Review

Stereotactic body radiotherapy for oligometastases

Alison C Tree, Vincent S Khoo, Rosalind A Eeles, Merina Ahmed, David P Dearnaley, Maria A Hawkins, Robert A Huddart, Christopher M Nutting,
Peter J Ostler, Nicholas J van As

The management of metastatic solid tumours has historically focused on systemic treatment given with palliative Lancet Oncol 2013; 14: e2837
intent. However, radical surgical treatment of oligometastases is now common practice in some settings. The Royal Marsden NHS
development of stereotactic body radiotherapy (SBRT), building on improvements in delivery achieved by intensity- Foundation Trust, London, UK
(A C Tree FRCR, V S Khoo MD,
modulated and image-guided radiotherapy, now allows delivery of ablative doses of radiation to extracranial sites.
M Ahmed MD, M A Hawkins MD,
Many non-randomised studies have shown that SBRT for oligometastases is safe and eective, with local control rates Prof C M Nutting MD,
of about 80%. Importantly, these studies also suggest that the natural history of the disease is changing, with 25 year N J van As FRCR); Institute of
progression-free survival of about 20%. Although complete cure might be possible in a few patients with Cancer Research, Sutton, UK
(V S Khoo,
oligometastases, the aim of SBRT in this setting is to achieve local control and delay progression, and thereby also
Prof D P Dearnaley FRCR,
postpone the need for further treatment. We review published work showing that SBRT oers durable local control R A Huddart PhD); Oncogenetics
and the potential for progression-free survival in non-liver, non-lung oligometastatic disease at a range of sites. Team, Institute of Cancer
However, to test whether SBRT really does improve progression-free survival, randomised trials will be essential. Research and Royal Marsden
NHS Foundation Trust,
London, UK
Oligometastases: denition and management radiotherapy [SBRT]), the subsequent metastatic load (Prof R A Eeles FRCR); and
The oligometastatic state: how do tumours metastasise? could theoretically be reduced. Cancer Centre, Mount Vernon
Knowledge of cancer biology and behaviour is advancing With the development of next-generation tumour Hospital, Northwood,
Middlesex, UK (P J Ostler FRCR)
constantly, and several theories about cancer progression sequencing, evidence is emerging that key driver
Correspondence to:
have been proposed. In 1907, Halsted suggested that mutations trigger catastrophic molecular changes that
Dr Alison C Tree, Royal Marsden
breast cancer always spreads via the locoregional cause cancer. Stephens and colleagues9 described a process NHS Foundation Trust, London
lymphatic vessels in a stepwise way. Thus, as described that they call chromothripsis, in which up to hundreds of SW3 6JJ, UK
in his surgical series, the disease can sometimes be genomic rearrangements occur in an isolated cellular alison.tree@rmh.nhs.uk

cured if diagnosed at an early stage.1 Towards the end of
the 20th century, an opposing theory gained acceptance.
This theory, which was also described initially in breast
cancer, proposed that cancer is a systemic disease that,
if it will ever metastasise, will already have done so early
in the disease course, and that local therapies are
therefore less important than the tumour micro-
environment or systemic therapies.2 A third theory, the
spectrum hypothesis, suggests that cancers range
between disease that remains local throughout its
course and disease that is already systemic at the time of
diagnosis.3,4 None of these theories has been tested
directly in a randomised trial, but they have all aected
oncology practice.
None of these paradigms describes the progression of
cancer at a biological level.5 Until recently, cancer was
thought to be driven by somatically acquired point
mutations and chromosomal rearrangements, con-
ventionally believed to accumulate gradually over a long
period (ie, many years).
Some cancer characteristics seem to be specic to a
metastatic phenotype, such as altered cell adhesion,
intravasation, and survival in the circulation.6 However,
some primary tumour cells have inadequate capability in
one or more of the biological requirements for meta-
stasis; tumour dormancy could be one such example.
Metastases arise through clonal expansion, as shown by
high-resolution, genome-wide single-nucleotide poly-
morphism and copy number analyses7 and next-
generation sequencing;8 clones with selective advantage
give rise to metastases. If these clones are destroyed
before this process occurred (eg, with stereotactic body
event. Genetic rearrangements oscillate across aected
regions and switch between two copy number states. The
hallmarks of this process are highly improbable if
rearrangements accumulate randomly over time; thus,
these rearrangements probably occur during one cellular
crisis. Chromothripsis occurs in at least 23% of all
cancers of many histological types. This process has
important implications for the way in which cancers
develop. Furthermore, if a few metastases (oligometastases)
occurred rst and others then seeded from the original
metastases when those became genetically unstable, the
process of oligometastases seeding further extensive
widespread metastatic disease would have a molecular
basis. This hypothesis is being tested by the International For the International Cancer
Cancer Genome Consortium at the molecular level by Genome Consortium see
http://icgc.org/
sequencing of primary and metastatic tumours.
Hellman and Weichselbaum5 rst proposed the idea of
an oligometastatic state in 1995. They suggested that for
many cancers a few metastases exist at rst, before the
malignant cells acquire widespread metastatic potential.
The role of radiotherapy in the management of metastatic
disease has been mainly limited to palliation, but we now
have an opportunity to challenge this idea. Theoretically,
if radical intervention (dened here as hypofractionated
radiotherapy) could be delivered during an oligometastatic
phase, the intervention could change disease progression
in patients who would otherwise have been treated
palliatively in most settings.
Surgical removal of metastases has good outcomes in
various settings, including liver and lung metastases.1012
Although surgical resection has proved this theory in
some situations, now that improved imaging, better

