Stereotactic radiosurgery for metastatic brain tumors

We report on a prospective phase TI study utilizing stereotactic radiosurgery for patients with intracranial parenchymal metastases. Fifty patients ranging in age from 38 to 77 years with 1 to 3 intraparenchymal brain metastases were treated with stereotactic radiosurgery either immediately following whole brain radiotherapy or at the time of intracranial disease progression following failure of whole brain radiotherapy. Twenty patients treated with adjuvant therapy received a median radiosurgical dose of 20 Gy. Thirty patients treated with salvage therapy received a median radiosurgical dose of 20 Gy. No immediate neurotoxicity was seen following radiosurgery however, 4 patients (8%) developed symptomatic radiation necrosis. Median survival was 6.5 and 6.0 months for patients treated with adjuvant and salvage radiosurgery respectively. In patients with oligometastatic brain metastases manifesting intracranial disease progression after whole brain radiotherapy, salvage radiotherapy appears to offer improved palliation when compared to retreatment with whole brain radiotherapy. The results of patients treated with up-front adjuvant radiosurgery when compared to historical controls treated with whole brain radiotherapy only are less clear as to benefit and require a phase III study before definitive recommendations can be made.     

Surgery, radiation therapy, and chemotherapy for metastatic tumors to the brain.

Recent literature has confirmed patient age, Karnofsky status, and the extent of extracerebral tumor as independent prognostic variables in patients with cerebral metastases. In a good-risk population, surgery followed by radiation therapy is superior to radiation alone for treatment of patients with solitary metastases. Stereotactic radiosurgery is feasible in the same select patient population, but questions regarding the extent of delayed toxicity, tumor response, and the impact on quality of life and longevity remain to be answered. Studies of external beam radiation therapy for patients with brain metastases have shown that 1) misonidazole does not improve the response rate, quality of life, or duration of survival, 2) 5 Gy for six fractions and 3 Gy for 10 fractions produce similar results, and 3) reirradiation at doses of 25 Gy for tumors progressing after initial radiation may be feasible in a selected population of patients. Chemotherapy can affect regression of brain metastases in patients with small cell lung and breast carcinoma, as well as melanoma, but the overall contribution to the quality and duration of the patient's life compared with radiation alone is unknown. Intracarotid chemotherapy is feasible for patients with brain metastases, but substantial toxicity precludes its use outside of an investigational setting. Brain metastases remain an important cause of morbidity and mortality for patients with cancer, but the majority of patients still succumb to widespread systemic disease. The goal of treatment of brain metastases should be palliation with minimal infringement upon the patient's quality of life.     

Current role of radiation therapy in the management of malignant brain tumors

The objective of this article is to explain how the current management of malignant brain tumors has evolved, using the foundation of evidence-based literature. Radiotherapy plays a central role in the multidisciplinary management of primary brain tumors and brain metastases. The techniques of radiotherapy continue to be refined to optimize local control while minimizing potential treatment-related neurocognitive toxicities.     

The role of radiosurgery in the management of malignant brain tumors

Opinion statement Stereotactic radiosurgery (SRS) provides the means for creating lesions in deep-seated areas of the brain inaccessible to invasive surgery, using single high doses of focused ionizing radiation, administered using stereotactic guidance. It is a surgical technique designed to produce a specific radiobiological effect within a sharply defined target region in a single treatment session. Its technical application requires a stereotactic coordinate system, highly accurate patient repositioning (usually fixed), and multiple convergent beams of photon radiation. SRS appears to provide no benefit in the upfront treatment of newly diagnosed malignant gliomas but may be used to effectively palliate small well-demarcated volumes of recurrent disease. For selected patients with brain metastases treated with whole-brain radiation therapy (WBRT), the addition of SRS improves median survival. In selected patients with brain metastases, it is also rational to withhold WBRT in favor of radiosurgery alone, with WBRT reserved for salvage without a decrease in median survival time.     

Leukoencephalopathy after whole‐brain radiation therapy plus radiosurgery versus radiosurgery alone for metastatic lung cancer

BACKGROUND:

As systemic therapies improve and patients live longer, concerns mount about the toxicity of whole‐brain radiation therapy (WBRT) for treatment of brain metastases. Development of delayed white matter abnormalities indicative of leukoencephalopathy have been correlated with cognitive dysfunction. This study assesses the risk of imaging‐defined leukoencephalopathy in patients whose management included WBRT in addition to stereotactic radiosurgery (SRS). This risk is compared to patients who only underwent SRS.

