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2548
Prognostic Factors for Survival in Patients with Brain
Metastases from Renal Cell Carcinoma
Stéphane Culine, M.D., Ph.D.1
Mohamed Bekradda, M.D.1
Andrew Kramar, Ph.D.2
Annie Rey, B.Sc.2
Bernard Escudier, M.D.1
Jean-Pierre Droz, M.D.3
1
Department of Medicine, Institut Gustave Roussy,
Villejuif, France.
2
Department of Biostatistics, Institut Gustave
Roussy, Villejuif, France.
3
Department of Medicine, Centre Léon Bérard,
Lyon, France.
BACKGROUND. Patients presenting with brain metastases from renal cell carcinoma
portend a poor prognosis, with a reported median survival of 4 – 6 months. Given
their short life expectancy, these patients generally have been excluded from
clinical trials that assess the efficacy of medical treatments. However, clinical
impression suggests that some patients may achieve long term palliation.
METHODS. The clinical features of 68 patients who were treated at the Institut
Gustave Roussy for brain metastases from renal cell carcinoma were collected
retrospectively. Using univariate and multivariate analyses, a prognostic model
based on independent prognostic factors was established. An external data set of
57 patients was used to validate the model.
RESULTS. The median survival was 7 months. On univariate analysis survival was
related significantly to the following adverse prognostic factors: no initial nephrectomy, left side and temporal location of brain metastases, presence of fever or weight
loss, erythrocyte sedimentation rate ⬎ 50 mm/h, and time from initial diagnosis to
brain metastases ⱕ 18 months. Multivariate analyses identified the previous variable
as well as the presence of other visceral metastases as independent prognostic factors.
Forty-four patients (65%) with no or 1 adverse prognostic factor (average risk group)
had a median survival of 8 months and a 26% 1-year survival rate. Twenty-four
patients (35%) with 2 adverse prognostic factors (poor risk group) had a median
survival of 3 months and a 1-year survival rate of 9%. This model proved to be
discriminant in an external data set; the median survival of patients assigned to the
average risk group was 11 months (46% 1-year survival rate) compared with 4 months
(9% 1-year survival rate) for patients assigned to the poor risk group.
CONCLUSIONS. Patients presenting with brain metastases from renal cell carcinoma
and poor risk prognostic factors are highly unlikely to benefit from medical treatments except symptomatic procedures. Conversely, the enrollment of patients
with average risk prognostic factors into clinical trials dealing with chemotherapy
or immunotherapy may be considered. Cancer 1998;83:2548 –53.
© 1998 American Cancer Society.
KEYWORDS: brain metastases, prognostic factors, renal cell carcinoma, risk, survival.
A
The authors thank S. Négrier, M.D., A. Ravaud,
M.D., and G. Chvetzoff for providing the clinical
charts of patients included in the external data set.
Address for reprints: Stephane Culine, M.D., Ph.D.,
Department of Medicine, CRLC Val d’Aurelle,
34298 - Montpellier Cedex 5, France.
Received April 8, 1998; accepted May 7, 1998.
© 1998 American Cancer Society
median survival ranging from 6 –12 months has been reported in
patients with metastatic renal cell carcinoma (RCC).1– 4 Patients
presenting with brain metastases from RCC specifically portend an
even poorer prognosis, with a median survival ranging from 17
weeks–7 months.5,6 Given their short life expectancy, these patients
generally have been excluded from clinical trials that assess the efficacy of medical treatments (i.e., immunotherapy or chemotherapy).
However, clinical impression suggests that some patients may
achieve long term palliation.
The current study presents the long term outcome of 68 patients
Brain Metastases in Renal Cell Carcinoma/Culine et al.
with brain metastases from RCC who were treated at
the Institut Gustave Roussy over a 17-year period. We
specifically investigated whether baseline clinical
characteristics could be of prognostic value in predicting survival with the aim of selecting a subgroup of
patients who could be included into clinical trials
dealing with chemotherapy or immunotherapy.
PATIENTS AND METHODS
The medical records of 1235 patients with RCC who
were registered at the Institut Gustave Roussy between
January 1975 and June 1993 were reviewed retrospectively. The clinical charts from 68 patients (5.5%) with
histologically proven RCC, confirmatory diagnostic
studies (i.e., isotope brain scan, computerized tomography [CT] scan, or magnetic resonance imaging) for
brain metastases, and adequate follow-up were selected. Using such criteria, only six patients who were
registered for therapeutic treatment but were neither
treated nor followed in the institution were eliminated
from the current study. As a rule, brain CT scans were
performed routinely for pretherapy staging at the time
of the first metastatic event and subsequently performed during the course of disease if symptoms were
present. Patient characteristics at the time of initial
diagnosis of RCC are depicted in Table 1.
