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.     

原发灶来源不明的脑转移瘤的临床特点及治疗

目的 探讨原发灶来源不明的脑转移瘤（BMUP）的临床特点及治疗方法。方法 回顾性分析26例BMUP患者的临床资料。结果 病灶位于额叶8例、顶叶13例、枕叶1例、小脑3例、基底节区1例。19例单发转移灶全切除,7例多发灶者行症状侧病灶全切除术。术后均接受普通放疗,其中3例多发转移瘤加行替莫唑胺辅助化疗。术后随访6~78个月,平均28个月;复发7例（单发灶2例,多发灶5例）,再次手术治疗2例,化疗3例,2例因颅内播散、恶性颅内压增高死亡。结论 BMUP影像学及病理学具有一定特征,治疗主要采取以手术为主的综合治疗,术后常规放化治疗可延缓肿瘤生长,提高患者生存率。     

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     

Targeted Treatment of Brain Metastases

Purpose of Review

Brain metastases are the most common intracranial tumors in adults. Historically, the median survival after the diagnosis of brain metastases has been dismal and medical therapies had a limited role in the management of these patients.

Recent Findings

The advent of targeted therapy has ushered in an era of increased hope for patients with brain metastases. The most common malignancies that result in brain metastases—melanoma, lung cancer, and breast cancer, often have actionable mutations, which make them good candidates for targeted systemic therapy. These brain metastases have been shown to have relevant and sometimes divergent genetic alterations, and there has been a resurgence of interest in targeted drug delivery to the brain by using standard or pulsatile dosing to achieve adequate concentration in the brain.

Summary

An increased understanding of oncogenic alterations, a surge in targeted drug development with good blood barrier penetration, and inclusion of patients with active brain metastases on clinical trials have led to improved outcomes for patients with brain metastases.

     

Brain metastases in patients with pelvic or abdominal malignancy do not prevail in the posterior fossa: a retrospective study

Pelvic and gastrointestinal tumors are generally considered to have a predilection to metastasize to the posterior fossa rather than to the supratentorial brain. Review of imaging of 100 patients with brain metastases from pelvic and gastrointestinal primary tumors and of 100 patients with brain metastases from other primary tumors did not reveal a difference in distribution of brain metastases between the two groups of patients. So, there is no evidence that pelvic and gastrointestinal tumors metastasize preferentially to the posterior fossa.     

Increased levels of plasma tissue factor pathway inhibitor in patients with glioblastoma and intracerebral metastases

Tissue Factor Pathway Inhibitor (TFPI) prevents further participation of Tissue Factor (TF) in the coagulation process by forming a stable quaternary complex of TF-FVIIa-FXa-TFPI. Recently, plasma TFPI level were found to be elevated in patients with malignant disease outside the brain. Therefore the aim of this study was to investigate the TFPI plasma level in patients with primary brain tumors and intracerebral metastases. From May 2000 to December 2001 the total tissue factor pathway inhibitor antigen (TFPI) was preoperatively determined in blood samples of 225 patients with primary or metastatic brain tumors. Tumor histology classified as benign (WHO grade I and II) and malignant (WHO grade III and IV, intracerebral metastases) was correlated to plasma TFPI-levels. Plasma TFPI was significantly higher in patients with malignant tumors including intracerebral metastasis compared to benign tumors (80.1 +/- 34.31 versus 64.3 +/- 25.8 ng ml-1 [p < 0.01; t-test]). To exclude the influence of primary systemic neoplasms with secondary brain metastasis on plasma TFPI-level a subgroup of patients with primary brain tumors (meningioma, astrocytoma, oligodendroglioma and glioblastoma) was separated. In this group TFPI-level was also significantly elevated in patients with malignant (n = 66) (78.6 +/- 29.9) compared to benign brain tumors (n = 127) (64.3 +/- 25.8 ng ml-1 [p < 0.01; t-test]). To the authors' knowledge this is the first study describing the correlation of increased plasma TFPI and malignancy in patient with brain tumors. Further studies are needed to clarify the pathogenic mechanism and the clinical relevance of this phenomenon.     

