An Overview of Radiotherapy Trials for the Treatment of Brain Metastases
An Overview of Radiotherapy Trials for the Treatment of Brain Metastases
Brain metastases are a common site of distant failure for epithelial
malignancies. They are often a harbinger of the final phase of
the cancer patient's course. The appropriate management approach
for a patient with a brain metastasis depends on the patient's
clinical status, the extent of the disease, and the patient's
wishes. Very few prospective or randomized studies have evaluated
the best treatment approach for a patient with a brain metastasis.
For example, no study has prospectively compared radiation therapy
to best supportive care. However, the clear efficacy of radiation
therapy in controlling, at least temporarily, the neurologic symptoms
of brain metastases makes it difficult to advocate withholding
radiation, except in the most extreme of situations . Corticosteroids
alone, although a temporizing measure, quickly loose their efficacy,
and their side effects may negatively impact on the patient's
quality of life.
With these issues in mind, a review of the English language literature
was undertaken in an to attempt to (1) determine the efficacy
of radiation therapy for the treatment of brain metastases, (2)
identify patient factors that have prognostic significance, and
(3) ascertain whether treatment technique has any effect on outcome.
Using Medline and journal references, relevant articles were reviewed
and abstracted. Randomized trials were preferentially selected.
The chosen articles were analyzed for treatment techniques, response,
Several randomized trials have looked at the effect of fractionation
and dose on response and survival. Harwood and Simpson of the
Princess Margaret Hospital in Toronto randomized 108 patients
to receive either 30 Gy in ten 3-Gy fractions over 2 weeks or
10 Gy in one fraction . Among the 101 evaluable patients, there
was no statistically significant difference in median survival
between the single-fraction and multiple-fraction arms (132 vs
121 days). Nor was there a difference in the frequency of response
between the two arms. Death from cerebral metastasis was reported
in 70% of patients, with no difference seen in the recurrence
rate between the two arms.
RTOG Trials of Whole-Brain Irradiation
The Radiation Therapy Oncology Group (RTOG) completed a series
of protocols designed to optimize palliative whole-brain radiation
therapy. The first trial, open from January 1971 to November 1973,
randomized 993 patients to one of four treatment regimens: 40
Gy in 4 weeks, 40 Gy in 3 weeks, 30 Gy in 3 weeks, or 30 Gy in
2 weeks . A total of 910 patients were evaluable. A follow-up
study, which ran from November 1973 to February 1976, randomized
1,001 patients to treatment with 40 Gy in 3 weeks, 30 Gy in 2
weeks, or 20 Gy in 1 week.
The results of these two trials were published together . The
response to treatment was equivalent among all of the arms, even
when patients were stratified by initial performance status. In
both studies, patients with the shortest treatment regimens responded
more quickly. For example, in the second study, 64% of the patients
receiving 20 Gy in 1 week responded within 2 weeks, as compared
with only 54% of the patients on the other arms.
There was no difference in the duration of improvement among the
dose schedules. Similarly, there was no difference by treatment
group for the time to progression. Overall, median survival was
18 weeks in the first study and 15 weeks in the second study.
Death was attributed to brain metastasis in 49% of the patients
in the first trial and 31% of the patients in the second.
The authors defined a "palliative index," which was
the percentage of remaining life spent in an improved or stable
neurologic state. For all patients in the study, 75% to 80% of
the remaining life was palliated, using this marker. Again, there
was no time or dose effect.
Ultra-Rapid High-Dose Arms--At the same time that these
two studies were run, individual participating centers had the
option to also randomize patients to ultra-rapid high-dose arms
. In the first study, 26 patients were offered 10 Gy in a single
fraction, and in the second study, 33 patients were treated with
12 Gy in two fractions. The percentage of these patients showing
neurologic improvement was the same as those receiving more protracted
fractionation (46%). The promptness of improvement was also consistent
with the previous studies.
In contrast, the duration of improvement was less satisfactory.
In the first study, the median duration of improvement (time to
failure or death) was 10 weeks for the longer-fractionation arms
and 4 weeks for the single 10-Gy fraction. However, in the second
study, patients given 12 Gy in two fractions had a 10-week duration
of improvement, which was the same as that seen in patients given
the other fractionation schemes. The response of symptoms to treatment
and treatment morbidity were the same on all arms. Median survival
times for all of the arms also were equivalent, as was the percentage
of deaths attributed to the brain metastases.
