Metastatic

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 tumors are glioblastomas, meningiomas, pituitary tumors, and acoustic neuromas. Secondary brain tumors that 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 hinder 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. Without 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 1970s, 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 one-half of patients with metastatic disease have a single tumor and about one-half of these patients have surgically accessible tumors. The remaining 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 an 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 underwent 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. 

Radiosurgery Plus Whole Brain Radiation Therapy:

Radiosurgery is an appealing substitute for open surgery in the treatment of brain metastases. It is noninvasive, cost-effective, safe and, in many cases, an outpatient procedure. The very nature of metastases lends them readily to radiosurgical technique: they are well-delimited on MR or CT images, usually do not invade the surrounding brain and are spherical, and most patients harbor 4 or less metastatic deposits. But is radiosurgery as effective as open surgery?


There are many retrospective studies to suggest radiosurgery is as effective as open surgery. Perhaps the most compelling is a multiinstitutional study where patients with single brain metastases treated by WBR and radiosurgery (RS) were identified as having the same prognostic criteria as the patients entered into the 1990 Patchell study comparing WBR and WBR + surgery groups. In this retrospective study Auchter, and others showed survivals in patients treated with radiosurgery+WBR comparable to the surgery+WBR group reported by Patchell (medial survival 56 weeks for RS v. 40 weeks for surgery). RS also controlled local disease (14% local recurrence) while distant recurrence was seen in 22%. Functional independence was 44 weeks similar to the Patchell study of 38 weeks.


Also compelling are the outcome of large numbers of patients treated by radiosurgery with control rates varying from 80% to 95%, largely dependent on tumor type and size. 

CENTER UNIT #PATIENTS RECURRENCE
Wisconsin linac 58 18%
Cologne linac 68 17%
Heidelberg linac 102 5%
Karolinska gamma 300 6%
Sapporo gamma 132 5%
Sendai gamma 77 1%
GK Users gamma 116 17%
Pittsburgh gamma 53 15%
Harvard linac 330 12%
Stanford linac 47 12%
Scripps linac 42 11%
TOTAL   1323 10%

Radiosurgery Alone:

Since brain metastases are a focal disease, non-invasive, outpatient focal treatment is appealing. In certain circumstances, radiosurgery alone may be the best treatment. Pirzkall and co-workers reviewed their experience with 311 metastases treated in 236 patients. Only 78 patients had WBR.  The rest were treated with radiosurgery alone. Interestingly, local recurrence was only 11% with radiosurgery alone v. 8% when WBR was added. Distant recurrences of 23% were reduced to 15% when WBR was added.

 

 Procedure  Local Recur. Distant Recur. Neuro. Death Median Survival (wks)
 WBR 50% 20% 50%  15-20
 Surgery 50% 40% 45%  40
 Surgery + WBR 10-20% 20% 15%  40
 Radiosurgery + WBR 15% 20% 25%  55
 Radiosurgery 11% 23%    

Conclusions:

Local control of intracranial metastases improves the quality and length of survival.


Local control reduces neurological death in vast majority of individuals.


Surgery depends upon adjuvant WBR to achieve local control.


Radiosurgery alone may achieve local control effectively without the need for WBR in terms of median survival.

 

Treatment Protocol:


Below is a flow chart for suggested management of patients with metastatic brain disease. Patients are parsed initially by the amount and control of systemic disease, as well as KPS rating, since these are the major determinants of treatment outcome. Individuals with no systemic disease or controlled disease respond best to local brain treatment (surgery or radiosurgery) followed by WBR. Surgery and radiosurgery seem to have the same effect in terms of local control of disease and survival.