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ConibearJ, etal. BMJ Open 2018;8:e020690. doi:10.1136/bmjopen-2017-020690
Open Access
Study protocol for the SARON trial: a
multicentre, randomised controlled
phase III trial comparing the addition of
stereotactic ablative radiotherapy and
radical radiotherapy with standard
chemotherapy alone for oligometastatic
non-small cell lung cancer
John Conibear,1 Brendan Chia,1 Yenting Ngai,2 Andrew Tom Bates,3
Nicholas Counsell,2 Rushil Patel,4 David Eaton,4 Corinne Faivre-Finn,5
John Fenwick,6 Martin Forster,7 Gerard G Hanna,8 Susan Harden,9 Philip Mayles,10
Syed Moinuddin,7 David Landau11,12
To cite: ConibearJ, ChiaB,
NgaiY, etal. Study protocol for
the SARON trial: a multicentre,
randomised controlled phase
III trial comparing the addition
of stereotactic ablative
radiotherapy and radical
radiotherapy with standard
chemotherapy alone for
oligometastatic non-small
cell lung cancer. BMJ Open
2018;8:e020690. doi:10.1136/
bmjopen-2017-020690
►Prepublication history and
additional material for this
paper are available online. To
view these les, please visit
the journal online (http:// dx. doi.
org/ 10. 1136/ bmjopen- 2017-
020690).
A poster abstract of this study
was published at the IASLC
17th World Conference on Lung
Cancer.
Received 1 December 2017
Revised 2 February 2018
Accepted 9 February 2018
For numbered afliations see
end of article.
Correspondence to
Dr David Landau;
david. landau@ kcl. ac. uk
Protocol
ABSTRACT
Introduction Following growing evidence to support the
safety, local control (LC) and potential improvement in
overall survival (OS) in patients with oligometastatic non-
small cell lung cancer (NSCLC) that have been treated
with local ablative therapy such as stereotactic ablative
radiotherapy (SABR) and stereotactic radiosurgery (SRS),
we initiate the SARON trial to investigate the impact and
feasibility of adding SABR/SRS and radical radiotherapy
(RRT) following standard chemotherapy on OS.
Methods and analysis SARON is a large, randomised
controlled, multicentre, phase III trial for patients with
oligometastatic EGFR, ALK and ROS1 mutation negative
NSCLC (1–3 sites of synchronous metastatic disease,
one of which must be extracranial). 340 patients will be
recruited over 3 years from approximately 30 UK sites
and randomised to receive either standard platinum-
doublet chemotherapy only (control arm) or standard
chemotherapy followed by RRT/SABR to their primary
tumour and then SABR/SRS to all other metastatic sites
(investigational arm). The primary endpoint is OS; the
study is powered to detect an improvement in median
survival from 9.9 months in the control arm to 14.3
months in the investigational arm with 85% power and
two-sided 5% signicance level. The secondary endpoints
are LC, progression-free survival, new distant metastasis-
free survival, toxicity and quality of life. An early feasibility
review will take place after 50 randomised patients.
Patients requiring both conventional thoracic RT to the
primary and SABR to a thoracic metastasis will be included
in a thoracic SABR safety substudy to assess toxicity
and planning issues in this subgroup of patients more
thoroughly.
Ethics and dissemination All participants are given a
SARON patient information sheet and required to give
written informed consent. Results will be submitted for
presentation at local and international conferences and
expected to be published in a peer-reviewed journal.
Trial registration number NCT02417662.
Sponsor reference UCL/13/0594.
BACKGROUND
Oligometastatic NSCLC
Unselected European patients with oligomet-
astatic non-small cell lung cancer (NSCLC)
treated with cytotoxic chemotherapy have a
median survival of 8.5–10.5 months.1 2 This
figure includes patients with any number of
metastases. There are increasing data though
Strengths and limitations of this study
►SARON is a large, randomised controlled, multi-
centre, UK phase III trial.
►340 patients will be recruited over 3 years from ap-
proximately 30 UK sites.
►The trials primary endpoint is overall survival and
is powered to detect an improvement in median
survival from 9.9 months in the control arm to 14.3
months in the experimental arm.
