Role of radiosurgery in the management of central nervous system metastases

Radiosurgery is being used more routinely to treat patients with inoperable, recurrent, or multiple brain metastases from systemic cancer. Results in >2000 treated patients have been published during the past 8 years. These results indicate that permanent local control can be obtained in >80% of treated lesions with complications in <10% of patients. Success is independent of the histology, ie, melanoma vs adenocarcinoma, of the treated lesion or number of lesions treated. The long-term results of radiosurgery compare favorably with those seen following surgical resection. The cost-effectiveness of radiosurgery compared to surgical resection favors an expanded role for this technology in the treatment of selected patients with brain metastases.     

Diagnosis and management of central nervous system metastases from breast cancer

The brain, cranial nerves, leptomeninges, spinal cord, and eye compose the central nervous system (CNS) and are at risk for the development of metastases from breast cancer. Such metastases are diagnosed on the basis of clinical suspicion and substantiated by neuroimaging, resection when indicated, and sampling of cerebrospinal fluid when leptomeningeal metastasis (LM) is suspected. Treatment is aimed at palliation of symptoms and preservation of neurologic function. Historically, conventional radiation therapy has been the mainstay of palliative treatment for brain, cranial nerve, spinal cord, and ocular metastases. However, additional treatment options for brain metastases have been brought about by technological advances in surgery to resect brain metastases, and stereotactic radiosurgery (SRS) to focally irradiate metastases, both of which have been substantiated by data from randomized trials. Ongoing research is aimed at refining criteria to select which patients with brain metastases should undergo surgery and SRS and how these focal therapies should be optimally integrated with whole-brain radiotherapy. Therapy for LM must carefully balance the potential risks and perceived benefits associated with CNS-directed therapies. Despite advances in neuroimaging, surgery, and radiation therapy, novel treatments are needed to improve the effectiveness of treatments for CNS metastases, especially LM, while reducing attendant neurotoxicity.     

Factors associated with long-term survival in central nervous system metastases

Background

Cancer is a leading cause of death worldwide; central nervous system metastases (CNSm) are amongst the most common complications of cancer and are associated with high morbidity and mortality. The aim of the study was to associate clinic and oncologic characteristics with the possibility of survival for ≥?1 year.

Materials and methods

A prospective cohort in two referral centers recollected clinical and oncologic data from patients diagnosed with CNSm. Chronic metastases were defined as those patients that survived for ≥?12 months after the diagnosis of CNSm.

Results

Of 613 patients with CNSm, 554 had solid tumors as the primary cancer and were included; 405 (73%) were women, the most common primary cancer site were breast, lung and urologic. Chronic CNSm were found in 260 (47%) and were compared to those who did not. After multivariate logistic regression analysis, variables associated with good prognosis (living?>?12 months) were: female sex (HR 0.55), single CNSm (HR 0.39), diagnosis of CNSm during initial extension studies or during presentation of cancer (HR 0.43), and occipital location (HR 0.62).

Conclusions

Long-term survival in patients with CNSm remains a topic of debate; their bad prognosis could be changing towards improvement. Clinical findings are typically overlooked in CNSm reports and prognostic scales. After our findings, we propose to include them in forthcoming studies to aid prognostic considerations. Factors associated with prolonged survival found in our study include female gender, timing of CNSm diagnosis, occipital lobe location, and single CNSm.

     

Diagnosis and management of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non‐Hodgkin lymphoma (NHL) that is confined to the brain, eyes, spinal cord, or leptomeninges without systemic involvement. The overall prognosis, diagnosis, and management of PCNSL differ from those for other types of NHL. Prompt diagnosis and initiation of treatment are vital for improving clinical outcomes. PCNSL is responsive to radiation therapy; however, whole‐brain radiotherapy (WBRT) inadequately controls the disease when it is used alone, and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High‐dose methotrexate (HD‐MTX)–based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced‐dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined; however, HD‐MTX–based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials are addressing the roles of rituximab and consolidative treatment with ASCT or reduced‐dose WBRT. Despite high tumor response rates with the initial treatment, many patients relapse with a very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on a patient's age, previous treatment and response, performance status, and comorbidities at the time of relapse. This review provides an overview of the clinical features, diagnosis, pathology, and management of PCNSL in immunocompetent patients, and it focuses on recent advances in treatment. Cancer 2017;123:4314‐24 . © 2017 American Cancer Society.     