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 Review
Prescription isodose
A 50% isodose
30% isodose
10% isodose
B
Figure 1: Stereotactic body radiotherapy for oligometastatic disease
(A) Radiotherapy plan for a patient with an isolated nodal metastasis from a previously treated prostate cancer,
which received 30 Gy in three fractions. (B) Treatment of a vertebral metastasis from a previously treated prostate
cancer, which received 27 Gy in three fractions. In both images, the orange line indicates the region that was
administered the prescription dose.
methods of planning treatment, and stereotactic
radiotherapy delivery are available, good outcomes can
be achieved without the risk and morbidity associated
with surgery. Since stereotactic radiotherapy is associated
with low toxicity rates, the quality-of-life benet is
probably greater.
Two major diculties have complicated assessment of
the benet of radical treatment of oligometastases. First,
in the past, delivery of truly ablative doses of radiation
has been limited by the risk to normal tissue, and the
need for extended fractionation. However, new
technologies for delivery of SBRT (gure 1) now allow
delivery of radical ablative doses of radiation. Second, the
identication of patients with truly oligometastatic
disease is inherently dicult. Most published surgical
oligometastatic series describe patients managed in an
era before modern imaging techniques such as PET-CT
became widely available. Thus, many patients were
probably understaged, potentially leading to under-
estimation of the eect of aggressive management on
truly oligometastatic disease, since some of those
e29
patients treated aggressively would have had more
extensive disease than was visible on CT or MRI.
Improved imaging will enable better selection of patients.
Various groups have identied three distinct cohorts of
patients with oligometastases:5,13,14 those who present with
oligometastatic disease, those with induced oligo-
metastatic disease after cytoreductive therapy, and those
with relapsed oligometastatic disease after curative
locoregional therapy. These dierent groups probably
have dierent prognoses, so therapeutic approaches
might dier.
Factors that favour a truly oligometastatic state include
a long latent interval between the treatment of the
primary tumour and the appearance of metastases, and a
high ratio of the metastasis growth rate to that of the
primary tumour. Withers and Lee15 summarise this idea
as The more micrometastatic doubling times elapsing
between removal of the primary and the clinical detection
of the 'leader' metastasis, the higher the probability of
an oligometastatic distribution. Similarly, if several
metastases develop soon after treatment of the primary
tumour, they are unlikely to indicate oligometastatic
disease, unless they grow very rapidly.
We, and others, hypothesise that a subset of patients
might have oligometastatic disease and that high-dose,
radical treatment could change their prognosis.5,16,17 If this
hypothesis is correct, it would challenge the dogma that
most patients with oligometastatic disease should be
treated only with palliative intent.
Surgical treatment of oligometastatic disease
Surgery for the management of oligometastatic disease
is now standard practice in several settings, with the
aim of improving local control and overall survival.12,1821
In the management of liver metastases from colorectal
cancer, liver resection produced 5-year survival of
3855%;11,18,19,22 however, this treatment has never been
tested in a randomised trial because randomisation of
patients to a conservative treatment option in this
setting would not be deemed ethical. In patients with
soft-tissue sarcoma, resection of pulmonary metastases
gave long-term (90-month) survival of 35% and, at
median follow-up of 37 months, 13 of the 77 patients in
this series were alive with no evidence of disease.23 In
various other tumours, resection of solitary lung
metastases has led to long-term survival,17,21,2427 which
supports the notion that metastasectomy enables good
long-term disease control.
SBRT and in-eld control of metastases
The American Society of Radiation Oncology denes
SBRT as external beam radiotherapy used to deliver a
high dose of radiation very precisely to an extracranial
target within the body, as a single dose or a small number
of fractions.28 In addition to increasing the accuracy of
treatment delivery, thus reducing the amount of normal
tissue irradiated, the high radiation dose per treatment
www.thelancet.com/oncology Vol 14 January 2013
 Review

