Download Best supportive care in patients with brain metastases

Support Care Cancer (2013) 21:2671–2678
DOI 10.1007/s00520-013-1840-5
ORIGINAL ARTICLE
Best supportive care in patients with brain metastases
and adverse prognostic factors: development of improved
decision aids
Carsten Nieder & Jan Norum & Astrid Dalhaug &
Gro Aandahl & Kirsten Engljähringer
Received: 31 January 2013 / Accepted: 25 April 2013 / Published online: 18 May 2013
# Springer-Verlag Berlin Heidelberg 2013
Abstract
Purpose This study aimed to develop a survival prediction
model that might aid decision making when choosing between best supportive care (BSC) and brain radiotherapy
(RT) for patients with brain metastases and limited survival
expectation.
Methods A retrospective analysis of 124 patients treated with
BSC, whole brain radiotherapy (WBRT), or radiosurgery was
conducted. All patients had adverse prognostic features defined as 0–1.5 points according to the diagnosis-specific graded prognostic assessment score (DS-GPA) or GPA if primary
tumor type was not among those represented in DS-GPA.
Kaplan–Meier survival curves were compared between patients treated with BSC or RT in different scenarios, reflecting
more or less rigorous definitions of poor prognosis. If survival
was indistinguishable and this result could be confirmed in
multivariate analysis, BSC was considered appropriate.
Results Irrespective of point sum examined, DS-GPA by
itself was not a satisfactory selection parameter. However,
we defined a subgroup of 63 patients (51 %) with short
survival irrespective of management approach (only 5 % of
irradiated patients survived beyond 6 months; they had newly
C. Nieder (*) : A. Dalhaug : G. Aandahl : K. Engljähringer
Department of Oncology and Palliative Medicine,
Nordland Hospital, 8092 Bodø, Norway
e-mail: [email protected]
C. Nieder : J. Norum : A. Dalhaug
Institute of Clinical Medicine, Faculty of Health Sciences,
University of Tromsø, 9037 Tromsø, Norway
J. Norum
Department of Oncology, University Hospital of North Norway,
9038 Tromsø, Norway
J. Norum
Northern Norway Regional Health Authority Trust, Bodø, Norway
diagnosed, treatment-naïve lung cancer), i.e., patients in
whom foregoing RT was unlikely to compromise survival.
These were patients with 0–1.5 points and aged ≥75 years, had
Karnofsky performance status ≤50, or had uncontrolled primary tumor with extracranial metastases to at least two
organs.
Conclusions BSC is a reasonable choice in patients with
limited life expectancy. After successful external validation
of the selection criteria developed in this analysis, identification of patients who are unlikely to benefit from WBRT
might be improved.
Keywords Brain metastases . Prognostic factors .
Radiotherapy . Best supportive care
Background
Recent attempts towards personalized cancer treatment are
expected to improve individual patient’s outcome and limit
the rapid growth of health care budgets. Development of
prediction tools might facilitate informed decisions about
which treatment is likely to work or to be futile. Avoiding
futile treatment efforts saves patients from unnecessary toxicity, travelling, and time spent in hospitals or oncology
practices [1]. Several studies have shown that patients with
noncurable metastatic cancer might receive too aggressive
and long-standing treatment during the last months of life.
The focus on optimal supportive care may be lost or prioritized too late. Many patients with brain metastases belong
to this group [2, 3]. These considerations led to the activation of a prospective randomized study of best supportive
care (BSC) vs. whole brain radiotherapy (WBRT) known as
the QUARTZ trial [4]. Inclusion was limited to patients with
inoperable brain metastases from non-small cell lung cancer
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(NSCLC) for whom the clinician and patient is uncertain of
the benefit of WBRT. Interim analysis of the results
suggested comparable quality-adjusted life years (QALY)
and survival gain in the two arms. Since many patients with
primaries other than NSCLC face the same difficult dilemma, we recently compared BSC to WBRT in patients with
different primary tumors and poor prognosis where uncertainty about the benefit of WBRT existed [5]. Our findings
confirmed that BSC did not shorten survival and was an
appropriate choice for the majority of these patients.