Local and systemic therapy in breast cancer patients with central nervous system metastases

Purpose

As survival of patients with central nervous system (CNS) metastases from breast cancer is poor and incidence rates are increasing, there is a growing need for better treatment strategies. In the current study, the efficacy of local and systemic therapies was analyzed in breast cancer patients with CNS metastases.

Methods

Medical records from breast cancer patients with brain and/or leptomeningeal metastases (LM) treated at a tertiary referral center and a teaching hospital between 2010 and 2020 were retrospectively studied. Main outcomes of interest were overall survival (OS) and CNS progression free survival. Analyses were performed among patients with brain metastases (BM) and patients with LM, for the different systemic and local therapies for CNS metastases, and for subgroups based on breast cancer subtypes.

Results

We identified 155 patients, 97 with BM and 58 with LM. Median OS was 15.9 months for patients with BM and 1.5 months for patients with LM. Median OS was significantly longer for HER2-positive patients with BM (22.8 months) vs triple negative (8.4 months) and hormone receptor positive/HER2-negative (5.9 months) (P?<?0.001). Patients with BM receiving both local and systemic therapy also had a longer median OS (21.8 months), compared to the other three subgroups (local therapy only: 9.9 months, systemic therapy only: 4.3 months, no therapy: 0.5 months, P?<?0.001). No significant difference in OS was observed between different systemic treatment regimens.

Conclusion

Breast cancer patients with BM show longest median OS when the subtype is HER2-positive and when they are treated with both local and systemic therapy.

     

Primary breast cancer phenotypes associated with propensity for central nervous system metastases

BACKGROUND: There is anecdotal evidence that the incidence of central nervous system (CNS) metastases in breast cancer patients is increasing. It is unclear whether specific tumor biological properties or the use of systemic therapies influence this risk. METHODS: Using a database of 10,782 patients, 2685 patients were identified who experienced recurrence distantly. Clinical and biological features were analyzed in 2 ways: (1) patients who ever had versus those who never had CNS metastases, and (2) CNS metastases as the first site of recurrence versus those who had other sites. Correlations of survival after CNS metastasis with clinical and biologic features were also analyzed. RESULTS: In the ever versus never analysis, CNS metastases were significantly associated with younger age, premenopausal status, infiltrating ductal carcinoma histology (IDC), estrogen receptor (ER) and progesterone receptor (PR) negativity, low Bcl-2, high S-phase, aneuploidy, and altered p53. Tumor size, lymph node status, and use of adjuvant systemic therapy played little role. HER-2 overexpression was not associated with an increased risk in these patients (none of whom were treated with trastuzumab) (P = .91). However, epidermal growth factor receptor (EGFR) overexpression was associated with increased risk (P = .02). A multivariate analysis revealed ER negativity (odds ratio [OR] 2.8, P < .001), IDC histology (OR 2.5, P = .02), and young age (P < .001) as independent factors for CNS metastases. The clinical and biologic profiles of primary tumors with CNS metastases at first recurrence did not differ from those with CNS metastases after recurrence to other sites, except for HER-2 status. HER-2-positive tumors were not more likely to undergo recurrence initially in the CNS (P =.04). The median survival after CNS metastases was 5.5 months and HER-2-positive patients had a shorter survival. CONCLUSIONS: Younger patients with hormone receptor-negative, highly proliferative, genomically unstable, and p53-altered tumors were at increased relative risk for CNS metastases. HER-2 expression and adjuvant systemic therapies did not increase this risk.     

Clinical management of primary central nervous system germ cell tumors

Despite excellent long-term results for patients with germinoma treated with radiation therapy, the potential for late effects makes the treatment controversial. On the other hand, most patients with non-germinomatous tumors treated by conventional treatment with surgery and radiation therapy fail to survive longer than 3 years. After combination chemotherapy with cisplatin was confirmed to be effective in gonadal germ cell tumors, germ cell tumors of the brain became candidates for chemotherapy. The author reviews several prospective phase II studies that are being investigated to assess the effect of combination chemotherapy and radiation therapy for germ cell tumors. The aim of these studies is to reduce the volume and dose of radiation therapy for germinoma and prolong the survival of patients of non-germinomatous tumors. For germinoma, a trial with chemotherapy alone failed, with a high rate of recurrence, but Japanese and European trials with reduced-dose chemotherapy and a smaller volume of radiation therapy have resulted in high event-free survival (EFS) rates. Ongoing phase II studies with combined chemotherapy and radiation therapy for non-germinomatous tumors will result in a 5-year survival rate of greater than 50%, which is better than that achieved by radiation therapy alone.     