(fraction) can potentially ablate all tissue in the treated
area.2831
Published studies of SBRT for metastatic disease can be
divided into three types: rst, studies in which various
types of primary tumour or a range of metastatic locations
are treated; second, those in which a single metastatic site
is treated, such as the lungs or liver; and third, those in
which investigators focus on one histological type.
Clearly, both primary histology and metastatic site are
important determinants of outcome, and the case mix in
all these studies should be analysed closely. Some
histological types are probably more amenable to radical
treatment of oligometastases than others.32
Management of lung and liver metastases
Emerging evidence suggests that liver and lung
metastases can be treated locally with low toxicity and
excellent outcomes, which supports the hypothesis that
radical treatment of oligometastatic disease can improve
outcomes.
Lo, Hyer, Schefter, and colleagues3335 have sum-
marised data supporting local ablative therapies in lung
and liver metastases, although some series included
patients with stable metastatic disease outside the treated
area. Control rates for lung and liver metastases are
generally high (mostly about 7090% for 2-year local
control), although many dierent doses and fractionation
regimens have been used.33 Several studies have been
published within the past 2 years, showing treated
metastasis control rates of around 80% for liver and lung
metastases.3639 Toxicity rates seem low, with less than 5%
severe (grade 3) toxicity,33,36,37,39,40 and will probably be
reduced further with increasing knowledge, standard
dose recommendations, and organ-at-risk constraints.41,42
The abundance of published studies on this topic, and
the excellent outcomes reported, mean that the
framework for patients with liver and lung metastases is
already changing, with more radical treatment, such as
SBRT, becoming more common.
SBRT for non-liver, non-lung extracranial
metastases
Can SBRT achieve control of treated metastases?
Tables 1 and 2 show an overview of published case series,
and phase 2 and 3 trials with a median follow-up of
12 months in patients with oligometastases. Although
the studies reviewed are heterogeneous in terms of site,
primary histology, and dose, control rates for treated
metastases are mostly around 80%.
In both tables 1 and 2, some series included patients
with metastatic disease outside the irradiated area.
Although these patients did not meet the criteria for
oligometastatic disease, the data for treated metastasis
control and toxicity in these settings are nonetheless
informative.
The largest series of mixed oligometastatic disease is
that of Milano and colleagues.53 The investigators
recruited 121 patients with ve or fewer metastases and

Study year Number of patients Dose Primary site Treated site(s) Treated metastasis control Toxicity
Bignardi et al 43
2010 19 45 Gy in 6 fractions Mixed Abdominal lymph nodes 778% at 2 years Grade 3 in 1 patient (5%)
(reduced in 6/19 cases)
Casamassima et al44 2011 25 Most common dose Prostate Pelvic, para-aortic, or 3-year local control 90% No grade 2 or higher
30 Gy in 3 fractions mediastinal lymph nodes
Choi et al45 2009 30 Most received 3345 Gy Mostly cervix, Para-aortic nodes 4-year local control 674% 20% grade 3 (but 16%
in 3 fractions some haematological because
endometrial most patients also had
chemotherapy)
Kim et al46 2009 7 Median 48 Gy in Gastric Para-aortic nodes 100% (median follow-up 26 No grade 3 recorded
3 fractions months)
Kim et al47 2008 23 Median 39 Gy in Rectal Pelvic/presacral lymph 4-year local control 743% Grade 3 in 1 patient
3 fractions nodes (4%): rectal perforation
Casamassima et al48 2012 48 Most common dose Mixed (mostly Adrenal 2-year local control 90% No grade 3 recorded
36 Gy in 3 fractions NSCLC and colon) (2-year overall survival
145%)
Chawla et al49 2009 30 patients (only Median dose 40 Gy in Mostly NSCLC Adrenal 2-year local control 27% No grade 2 or higher
14 had 10 fractions
<5 metastases)
Holy et al50 2011 13 with only adrenal Median dose 40 Gy in All NSCLC Adrenal 21-month local control 77% 2 patients had gastric
metastases 5 fractions ulcer (probably grade 2
toxic eect)
Scorsetti et al51 2012 34 Median dose 32 Gy in 64% NSCLC Adrenal 1-year local control 66%, No grade 3, 6% grade 2
4 fractions 2-year local control 33% nausea
Torok et al52 2011 7 patients Median 16 Gy in NSCLC in 4 of 7 Adrenal 1-year local control 63% Not known
(9 metastases) 1 fraction

NSCLC=non-small-cell lung cancer.

