120Radiotherapy dose fractionation Third edition
Background
This is a heterogeneous population of patients with diverse underlying histologies,
dierences in disease burden outside the central nervous system (CNS) and diering
systemic therapy options. As such, it is helpful to classify patients according to a simplified
system. The original recursive partitioning analysis (RPA) based system of the Radiation
Therapy Oncology Group (RTOG) is simple and robust, but has now been replaced by the
Graded Prognostic Assessment (GPA) and the disease-specic GPA (dsGPA).
1–9
These
prognostic scores continue to evolve, and still do not fully reect the latest systemic
therapies.
5,10
Patients can be divided into three groups according to disease specic factors, but in
general these three of importance:
• Karnofsky Performance Status (KPS) (at least 70)
• Control of the primary tumour
• Brain as the only site of disease.
Patients who fail to meet all three criteria tend to have a very poor prognosis, and may not
benet from treatment.
The regimens most commonly used for the whole-brain radiotherapy (WBRT) treatment of
cerebral metastases are 30 Gy in ten fractions over two weeks or 20 Gy in ve fractions over
one week. For patients with limited disease, other approaches, including gamma knife or
stereotactic radiosurgery (SRS) and intraoperative radiotherapy are feasible. The following
discussion draws heavily on a systematic review performed as part of the Cancer Care
Ontario programme in evidence-based care.
11
Solitary or oligo-metastases
The evidence from one systematic review and three randomised trials suggests benefit
from adding surgery to whole brain radiotherapy (WBRT) for patients of good performance
status with a solitary metastasis (Level 1a).
11–14
Stereotactic radiosurgery (SRS) added to
WBRT oers a survival benet for selected patients with a solitary metastasis, as well as
for patients of RPA Class I with up to three metastases.
15
In patients with up to three brain
metastases and KPS ≥70, adding SRS to WBRT improves functional independence and
reduces steroid requirements at six months (Level 1b).
15,16
Patients with more than three brain metastases were not included in these trials.
Moreover, it is recognised that the number of brain metastases detected on magnetic
resonance imaging (MRI) is technique dependent. For small-volume disease, a
prospective observational study (Level 2+) in patients with up to ten metastases (largest
<10 centimetres
3
[cm
3
] , total volume ≤15 cm
3
) has suggested that overall survival is
equivalent for patients with ve to ten as compared to two to four metastases and therefore
the number of metastases treated using SRS without WBRT may not correlate with
outcome.
16,17
Several retrospective studies (Level 3) have shown that the total volume
of brain metastases correlates better with outcomes, including local control, distant
intracranial relapse and overall survival after SRS than number of brain metastases.
7,16,18–20
19.
Brain metastases
121Radiotherapy dose fractionation Third edition
Recommendations
Solitary metastases:
Surgery or SRS:
Lesion diameter
<20 millimetres (mm) – 24 Gy single dose (Grade B)
21–30 mm – 18 Gy single dose (Grade B)
31–40 mm – 15 Gy single dose (Grade B)
Multiple metastases up to total volume of 20 cm
3
with good performance status
(Karnofsky Performance Status ≥70) and controlled extra-cranial disease:
2
SRS:
Lesion diameter
<20 mm – 24 Gy single dose (Grade C)
21–30 mm – 18 Gy single dose (Grade C)
31–40 mm – 15 Gy single dose (Grade C)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
16
Whole-brain radiotherapy with SRS
While WBRT was part of the initial treatment of patients in the above-mentioned trials of
surgery or SRS, three randomised trials have now investigated the addition of WBRT to
surgery or SRS for patients with one to four brain metastases.
21–24
A meta-analysis of these
trials has also been published.
25
Adding WBRT to local therapy by surgery or SRS appears
to improve intracranial control and reduce neurological deaths without inuencing overall
survival (Level 1a).
16
However, the addition of WBRT to SRS has been shown in one small
randomised trial to result in a signicantly greater risk of neurocognitive decits at three
months, and for this reason many groups now choose to defer WBRT.
26
Post-treatment
MRI surveillance was used in all three trials and is recommended by some expert groups,
but high-level evidence about the value of MRI surveillance is lacking.
27
Avoidance of the
hippocampus has been suggested as a method to limit the neurocognitive eects of WBRT,
but as yet there is little data to support this.
Recommendation
WBRT with SRS:
30 Gy in 10 fractions over 2 weeks (Grade A)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
16
Adjuvant postoperative SRS and hypofractionation
While WBRT reduces the risk of intra-cranial relapse postoperatively, the lack of impact
on overall survival has led to the exploration of SRS to the stereotactic cavity.
16
In line
122Radiotherapy dose fractionation Third edition
with previous data, radiotherapy after surgery reduces the risk of intra-cranial relapse,
and radiotherapy restricted to the tumour bed appears to be non-inferior to whole brain
radiotherapy.
28,29
However, technical problems and optimal dose and fractionation
schedules are as yet unclear. For patients with larger metastases >2 cm diameter, there has
been interest in hypofractionated SRS, delivered as 3–5 fractions. As yet, there is no data to
support an optimal dose-fractionation schedule.
Whole-brain radiotherapy for multiple metastases
Background
Several randomised trials have compared dierent radiotherapy regimens for patients with
multiple cerebral metastases. Most have used 30 Gy in ten fractions as the control arm and
have compared this regimen to either higher or lower doses.
30–33
Only one small study of 70
patients has compared the six-month survival rate after 30 Gy in ten fractions to that after
20 Gy in ve fractions. There was no significant dierence.
26
A Radiation Therapy Oncology
Group (RTOG) study reported in 1980 compared three regimens: 40 Gy in 15 fractions; 30
Gy in ten fractions; and 20 Gy in ve fractions.
34
The median survival in all three groups was
between 3.2 months and 3.5 months (P>0.05). There is, therefore, no clear evidence that 20
Gy in ve fractions is inferior to, or better than, 30 Gy in ten fractions (Level 1b).
16
Other regimens assessed in RTOG randomised trials included: 10 Gy single-dose and 30–
40 Gy in 10–20 fractions; 40 Gy in 20 fractions; 40 Gy in 15 fractions; 30 Gy in 15 fractions
and 30 Gy in ten fractions.
34,35
There was no statistically significant dierence in median
survival. The trial results suggest that regimens using only one or two fractions are inferior
to 30 Gy in ten fractions, but that there is no improvement in survival when dose is increased
beyond 30 Gy in ten fractions (Level 1b).
16
Patients in RPA Class III have such a poor prognosis that it may be difficult to justify any
radiation treatment at all. Careful consideration should be given to patients with
non-small cell lung cancer. The Medical Research Council (MRC) QUARTZ study shows no
signicant benet in terms of survival or quality adjusted life years for WBRT over optimal
supportivecare.
36
Recommendation
Multiple cerebral metastases:
30 Gy in 10 fractions over 2 weeks (Grade A)
20 Gy in 5 fractions over 1 week (Grade A)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
16
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123Radiotherapy dose fractionation Third edition
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