Metastatic Brain Tumors

Summary

Metastatic disease can be viewed as two simultaneously occurring diseases. Brain cancer and systemic cancer (elsewhere in the body). Each disease has quite different mortality rates. Untreated brain metastases are rapidly fatal, while systemic cancer may not be.

Metastatic brain disease is a focal disease and focal control of the tumor is paramount to patient survival. The approach in the past has been to treat metastatic brain disease as a whole brain disease, with whole brain radiation (WBR). Because of poor local control of tumor growth when treated solely by WBR, brain metastases in the past were rapidly lethal. Therefore patients with brain metastases did not benefit from many advances in cancer therapy (immuno therapy, chemo therapy, conformal radiotherapy etc.) because these therapies do no effectively reach brain metastases and individuals died quickly from neurological progression.



Now neurological progression can be effectively controlled in most patients harboring a few intracranial metastases with aggressive focal treatment (surgery or radiosurgery) in combination with WBR. WBR can be given immediately following focal treatment or at the time of recurrence. Control can be extended by frequent MR surveillance of the brain and radiosurgical treatment of new metastases months or years later. With control of intracranial disease, advances in cancer therapy will prolong survival, since most patients now succumb later to systemic, rather than intracranial disease. Aggressive, focal treatment is only beneficial in patients with controlled or no systemic disease and independent health (Karnofsky Performance Score (KPS)> 70). Age is also a determinant of outcome, with better outcomes in individuals less than 60 years old.

Introduction

Tumors of the brain can be divided into two categories. Tumors which arise from the tissues of the brain, its blood vessels, bony and membrane coverings are termed primary brain tumors. These primary tumors may be benign or malignant. Examples of these are glioblastomas, meningiomas, pituitary tumors and acoustic neuromas. Secondary brain tumors arise from malignant sources outside the brain may invade the intracranial cavity, usually as blood- borne metastases. Common sources of these malignant tumors are carcinoma of the lungs, breast, and skin (melanoma). There are more than 1,200,000 new cases and 130,000 deaths from brain metastases each year.

Recent outcome studies of the various treatments for brain metastasis have enlarged our understanding of the management of this disorder. Untreated, patients with metastatic brain tumors may survive only a few weeks, and the addition of steroids to treat brain swelling may add a month to survival. The sensitivity of the brain to external radiation and the failure of chemotherapeutic agents to effectively penetrate the brain greatly hinders treatment.



The development of optimal treatment strategies for brain metastases has been difficult for two reasons. Virtually all studies have been retrospective reviews of various treatment paradigms. With out prospective, controlled studies no realistic comparisons of treatment can be made. Secondly there are many factors which influence the outcome of treatment, such as patient age, disability status, tumor origin, extent of disease outside the brain, tumor location and prior treatment. Controlling for these multiple risk factors has made the design of scientifically controlled studies a daunting task.

Recent Results of Common Treatments for
Brain Metastases


Whole Brain Radiation Therapy Alone:

For nearly 50 years radiologists have appreciated the fact that fractionated external beam brain radiation is effective in the treatment of brain metastases. During the 1970's the Radiation Therapy Oncology Group (RTOG) carried out a number of studies to determine an effective dose of whole brain radiation in the treatment of brain metastases. Comparing various total doses and dose fractions (radiation therapy is given in small doses each day until an effective total dose is achieved) it was determined that 30 Gy given over 10 to 15 fractions was as effective as increasingly greater doses. Total doses over 60 Gy to the brain bring higher risks of brain damage, so it is best to limit total brain radiation.

More recent RTOG studies of hyperfractionation...using 1.6 Gy doses twice a day until total doses of 48 to 70.4 Gy are reached show significant advances in intracranial control, survival and neurologic improvement. This is strong evidence that the control of intracranial disease is dose related. Also the effects of radiation on the brain are accumulative, so that further treatment at a later time adds to the possibility of injuring normally functioning brain tissue. Unfortunately whole brain radiotherapy only increases median survival from a few weeks to 15 to 20 weeks and a large number of patients die from neurologic progression of disease. A high local recurrence rate of 30 to 60%, in spite of WGR, contributes to this limited response to external, fractionated radiation therapy.



Surgery Alone:

Surgery for metastatic deposits is an appealing treatment, but only applicable in a minority of patients. Less than 1/2 of patients with metastatic disease have a single tumor and about 1/2 of these patients have surgically accessible tumors. The remainder of patients have many tumors or deeply-situated deposits which increases the surgical complexity if not the risk.

There are few studies of the utility of surgery as the only treatment for brain metastases. A retrospective study by Smally and others found a 21% intracranial relapse rate when surgery was used in conjunction with whole brain radiation (WBR), and an 85% intracranial relapse rate in patients who only had surgery only. In a important and recent prospective study, Patchell et al. compared the results of surgery alone to surgery + WBR. Ninety-five patients had their single brain metastasis removed. One half of the patients under went WBR, while the other half had no further treatment. Both groups were comparable in terms of various risk factors for treatment outcome. Similar to Smally's findings the intracranial relapse rate was 18% in the radiated group and 70% in the non-radiated group. Patients treated by surgery alone had high rates of local recurrence (46 %) and distant recurrence (37 %) and 44 % died of neurological progressions. It was clear the local control by surgery depends on the addition of WBR. Adjuvant WBR reduced the rate of recurrence of the tumor at the surgical site (46% v. 10%), and reduced the chance that additional metastases will appear in other areas of the brain (37% v. 14%). WBR reduced the potential that the patient will die from brain disease (44% v. 14%). There was no significant difference in survival or functional independence between the groups.



Current image guidance neurosurgical technology marries the MR or CT image with the patient's anatomy in the operating room. This advance allows the surgeon to craft a small and accurate bony opening to expose and remove brain tumors with much precision.



Surgery Plus Whole Brain Radiation Therapy:

In the 1990 study from Lexington, Kentucky group, Patchell et al. sought to compare the outcome of treatment by whole brain radiation (WBR) to WBR + surgical removal. They found recurrence at the original metastasis location was reduced in the WBR+surgical group (20%) compared to the WBR only group (52%). One would expect no difference in the rate of subsequent metastases elsewhere in the brain (20% and 13% was not significant). Importantly, the patients survived longer following surgery (median survival 40 weeks v. 15 weeks), and they had a better quality of life reflected in a longer period of functional independence. This important study first showed the value of focal treatment (surgery) in addition to WBR in improving outcome.

These results were confirmed and extended in a study from the Hague, Netherlands. Nordik and coworkers also compared the outcome in patients treated with WBR or WBR + surgery. This was a prospective study with individuals with single brain metastases randomly assigned to each treatment group after stratification for certain risk factors. Again the operated patients survived longer (median survival 40 weeks v. 24 weeks) with a better quality of life. In this study only individuals with inactive or controlled systemic disease benefited from brain surgery in addition to WBR: 52 week median survival v. 28 weeks. Those with uncontrolled disease elsewhere in the body did not benefit ( 20 week medial survival for both groups). There were 13 complications, 4 serious in the operated group.