Table 1: Stereotactic body radiotherapy for lymph-node or adrenal oligometastases

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 Review

Study Number of patients Dose Primary site Treated site(s) Treated metastasis control Toxicity
year (number of lesions)
Milano 2008 121 (293) Various; median 50 Gy in All (mostly breast Lung, liver, bone, 2-year LLC 77%; 4-year LLC 74% Grade 3 in 1 patient (1%)
et al53,54 10 fractions and colorectal) lymph node, 7 CNS
Salama et al55 2011 61 (113) Increasing from 24 Gy in All (26% NSCLC) Lung, liver, lymph 2-year LLC 667%; 880% if dose Acute grade 3 in 2 (3%), 6 possible
3 fractions to 48 Gy in node, bone 30 Gy in 3 fractions late grade 3 (10%)
3 fractions
Kang et al56 2010 59 (78) 42 Gy in 3 fractions Colorectal Lung, liver, lymph 3-year local control 66% (note No grade 3, 3% grade 4
node, other 69% of patients had PD after (gastrointestinal perforation/
chemotherapy) obstruction)
Inoue et al57 2010 44 (60) 48 Gy in 8 (adrenal), Mostly lung Lung, adrenal, brain 3-year local control 80% 98% grade 2; no grade 3 or higher
3560 Gy in 48 fractions
(see text for details)
Stinauer et al58 2011 30 (53) 4050 Gy in 5 fractions or Renal-cell and Lung, liver, bone 18-month local control 88% One grade 3 hypoxia (3%)
4260 Gy in 3 fractions melanoma
Bae et al59 2012 41 (50) Median 48 Gy in Colorectal Lymph node, lung, 3-year local control 64% No acute grade 3, 7% late grade 3
3 fractions liver
Jereczek-Fossa 2011 34 (38) 30 Gy in 5 fractions to Prostate Lymph node, bone, 88% local control 6% grade 3 urinary, 3% grade 3
et al60 36 Gy in 3 fractions prostate recurrence rectal (all prostate recurrence
patients), 6% grade 3 late urinary
Hoyer et al61 2006 64 (141) 45 Gy in 3 fractions Colorectal Liver, lung, nodes, 2-year local control 63% (86% 30% grade 3: pain, nausea, skin
other LLC) reaction; 9% grade 4
Wersall et al62 2005 58 (162) 3040 Gy in 3 fractions Renal-cell Lung (majority), Local control 90% or higher 40% had grade 1 or higher toxicity,
was most common dose carcinoma renal bed, lymph with a high proportion of grade 3
node, adrenal events (some perhaps in the same
patient); one death (gastric
haemorrhage)
Svedman 2006 30 (82) Various: 40 Gy in Renal-cell Lung (majority), Only 2% documented progression 4% of side-eects were grade 3
et al63 4 fractions was most carcinoma renal bed, adrenal at median follow-up 52 months
common dose
Nuyttens 2007 14 (15) Median 7 Gy/fraction, Mixed Mixed 100% local control at median No grade 3
et al64 median 6 fractions follow-up 18 months
Greco et al65 2011 103 (126) 1824 Gy in 1 fraction Prostate, renal, Majority bone, lymph Local control at 2 years 64% (82% <4% grade 3 late (stricture, neuritis)
colorectal node, soft tissue if >22 Gy, 25% for 1820 Gy)

LLC=lesion local control. NSCLC=non-small cell lung cancer. PD=progressive disease.

Table 2: Stereotactic body radiotherapy for mixed oligometastatic sites

gave them a median dose of 50 Gy in 5-Gy fractions over
2 weeks,53 although the target volume was covered only by
the 80% isodose and thus the actual dose to some parts of
the tumour would be less than 50 Gy. These doses are at
the lower end of the dose range presently used for
stereotactic radiotherapy. Most patients had lung, liver, or
lymph-node metastases. The only grade 3 toxic eect was
a non-malignant pleural and pericardial eusion, and no
higher-grade adverse eects occurred. The 2-year and
4-year treated metastasis control rates were 77% and
74%.54 The investigators found that the net gross tumour
volume correlated with overall survival and local control.
Salama and colleagues55 did a dose-escalation trial in
61 patients with 113 metastases. The rst patients were
given 24 Gy in three fractions, increased sequentially to
48 Gy in three fractions. For those who received 24 Gy in
three fractions, control of the treated metastases was
poor at 457%, whereas in the four patients given 48 Gy in
three fractions, 100% control was achieved. Two patients
experienced acute grade 3 toxic eects (vomiting in one
patient and fatigue in the other). Six patients experienced
late grade 3 toxic eects, including gastrointestinal
bleeding, neuritis, and pneumonitis, although causality
from treatment was not conclusive in all cases.
Inoue and colleagues57 studied a mixed cohort of
patients treated with various radical (ie, lesion-ablative)
strategies, including surgery, SBRT, and stereotactic
cranial treatment. 44 patients with 60 metastases were
treated with radical intent. The investigators noted good
treated metastasis control at 3 years (80%). They
identied the interval from primary tumour to recurrence
as an important prognostic factor, with 5-year survival of
10% for patients with an interval to recurrence of less
than 12 months, compared with 40% if that interval was
longer than 12 months. Adverse eects were limited to
three instances of grade 2 brain necrosis and one case of
grade 2 intercostal neuralgia.
In general, the toxicity of SBRT is moderate. With the
exception of the study by Hoyer and colleagues61 (see
table 2), the proportion of patients with grade 3 acute or
late adverse eects is less than 10%, and in many studies
no grade 3 eects were recorded.44,48,50
Most in-eld recurrences occur within the rst 2 years
after SBRT. The update of Milano and colleagues case