Survival of breast cancer patients with synchronous or metachronous central nervous system metastases

BackgroundCentral nervous system (CNS) metastases represent a devastating complication for advanced breast cancer patients. This observational study examines the influence of patient, tumour and treatment characteristics on overall survival after synchronous or metachronous CNS metastases.MethodsInformation on 992 breast cancer patients with CNS metastases (whose primary tumour was diagnosed between 2004 and 2010) was retrieved from the Netherlands Cancer Registry (NCR). Overall survival was calculated from the date of CNS metastatic diagnosis, and the impact of prognostic factors on survival was assessed using univariate and multivariate extended Cox-regression models.ResultsWe identified 165 patients with synchronous and 827 patients with metachronous CNS metastases. The majority of patients (88%) presented with brain metastases only, 12% had leptomeningeal metastases. Overall median survival was 5.0 months. Non-triple-negative breast cancer and systemic therapy were associated with improved survival in both groups. In patients with synchronous CNS metastases, surgery for the primary tumour and the metastases also improved survival. In patients with metachronous metastases, younger age (<50 years), lower initial tumour stage (I), ductal carcinoma, a prolonged time interval until diagnosis of CNS metastasis (>1 year), and absence of extracranial metastases were associated with improved survival. Metastasectomy and radiation therapy did not provide benefit beyond the first six months.ConclusionsNo difference in survival was established between synchronous and metachronous CNS metastases. Triple-negative disease is prognostically unfavourable in both groups, while those receiving treatment have a better outcome. Metastasectomy and radiotherapy improve survival within the first six months, and additional benefit may be derived from systemic therapy.     

Conventional radiation therapy in the management of arteriovenous malformations of the central nervous system

Between 1967 and 1981, five patients were treated for vascular malformation of the central nervous system using conventional radiotherapy at Stanford University Medical Center. Two patients had arteriovenous malformations (AVM's) of the spinal cord, two patients had intracranial AVM's, and one patient had a hemangio-epithelioma of the occiput. All patients demonstrated clinical improvement after high dose radiation therapy with follow-up from 5 to 20 years. There have been no complications directly attributable to radiation therapy.     

Haemangiopericytoma of the central nervous system

The records of four patients presenting with a histological diagnosis of haemangiopericytoma of the central nervous system, in Auckland, New Zealand, between 1970 and 1990 were reviewed retrospectively, with the aim of determining the natural history of the disease and response to various treatment modalities. Three out of the four patients reviewed presented with primary cerebral disease and the fourth with a primary spinal cord tumour. All three cerebral primary patients were initially treated with local surgical excision. All three patients received radical radiotherapy following local recurrence. The first two patients remained disease-free locally although one patient developed a solitary liver metastasis 5 years after radiotherapy. The third patient was referred with multiple cerebral metastases and failed to respond to radiotherapy. The patient with the primary lesion in the spinal cord was treated with local excision followed by postoperative radiotherapy and remains disease-free 17 years after treatment. One patient failed to respond to chemotherapy, prescribed to treat a local recurrence adjacent to the previous radiotherapy field. This was successfully excised subsequently. The patient presenting with multiple cerebral metastases was the only patient to die of this disease. Results suggest that local recurrence is avoidable with adequate wide excision of the primary tumour followed by local radical radiotherapy. The role of chemotherapy remains controversial and no conclusion could be drawn regarding the role of palliative radiotherapy from this study. Active treatment and long-term follow-up are necessary because of the relative aggressiveness of this disease and the propensity for late relapses.     