We concluded that it would be desirable to develop
objective selection criteria which allow for prediction of
whether or not a given patient can safely forego WBRT.
Not all clinicians are comfortable basing important treatment decisions upon subjective statements such as “when
the clinician and patient is uncertain of the benefit of
WBRT.” For this purpose, many clinicians prefer to rely
on well-defined prognostic factors. Attempts have been
made to predict survival by the use of prognostic scores
such as the Radiation Therapy Oncology Group (RTOG)’s
recursive partitioning analysis (RPA) classes [6]. More recently, the RTOG proposed a new index, the graded prognostic assessment (GPA) [7], which was followed by the
diagnosis-specific GPA (DS-GPA) scores for patients with
renal cell carcinoma, malignant melanoma, lung, breast, and
gastrointestinal cancers [8]. We were able to confirm that
each of these scores is valid in real-world patients treated
outside clinical trials [9–11]. Nevertheless, substantial variations of actual survival make it impossible to rely solely on
RPA, GPA, or even a combination of GPA and two other
scores when deciding about management of individual patients with adverse prognostic features [12]. In extension of
our previous work that was performed before the DS-GPA
became available, we aimed at the development of less
error-prone survival prediction models for patients who
might be candidates for BSC. We hypothesized that the
DS-GPA might be a better fundament than the previously
tested scores.
Methods
For this retrospective single-institution study, consecutive
patients treated during the 8-year time period between 2005
and 2012 were chosen. All patients had adverse prognostic
features, arbitrarily defined as 0–1.5 points according to the
definitions of the DS-GPA score. The GPA score was used
in patients with primary tumors not covered by the DS-GPA
because it was previously shown that GPA is a pragmatic
and valid choice [13]. All 124 patients were derived from a
previously described brain metastases database, which is
maintained and updated at the first author’s institution in
Bodø [14, 15]. All patients with brain metastases presented
Support Care Cancer (2013) 21:2671–2678
to this institution were registered in the database, regardless
of prognosis or management approach (BSC or radiotherapy
[RT]). Irradiated patients had immediate WBRT or stereotactic radiosurgery (SRS) without preceding systemic therapy after the diagnosis of brain metastases. None of the
patients had previous brain RT (prophylactic or other). A
shared decision towards treatment approach was made by
the patient, caregiver(s), and treating physician(s), taking
into account the life expectancy, local and systemic disease
extent, and patient preferences (no standardized use of any
particular prognostic model).
Six patients (5 %) were alive at date of last follow-up
(November 1, 2012) and thus censored. Their median
follow-up was 4.9 months (range, 2.6–12.4 months). Date of
death was known in all other patients. We analyzed survival
outcomes and prognostic factors (baseline and treatmentrelated). For the comparison of dichotomous variables, the
chi-square test and Fisher’s exact test, where applicable, were
employed, and for continuous variables, the Mann–Whitney
U test was used. Survival from imaging diagnosis of brain
metastases was calculated with the Kaplan–Meier method and
compared between different groups (BSC vs. active treatment)
with the log-rank test. For multivariate prediction of survival,
Cox regression analysis was used (forward stepwise data
selection method). A p value ≤0.05 was considered statistically significant.
Results
Table 1 shows detailed information on all 124 patients with
adverse prognostic features, i.e., 0–1.5 points according to
the DS-GPA (GPA if DS-GPA was not applicable, n=7) in
this study. As this was an intention-to-treat analysis, we
included patients who failed to complete their course of
WBRT. Initially, we tested in all 124 patients whether or
not active treatment improved survival compared to BSC.