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 Review

series32 indicated that the 2-year and 6-year in-eld control
rates were very similar, and were identical for patients
with primary breast tumours. For abdominal lymph-node
oligometastases, no further in-eld failures occurred after
the rst year of follow-up.43 Any further relapses after this
point are more likely to occur at other metastatic sites. In
the series of patients with lung metastases analysed by
Okunie and colleagues,66 all in-eld failures occurred
within the rst 15 months. By contrast, in Kang and
colleagues study of mixed oligometastatic sites from
colorectal cancer,56 in-eld control decreased from 66% to
24% between 3 and 5 years of follow-up.
Table 3 show selected series of published work
supporting the use of SBRT to treat spinal metastases
that has recently been reviewed.73 Doses varied, but in
most studies were delivered in between one and ve
fractions, often 1620 Gy in one fraction,70,74,75 or 27 Gy in
three fractions,75 and the reported in-eld control rate
was 84100%. Almost all data are from single-institution
series. Although not frequently referred to in the
aforementioned studies, concern remains about the rate
of vertebral fracture after SBRT, which can be as high as
20%, with the amount of risk related to the patients age,
pre-existing fracture, and local pain.76 A large recent
series published in 2012 has reported the risk of vertebral
compression fracture was 11%, with median follow-up of
74 months and a median time to fracture of 3 months.77
Myelopathy is a rare but greatly feared complication of
spinal SBRT. In the largest series of 1075 patients,
retrospective review of case records identied six patients
(06%) who had developed myelopathy, with a median
time to onset of 63 months.74
Muacevic and colleagues67 reported a series of 64 bony
metastases in 40 patients with prostate cancer, many of
which were spinal, but metastases in the skull, pelvis,
and hip also occurred. All patients were staged by choline
PET-CT to exclude other disease (only one to two treatable
lesions allowed) and were given a median single dose of
20 Gy. Patients were followed up with regular MRI and
choline PET-CT. The in-eld control rate at 24 months
was 955%. Median overall survival had not been reached
at the time of writing (median follow-up 14 months).
A trial (RTOG 0631) by the Radiation Therapy Oncology
Group is comparing SBRT with conventional radio-
therapy; patients are randomly assigned 1618 Gy single-
fraction SBRT versus 8 Gy in a single fraction. The
primary endpoint of this study is pain control which
emphasises the importance of symptom control in these
patients.
Does everyone relapse with distant metastases even if
in-eld control is achieved?
Despite the heterogeneous nature of the studies listed
above, the methods used to categorise oligometastatic
disease, and the inherent diculties of non-randomised
studies, the ndings indicate that a substantial
proportion of patients, generally around 20%, remain
disease-free 24 years after SBRT (gure 2). In the series
reported by Inoue and colleagues,57 a mixture of surgery
and radiotherapy was used, and progression-free survival
seemed to plateau at about 20% at 5 years, although the
median follow-up was only 20 months. That study
included a large number of patients with brain
metastases, which might be associated with lower
progression-free survival than in a population who had
extracranial metastases. In a cohort of patients with
prostate cancer and nodal relapse alone on carbon-11-
labelled choline PET-CT scan, the 3-year disease-free
survival after SBRT was only 17%,44 but the treated
metastasis control rate was 90%. Khan and colleagues78

Study year Number of patients Dose Primary site Treated site(s) Treated metastasis control Toxicity
(number of lesions)
Muacevic et al67 2011 40 (64) 20 Gy in 1 fraction Prostate Bone 2-year control 955% No grade 3 or higher
(median) (34/64 spine)
Wang et al68* 2012 149 (166) 2730 Gy in 3 fractions Mixed (32% renal) Spine 72% (median follow-up 7% grade 3 (non-cardiac
159 months) chest pain, other pain,
nausea, fatigue)
Yamada et al69* 2008 93 (103) 1824 Gy in 1 fraction Mixed (high Vertebrae 90% at 15 months 1 acute grade 3 (1%), 1 late
proportion of grade 3 (1%)
renal-cell carcinoma)
Gerstzen et al70* 2007 393 (500) Mean maximum dose Mixed Vertebrae 88% at median follow-up No signicant neurological
20 Gy in 1 fraction 21 months (100% for breast and eects recorded
lung primaries, 75% for melanoma)
Zelefsky et al71 2011 105 (105) Varied, but mostly Renal-cell carcinoma 99% bone 3-year local control 44%, but 88% 1 grade 4 skin (1%),
24 Gy in 1 fraction or metastases for 24 Gy in 1 fraction 4 fractures (not graded)
30 Gy in 5 fractions
Nguyen et al72* 2010 48 (55) 24 Gy in 1 fraction, Renal-cell carcinoma Spine (one or 82% 1-year spine progression-free 2% pain, 2% anaemia
27 Gy in 3 fractions, or two sites) survival
30 Gy in 5 fractions

*Percentage of patients with oligometastatic disease is not known for these studies.

