Temozolomide given on a prolonged schedule plus thalidomide has been tested in a phase II study of patients with brain metastases,but the high toxicity and lack of response rendered the regimen inappropriate.249
A study of high-dose methotrexate in patients mostly with breast cancer achieved disease control in 56%of patients.250
Other agents shown to have activity in breast cancer include platinum plus etoposide,251,252 and capecitabine.253
A phase I/II study of topotecan plus WBRT has shown a 72%response rate in 75 patients with brain metastases.254
Unfortunately,a follow-up phase III trial was closed early due to slow accrual.255
NCCN Recommendations Work-up
Patients who present with a single mass or multiple lesions on MRI or CT imaging suggestive of metastatic cancer to the brain,and do not have a known primary,require a careful systemic workup with chest x-ray or CT,abdominal or pelvic CT,or other tests as indicated.
FDG-PET can be considered if there are one than one brain lesions,and no primary has yet been found.
If no other readily accessible tumor is available for biopsy,a stereotactic or open biopsy resection is indicated to establish a diagnosis.
Among patients with a known history of cancer,if there are concerns regarding the diagnosis of CNS lesions,a stereotactic or open biopsy resection or subtotal resection is alsoneeded.
Because brain metastases are often managed by multiple modalities,the NCCN panel encourages multidisciplinary consultation prior to treatment for optimal planning.
Treatment for limited(1-3)metastatic lesions
For patients with limited systemic disease or for whom reasonable systemic treatment options exist,aggressive management should be strongly considered.
For surgical candidates,high level of evidence supports category 1 recommendations for surgical resection plus post- operative WBRT,and for SRS plus WBRT if only one brain lesion is involved.
SRS alone or following resection are also reasonable options.
Macroscopic total removal is the objective of surgery.
The choice between open resection and SRS depends on multiple factors such as tumor size and location.
The best outcome for SRS is achieved for small,deep lesions at institutions with experienced staff.
If the tumor is unresectable,WBRT and/or radiosurgery can be used.
Patients with progressive extracranial disease whose survival is less than 3 months,should be treated with WBRT alone,but surgery may be considered for symptom relief.
The panel did not reach a consensus on the value of chemotherapy(category 2B).
It may be considered in select patients using regimens specific to the primary cancer.
Patients should be followed with MRI every 3 months for 1 year and then as clinically indicated.Recurrence on radiograph can be confounded by treatment effects.
Strongly consider tumor tissue sampling if there is a high index of suspicion of recurrence.
Upon detection of recurrent disease,prior therapy clearly influences the choice of further therapies.Patients with recurrent CNS disease should be assessed for local versus systemic disease,because therapy will differ.
For local recurrences,patients who were previously treated with surgery can receive the following options:1)surgery;2)SRS;3) WBRT;or 4)chemotherapy.
However,patients who previously received WBRT or SRS should not undergo WBRT at recurrence.
If the patient had previous SRS with a durable response for greater than 6 months, reconsider SRS if imaging supports active tumor and not necrosis.
The algorithm for distant brain recurrences branches depending on whether patients have either 1-3 lesions or more than 3 lesions.
In both cases, patients may receive WBRT or consider local/systemic chemotherapy,but patients with 1-3 recurrent tumors have the additional options of surgery or SRS.
WBRT should be used(30-45 Gy,given in 1.8 to 3.0 Gy fractions depending on the patient’s performance status,if this modality was not used for initial therapy.
Local or systemic chemotherapy may be considered for select patients,if the multiple lesions cannot be controlled by a combination of surgery and radiosurgery.256
If systemic CNS disease progression occurs in the setting of limited systemic treatment options,WBRT should be administered if the patients have not been previously irradiated.
For patients who have received prior WBRT,reirradiation is an option only if they had a positive response to the first course of RT treatment.
Best supportive care is also an option in either case.
Treatment for multiple(>3)metastatic lesions
All patients diagnosed with more than three metastatic lesions should be treated with WBRT as primary therapy.
The standard regimens for WBRT are 30 Gy in 10 fractions or 37.5 Gy in 15 fractions,but no significant impact to survival was reported with variations in fractionation and dosing according to a meta-analysis of nine randomized trials.257
For patients with poor neurologic performance,a more rapid course of RT can be considered(20 Gy,delivered in 5 fractions).
SRS may be considered in select patients(eg.,four small lesions).
Palliative neurosurgery should be considered if a lesion is causing a life-threatening mass effect,hemorrhage,or hydrocephalus.
After WBRT,patients should have a repeat contrast-enhanced MRI scan every 3 months for 1 year.
If a recurrence is found,the algorithm branches depending on whether patients have(1)systemic disease progression with limited systemic treatment options;or(2)stable systemic disease or reasonable systemic treatment options.
For patients with systemic disease progression,options include best supportive care or reirradiation.
For patients with stable systemic disease,options include surgery,reirradiation,or chemotherapy.
Leptomeningeal Metastases
Leptomeningeal metastasis or neoplastic meningitis refers to the multifocal seeding of the leptomeninges by malignant cells.
It is known as leptomeningeal carcinomatosis or carcinomatous meningitis when these cells originate from a solid tumor.
When it is related to a systemic lymphoma,it is called lymphomatous meningitis,and when associated with leukemia,it is termed leukemic meningitis.
Leptomeningeal metastasis occurs in approximately 5%of patients with cancer.258
This disorder is being diagnosed with increasing frequency as patients live longer and as neuroimaging studies improve.
Most cases arise from breast and lung cancers;melanoma has the highest rate of leptomeningeal spread.259,260
Tumor cells gain access to the leptomeninges by hematogenous dissemination,lymphatic spread,or direct extension.
Once these cells reach the CSF,they are disseminated throughout the neuraxis by the constant flow of CSF.
Infiltration of the leptomeninges by any malignancy is a serious complication that results in substantial morbidity and mortality.
Cranial nerve palsies,headaches,cerebral disturbances,mental changes,and motor weakness are among the most common presenting symptoms.258
The median survival of patients diagnosed with this disorder is less than 3 months with death resulting from progressive neurologic dysfunction but may be extended by early detection and intervention.259,260
Treatment Overview
The goals of treatment in patients with leptomeningeal metastases are to improve or stabilize the neurologic status of the patient and to prolong survival.
Unfortunately,there is a lack of standard treatments due to meager evidence in literature.
Because treatment is palliative,aggressive chemotherapy should only be given to patients most likely to benefit (see“Patient stratification”).
Radiation therapy
Radiation is mainly given for symptom alleviation,CSF flow correction, or for debulking to facilitate chemotherapy.260-262 Surgery
The role of neurosurgery for leptomeningeal metastases is mainly to place an intraventricular catheter and subcutaneous reservoir for drug administration.263
This is preferred over lumbar punctures because of