METHODS:

We retrospectively compared 37 patients with non–small cell lung cancer who underwent WBRT plus SRS to 31 patients who underwent only SRS. All patients survived at least 1 year after treatment. We graded the development of delayed white matter changes on magnetic resonance imaging using a scale to evaluate T₂/FLAIR (fluid attenuated image recovery) images: grade 1 = little or no white matter hyperintensity; grade 2 = limited periventricular hyperintensity; and grade 3 = diffuse white matter hyperintensity.

RESULTS:

Patients treated with WBRT and SRS had a significantly greater incidence of delayed white matter leukoencephalopathy compared to patients who underwent SRS alone (P < .001). On final imaging, 36 of 37 patients (97.3%) treated by WBRT developed leukoencephalopathy (25% with grade 2; 70.8% with grade 3). Only 1 patient treated with SRS alone developed leukoencephalopathy.

CONCLUSIONS:

Risk of leukoencephalopathy in patients treated with SRS alone for brain metastases was significantly lower than that for patients treated with WBRT plus SRS. A prospective study is necessary to correlate these findings with neurocognition and quality of life. These data supplement existing reports regarding the differential effects of WBRT and SRS on normal brain structure and function. Cancer 2013. © 2012 American Cancer Society.     

The role of gamma knife radiosurgery in the treatment of primary and metastatic brain tumors

With the widespread diffusion of stereotactic radiosurgical procedures, GKR treatments have gained considerable momentum as a major therapeutic option for patients harboring primary or metastatic brain tumors. Present results in high grade gliomas indicate a potential palliative role of this technique. The overall low radiosensitivity of these oncotypes and their infiltrative nature-with the resulting problems in properly defining the tumor target-are still a major obstacle to further development of the approach. In this regard, useful contributions are expected from advances in molecular neurobiology and functional neuroimaging as shown by preliminary investigations with MR spectroscopy. Surgery maintains a dominant role in the therapeutic armamentarium for low grade gliomas. However, in unfavorable cases (unresectable tumors, recurrences), GKR seems to be an effective alternative to conventional radiochemotherapy. In grade 2 astrocytomas and specifically in grade 1 pilocytic forms, short-to-mid-term reported studies have documented encouraging 70 to 93% local tumor control rates, with minimal cerebral toxicity. Finally, during the last decade, GKR has become a primary treatment choice for patients harboring small-to-medium-size brain metastases, with reasonable life expectancy and no impending intracranial hypertension. Focal tumor responses are consistently elevated, even in the most radioresistant oncotypes (melanoma, renal carcinoma); median and actuarial survival rates are far better than with conventional radiation treatments and are comparable to those observed in accurately selected surgical-radiation series.     

Gamma knife radiosurgery for metastatic brain tumors from thyroid cancer

Objective We report our experience using gamma knife radiosurgery (GKR) for brain metastasis from thyroid cancer, which is extremely rare. Methods Between 1995 and 2007, 9 patients with 26 metastatic brain tumor(s) from thyroid cancer underwent GKR. The mean patient age was 58 years (range: 10–78). Seven patients had metastases from papillary thyroid cancer, and two from medullary thyroid cancer. Five patients had solitary tumors, and four patients had multiple metastases. Three patients who had multiple metastases also underwent whole brain radiation therapy (WBRT). The mean tumor volume was 2.4 cc (range: 0.03–14.0). A median margin dose of 18.0 Gy (range: 12–20) was delivered to the tumor margin. Results Tumor control was obtained in 25 out of 26 tumors (96%). The median progression-free period after GKR was 12 months (range: 4–53). The overall median survival after GKR was 33 months (range: 5–54). There were no procedure-related complications and six patients are still living 5–54 months after GKR. Conclusions Radiosurgery is an effective and minimally invasive strategy for management of brain metastases form thyroid cancer.     

