half the patients with brain metastases die of systemic cancer, for most the benefit of intensive local treatment (surgery or stereotactic radiosurgery) of brain metastases will be minimal. In particular, patients with controlled systemic disease and one to three brain metastases are candidates for intensive local treatments. Combined local treatment with whole-brain irradiation therapy improves the local control of brain metastases in comparison with whole-brain irradiation only. After the local treatment of brain metastases by either surgery or radiosurgery, overall survival is not adversely affected if whole-brain irradiation is only administered as salvage treatment at the time of relapse. New randomized trials are needed, however, to investigate this further. The response rate of brain metastases to chemotherapy is similar to the response rate of the primary tumour and non-cerebral metastases.     

Cerebral radioprotective effects of high-dose pentobarbital evaluated in an animal radiosurgery model

Abstract

Because pentobarbital has been shown to reduce cerebral toxicity to single-fraction whole brain irradiation in a rat model, we sought to evaluate its cerebral radioprotective effects for stereotactic radiosurgery. We hypothesized that concurrent high-dose pentobarbital anaesthesia (50 mg kg^–1) during irradiation could delay or prevent the onset of radiation necrosis within the radiosurgical volume. Six rats were placed in pentobarbital or control groups, irradiatedand then evaluated at different intervals (60, 100; 750, 365 days; total = 48 animals studied). All rats had 100 Gy radiosurgery to the right frontal brain region (a threshold dose for focal necrosis at 90 days). The radioprotective effects of pentobarbital were compared to ketamine anaesthesia (control) and evaluated for observed focal necrosis, size of necrotic lesion, blood vessel alterations, and to changes in cell nuclei. There was no difference between groups in the numbers of rats with necrosis at 100 days (p = 0.72), at 150 days (p = 0.77), or at 365 days (p = 0.77); no necrosis was observed in either group at 60 days. There was no difference in the size of the necrotic lesion at 100 days (p = 1.0), at 150 days (p = 0.39), or at 365 days (p = 0.07). There was no difference between groups in observed blood vessel changes or nuclear changes at any time interval (p > 0.6).m There was no animal morbidity related to radiosurgery. While pentobarbital may exhibit a radioprotective effect to lower dose, whole brain irradiation on a metabolic or cellular level, we could not identify any protective benefit for the prevention of focal radiation necrosis or other radiation-related histologic changes in this experiment. The model can be used to evaluate other potential radioprotective agents, and to improve assessments of blood-brain barrier integrity and ultrastructure. [Neurol Res 1994; 16: 456-459]