Table 3: Stereotactic body radiotherapy for treatment of spinal metastases

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 Review

Factors aecting local control, progression-free survival,

60
Series with <30 patients and overall survival
Series with 3050 patients Histology
Series with >50 patients In Milano and colleagues series,32 patients with breast
cancer were analysed separately from those with other
types of cancer (mainly colorectal or lung), because
40 patients with breast cancer have much better survival:32
Disease-free survival (%)

progression-free survival at 2 years was 36% for patients

with breast cancer compared with 13% for those with
non-breast cancers, and overall survival at 6 years was
47% versus 9%. The rate of local control is also higher
20
in breast cancers (87%) than in non-breast cancers
(74%), which suggests that better treated metastasis
control results in improved progression-free survival,
although breast cancer histology itself confers a better
prognosis than cancers at other primary sites. Takeda
and colleagues80 reported that lung metastases from
0 colorectal cancer had a substantially worse in-eld
8

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46

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47

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e 59
3,5
an 7

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control rate than did lung metastases from other

08
09
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lam

Ba
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ar

Ch
Kh

Ka

20
20

Ho
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ila

primary cancers (mostly non-small-cell lung cancer and

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Sa

m
m
Bi

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Ki
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head and neck primaries). However, in the larger

Ca

Milano series no signicant dierence in outcomes

Figure 2: Disease-free survival in patients with oligometastatic disease at 1748 months follow-up
Dotted line represents mean proportion of patients who were disease free at the reported timepoint, weighted for between colorectal and other non-breast histology was
number of patients in each cohort. Error bars represent 95% condence intervals. found.32

described a retrospective cohort of 23 patients with Disease-free interval

oligometastatic disease from non-small-cell lung cancer.
They received chemotherapy and local therapy, in the
form of surgery, radioablation, or both. At median follow-
up of 28 months for surviving patients, 30% were alive
with no evidence of disease.
In a study in which the patterns of failure after SBRT to
treat oligometastases in one organ were assessed, 73% of
patients eventually developed new metastases, at median
follow-up of 45 months for surviving patients.79 More
than 80% of new metastases occurred in the index organ.
However, in that series, 27% of patients did not develop
distant metastases during follow-up, and all patients
without progression had been treated for metastases to
just one organ. Overall, for those treated with SBRT in
Salama and colleagues series,55 50% had either no
metastatic progression or very little progression in terms
of number and site of metastases. This group could be
suitable for further radical intervention to the new
metastatic sites, such as resection or further SBRT. Data
from the International Registry of Lung Metastases
suggest that patients undergoing repeated removal of
metastases have similar survival to those who need only
one procedure.12
These ndings support the idea of an oligometastatic
state in which aggressive local therapy could improve
cause-specic survival. The study by Kang and
colleagues56 shows progression-free survival of 25% at
3 years and 19% at 5 years. Whether patients in this
cohort without disease 5 years from SBRT relapse at a
later date or whether some of them can be truly cured
will be interesting to discover.
Disease-free survival after SBRT seems to be associated
with time to recurrence. In Inoue and colleagues' series,57
3-year survival after SBRT was 53% for patients with a
time to recurrence of more than 12 months, compared
with 19% for patients with a recurrence time of less than
12 months.In a cohort of 71 patients who underwent
SBRT for lung metastases, Zhang and colleagues38
reported that a disease-free interval of more than 12 months
was signicantly related to overall survival (hazard
ratio 051, 95% CI 030087).
Location of metastases
A retrospective review of patients with metastases
conned to one organ showed that those with bone or
thoracic lymph-node metastases have better survival
than those with lung or liver metastases, and that they
also tend to have a better progression-free survival.79
Adrenal metastases seem to confer worse overall and
progression-free survival than other sites,53 possibly
because of the haematological mechanism of spread for
adrenal metastases. However, progression-free survival
has been more encouraging in some later series of
patients with adrenal metastases treated with SBRT.
Holy and colleagues50 recorded progression-free survival
of 12 months for patients with an isolated metastasis in
the adrenal gland. In another series, mean time to
systemic progression was 103 months after adrenal
SBRT,50 and at 2 years after SBRT, 14% do not have
distant metastases.81 The eects of metastasis location
and of histology are dicult to separate, because some
tumour types have strong tendencies to metastasise to