We found that actuarial median survival from imaging diagnosis was longer in each of the RT arms compared to BSC
(BSC, 1.5 months; WBRT 20 Gy, 2.2 months (p=0.07);
WBRT 30 Gy, 3.0 months (p=0.0001); WBRT with or
without boost to doses higher than 30 Gy, 5.7 months
(p=0.01); SRS, 5.3 months (p=0.009); note that all patients
with incomplete RT always were included in the appropriate
group). Besides median survival, survival beyond 6 months
was also improved (Fig. 1). Multivariate analysis with treatment arms (p=0.001), RPA classes (p=0.08), and DS-GPA
(or GPA in seven patients; p=0.04)) confirmed that survival
after BSC was not equivalent to that after RT. A second
multivariate model included individual prognostic factors
(age, number of brain metastases, Karnofsky performance
status (KPS), presence of extracranial metastases, primary
tumor control, and gender) in addition to those included in
Support Care Cancer (2013) 21:2671–2678
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Table 1 Patient characteristics (n=124)
Parameter
Number
Percent
Treatment
BSC
WBRT 20 Gy intended dose
WBRT 30 Gy intended dose
WBRT±boost>30 Gy
SRS
Incomplete RT course
Female patients
Male patients
Small cell lung cancer
NSCLC
Breast cancer
Malignant melanoma
Renal cell carcinoma
Gastrointestinal cancer
Unknown primary
Other
33
28
54
5
4
9
64
60
16
54
10
13
7
17
3
4
27
23
44
4
3
7
52
48
13
44
8
10
6
14
2
3
67
57
11
113
62
14
40
70
106
18
1
40
83
66 (40–88)
60 (30–90)
54
46
9
91
50
11
32
57
85
15
1
32
67
Controlled primary tumor
Uncontrolled primary tumor
Extracranial metastases absent
Extracranial metastases present
At least two organs involved
Single brain metastasis
Two or three brain metastases
More than three brain metastases
DS-GPA poor
DS-GPA intermediate–poor
RPA class 1
RPA class 2
RPA class 3
Median age, years (range)
Median KPS, range
Median intervala, months (range)
Median number of brain metastases
Median DS-GPA (or GPA)
6 (0–120)
4 (1–51)
0.5 (0–1.5)
BSC best supportive care, WBRT whole brain radiotherapy, SRS stereotactic radiosurgery, DS-GPA diagnosis-specific graded prognostic
assessment (0–1 point, poor; 1.5–2 points, intermediate–poor; 2.5–3
points, intermediate–good), RPA recursive partitioning analysis, KPS
Karnofsky performance status
a
Interval from initial cancer diagnosis to brain metastases
the first model. Again, survival was not equivalent (p=0.01
for treatment arms, p=0.03 for DS-GPA/GPA, and p=0.05
for KPS). In addition to being statistically significant (with
one exception of p=0.07), the survival improvement in the
RT arms appeared clinically meaningful because it was
longer than the time spent on RT, even for the 20-Gy WBRT
group where the survival difference was minor (0.7 months).
Based on these findings, we cannot recommend the use of
DS-GPA/GPA 0–1.5 points as selection criterion for BSC.
Next we tested whether or not restricting DS-GPA/GPA
to 0–1 points would be more appropriate. This analysis
followed the same path and included 106 patients. Based
on the almost identical survival differences observed (BSC,
1.5 months; WBRT 20 Gy, 1.9 months; WBRT 30 Gy,
2.7 months; WBRT with or without boost to doses higher
than 30 Gy, 5.7 months; SRS, 5.3 months) and confirmatory
multivariate analyses identical to those described previously, we rejected the use of this criterion too.
Then, we chose to restrict DS-GPA/GPA to 0–0.5 points
(n =68). Again, significant differences were seen (BSC,
0.9 months; WBRT 20 Gy, 2.2 months; WBRT 30 Gy,
2.1 months; no patients with other RT approaches), p=0.049
and p=0.005, respectively, which were confirmed in multivariate analyses as described previously. Even limiting the analysis
to patients with 0 points only (n=40) did not result in satisfactory survival differences, i.e., less than the 2 weeks spent on a
30-Gy WBRT regimen. Median actuarial survival was
0.8 months (BSC), 1.7 months (20 Gy WBRT), and 2.1 months
(30 Gy WBRT), p=0.03 and p=0.001, respectively.