Subsequent data extracted from the charts included disease free interval (DFI) (defined as the time
from diagnosis of RCC to the diagnosis of brain metastases), performance status (PS), constitutional and
neurologic symptoms, anatomic locations, erythrocyte sedimentation rate (ESR), and other concomitant
metastases at the time of diagnosis of brain metastases; treatment of brain metastases; and survival (defined as the time from diagnosis of brain metastases to
death or last follow-up visit).
Survival was evaluated according to the Kaplan–
Meier method and differences between the survival
curves were assessed by the log rank test.7 Independent prognostic factors were identified by the Cox
regression analysis according to a forward stepwise
procedure.8 The statistical analysis was performed using STATA Statistical Software (Stata Corporation, College Station, TX).
The clinical charts of patients who entered the
external data set were collected in the Centre Léon
Bérard (Lyon, France) and the Institut Bergonié (Bordeaux, France) using criteria similar to those described for the Institut Gustave Roussy.
RESULTS
Patient Characteristics at Diagnosis of Brain Metastases
The characteristics of 68 patients at the time of diagnosis of brain metastases are shown in Table 2. The
2549
TABLE 1
Patient Characteristics at the Time of Initial Diagnosis of Renal
Cell Carcinoma
Characteristics
Gender
Male
Female
Age (yrs)
Median
Range
Location of primary tumor
Right side
Left side
Bilateral
Initial nephrectomy
No
Yes
Perioperative radiotherapy (N ⫽ 59)
No
Yes
TNM staging (N ⫽ 56)
T1
T2
T3a
T3b
T3c
T4
N0
N1
N2
N3
M0
M1
Robson stage (N ⫽ 66)
I
II
III
IV
No.
50
18
53
15–73
30
36
2
9
59
54
5
2
14
17
14
7
2
41
7
7
1
40
16
2
15
20
29
median age was 56 years (range, 21–74 years). The
median DFI was 18 months (range, 0 –142 months).
Brain metastases were present at diagnosis of RCC in
seven patients, four of whom had neurologic symptoms. The brain was the first metastatic location in
eight nephrectomized patients. In 53 patients brain
metastases occurred during the course of a previously
known metastatic disease. Metastases that were diagnosed before brain involvement were located in the
lung (40 patients), bone (16 patients), and liver (6
patients). The diagnosis of brain metastases was performed on systematic brain CT scan in 13 patients
without any neurologic symptoms. Neurologic signs
were noted in 55 patients and varied depending on the
location and extent of brain metastases (Table 2). The
PS was equal to 0 or 1 in 25 patients, 2 in 30 patients,
and 3 or 4 in 13 patients. Weight loss of ⬎ 10% of total
body weight was observed in 49 patients. Ten patients
2550
CANCER December 15, 1998 / Volume 83 / Number 12
TABLE 2
Patient Characteristics at the Time of Diagnosis of Brain Metastases
Characteristics
Age (yrs)
Median
Range
Disease free interval (mos)
Median
Range
Performance status
0 or 1
2
3 or 4
Neurologic symptoms
None
Motor weakness
Intracranial hypertension
Cranial nerve palsy
Confusion/disorientation
Cerebellar ataxia
Seizure
Aphasia
Sensitive deficiency
Weight loss
No
Yes
Fever
No
Yes
Erythrocyte sedimentation rate (N ⫽ 42)
Median
Range
Treatment
Surgery
Radiotherapy
Immunotherapy
Chemotherapy
None
TABLE 3
Distribution of Supratentorial Metastases
No. (%)
56
21–74
18
0–142
Side
Location
Left
Right
Total
Frontal
Parietal
Temporal
Occipital
Total
13
25
12
14
64
11
9
3
4
27
24
34
15
18
91
25 (37)
30 (44)
13 (19)
13 (19)
22 (32)
20 (29)
15 (22)
13 (19)
8 (12)
7 (10)
6 (9)
3 (4)
19 (28)
49 (72)
58 (85)
10 (15)
50
(2–130)
10
57
14
13
8
volved. Conversely, in patients with multiple brain
metastases, 54 metastases were identified in the left
side of the brain, mostly in the parietal area.
Treatment of Brain Metastases
Eight patients received no specific treatment. Ten patients underwent complete surgical resection of a solitary metastasis; seven of these ten patients received
postoperative radiation therapy. Radiotherapy was delivered to the whole brain by parallel opposed lateral
fields in fifty-seven patients. The tumor doses were 18
gray (Gy) in 3 fractions (31 patients); 36 Gy in 6 fractions (8 patients); 30 Gy in 12 fractions (15 patients);
and 30 Gy in 5 fractions (3 patients). A significant
symptomatic improvement was observed in 38 of 50
patients who received radiotherapy alone. However,
no objective response was observed among the 32
patients who underwent a postirradiation brain CT
scan. Additional symptomatic therapy included corticosteroids in 61 patients and antiepileptic drugs in 43
patients.
