Stereotactic radiosurgery with and without whole-brain radiotherapy for newly diagnosed brain metastases

Brain metastases develop in 20-40% of cancer patients and can cause significant morbidity. In selected patients with one to three lesions, stereotactic radiosurgery may be used to improve local control. However, it is unclear whether whole-brain radiotherapy is necessary for all patients who are candidates for stereotactic radiosurgery. While whole-brain radiotherapy may improve the locoregional control of brain metastases, it may cause long-term side effects and may not improve overall survival in some patients. Its benefits should be evaluated in the context of risks of neurocognitive deterioration, either from whole-brain radiotherapy or from uncontrolled brain metastases, and the possible need for salvage treatments with the omission of initial whole-brain radiotherapy. For certain radioresistant brain metastases, the benefit of whole-brain radiotherapy to patients who have stereotactic radiosurgery is uncertain.     

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     

Current management of metastatic brain disease

Brain metastases are the most common intracranial tumor in adults. The incidence of metastases is thought to be rising due to better detection and treatment of systemic malignancy. More widespread use and improved quality of MRI may lead to early detection of brain metastases. Available evidence suggests that survival is longer and quality of life improved if brain metastases are treated aggressively. This article reviews current therapeutic management used for brain metastases. To select the appropriate therapy, the physician must consider the extent of the systemic disease, primary histology, and patient age and performance status, as well as the number, size, and location of the brain metastases. Available treatment options include whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), surgery, and chemotherapy. Multidisciplinary approaches such as the combination of WBRT with SRS or surgery have shown superior results in terms of survival time, neurocognitive function, and quality of life. The utility and optimal use of chemotherapy and radiosensitizing agents is less clear. It is hoped that further advances and multidisciplinary approaches currently under study will result in improved patient outcomes.     

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.     

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.     

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.     

Stereotaktische Strahlentherapie am adaptierten Linearbeschleuniger bei Patienten mit Hirnmetastasen

The aim of the study was to analyze the results of stereotactic radiotherapy using a linear accelerator in patients with brain metastases. We quantified the following clinical parameters: tumor response and tumor control after therapy, survival, and side effects. Results of the treatment were compared with those from traditional treatment strategies such as surgery and whole brain irradiation. Sixty patients with brain metastases (80 lesions, 36 men and 24 women, mean age 57 years) were treated with stereotactic radiotherapy. The mean follow-up time was 13 months. CONCLUSION: Stereotactic radiotherapy is an important option in the treatment strategy for patients with brain metastases. In comparison to whole brain irradiation, stereotactic radiotherapy achieved a higher local tumor control with a lower rate of side effects. In comparison to surgery, stereotactic radiotherapy has the advantages of shorter treatment time and lower treatment-related morbidity and mortality.     

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.     

Brain metastases

Despite advances in the treatment of cancer, brain metastases appear to be increasing in frequency and are associated with a poor prognosis. Type of tumor, age, performance status, and extent of systemic disease are important prognostic factors that should be taken into consideration when making treatment decisions. Patients with a good performance status and controlled systemic disease may benefit from aggressive focal therapies (surgery or radiosurgery). Whole brain radiotherapy seems to increase local control but is associated with the risk of delayed cognitive deterioration in long-term survivors. In spite of this, whole brain radiotherapy remains the standard of care for those patients with poorer prognosis and for the treatment of recurrence after focal therapy. Chemotherapy has a limited role in the treatment of brain metastases but should be considered in selected patient populations.     

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.     

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.

     

脑转移瘤治疗方法的选择及疗效分析

目的探讨脑转移瘤的治疗方法并分析疗效。方法对103例脑转移瘤的肿瘤来源、大小、数目及不同治疗方法进行比较分析。结果46例（44．7％）存活1年以上。单发肿瘤行手术切除或立体定向放射外科治疗,2cm以下的多发肿瘤行放疗加化疗或行立体定向放射外科治疗其生存期较长。结论对于4cm以上大型转移瘤可行手术切除,小于4cm的单发或3cm以下的多发肿瘤应首选立体定向放射外科治疗。     

旋转式头部伽玛刀治疗脑转移瘤171例临床分析

目的 探讨旋转式头部伽玛刀在脑转移瘤治疗中的作用及疗效.方法 2010年9月至2011年10月间,我院共有171例脑转移患者接受了放射治疗,其中49人接受单纯全脑放疗（WBRT组）,占28.7％;102例接受了伽玛刀治疗,其中单独伽玛刀治疗（SRS组）50例,占29.2％;伽玛刀联合全脑放疗（WBRT＋ SRS组）72例,占42.1％.WBRT组患者接受全脑放疗40 Gy/20f/4w; SRS组患者接受旋转式头部伽玛刀治疗16 ～ 24 Gy/1f;WBRT＋ SRS组患者接受全脑放疗30 Gy/15f/3 w,后加旋转式头部伽玛刀治疗12 ～16 Gy/1f.观察3组患者的临床效果和并发症,并进行统计处理,分析三组患者的1年局部控制率和1年生存率.结果 3组患者均取得良好效果,未出现严重毒副作用;1年局部控制率分别为52.8％、81.7％、88.1％;1年生存率分别为47.6％、87.8％、92.9％.SRS组、WBRT＋ SRS组1年局部控制率和1年生存率明显高于WBRT组（P＜0.005）,差异有统计学意义;而SRS组和WBRT＋ SRS组1年局部控制率及1年生存率差异无统计学意义（P＞0.10）.结论 单纯头部伽玛刀治疗以及头部伽玛刀联合全脑放疗治疗脑转移瘤,安全有效,较传统的外照射全脑放疗,可以提高患者的生存时间及生存质量.     