The management of thromboembolic disease in patients with central nervous system malignancies

Opinion statement Venous thromboembolic disease (VTE) is a common complication of malignancies affecting the central nervous system (CNS), both in the perioperative period and throughout the disease course. Until recently, the perceived risk of intracranial hemorrhage in patients with CNS malignancies was felt to be a relative contraindication to systemic anticoagulation, and most patients were managed with nonpharmacologic methods in both the prophylactic and treatment setting. However, several studies of the safety and efficacy of anticoagulation in both neurosurgical and cancer patients have challenged the previous dogma, and routine use of unfractionated heparin or low molecular weight heparin (LMWH) for VTE prophylaxis in patients undergoing craniotomy for CNS malignancy is recommended. Likewise, treatment of established VTE in this population with heparins is recommended, at least initially, followed by long-term treatment either with heparin or oral warfarin. Complications of inferior vena cava (IVC) filters, used as an alternative to systemic anticoagulation, appear to be more common in brain tumor patients with VTE, lending further support to treatment with systemic anticoagulation when possible. We advocate a multimodality approach utilizing compression stockings, intermittent compression devices, and heparin in the perioperative setting as the best proven method to reduce the risk of VTE. In the absence of a strict contraindication to systemic anticoagulation, such as previous intracranial hemorrhage or profound thrombocytopenia, LMWH is recommended in brain tumor patients with newly diagnosed VTE, followed by long-term warfarin or LMWH.     

Tumoral invasion in the central nervous system

Summary We have characterized two human glioblastoma cell lines, which were designated as YH cells and AM cells. The two cell lines maintained morphological appearance observed in the primary culture and immunohis-tochemically expressed glial fibrillary acidic protein (GFAP) and S-100 protein. Population doubling time for YH cells and AM cells indicated 30 hours and 25 hours, respectively, in an exponential phase of culture. Inoculation of AM cells into athymic nude mice formed large tumors at a high incidence. As with chemo-sensitivity to chloroethylnitrosourea, O⁶-methylguanine-DNA methyltransferase (MGMT) activity was measured inin vitro cultured cells as well as tumor specimens obtained at surgery. YH cells showed a high MGMT activity of 1196 fmol/mg and drug resistance to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-cloroethyl)-3-nitrosourea hydrochloride (ACNU) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. YH tumor specimens indicated an MGMT activity of 301 fmol/mg, which reflected poor effectiveness of ACNU chemotherapy in the clinical evaluation. AM cells had an extremely low MGMT activity of 16 fmol/mg and were vulnerable to ACNU. Original tumor specimens of AM cells however expressed a high value of 628 fmol/mg. Considering that ACNU chemotherapy was not effective in the both patients, an MGMT activity of original tumors related with responsiveness to ACNU. Discrepancy in an MGMT activity between thein vitro cell lines and the respective tumor specimens comes from selection of ACNU-sensitive cells or alteration in biological characteristics during long term culture. These results suggest that cell lines derived human brain tumors are useful targets for understanding the chemosensitivity of human malignant gliomas and for establishing a pertinent chemosensitivity test.     

Seven cases of breast cancer recurrence limited to the central nervous system without other visceral metastases

We report 7 rare cases of recurrent breast cancers who presented with central nervous system (CNS) metastases as the initial relapse site without any other organ metastases. The average age of the patients at surgery was 42.6 years old of age (median 45:range 32-60), and 6 of the 7 cases (86%) were premenopausal. The mean disease-free period was 25.7 months (median 22, range 2-60 months). The primary tumors were all invasive ductal carcinomas. The estrogen receptor and progesterone receptor status of the 3 tumors available for study were all negative. The metastatic CNS lesions included the cerebrum (4 cases), cerebellum, cervical spinal cord, and meninges. In 6 out of these 7 cases (86%), the CNS metastasis was the initial recurrent lesion. Multidisciplinary treatments including surgery, radiotherapy and systemic or intrathecal chemotherapy were given. Although the mean survival time from clinical manifestations of the metastases of the 4 deceased patients was 20 months (median 20.5; range 6-33), one patient treated with surgery and radiotherapy is been still alive18 years later. These cases were also notable for the fact that the only metastatic site was in the CNS only during the entire clinical course, except for 2 cases, one with ocular adnexa metastasis, and the other with cervical lymph node metastasis. Premenopausal patients with negative hormone receptor status are more likely to develop this type of recurrence, regardless of the histological type. It is necessary to pay attention to neurological symptoms and signs during follow-up of breast cancer patients.