►Patients requiring both conventional thoracic ra-
diotherapy to the primary and stereotactic ablative
radiotherapy (SABR) to a thoracic metastasis will be
included in a thoracic SABR safety substudy to as-
sess toxicity and planning issues in this unique and
challenging subgroup of patients more thoroughly.
►The trial will undergo an early feasibility review after
50 randomised patients to ensure full recruitment is
likely to be achievable.
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showing that patients with fewer sites of metastases seem
to have a better overall survival (OS).
The MD Anderson group reported a retrospective review
of outcomes in 1284 patients with metastatic NSCLC.3 It
reported that patients with a single organ involved site
had better OS than those with two or more. In 137 patients
with lung metastases only, the risk of death was correlated
with the number of metastases. Another study, the FLEX
study, enrolled 1125 patients with metastatic NSCLC and
reported similar OS benefit in patients with metastases in
one site versus two sites versus three or more sites (12.4
months vs 9.8 months vs 6.4 months, p<0.001).4 Similarly,
the Southwest Oncology Group published an analysis of
prognostic factors in 2531 patients enrolled in 14 phase
II–III trials.5 The results confirm the prognostic signifi-
cance of single versus multiple metastases on multivariate
analysis. These studies support the hypothesis that a lower
tumour burden is associated with improved outcome.
The concept of oligometastatic disease was established
in an editorial by Hellman and Weichselbaum.6 In it,
they described that patients with a lower tumour burden
might be candidates for a more radical approach to
management. The key issues needed were the definitive
demonstration that alternative treatment strategies would
improve patient outcomes and the ability to prospectively
identify patients with the least propensity to develop
further systemic metastases.
Existing knowledge
Numerous retrospective studies7 have been published
establishing the safety and efficacy of stereotactic ablative
radiotherapy (SABR)/stereotactic radiosurgery (SRS) in
achieving durable local control (LC) in many different
single and multiorgan sites (lung,8 spine,9 liver,10–12 lymph
nodes,13–15 adrenal glands,16 17 multiple metastases in indi-
vidual organs (liver,10–12 lung18 19 or multiple organs19 20).
In metastatic NSCLC, approximately 44% of patients
will have brain metastases at first diagnosis.21 There is
now evidence to suggest though that aggressive Central
Nervous System directed treatment improves progres-
sion-free survival (PFS) and/or OS in some patients.22
Table 1 summarises the results of some of these SABR/
SRS studies and highlights the 1-year and 2-year control
rates and low incidence of grade 3+ toxicities seen so far
in the literature.
A few prospective studies have also been reported. De
Ruysscher et al reported a single-arm phase II trial investi-
gating whether it would be possible to obtain a significant
2-year and 3-year survival in patients when all macroscopic
sites in oligometastatic NSCLC are treated with radical
RT. 21 The median OS was 13.5 months and PFS was 12.1
months. In comparison, PFS in systemic therapy-only
trials is reported to be around 4–6 months.1 Interestingly,
the 2-year and 3-year PFS were maintained at 13.6%.
Another report is by Holy et al,16 treating patients with
NSCLC and adrenal metastases. Median PFS was 4.2
months for the entire patient group, but in those with
isolated adrenal metastases, the PFS was 12 months. At
21 months median follow-up, 10 of 13 patients (77%)
with an isolated adrenal metastasis maintained LC with a
median OS of 23 months.
Recently, Gomez and colleagues published the first,
randomised trial supporting the first point made by
Hellman and Weichselbaum.8 23 The trial was a phase II,
multicentre study which randomised patients with NSCLC
with oligometastatic disease (defined as ≤3 metastases)
who did not progress after first line systemic treatment to
either local consolidative therapy to all metastases, with or
without systemic therapy or to standard systemic therapy
alone. Local consolidative treatments included surgery,
RT, chemo-RT or a combination thereof. The study was
closed early after 49 patients were enrolled, as interim
analysis found the median PFS in the local consolida-
tive therapy arm to be 14.4 months compared with 3.9
months in the standard systemic therapy arm.23 Median
OS was not reached. Recently, another phase II trial was
reported by Texas Southwestern Medical Centre.24 They
enrolled 29 patients with similar enrolment criteria,
but their study design allowed for ≤6 sites of metastatic
disease. The study was stopped early as interim analysis
showed a significant PFS advantage in the SABR arm (9.7
vs 3.5 months). SABR resulted in no in-field failure vs
seven in the maintenance only arm. No additional toxic
effect was noted in the SABR arm and median OS was also
not reached.