The authors concluded that the duration of improvement, time to
progression, and complete disappearance of headache was generally
poorer in both the 10-Gy arm and the 12-Gy arm. A review of the
data indicates that this conclusion appears to hold true for the
10-Gy arm but is more equivocal with regard to the 12-Gy-in-two-fraction
Factors Predicting Improved Survival--The complete study
was analyzed to identify patients having a favorable survival
. Patients with breast cancer and no soft-tissue metastases,
ambulatory lung cancer patients with an absent primary or no extracerebral
metastases, and other ambulatory patients with no extracerebral
metastases had a median survival of 28 weeks, as compared with
11 weeks for the remaining patients (see Table 1). There was no
outcome advantage to any fractionation scheme among even this
selected subgroup of patients. The median time to progression
was 24 weeks for the breast cancer patients and 13 weeks for the
lung cancer patients.
Follow-up of Favorable Patients--A follow-up study by the
RTOG enrolled 309 patients with a favorable prognosis (ie, those
who had a positive brain isotope scans with no other evidence
of disseminated disease, no severe neurologic impairment, and
a controlled primary) . These patients were randomized between
30 Gy in ten 3-Gy fractions and 50 Gy in twenty 2.5-Gy fractions.
The primary tumor was located in the lung in 80% of patients and
in the breast in 7%. (In the remaining patients, the primary was
either unknown or at another site.) Of the patients in the 30-Gy
arm, 93% completed treatment. In contrast, 21% of the patients
in the 50-Gy arm failed to get full therapy, receiving a median
dose of 30 Gy (range, 2.5 to 47.5 Gy).
The median survival of patients in the 30-Gy arm was 18 weeks
and that of patients in the 50-Gy arm was 17 weeks. The 1-year
survival rates of both arms were approximately 25%. The two arms
were equivalent with regard to the percentage of patients achieving
response, time to achieving response, duration of response, and
time to progression. Overall, 47% of the patients died with an
improved or stable neurologic function.
Radiation With and Without a Radiosensitizer
Between 1979 and 1983, the RTOG then randomized 859 patients between
30 Gy in 10 fractions and 30 Gy in 6 fractions over 3 weeks, with
or without the administration of the putative radiosensitizer
misonidazole. Again, among the 779 analyzable cases, there were
few differences in outcome among the arms . The overall median
survival was 3.9 months, with 60% of patients alive at 3 months,
35% at 6 months, and 15% at 1 year. Brain metastases were considered
the cause of death in one-third of the patients.
As a measure of a palliative index, 44% of the patients spent
90% to100% of their remaining survival time in a stable or improved
Karnofsky status, and 65% maintained a stable or improved neurologic
function. The median time to deterioration of performance status
was 1.8 months.
Analyses for Prognostic Factors--Two papers have been published
analyzing the patients who participated in this study (see Table
1). The first paper, by Diener-West and colleagues, identified
four factors associated with improved survival: Karnofsky performance
status of 70 to 100, an absent or controlled primary, age less
than 60 years, and metastatic spread limited to the brain .
Patients with all four charac-teristics had a 200-day survival
of 52%; those with three characteristics, a survival of 38%; those
with two characteristics, 24%; those with one characteristic,
18%; and those with no characteristics, 8%.
The second paper, by Swift and colleagues, looked at the CT characteristics
of patients in the study in an attempt to identify a favorable
subgroup . Pretreatment CT scans were available for over 750
patients. CT scan quality was variable, with 7% judged excellent;
45%, good; 34%, fair; 11%, poor; and 3%, absent or useless. Among
the 408 patients who had at least one follow-up scan, 50% were
responders and 21% were complete responders. Of the patients without
a follow-up CT scan, 59% died within 6 weeks of initiation of
treatment and 80%, within 12 weeks. The only prognostic factors
that were statistically correlated with increased survival were
one to three lesions (median survival of 4.0 months, vs 3.2 months
in those with more than three lesions) and the absence of mid-line
shift (4.3 months, vs 3.7 months in those with such a shift).