Prognostic Factors for Survival
presented with fever. The ESR was noted in 42 patients
and the median value was 50 mm/h (range, 2–130).
Characteristics of Brain Metastases
All 68 patients had confirmed brain metastases on CT
scan (63 patients), magnetic resonance imaging (2
patients), or isotopic brain scan (3 patients). The number and location of brain metastases could be described accurately in 66 patients. A total number of
104 brain metastases were identified, 13 of which were
located in the infratentorial area. Among the 91 supratentorial metastases, 64 (70%) were located in the left
side of the brain and the parietal area was predominantly involved (Table 3). Thirty-three patients (50%)
had a solitary metastasis, which in 3 cases was a
unique infratentorial metastasis. Twenty metastases
were located in the right side of the brain and the
frontal and parietal areas were predominantly in-
The median survival for all 68 patients was 7 months
(Fig. 1). Five patients were still alive 6, 6, 17, 23, and 61
months, respectively, after the diagnosis of brain metastasis. The median survival of the 8 patients who
received no specific therapy was 1 month. The median
survival of the patients who underwent surgery (10
months) was statistically better than the median survival of the patients treated by radiotherapy alone (7
months) (P ⫽ 0.04).
Using P ⬍ 0.1 as a cutoff point in univariate analysis, survival was related significantly to the following
pretreatment adverse prognostic factors: no initial nephrectomy, left-sided brain metastases, temporal location, presence of fever or weight loss, ESR ⬎ 50, and
time from initial diagnosis to brain metastases ⱕ 18
months (Table 4). PS was not statistically significant
mainly due to the PS 2 category, which followed a
survival pattern similar to the PS 3 category during the
Brain Metastases in Renal Cell Carcinoma/Culine et al.
2551
TABLE 4
Univariate Analysis of Prognostic Factors
Variable
FIGURE 1.
Overall survival of the 68 patients with brain metastases from
renal cell carcinoma.
first 3 months and joined the survival pattern of the PS
0/1 category after 9 months. This fact led to a univariate nonsignificant statistical result due to nonproportional hazard rates.
The multivariate analysis first was performed using all variables found to be significant in the univariate analysis except ESR, which was omitted because it
was only available in 42 patients. The other variables,
which were not significant in the univariate analysis,
then were added to the model to assess how they were
likely to contribute significant information when adjusted for the factors in the multivariate analysis. Two
independent adverse prognostic parameters were retained: the presence of other metastases (P ⫽ 0.017)
and a DFI ⱕ 18 months (P ⫽ 0.002). A classification
into average risk or poor risk groups then was made
depending on the number of adverse prognostic factors (Table 5). Forty-four patients (65%) with no or
only 1 adverse prognostic factor (average risk group)
had a median survival of 8 months and a 1-year survival rate of 26%. Twenty-four patients (35%) with 2
adverse prognostic factors (poor risk group) had a
median survival of 3 months and a 1-year survival rate
of 9% (Fig. 2).
This prognostic model proved to be discriminant
in an external data set of 57 patients treated in 2
independent cancer centers. In general patient characteristics did not differ significantly from those used
in obtaining the prognostic groups. However, there
were significantly more patients assigned to the poor
risk group (60%) because of a higher proportion of
patients with a short DFI. The median survival of
patients assigned to the average risk group was 11
months (1-year survival rate of 46%) compared with 4
months for patients assigned to the poor risk group
(1-year survival rate of 9%).
Side of primary tumor
Right
Left
Bilateral
Initial nephrectomy
No
Yes
Robson stage
I–II
III
IV
Number of brain metastases
1
⬎1
Right side
No
Yes
Left side
No
Yes
Frontal location
No
Yes
Parietal location
No
Yes
Temporal location
No
Yes
Occipital Location
No
Yes
Infratentorial location
No
Yes
Performance status
0/1
2
3
Fever
No
Yes
Weight loss
No
Yes
ESR
ⱕ50
⬎50
Other metastases
No
Yes
Disease free interval (mos)
ⱕ18
⬎18
ESR: Erythrocyte sedimentation rate.
No. of
patients
Median
survival (mos)
30
36
2
7
4
4
9
59
3
7
17
20
29
5
8
4
33
33
7
7
0.3
14
52
3
7
0.1
27
39
9
5
0.04
41
24
7
5
0.5
31
34
6
7
0.2
50
15
7
6
0.06
47
18
7
7
0.8
52
13
6
7
0.4
25
30
13
8
4
3
58
10
7
3
0.03
19
49
9
4
0.07
25
17
8
4
0.09
15
53
9
4
0.16
34
34
4
9
0.01
P value
0.9
0.07
0.8
0.2
2552
CANCER December 15, 1998 / Volume 83 / Number 12
TABLE 5
Prognostic Model for Survival
Prognostic group
Model set
Average risk
Poor risk
Validation set
Average risk
Poor risk
No. of adverse
prognostic
variables
No. of
patients
(%)
Median
survival
(mos)
0 or 1
2
44 (65%)
24 (35%)
8
3
0 or 1
2
23 (40%)
34 (60%)
11
4
FIGURE 2.