There are several ongoing trials, either recruiting or
in planning, such as ROLE (NCT01796288) and CORE
(NCT02759783) that could support the role of radical
radiotherapy (RRT)/SABR in oligometastatic disease
further.
Need for a trial
Currently there is no internationally agreed management
strategy of oligometastatic NSCLC. Management recom-
mendations are thus widely variable and depend on local
and patient-specific factors.
A large randomised phase III trial specific to NSCLC
is therefore needed to ascertain if the addition of RRT
with SABR/SRS or conventional radiotherapy to chemo-
therapy is safe and effective in improving the outcomes of
patients with oligometastasis.
Choice of comparator
Without the ability to predict lack of systemic progres-
sion, the standard first-line management for patients with
oligometastatic NSCLC remains to be chemotherapy.
In the SARON trial, the control arm will therefore be
four cycles of platinum-based doublet chemotherapy
followed by maintenance systemic therapy as per local
policy. The type and dose regimen of chemotherapy
given will be based on institution protocols.
Patients with sensitising EGFR, ALK-fusion and ROS1
mutations have a different natural history and outcome
to those without.33 To maintain as homogeneous a popu-
lation as possible, these patients are excluded from
SARON.
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STUDY OBJECTIVES AND HYPOTHESIS
Study hypothesis
We propose that radical treatment with SRS/SABR or
conventional radiotherapy to the primary lung and meta-
static lesions is safe, feasible and effective in improving
the survival outcomes of oligometastatic NSCLC that
have responded to initial treatment with systemic
chemotherapy.
Primary objective
To investigate the impact the addition RRT using SABR/
SRS or conventional RT has on OS in oligometastatic
NSCLC that are treated with first-line standard systemic
therapy.
Secondary objectives
To demonstrate the impact of a RRT strategy on:
►Progression-free survival
–Includes loss of LC of target lesions and develop-
ment of new distant metastases which will be re-
corded separately.
–Also includes non-measurable radiological
progression.
►Toxicity
–RT-related toxicity.
–Early and late toxicity.
►LC of primary and all metastases (refers to all lesions
present at time of randomisation. A record will be
kept of primary versus metastatic progression)
►Quality of life
Feasibility substudy
To demonstrate that the recruitment and withdrawal
rates are consistent with achieving the aims of the trial
and that there are no unforeseen logistical challenges
Table 1 Summary of referenced studies of SABR in the treatment of oligometastatic disease
Reference
No. of
patients/lesions Primary
Site(s) of
metastases Dose/Fractions
Gd3+
toxicity
Local control
1 year 2year
Rusthovenetal,200925 38/63 Multiple colorectal Ca
24%; sarcoma 18%;
renal cell Ca 18%; lung
13%
Lung 48–60Gy/3# 7% 100% 96%
Ernst-Steckenetal,
200626
21/39 Multiple lung* 43% Lung 35–40Gy/5# 5%
Siva20108
Review of 19 papers8 19
334/564 Multiple Lung 2.6%
4%
78%
Herfarthetal, 200127 37/60 Multiple Liver 14–26Gy/1# 0% 71%
Mendez Romero200612 17/34 Multiple
colorectal Ca 82%
Liver 36–60Gy/3# 24% 100% 86%
Rusthovenetal,200928 47/63 Multiple colorectal Ca
32%; lung 21%
Liver 36–60Gy/3# 2% 95% 92%
Leeetal,200910 70/143 Multiple
CRC 57%
Liver 54–60Gy/6# 10% 71%
Holyetal,201116 18/18 NSCLC Adrenal 20–40Gy/5# 77%†
Chawlaetal,200929 30/35 Multiple
NSCLC 67%
Adrenal 16–50Gy/4–16#
Hoyeretal,200630 64/142 Colorectal Ca Multiple liver 69%;
lung 19%
45Gy/3# 79%
Milanoetal, 200831 121/293 Multiple breast 32%;
colorectal Ca 26%
Multiple liver 45%;
lung 41%;
thoracic nodes
20%; bone 12%
50Gy/5# <1% 67%
Salamaetal, 201120 61/113 Multiple NSCLC 18%;
breast 11%;
renal cell Ca 13%;
colorectal Ca 10%
Multiple lung 36%;
nodes 19%; liver
19%; bone 13%
24–48Gy/3# 13% 67% 53%
Gersztenetal, 2006977/87 Lung Spine 15–25Gy/1# 0%
Gersztenetal, 2005928/36 Melanoma Spine 17.5–25Gy/1# 0%
Stinaueretal, 201132 17/28
13/25
Melanoma
Renal cell Ca
Multiple lung 74%;
liver 21%
40–50Gy/5# or
42–60Gy/3#
2% 88%‡
*These were primary lung cancers.