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particular organs. For example, prostate cancer
metastasises frequently to bones, but rarely to visceral
organs. Non-small-cell lung cancer commonly
metastasises to the adrenal glands, whereas the adrenals
are an uncommon site of isolated metastases for many
other tumour origins, including prostate, colorectal, and
breast cancers. Some of the eect of metastasis location
is associated with the ability to deliver high doses to, for
example, spinal metastases, which are immediately
adjacent to the radiosensitive spinal cord. Conversely,
pelvic bony metastases can be given a high dose without
any danger to the surrounding organs.
Number of metastases
In Salama and colleagues series,55 patients with three or
fewer metastases had better progression-free and overall
survival than those with four to ve metastases, all of
whom had experienced progression within 9 months of
treatment. 75% of these patients developed widely
metastatic disease compared with 46% of those with one
to three metastases at the time of treatment. Bignardi
and colleagues43 reported 2-year progression-free
survival of 417% for solitary metastases but 0% for
more than one metastasis after SBRT. Wersall and
colleagues62 showed that the overall survival of patients
treated for oligometastatic disease was associated with
the number of metastases. The patients with one to
three metastases had median survival of 37 months,
compared with 19 months in patients with more than
three metastases.
Size
Size of metastases is also predictive of in-eld control.45
Rusthoven and colleagues82 reported that lesions smaller
than 3 cm had 100% control at 2 years, compared with
77% for lesions larger than 3 cm. In Milano and
colleagues series,32 for patients with non-breast cancers,
gross tumour volume correlated inversely with in-eld
control, which was similar to Kang and colleagues
ndings.56 However, for breast cancer patients, in-eld
control was signicantly better for bone metastases
(100%) than for non-bony metastases (68%), even though
the bony metastases were larger on average.
However, target volume size does not predict for cancer
control in all series: in a series of 105 patients with renal-
cell carcinoma, the planning target volume (range
1291462 cm) was not related to control.71 These data are
confounded by the fact that some metastases, such as
those of the liver and lung, are probably bigger than
nodal and bony metastases, so separation of the eects of
size and location is dicult.
Dose
Various dose-fractionation models have been proposed
to predict the eectiveness of radiotherapy doses and
fractionation regimens. The most widely used is the
linear quadratic model, which models cell kill from both
www.thelancet.com/oncology Vol 14 January 2013
Review
double-stranded and potentially repairable single-
stranded DNA breaks. However, it overestimates cell kill
at high doses per fraction (eg, the doses used in SBRT),
because there is proportionally more lethal damage to
DNA and less sublethal damage.83 The generalised
linear quadratic model has been suggested to
incorporate the conversion of sublethal to lethal DNA
damage at high doses per fraction more accurately.
Another model, the universal survival curve,
incorporates both the linear quadratic and multi-target
models and can thus predict cell kill at both high and
low doses per fraction.84
Ablative radiotherapy doses (ie, those that destroy all
living tissue in an area) need to have a higher biologically
eective dose than do most conventionally fractionated
regimens. Biologically eective dose is a measure of the
eectiveness of dierent dose fractionation regimens,
to allow comparison of dierent doses or doses per
fraction. No denition of the doses needed for ablative
radiotherapy is universally accepted, but regimens
resulting in a biologically eective dose larger than
100 Gy (/=10 Gy) would be deemed ablative. However,
whether an SBRT regimen needs to ablate all tissue in
the treated area to be eective is open to question.
Lower doses, such as those used successfully in Milano
and colleagues series,32 might be sucient to eradicate
viable tumour cells. Results from a series of patients
with oligometastatic disease from non-small-cell lung
cancer suggest that a regimen of 50 Gy in ten fractions
is at least as eective as a moderately dosed three-
fraction regimen.85
In Stinauer and colleagues study,58 despite the small
number of patients included, dose per fraction (<11 Gy vs
>11 Gy), biologically equivalent dose (<100 Gy vs >100 Gy),
single fraction equivalent dose, and number of fractions
(three vs ve) were signicant predictors of in-eld
control. The investigators modelling studies predicted
that at least 48 Gy in three fractions would be needed to
achieve greater than 90% 2-year control, although the
majority (74%) of lesions treated in this study were lung
metastases, so this dose might not represent that needed
for other oligometastases. However, in multivariate
analysis, a dose of 48 Gy or more in three fractions was
also associated with better in-eld control in a series of
41 patients with metastases from colorectal cancer.59
Additionally, in a large retrospective analysis of a series
of 141 patients with lung or liver metastases,86 a dose of
54 Gy or higher in three fractions was associated with a
higher treated metastasis control rate (893%) than a
dose of 36539 Gy (59%).
Similarly, from a multivariate analysis on their series,