The role of surgery in the management of metastatic spinal tumors

The role of surgery in the treatment of metastatic spinal tumors causing epidural compression traditionally consisted of posterior decompression. This procedure plus radiotherapy, however, could not be demonstrated to provide any benefit over radiotherapy alone, and surgery fell into disfavor in managing metastatic vertebral tumors. The advent of newer, more sophisticated approaches, along with improved spinal instrumentation and reconstruction techniques, which allowed direct decompression of neural elements and resection of the tumor, have revived the use of surgery in these tumors. These modern spinal surgery techniques, in combination with radiotherapy, have yielded significantly superior functional outcomes and prolonged survival in symptomatic metastatic epidural compression when compared to radiotherapy alone. Management of spinal metastases is evolving, and a multitude of factors determine the indication for and the technique and goals of surgical intervention. Between 1993 and 2005, 21.1% of patients with metastatic spinal tumors evaluated at The University of Texas M.D. Anderson Cancer Center were treated surgically by the Department of Neurosurgery. The most common spinal metastasis operated upon was metastatic kidney cancer (31.5%), even though kidney cancer was only the third most common primary tumor (after lung and breast cancers) giving rise to vertebral metastases observed during the same time period at this institution. This highlights the importance of the histology of the primary cancer (among other factors) in determining the indication for surgical intervention.     

Long-term survival after gamma knife radiosurgery for primary and metastatic brain tumors

In this paper, we studied factors related to long-term survival after gamma knife radiosurgery (GKS) for primary and metastatic brain tumors. We examined all cases of brain metastases and malignant glioma treated with GKS between September 1994 and December 1998. All patients with survival exceeding 2 years were studied retrospectively using prospectively acquired data. A total of 22 patients, with an average age of 56, were identified, which accounts for 11% of the total patients treated during this time interval. Seventeen of 22 are still alive with a mean follow-up of 48 months. Sixteen patients had metastatic tumors, whereas 6 had a malignant glioma. Thirteen of 15 patients with metastases had a controlled primary site, and the other 2 patients did not have a primary site identified. These 2 patients were among the 3 that died during the follow-up period. Fourteen patients developed symptomatic radiation necrosis by MRI criteria with 4 confirmed by biopsy. Quality-of-life factors were assessed in 20 of 22 patients using a modified Spitzer scale, which showed a high level of functioning in all of the long-term survivors (mean score 8.65 of 10), and only 1 patient had a Karnofsky Performance Score of less than 70. We conclude that radiosurgery provides a noninvasive and effective way of controlling brain tumors, while preserving quality of life.     

Antiangiogenic therapy for primary and metastatic brain tumors

We first provide the theoretic foundation of antiangiogenic therapy by describing the biology of angiogenesis as it applies to brain tumors. We then outline experimental antiangiogenic therapies that are being applied preclinically to brain tumors, as well as published clinical trial data and ongoing clinical trials in patients. Primary and metastatic brain tumors are covered, although there is far less exploration in the literature of brain metastases.     

The role of whole-brain radiation therapy after stereotactic radiation surgery for brain metastases

The benefit of whole-brain radiation therapy (WBRT) following stereotactic radiation surgery (SRS) for brain metastases is controversial. We conducted a systematic analysis of published literature to explore the outcome of brain metastases treated with SRS and WBRT versus SRS alone using PubMed and MEDLINE. Outcomes including survival, control, salvage therapy, and other quality of life measures were reported. Three randomized controlled trials involving 389 patients with 1 to 4 brain metastases were selected. In 2 of these trials (n = 190), the mean 1-year survival was 33.2% for SRS + WBRT and 38.7% for SRS alone (P = .5233); 1-year local control was 89% for SRS + WBRT and 71% for SRS alone (P < .001). Mean crude distant recurrence rate for SRS + WBRT was 36.6% and 54% for SRS alone (P < .001). Patients without WBRT were over 3 times more likely to require salvage therapy (P < .001). The addition of WBRT was associated with a decreased health-related quality of life assessment, mini mental status exam, and Hopkins Verbal Learning Test (P < .05). Five retrospective studies (n = 1122) were also included in a separate analysis and yielded findings that supported results from the randomized trials. Our systematic analysis demonstrates that adjuvant WBRT following SRS for the treatment of oligometastases in the brain is more effective at controlling local and distant recurrence than SRS alone, but there is no apparent benefit for survival or symptomology. The proven cognitive decline and neurotoxicity present with WBRT should be weighed against the benefit of local control. Prognosis of brain metastasis is poor regardless of current treatment and further exploration for alternative adjuvant treatment for SRS is warranted.     