†At a median follow-up of 21 months.
‡At 18 months.
NSCLC, non-small cell lung cancer; SABR,stereotactic ablative radiotherapy.
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which would prevent achieving full recruitment within
the timescales set out for the study.
Thoracic SABR safety substudy
This will be done to document the toxicity and feasibility
of delivering SABR to thoracic metastases with or imme-
diately following radical thoracic RT. Additionally, we will
be able to assess processes for RT planning and dosim-
etry and have quality assurance (QA) for this group of
patients.
TRIAL DESIGN AND METHODS
SARON is a randomised, multicentre, non-blinded,
parallel-phase III trial (including trial feasibility and
thoracic metastatic SABR safety components) for
patients with oligometastatic (1–3 metastases) NSCLC.
As already stated, the SARON trial will also include two
substudies on feasibility and thoracic radiation safety
(figure 1).
Main trial
Patients will be randomised in a 1:1 ratio to receive either
standard systemic therapy only (Control Arm) or stan-
dard systemic therapy plus radical RT or SABR to their
primary tumours (and N1–3 mediastinal nodes where
present) and SABR/SRS to all the metastatic deposits
(Investigational Arm) (figure 2).
Allocation to either arm will be decided by a comput-
er-generated randomisation schedule. Patients will be
stratified by investigational site (hospital), histology
(adenocarcinoma vs non-adenocarcinoma), nodal stage
(N0/1 vs N2/3), number of oligometastatic sites (1 vs 2
or 3), brain metastases (present vs absent).
Due to the different treatment modalities in the study,
it is not possible to blind the patient or the physician to
the treatment arm.
Setting
The trial will be held in the UK with a target of 30 hospi-
tals/cancer centres that are able to give chemotherapy and
conventional RRT and to provide SABR/SRS (whether
in their own centre or via referral to another centre). All
sites giving RT must have QA accreditation, as guided by
the Radiotherapy Treatment Quality Assurance (RTTQA)
group of the National Cancer Research Institute (NCRI).
Cancer Research UK & UCL Cancer Trial Centre (UCL
CTC), acting on behalf of the sponsor UCL, will need to
ensure all documents and requirements are reviewed and
approved before activating the trial and sites.
Intervention
In the intervention arm, the patients will receive up to
another two cycles of the same chemotherapy regime
as the control arm, followed by RRT within 2–6 weeks
of day 1 of cycle 4 of chemotherapy. RRT can be deliv-
ered to the primary lung tumour either by conventional
radiotherapy or SABR, if appropriate, followed by SABR/
SRS to the oligometastatic lesion(s) (figure 3). Main-
tenance chemotherapy is permitted according to local
practice.
The radiotherapy must be performed by an approved
site principal investigator who is experienced in
treating NSCLC. Patients will be planned and treated
per the SARON RT Planning and Delivery Guidelines
(online supplementary appendix 1).
Safety monitoring
The treating physician will be able to modify or discon-
tinue a patient treatment in either arm for various reasons,
including perceived harm or toxicities. The treating physi-
cian will have to enter protocol deviations, treatment inter-
ruptions and adverse toxicities in the case report form
(CRF) and submit it to the UCL CTC.
Figure 1 SARON substudy schema. QA, quality assurance; RT, radiotherapy; SABR, stereotactic ablative radiotherapy.
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All serious adverse events must be reported to UCL
CTC within 24 hours. The Trial Management Group
(TMG) and Independent Data Monitoring Committee
(IDMC) will also adopt a safety monitoring role and will
review safety issues. Protocols amendments if required
will be disseminated to all relevant parties.