Given that DS-GPA/GPA alone was not sufficient to
decide that withholding WBRT would be appropriate because survival would not be compromised, we hypothesized
that adding other factors to this validated prognostic score
could improve prediction of short survival. We looked at
age, KPS, primary tumor control, and extracranial metastases, i.e., established factors forming the basis of the RPA
classes, and combinations of these factors such as
uncontrolled primary tumor plus extracranial metastases or
metastases to at least two organs (liver plus lung, bone plus
adrenal gland, etc.). For age and KPS, different cutoffs were
analyzed in order to optimize the performance of each
parameter. In each case, we compared Kaplan–Meier curves
for three groups of patients with DS-GPA/GPA 0–1.5 points
plus one additional adverse factor, e.g., KPS <50, treated
either with BSC or RT (WBRT 20 Gy vs. all other types and
doses combined, termed more aggressive RT). After optimization of cutoff and parameter combinations, we found
identical survival curves for patients managed with BSC or
RT who fulfilled the following criteria: DS-GPA/GPA 0–1.5
points and age at least 75 years, DS-GPA/GPA 0–1.5 points
and KPS ≤50, and DS-GPA/GPA 0–1.5 points and
uncontrolled primary tumor with extracranial metastases to
at least two organs. The performance of our survival prediction model did not improve by altering the DS-GPA/GPA
requirement, e.g., limiting inclusion to 0–1 or 0–0.5 points.
Finally, we grouped together all patients from the three
subgroups with DS-GPA/GPA 0–1.5 points and age at least
75 years or KPS ≤50 or uncontrolled primary tumor with
extracranial metastases to at least two organs, i.e., those who
are unlikely to experience improved survival from RT.
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Support Care Cancer (2013) 21:2671–2678
Fig. 1 Actuarial Kaplan–Meier
survival curves for patients
treated with short-course
WBRT (20 Gy intended dose)
or more aggressive RT
(intention to treat) or BSC;
differences were statistically
significant, except for BSC vs.
20 Gy WBRT (p=0.07), logrank test
Diagnosis-specific graded prognostic assessment (DS-GPA) 0-1.5 points in all patients
Table 2 shows the characteristics of these 63 patients (51 %).
Median survival was 1.5 months (BSC), 1.7 months (WBRT
20 Gy), and 2.1 months (more aggressive RT), p=0.87,
p=0.24, and p=0.21, respectively (note that significantly
more patients who had aggressive RT belonged to RPA class
2 (Table 2), which explains most of the survival difference
seen here). Multivariate analysis confirmed that treatment
arm was not significantly associated with survival (p=0.53,
further variables included were DS-GPA/GPA with p=0.05,
gender with p=0.2, age with p=0.36, RPA with p=0.9, and
KPS with p=0.98). The survival curves are shown in Fig. 2.
In contrast to our first, purely DS-GPA/GPA-based analyses,
which gave unsatisfactory results with both significantly
better median survival and considerable proportions of irradiated patients who survived for more than 6 months, very
few irradiated patients survived for more than 6 months
(0 out of 11 with age 75 years or older, 1 out of 41 with
KPS ≤50, and 1 out of 25 with uncontrolled primary tumor
and extracranial metastases to at least two organs; some
patients fulfilled two or three criteria at the same time).
Thus, only 2 out of 41 irradiated patients (5 %, both had
newly diagnosed untreated NSCLC) survived for more than
6 months. In other words, applying these criteria to recommend BSC has a very low risk of compromising patients’
survival.
The last step consisted of comparing these selection
criteria to those identified in our previous, smaller analysis
from the year 2010 [12]. At that time, we had relied on older
scores and recommended that patients with KPS <80,
uncontrolled primary tumor, presence of extracranial
metastases, and no intent to treat systemically might best
be managed with BSC. We selected all patients fulfilling
these four criteria from our database. Among 37 patients, 36
also fulfilled the criterion of DS-GPA/GPA 0–1.5 points,
while 1 patient scored 2 points. Eighteen patients were
managed with BSC, 8 with WBRT 20 Gy intended dose,
and 11 with WBRT 30 Gy intended dose. Median survival
was 1.8 months after BSC, 1.9 months after short-course
WBRT (p = 0.89), and 3.0 months after longer-course
WBRT (p=0.28). Figure 3 shows the survival curves. It
should be noted that RT did not result in long-term survival.