Zelefsky and colleagues71 reported that a single versus a
hypofractionated dose, and a single dose larger than
24 Gy compared with a dose smaller than 24 Gy, predicted
improved in-eld control in renal-cell carcinoma. Any
doseresponse in single-fraction spine treatments is not
yet clear.70,87
e34
 Review
Panel: Evidence-based practice for extracranial oligometastases
Stereotactic body radiotherapy results in a high control rate of treated metastases
(~80%)
About 20% of patients are progression free at 23 years after stereotactic body
radiotherapy
Toxicity is low
Stereotactic body radiotherapy should be considered in patients with isolated
metastases, especially if the disease-free interval is longer than 6 months
Randomised trials are needed to establish whether stereotactic body radiotherapy
improves progression free and/or overall survival
Patients most likely to benet from stereotactic body radiotherapy have:
Long disease-free interval
Breast histology
One to three metastases
Small metastases
Higher radiation dose delivered (biologic eective dose >100 Gy)
Conclusions
The evidence reviewed here allows us to reach some
conclusions (panel) about the patients who could benet
from SBRT. Many non-randomised studies have shown
that SBRT for oligometastases is safe and eective, and
that treated metastasis control rates of about 80% are
achieved. Toxicity seems to be moderate in most cases,
although complications that are rare with conventional
fractionation, such as vertebral fracture, have been
reported. Importantly, these studies also suggest that the
disease natural history is changing, with 25-year
progression-free survival of about 20%. These early
clinical data are supported scientically by accumulating
molecular evidence that the development of widespread
metastases occurs because of seeding from oligo-
metastases when the genome is deranged. This evidence
indicates that, for at least some patients, we have an
opportunity to control these oligometastases prior to
them acquiring the genetic alterations which confer
widespread metastatic potential.
For most oncological interventions in metastatic
disease, cure is not the aim of treatment. Although true
cure might be an option in a few patients with
oligometastases, the objective of SBRT in most patients
with metastatic diseases is to control the treated
metastasis and delay progression, thereby also delaying
the need for further treatment. This goal is a useful
endpoint in a population whose quality of life is often
adversely aected by their treatment as well as the disease.
Whether SBRT improves progression-free and overall
survival can only really be proved by means of randomised
trials that compare the standard of care (including all
appropriate systemic and palliative treatments) alone or
with the addition of SBRT. As use of SBRT becomes
more widespread worldwide, such trials will become
increasingly more dicult to start because the treatment
will be given as standard in accordance with patients
best interests. We believe that randomised trial evidence
e35
Search strategy and selection criteria
Studies were identied in April, 2012, by searches of PubMed,
EBSCOhost, and Web of Knowledge (search terms included
combinations of oligometastases, stereotactic, radiotherapy,
metastases, radiosurgery, SBRT, and SABR), and by review of
cited papers in selected articles. We identied 810 papers. We
assessed retrospective and prospective studies published in
English. We excluded duplicates or studies reporting only liver
or only lung metastases, but those including a mixture of sites
including some liver or lung metastases were permitted. We
included mixed studies of primary tumours (eg, lung) and
metastases in which more than half the patients had
oligometastatic disease. Studies were eligible if the dose per
fraction was 6 Gy or higher for a total dose of more than 36 Gy,
or 5 Gy per fraction for a total dose of more than 45 Gy. Studies
were excluded if fewer than seven patients were reported or if
median follow-up was less than 12 months. 24 studies met the
eligibility criteria for this Review, and four additional studies of
spinal metastases were selected (table 3) for comparison.
is essential, and are therefore presently designing such a
trial. The rst phase of the study will test whether
randomisation is feasible in this cohort of patients; if it
is, we will progress to an international phase 3 study.
Contributors
VSK, RAE, MA, DPD, MAH, RAH, CMN, and PJO wrote and reviewed
the paper. ACT did the literature search, made the gures and tables,
and wrote and reviewed the paper. NJvA designed the Review, and wrote
and reviewed the paper.
Conicts of interest
PJO, ACT, and NJvA have received educational travel grants from
Accuray to facilitate attendance at international conferences. RAE has
received educational grants from Tepnel (now GenProbe) and Vista
Diagnostics. The other authors declare no conicts of interest.
Acknowledgments
This work was done in the Royal Marsden NHS Foundation Trust, which
received a proportion of its funding from the NHS Executive. The views
expressed in this Review are those of the authors and not necessarily
those of the NHS Executive. This work was supported by the Institute of
Cancer Research, the Bob Champion Cancer Trust, and Cancer Research
UK Section of Radiotherapy, grant number C46/A2131. We acknowledge
NHS funding to the NIHR Biomedical Research Centre.
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