Initial feasibility substudy
The aims of the feasibility substudy are:
►To satisfy the TMG and IDMC that recruitment targets
are likely to be met for the remainder of the main
trial.
Figure 2 SARON trial schema.RT, radiotherapy; SABR, stereotactic ablative radiotherapy; SRS, stereotactic radiosurgery.
Figure 3 Summary of treatment in investigational arm.RT, radiotherapy; SABR, stereotactic ablative radiotherapy; SRS,
stereotactic radiosurgery.
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►To determine that the dropout/progression rate in
the first 50 randomised patients is <30% (ie, for at
least 50 patients randomised and treated, no more
than 72 patients have been registered).
►That there are no major logistical problems identified
in the delivery of SABR/SRS.
Trial recruitment will not be suspended during the
period of feasibility assessment.
As well as the aims above, the feasibility assessment will
assess:
►Practicality of achieving recruitment targets
–Compare actual recruitment rate with expected re-
cruitment rate.
–Explore reasons for screening failures/ineligibility.
–Review drop-off rate between registration and ran-
domisation, including PFS rate following two cycles
of chemotherapy prior to randomisation.
►Logistics of delivering the investigational treatment
–Practicalities associated with delivering SABR/SRS,
including:
–Technicalities in the QA.
–Access to SABR/SRS for all recruiting centres.
–Funding.
►Potential for contamination, as patients may seek
SABR/SRS if randomised to the chemotherapy only
arm.
Thoracic SABR safety substudy
Patients treated with SABR to their thoracic metastases
(including lung and other intrathoracic metastases,
that is, thoracic spine and rib) will be monitored more
closely for toxicity (figure 4). The first 20 patients in
the experimental arm with thoracic metastases (these
patients can also have non-thoracic metastases) will
be treated and followed up for 3 months to assess
adverse events. Until confirmation of safety, all thoracic
metastases will be treated in one of approximately 10
centres, selected by the following criteria:
►Most treatment platforms (ie, manufacturers) are
represented.
►All geographical locations of the UK have
representation.
►An existing active SABR/SRS clinical programme is
in place.
Eligibility criteria
Inclusion criteria
1. Patient ≥18 years.
2. Histologically or cytologically confirmed NSCLC.
3. Staging with FDG PET-CT whole body scan and MRI
brain or CT brain scan with IV contrast within 42 days
prior to registration.
4. ECOG performance status 0–1 at time of registration.
5. Patient presenting with synchronous primary disease
and oligometastatic disease.
6. Patient is fit to receive four cycles of platinum-based
doublet chemotherapy, cisplatin or carboplatin, as
per local guidelines and assessment.
7. Primary tumour and involved nodes included in the
radical RT volume must be suitable for radical RT
(either conventional RT or SABR)—conventional RT
fields do not need to be contiguous.
8. Patient is deemed fit to receive conventional RT and
SABR/SRS as per local guidelines and assessment.
9. Between one and three metastatic lesions, assessable
as per RECIST V.1.1 and suitable for SABR and/or
SRS (only one site of metastases OR the primary tu-
mour needs to be measurable as per RECIST V.1.1).
i. Nodes included in the radical RT volume
will not count towards the number of sites of
metastases.
Figure 4 Table detailing number of patients required with≥grade 3 to action a stoppage on treatment of thoracic metastases
SABR.RTPN,radiation-induced pneumonitis; SABR, stereotactic ablative radiotherapy.
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ii. Nodes not treated in the radical RT volume are
counted as metastases. The patient, though, must
have stage IV disease. The same RT dose con-
straint eligibility criteria will apply to these nodes
as to other metastases.
iii. Lower cervical supraclavicular lymph nodes and
sternal notch nodes are considered N3. Higher
neck nodes are considered as metastases (IASLC
2009 criteria).
10. Note: If brain metastasis present, at the time of ran-
domisation, the following parameters must be met
(table 2).
11. Acceptable lung function for radical lung radio-
therapy as assessed according to local policy. Note:
Potential thoracic substudy patients will need to com-
plete pulmonary function tests preregistration.
12. No relevant comorbidities, including pulmonary fi-
brosis and connective tissue disorders.
Further inclusion notes
►For bone metastases, pre-SABR stabilisation should
be considered as clinically appropriate. This does not
exclude the patient from the study.