Evolving management of newly diagnosed brain metastases: expanding role of radiosurgery in lieu of whole brain radiation

The use of stereotactic radiosurgery has grown increasingly prevalent in the management of patients with brain metastases. In this perspective we contend that a large number of patients can be offered the alternative of treatment with this modality alone, reserving whole brain radiation for salvage. The relevant data will be presented supporting this approach, with emphasis on the toxicities of whole brain radiation and equivalence of survival outcomes regardless of treatment approach. Patient selection for radiosurgery alone will also be addressed.     

Evidence-based radiation therapy for primary brain tumors

Radiation therapy for five primary brain tumors is discussed based on the results of prospective trials. Many randomized studies have revealed the usefulness of radiation and radiochemotherapy for treating malignant gliomas, and the ineffectiveness of many new treatments modalities. However, novel treatments should be tested further against this tumor. In low-grade gliomas, the usefulness of radiotherapy was shown but a dose-effect relationship was not observed in recent randomized studies. In medulloblastoma, the difficulty in reducing the dose to the cerebrospinal axis has been shown even in low-stage patients. On the other hand, reliable randomized studies are still lacking for germinoma and primary central nervous system lymphoma, and the usefulness of combination chemotherapy remains uncertain. In the future, more prospective studies are needed for primary brain tumors other than glioma. Establishment of IMRT and controlled studies to prove its efficacy are important in the field of neuro-oncology.     

SRS、WBRT 及 WBRT ＋SRS 治疗1～4个脑转移瘤的 Meta 分析

目的：探讨立体定向放射外科（SRS）、全脑放疗（WBRT）及全脑放疗联合立体定向治疗1～4个脑转移瘤,并为进一步研究提供循证医学依据。方法：根据设定的纳入、排除标准,在 PubMed、Springer －link、Cancer list 数据库、中国生物医学文献数据库（CBM）、万方数据库、CNKI 知识网络服务平台及其他期刊进行相关随机对照试验检索。单变量计数资料的效应量用优势比（OR）和95％可信区间（95％CI）表示,用 Rev-man 5．2软件对数据进行异质性检验后采用固定效应模型或随机效应模型对数据进行分析。结果：共检索出1985－2014年间发表的126篇相关文献,最终得到8篇包含1213例脑转移瘤患者的随机对照试验符合所纳入的标准。SRS 与 WBRT ＋SRS 比较：WBRT ＋SRS 虽能提高脑转移瘤1年局部控制率及远处肿瘤控制率（OR ＝0．43,95％CI：0．29～0．63,P ＜0．0001;OR ＝0．42,95％CI：0．30～0．57,P ＜0．00001）;但不能提高1年生存率且不良反应及神经认知异常发生率高（OR ＝1．27,95％CI：0．93～1．73,P ＝0．14;OR ＝0．50,95％CI：0．28～0．89,P ＝0．02;OR ＝0．41,95％CI：0．21～0．78,P ＝0．006）。SRS 与 WBRT 比较：SRS 治疗脑转移瘤可明显提高患者1年生存率及1年局部肿瘤控制率,但远处肿瘤控制率与WBRT相当（OR＝2．78,95％CI：1．57～4．92,P ＝0．0004;OR ＝4．8,95％CI：2．69～8．57,P ＜0．00001;OR ＝0．52,95％CI：0．15～1．83,P ＝0．31）。WBRT ＋SRS 与单独 WRBT 比较：1年局部肿瘤控制率及1年生存率无明显差别（OR ＝1．23,95％CI：0．81～1．86,P ＝0．32;OR ＝1．21,95％CI：0．76～1．93,P ＝0．42）。结论：1～4个脑转移瘤患者,单独 SRS 是理想治疗方法。     

The role of radiation therapy in the management of plasma cell tumors

A retrospective review is reported of 128 patients presenting with multiple myeloma and 16 patients presenting with solitary plasmacytoma. Ninety-one percent of 116 evaluable patients treated for palliation of painful bone disease received some degree of subjective pain relief. The radiation dose most frequently prescribed was between 1500 and 2000 rad. Of the 278 ports treated, only 17 (6.1%) were re-treated to the same area at a later date. There was no increase in incidence of re-treatment with lower radiation doses. Ten of the 13 patients treated for a solitary plasmacytoma with a minumum follow-up period of three years have local tumor control. The median survival in the solitary plasmacytomas is five and one-half years. Data from the literature on 27 additional solitary plasmacytomas combined with our data suggest an improved local control and a decrease in dissemination with doses greater than 5000 rad. It is concluded that low doses of radiation are usually adequate to treat painful bone lesions of multiple myeloma and doses of 5000-6500 rad in six to seven weeks are recommended for solitary plasmacytomas.     