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.     

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.     

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.     

Chemotherapie von Hirntumoren bei Erwachsenen

Chemotherapy has become a third major treatment option for patients with brain tumors, in addition to surgery and radiotherapy. The role of chemotherapy in the treatment of gliomas is no longer limited to recurrent disease. Temozolomide has become the standard of care in newly diagnosed glioblastoma. Several ongoing trials seek to define the role of chemotherapy in the primary care of other gliomas. Some of these studies are no longer only based on histological diagnoses, but take into consideration molecular markers such as MGMT promoter methylation and loss of genetic material on chromosomal arms 1p and 19q. Outside such clinical trials chemotherapy is used in addition to radiotherapy, e.g., in anaplastic astrocytoma, medulloblastoma or germ cell tumors, or as an alternative to radiotherapy, e.g., in anaplastic oligodendroglial tumors or low-grade gliomas. In contrast, there is no established role for chemotherapy in other tumors such as ependymomas, meningiomas or neurinomas. Primary cerebral lymphomas are probably the only brain tumors which can be cured by chemotherapy alone and only by chemotherapy. The chemotherapy of brain metastases follows the recommendations for the respective primary tumors. Further, strategies of combined radiochemotherapy using mainly temozolomide or topotecan are currently explored. Leptomeningeal metastases are treated by radiotherapy or systemic or intrathecal chemotherapy depending on their pattern of growth.     

Strategies to target drugs to gliomas and CNS metastases of solid tumors

The treatment for central nervous system metastases of solid tumors and gliomas is limited as the blood–brain barrier (BBB) is an obstacle to systemic therapy. Here, we review the physiochemical properties of the BBB and both current and new drug strategies to penetrate brain tumors. We focus on targeting receptor- or carrier-mediated transport mechanisms over the BBB used by drug conjugates, nanoparticles, polymer-based nanocarriers, siRNA, and antibodies.     

Unusual CNS presentation of thyroid cancer

As advanced therapies allow cancer patients to live longer, disease failure in the central nervous system increases from limited therapeutic penetration. Primary thyroid malignancies rarely metastasize to the brain and have a small number of investigations in literature on the subject. The majority of brain metastases involve the brain parenchyma, reflecting the mass and blood distribution within the brain and central nervous system. Here, we report two cases of the most common differentiated thyroid cancers; follicular thyroid cancer having brain involvement from extra-axial growth and papillary thyroid cancer having brain involvement from a single intraventricular metastasis, presumed as metastasis from the vascular choroid plexus. Both of our cases had widespread systemic involvement. For our follicular thyroid cancer, brain involvement was a result of extra-axial growth from cavarial bone, and our papillary thyroid cancer had brain involvement from a single intraventricular metastasis that was initially resected and nearly a year later developed extensive brain involvement. Unlike the usual gray-white junction metastases seen in the majority of metastatic brain tumors, including thyroid, our cases are uncommon. They reflect differences in tumor biology that allows for spread and growth in the brain. Although there is growing genetic knowledge on tumors that favor brain metastases, little is known about tumors that rarely involve the brain.     

The spectrum of neurological disease in patients with systemic cancer.