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.     

Single brain metastases: surgery plus radiation or radiation alone

We reviewed the records of patients treated for single brain metastases from non-small-cell lung cancer for 1978 through 1982. Forty-three patients received surgical treatment, including 37 who had surgery plus postoperative whole-brain radiation therapy and 6 patients who had surgery after failing to respond to radiation therapy. The surgically treated patients were matched with 43 patients treated with radiation therapy alone. The combined therapy group had significantly longer survivals than those treated with radiation therapy alone (19 months versus 9 months). The rates of local recurrence and neurologically related deaths were significantly higher in the radiation therapy-alone group. Patients treated with combined therapy survived longer, and the increased survival was due to lower recurrence of brain metastases after surgery and fewer neurologically related deaths.     

Current strategies in the surgical management of cerebral metastases: an evidence-based review

Metastatic tumours are the most common form of cerebral neoplasm, occurring in up to 40% of patients with systemic cancer. Although the presence of metastatic disease portends limited survival, aggressive management of cerebral metastases is vital to preventing death from neurological causes and prolonging functional independence. Due to advancement in neurosurgical techniques and the advent of stereotactic radiosurgery as a non-operative alternative, current decision making for selecting the appropriate local treatment often results in clinical equipoise. In addition, the traditional blanket application of whole brain radiation has come under scrutiny as new evidence regarding the deleterious neurocognitive effects of ionizing radiation emerges. The completion of a series of randomized studies comparing the efficacy of surgery, radiosurgery, whole brain radiotherapy and various combined approaches for cerebral metastases in recent years has shed important light on addressing some of these issues. The focus of this review is to summarize the key findings and outline a practical approach for the management of cerebral metastases.     

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.     

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.     

Brain metastases from unknown primary tumour

The best management of patients with brain metastases from an unknown primary tumour is still unclear, as data are scarce and studies are retrospective. We report 33 patients with biopsy-proven brain metastases from a primary tumour not found at the first investigations, who were treated by surgery and/or radiotherapy and followed with serial CT until death. Median survival time for all patients was 10 months and survival rates at 6 months, 1 year and 2 years were 76 %, 42 % and 15 % respectively. Patients with single brain metastasis treated by gross total resection and whole-brain radiotherapy (WBRT) had a median survival of 13 months with 76 % alive at 6 months, 57 % at 1 year and 19 % at 2 years. Patients with multiple brain metastases who underwent either WBRT alone or WBRT preceded by gross total resection of the symptomatic lesions had a poorer prognosis: median survival of 6–8 months with 50–100 % alive at 6 months, 17–20 % at 1 year and none alive at 2 years. In 85 % of patients with a single brain metastasis a significant improvement in neurological functions was observed after surgical resection; among patients with multiple brain metastases a neurological improvement was observed in all patients who had a resection of symptomatic lesions and only in a half of patients who had WBRT alone. During the follow-up the primary tumour was found in 27/33 patients (82 %) and was located in the lung in 78 %. Between 1987 and 1991 (with limited screening for the primary tumour in the follow-up) the unknown tumours were 6/15 (40 %); in the more recent period (1992–1996) (CT-based screening for the primary tumour in the follow-up) no primary tumour remained unknown but overall survival has not significantly improved. The number of brain metastases was the only significant factor affecting survival after both univariate and multivariate analysis. This study suggests that, in patients with both single and multiple brain metastases from an undetected primary site when first studied, surgery and/or WBRT enable the control of the brain disease, partly because the systemic disease may be silent for a prolonged time. Only a few asymptomatic patients may benefit from an early detection and treatment of the primary tumour during the follow-up. Received: 1 May 2000 / Received in revised form: 13 October 2000 / Accepted: 10 December 2000     

Surgical treatment of brain metastasis: a review

Brain metastasis is the most common intracranial tumor in adults. Currently, treatment of brain metastasis requires multidisciplinary approach tailored for each individual patient. Surgery has an indispensible role in relieving intracranial mass effect, improving neurological status and survival while providing or confirming neuropathological diagnosis with low mortality and morbidity rates. Besides the resection of a single brain metastasis in patients with accessible lesions, good functional status, and absent/controlled extracranial disease; surgery is proven to play a role in management of multiple metastases. Surgical technique has an impact on the outcome since piecemeal resection rather than en bloc resection and leaving infiltrative zone behind around resection cavity may have a negative influence on local control. Best local control of brain metastasis can be accomplished with optimal surgical resection involving current armamentarium of preoperative structural and functional imaging, intraoperative neuromonitoring, and advanced microneurosurgical techniques; followed by adjunct therapies like stereotactic radiosurgery, whole brain radiotherapy, or intracavitary therapies. Here, treatment options for brain metastasis are discussed with controversies about surgery.