Effectiveness of radiation therapy in metastatic bone tumors

The effectiveness of radiation therapy for metastatic bone tumor in 61 patients with 80 lesions has been evaluated. Relief from pain resulted in 87% all the treated lesions and this continued for more than two years in eight lesions of seven patients. There was no statistical difference in the pain relief achieved among the sites and the histologies of the primary tumors, and also no difference was noted as to the treated regions. Pain relief from the lesions of a squamous cell carcinoma tended to begin with smaller doses when compared with that of an adenocarcinoma. Our results suggest that radiation therapy in general appears to be an effective technique in achieving long term control of pain, but for some patients those with a generalized metastases or an uncontrolled primary tumor, for example, this tedious treatment has limited value and so should be withheld.     

Phase II study--intra-arterial BCNU therapy for metastatic brain tumors

Thirty-one patients with metastatic brain tumors (MBT) from lung cancer and ten patients with MBT from melanoma received BCNU, 100 mg/m2, every four weeks by intracarotid and/or vertebral artery infusion into each involved site. Twenty-five patients with lung cancer and all melanoma patients are currently evaluable. Twelve patients with lung cancer had complete and partial responses lasting from 1 to 14 months. Four of them with the histologic diagnosis of small cell carcinoma, one with large cell carcinoma and one with squamous cell carcinoma showed complete response. None of the patients with melanoma MBT experienced any response. All of the patients had periorbital erythralgia and/or occipital pain during the infusion. Four patients manifested mild focal seizures during the infusion or 6 to 24 hours after the treatment. Transient confusion with disorientation was observed in two patients 4 and 24 hours, respectively, after a BCNU infusion. Two patients developed reversible thrombocytopenia after the fifth course of the IA chemotherapy. Median survival of patients with MBT from lung carcinoma was 4 months, with two of them still alive at 10 and 14 months, respectively. Only one patients of the 25 with lung carcinoma died from MBT. Failure to control the primary disease resulted in the deaths of a vast majority of the patients.     

The role of radiation therapy in the treatment of locally unresectable or metastatic carcinoid tumors

Forty-four patients irradiated for metastatic or unresectable carcinoid tumors at Memorial Sloan-Kettering Cancer Center from 1950 to 1986 were studied. The response to radiation was analyzed at four sites: epidural space (11 pts), brain (8 pts), bone (8 pts), and abdominal (17 pts). Although survival was generally poor, substantial palliation was achieved in most cases. No patient with brain metastases had progression of intracranial disease after radiation therapy (median dose: 3300 cGy); all died of progression of systemic metastases (median survival: 4 months). Infield control following radiation therapy for epidural and osseous metastases was achieved in 77% and 78% of sites, respectively, with median doses of 3000 cGy and 4000 cGy. Median survival for epidural and bone metastases was 11 and 13 months, respectively. In-field control was obtained in 62% of patients with intraabdominal disease (median dose: 2700 cGy). Among the subset of seven patients who were irradiated at ten sites of unresectable abdominal (non-hepatic) disease, the median survival was 23 months with 80% achieving a complete or partial response and 50% maintaining permanent in-field control. No dose-response relationship was demonstrated. Radiation therapy can achieve local control and symptomatic palliation in most patients with metastatic carcinoid tumors. Our current recommendation would be to treat non-hepatic sites with 4500-5000 cGy in 4-5 weeks. More rapid fractionation schemes could be used for patients with limited life expectancies.     

Strategy of surgery and radiation therapy for brain metastases

Cancer patients with brain metastases have poor prognoses and their median survival time is about 1 year. Surgery with whole-brain radiation therapy (WBRT) has been used in the treatment of single brain metastasis measuring 3 cm or more. Stereotactic radiosurgery (SRS) including the use of the Gamma knife and Cyberknife is widely used for the treatment of small and multiple brain metastases; however, recent clinical studies have revealed that SRS + WBRT is superior to WBRT or SRS alone in terms of survival time and local tumor control rates. Here, surgical indications and the strategy of surgery and radiation therapy are discussed, based on many clinical trials of treatments for brain metastases. To improve the survival rate and quality of life for these cancer patients with brain metastases, it is necessary to choose the most suitable mode of surgery and radiotherapy with the close cooperation of physicians, surgeons, radiologists, and neurosurgeons, based on accumulated evidence.