Survival curves according to the prognostic model. Solid line:
average risk group; dashed line: poor risk group.
DISCUSSION
Of 1235 patients with RCC registered at Institut
Gustave Roussy over a 17-year period, we selected 68
patients (5.5%) who presented with brain metastases.
This incidence is similar to that reported in another
clinical series.5 However, autopsy studies have noted a
larger incidence of brain metastases from RCC ranging
from 10 –20%.9,10 These discrepancies may result from
the observation that many patients have clinically unrecognized intracranial disease and often experience
greater morbidity and mortality related to other visceral metastases.11 Indeed, brain metastases were diagnosed fortuitously on CT scans in 13 patients who
had no neurologic symptoms. Conversely, symptomatic brain metastases caused four patients with no
previously diagnosed primary neoplasm to seek medical attention. The kidney was reported to be the site
of primary tumor in 5–10% of patients presenting with
initial brain metastases.12–14 In another eight patients,
the brain was the first metastatic location. Although
rather unusual in RCC, such a dissemination pathway
without any other evidence of disease has been described previously.15,16
With regard to therapeutic approaches, corticosteroids should be the first intervention for every pa-
tient with brain metastases.17 Although their exact
biochemical mechanisms are not known, they reduce
peritumoral edema, thus diminishing the total mass of
brain metastases as well as local brain compression
and reduce neurologic signs.18 However, corticosteroids customarily are contraindicated during the
course of immunotherapy because they may abrogate
the immune response. Therefore, patients should discontinue steroid use to be eligible for potential treatment with immunotherapy. This means that the brain
metastases do not progress after local treatment (i.e.,
surgery and/or radiotherapy).
In our series local therapies included surgery in
10 patients with a solitary metastasis and external
beam whole brain irradiation alone in 50 patients.
Although the objective of the current study was not
to compare the results of treatment, we observed a
significantly better survival in favor of surgery in
univariate analysis. However, this prognostic significance was not retained in the multivariate analysis.
Two prospective randomized studies have suggested the superiority of surgery plus radiotherapy
over radiotherapy alone in patients with a single
brain metastasis.19,20 However a third trial failed to
confirm these results.21 Although these studies were
not restricted to patients with brain metastases from
RCC, it appears appropriate that a patient with a
single brain metastasis should be considered for
surgical resection as the primary treatment, especially young patients with controlled or absent extracranial tumor activity.22 Cranial irradiation remains the mainstay of therapy when surgery is
contraindicated. The majority of patients in the current study experienced neurologic improvement but
no objective response was observed. These results
are in agreement with other series in which RCC
usually was unresponsive to conventional photon
therapy and only a subjective improvement was observed.23,24
Recent publications have focused on prognostic
factors for survival in patients with metastatic RCC
who were treated by chemotherapy,3,4 interleukin-2,
or interferon-␣.25–27 Multivariate analyses identified
PS, weight loss, sarcomatoid histology, number of
metastatic sites, time from initial diagnosis to systemic
therapy, and ESR as strong predictors for survival. To
our knowledge, no multivariate analysis has been
published so far in patients with brain metastases
from RCC. Only one previous study focused on variables influencing survival in those patients.6 PS was
the most significant prognosticator in this univariate
analysis performed on 34 patients.6 In our series of 68
patients, the median survival was 7 months. This observation is similar to that published by other re-
Brain Metastases in Renal Cell Carcinoma/Culine et al.
searchers.5,6 Systemic symptoms such as fever and
weight loss only were selected as prognostic variables
in the univariate analysis. The multivariate analysis
retained the presence of other visceral metastases and
a short DFI (ⱕ 18 months) as adverse prognostic factors. The ESR also retained a significant prognostic
value but was omitted from the prognostic model
because it was available in only a small number of
patients. Using our prognostic model, which was validated in an external data set of patients, a poor risk
subgroup of patients with two adverse variables who
are highly unlikely to benefit from medical treatments
except symptomatic procedures can be distinguished.
Conversely, for these patients (assigned into the average risk group) the median survival was 8 months,
which is not significantly different from the median
survival of patients with other metastatic sites from
RCC. We suggest that patients with such characteristics are likely to benefit from optimal treatment plans.
They should be treated primarily with surgery and/or
radiotherapy. Subsequently, provided that brain metastases are not progressive after local treatment(s),
enrollment in trials dealing with chemotherapy or immunotherapy may be considered.
12.
13.
14.
15.
16.
17.
18.
19.
20.
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