Imbalances in baseline prognostic factors favored the
longer-course WBRT group. Multivariate analysis, including baseline prognostic factors according to the methods
described previously, did not confirm that treatment arm
independently influenced survival. A disadvantage of these
4 selection criteria is that only 37 patients would be considered appropriate for BSC, while the new model would
recommend BSC for 63 patients.
Discussion
There is increasing awareness and acceptance of terminal
care strategies for patients with metastatic cancer, which
avoid overtreatment and rather focus on optimal palliation.
Evidence from several sources, including interim data from
a randomized trial, suggest that avoiding RT and providing
BSC for patients with brain metastases and adverse prognostic features does not shorten survival [4, 5]. The already
Support Care Cancer (2013) 21:2671–2678
Table 2 Characteristics of patients (n=63) considered appropriate candidates for BSC (n=22
managed with BSC, 18 who received short-course WBRT with
20 Gy intended dose, and 23 who
received more aggressive RT)
Note that patients who received
more aggressive RT had more
favorable baseline prognostic
factors, including younger median age, better median KPS,
and higher proportion of RPA
class 2
WBRT whole brain radiotherapy,
DS-GPA diagnosis-specific graded prognostic assessment (0–1
point, poor; 1.5–2 points, intermediate–poor), RPA recursive
partitioning analysis, KPS
Karnofsky performance status
a
Interval from initial cancer diagnosis to brain metastases
Parameter
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BSC
20 Gy
Number
Percent
Female patients
Male patients
Small cell lung cancer
NSCLC
Breast cancer
Malignant melanoma
Renal cell carcinoma
Gastrointestinal cancer
Other
Controlled primary tumor
Uncontrolled primary tumor
Extracranial metastases absent
Extracranial metastases present
Single brain metastasis
Two or three brain metastases
More than three brain metastases
DS-GPA poor
DS-GPA intermediate–poor
RPA class 3
12
10
3
10
1
5
1
0
2
9
13
3
19
1
7
14
22
0
22
55
45
14
45
5
23
5
0
9
41
59
14
86
5
32
64
100
0
100
RPA class 2
Median age, years
Median KPS
Median intervala, months
0
75
5
0
Incomplete RT course
>20 Gy
Number
Percent
Number
Percent
1
6
6
26
9
9
2
10
0
0
0
3
3
9
9
1
17
3
4
11
17
1
17
50
50
11
56
0
0
0
17
17
50
50
6
94
17
22
61
94
6
94
16
7
1
11
3
2
3
1
2
5
18
2
21
1
8
14
21
2
13
70
30
4
48
13
9
13
4
9
22
78
9
91
4
35
61
91
9
57
1
68
5
6
10
67
6
43
Median number of brain metastases
6
4
5
4
2
5
Median DS-GPA (or GPA)
0
0.5
0.5
mentioned QUARTZ trial also suggested that comparable
QALY results can be obtained [4]. Ideally, unequivocal
objective selection criteria such as RPA class 3 or low DSGPA score would allow for straightforward decision making
when clinicians consider referral for palliative RT. However,
as shown in our previous studies, prediction of short survival is more complex [9–12]. In the absence of generally
accepted tools or decision aids, the QUARTZ trial included
patients for whom the clinician and patient was uncertain of
the benefit of WBRT. With the present study, we attempted
to develop a more objective model for patient selection.