To ascertain the range of neurological problems in patients with systemic cancer, we prospectively evaluated neurological symptoms, neurological diagnoses, and primary tumors in all patients with a history of systemic cancer examined by the Department of Neurology at the Memorial Sloan-Kettering Cancer Center, from Jul 1, 1990, to Dec 31, 1990. Of the 815 patients seen for neurological symptoms, less than half (45.2%) had metastatic involvement of the nervous system. The three most common symptoms were back pain (18.2%), altered mental status (17.1%), and headache (15.4%). The most common neurological diagnosis was brain metastasis (15.9%), followed by metabolic encephalopathy (10.2%), pain associated with bone metastases only (9.9%), and epidural extension or metastasis of tumor (8.4%). Of 133 patients with undiagnosed back or neck pain, 44 (33%) had epidural extension or metastases from tumor and 40 (30%) had pain associated with vertebral metastases only. In 15 (11%) the cause for the back pain was unrelated to metastatic disease. Of 132 patients seen on initial consultation for altered mental status, metabolic encephalopathy was the major neurological diagnosis (80; 61%); 20 (15%) had intracranial metastases. Of 97 patients with undiagnosed headache, 59 (61%) had a nonstructural cause. Fifty-three of these patients had either migraine, tension headache, or headache related to systemic illness (e.g., fever, sepsis). These results indicate that even in patients with systemic cancer, a group particularly prone to developing neurological disease that can be diagnosed radiologically, the role of clinicians remains important in helping distinguish noncancer-related and nonmetastatic neurological problems.     

Epilepsy in patients with brain tumors and other cancers

Epilepsy is common among patients with supratentorial, especially slow-growing tumors. Several newer antiepileptic drugs have fewer side effects and drug interactions than do older drugs. Seizure control, however, may require complete lesion resection, with or without removal of an additional "epileptogenic zone." Among patients with systemic cancer, parenchymal or leptomeningeal metastases can cause epilepsy, and potentially reversible medical and neurologic perturbations can lead to acute symptomatic seizures.     

Distribution of brain metastases

The number and site of brain metastases were identified on the computed tomographic scans of 288 patients. There was one brain metastasis in 49%, two in 21%, three in 13%, four in 6%, and five or more in 11% of scans. In patients with one metastasis, the posterior fossa was involved in 50% of patients when the primary tumor was pelvic (prostate or uterus) or gastrointestinal, but it was involved in only 10% of patients with other primary tumors. Hemispheral metastases preferred the anatomic "watershed areas" (29% of the brain surface contained 37% of the metastases), indicating that tumoral microemboli tend to lodge in the capillaries of the distal parts of the superficial arteries. The charts of 134 patients with brain metastases from a primary tumor originating outside the lung revealed that the incidence of lung and spine metastases was the same, whether the primary tumor was pelvic or gastrointestinal or from another site. These data suggest that the high incidence of subtentorial lesions in patients with pelvic and gastrointestinal primary tumors cannot be explained by arterial embolization alone, and that this peculiar distribution is probably not explained by seeding of the brain through Batson's plexus.     

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.     

Metastatic brain tumor in the elderly

Authors have reviewed 322 consecutive patients with malignant tumors confirmed by pathological studies between October 1973 and August 1987 in order to determine the frequency, clinical presentation, and lesion localization of metastatic brain tumor in the elderly. Among 322 patients with malignant tumor, 7 patients with primary brain tumor and 21 patients with metastatic brain tumors were found. The over-all frequency of metastases to the brain was 5.8%. This frequency of brain metastasis in the elderly was lower than those of the previous literature which have varied from 9 to 35%. The patients' ages with metastatic brain tumor ranged from 65 to 88 years with a median age of 77.5 years. The primary tumor sites of metastatic brain tumors were limited to 5 kinds of organs. These metastases were found in 27.3% of 11 patients with breast cancer, 17.5% of 80 patients with lung cancer, 6.7% of 15 patients with bile duct system cancer, 5.0% of 20 patients with pancreatic cancer, and 2.0% of 91 patients with gastric cancer. There was no brain metastasis in the other kinds of carcinoma. Among 21 metastatic brain tumors, there were 14 patients with lung cancer, 3 patients with breast cancer, 2 patients with gastric cancer, 1 patient with cholangiocarcinoma, and 1 patient with pancreatic cancer. In this series, the frequency of single and multiple metastases were 13 and 8 cases, respectively. The multiple brain metastases ranged from 2 to 6 nodules. In 21 metastatic brain tumors, there were 42 metastatic nodules in total.(ABSTRACT TRUNCATED AT 250 WORDS)