For at least two to three decades, researchers have
attempted to predict survival of patients with brain metastases [6–8, 16–18]. Several score instruments have been developed and compared, resulting in the identification of
subgroups with limited median survival, yet difficult to
predict individual outcome. In other words, even the most
unfavorable group contained patients with very short, intermediate, and longer survival. We assumed that the recently
published and validated DS-GPA score [8, 11, 19] might be
a better tool than previous scores. We decided not to limit
our study to patients with 0–1 points, which comprise the
most unfavorable prognostic group as originally defined by
Sperduto et al. [8], because, in our experience, those with
1.5 points had only marginally better survival [11]. Our
retrospective intention-to-treat analysis was designed to prevent bias to the largest possible degree and included all
patients managed with BSC and different types of RT at
our institution. However, the methodological limitations of
retrospective studies must be acknowledged. We cannot
exclude that our strategy of optimizing prognostic models
as far as possible and looking at a large number of potential
variables and cutoffs might have resulted in overfitting of
data. Our database was not large enough to confirm our
results in a validation group. It is, therefore, necessary to
validate the results externally in other databases before
recommending widespread clinical use. We also acknowledge that survival is only one aspect when patients with
advanced cancer are diagnosed with brain metastases and
that symptom burden and quality of life should be considered when recommending treatment strategies [20–23]. Individual patients might have variable conceptions of what
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Support Care Cancer (2013) 21:2671–2678
Fig. 2 Actuarial Kaplan–Meier
survival curves for patients
treated with short-course
WBRT (20 Gy intended dose)
or more aggressive RT
(intention to treat) or BSC;
differences were not significant,
log-rank test
Diagnosis-specific graded prognostic assessment (DS-GPA) 0-1.5 points, age 75 years or older or
KPS <=50 or uncontrolled primary tumor with extracranial metastases to at least 2 organs
can be considered a meaningful prolongation of survival.
From our point of view, minimal prolongation of survival by
2–3 weeks does not justify additional burden and toxicity
during the terminal phase of disease (notably if the gain
equals the time spent on active RT).
We cannot recommend the use of DS-GPA alone for the
purpose of our study because such a strategy could result in
undertreatment and compromised survival. However, patients with DS-GPA score 0–1.5 points and one or more of
three additional features might be appropriate candidates for
BSC (age at least 75 years, KPS ≤50, or uncontrolled
primary tumor with extracranial metastases to at least two
organs). We were able to confirm that a previous selection
model is valid too (KPS <80, uncontrolled primary tumor,
Fig. 3 Actuarial Kaplan–Meier
survival curves for patients
treated with short-course
WBRT (20 Gy intended dose)
or longer-course WBRT (30 Gy
intended dose) or BSC;
differences were not significant,
log-rank test
KPS <80, uncontrolled primary tumor with extracranial metastases, no intent to treat systemically
Support Care Cancer (2013) 21:2671–2678
presence of extracranial metastases, and no intent to treat
systemically), but fewer patients were assigned to BSC
when using this model. Lagerwaard et al. reported on 118
patients (9 % of their total patient population with different
primary tumors) who were treated with BSC after the diagnosis of brain metastases [17]. Median survival was
1.3 months, and the 6-month survival rate was 4 %. They
defined a poor prognosis group with reduced performance
status (ECOG 2 or 3), little or no response to steroids, and
limited or extensive systemic tumor activity. These patients,
about 10 % of patients in their series, had a median survival
of only 1.3 months after palliative RT, leading the authors to
conclude that a conservative approach in the treatment of
this group of patients seems justified. We were not able to
examine these criteria in our database due to a lack of
recorded steroid response. A large Australian series included
327 melanoma patients managed with BSC between 1952
and 1984 and another 210 patients from the era 1985–2000
[24]. Median survival was 1.7 months (range, 0.8–3.4) in
patients treated in the earlier part of the study and 2.1 months
(range, 0.9–5.0) in those treated after 1984. This group
reported a hazard ratio of 0.85 (95 % confidence interval,
0.7–1.04; p=0.11) for the survival comparison between
brain RT and BSC (1985–2000; 210 and 236 patients,
respectively). During the time period 1996–2000, 26 % of
patients were managed with BSC. Predictive factors were
not analyzed in this study.
Conclusions
Increasing evidence suggests that BSC is appropriate in
patients with brain metastases and limited life expectancy.
The predictive model presented in our study should be
externally validated. It might facilitate the identification of
patients who are unlikely to benefit from WBRT.
Conflict of interest The authors declare that they have no conflict of
interest.
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