►For patients with brain metastases, there must be
another metastatic lesion at another site to be eligible
for the study (sum of intracranial and extracranial
metastases must be ≤3), as patients with brain only
metastases would naturally be offered SRS/surgery to
their intracranial disease in accordance with the
published commissioning criteria for SRS set by NHS
England.
►Patients with lung cancer and an additional malignant
nodule are difficult to categorise, and the current stage
classification rules are unclear. Such patients should
be evaluated by the local multidisciplinary team to
determine whether the additional lesion represents a
second primary lung cancer or an additional tumour
nodule corresponding to the dominant cancer. The
SARON TMG will accept local MDM decisions on this
and will aim to centrally review all baseline PET-CT,
chest/abdomen CT scans (if performed) and brain
MRI scans.
Exclusion criteria
1. Patient has had palliative radiotherapy to any tumour
site prior to registration or requires palliative radio-
therapy prior to randomisation.
2. Presence of EGFR or ALK/ROS-1 mutation (EGFR
and ALK/ROS-1 testing is only mandatory for pa-
tients with adenocarcinoma).
3. One or more metastases previously treated with al-
ternative ablative treatment, for example, RFA or
surgery.
4. Patient has received any previous treatment for this
NSCLC malignancy.
5. Patients who present with brain metastasis only and
no sites of extracranial metastatic disease, that is, the
presence of more than two brain metastases is an ex-
clusion criterion.
6. Metastasis in sites where normal radiotherapy con-
straints cannot be met.
7. Brain metastasis within the brainstem.
8. Patients who have more than three metastases prior
to trial registration.
9. Primary tumour or metastases causing direct invasion
or high clinical suspicion of direct invasion of the
wall of a major blood vessel.
10. Malignant pleural or pericardial effusion.
11. Patients with bilateral adrenal metastases.
12. History of prior malignant tumour likely to interfere
with the protocol treatment or comparisons, unless
the patient has been without evidence of disease for
at least 3 years or the tumour was a non-melanoma
skin tumour or early cervical cancer.
13. Women who are pregnant or breast feeding.
14. Stage III disease even with extensive nodal disease
(ie, N3 nodal disease but no distant metastases).
15. Leptomeningeal disease.
Eligibility criteria for randomisation
Following cycle 2 of chemotherapy, patients must meet
the following eligibility criteria for randomisation:
►No disease progression on postcycle 2 CT (as per
RECIST V.1.1)
–Patients who cannot be randomised, only progres-
sion and OS data will be collected for these patients.
►Patients with no or less visible metastases following
two cycles of chemotherapy are still eligible for
randomisation
–If randomised to the investigational arm, these pa-
tients will receive SABR/SRS to visible and SABR/
SRS on relapse of existing metastases.
–Patients who experience progression with new me-
tastases are not eligible for randomisation or for
trial treatment.
►Patients with complete response of the lung primary
following two cycles of chemotherapy are eligible for
randomisation. If randomised to the Investigational
Arm, these patients will still receive conventional
RT to the site of the original primary tumour per
protocol.
►ECOG Performance Status 0–2.
►Continued suitability for trial treatment as deemed by
the treating clinician.
Table 2 Acceptable brain metastases diameters
Largest lesion diameter
Second metastasis
diameter
3 cm ≤2 cm
2.8 cm ≤2.4 cm
2.6 cm ≤2.6 cm
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TRIAL ENDPOINTS
Main trial
Primary endpoint
►OS: Measured from date of randomisation until date
of death from any cause.
Secondary endpoints
►PFS: Time from randomisation until progression or
death from any cause. Progression will be assessed
using RECIST V.1.1.
►LC of primary and all metastases: This refers to
tumours present at randomisation. Assessed as
progression at one or more of these tumour sites.
►New distant metastasis-free survival: Time from rando-
misation until presence of new distant metastasis (ie,
the emergence of tumour on imaging at anatomical
sites where cancer was not present at the time of diag-
nosis) or death from any cause.
►Quality of life: As measured by EORTC QLQ-C3034
and LC13.35
►Adverse events, assessed using CTCAE V.4.03, and dose
delays, reduction and compliance to trial treatment.
Feasibility substudy
Primary endpoint
►Recruitment rate, logistical challenges, contamina-
tion, as patients may seek SABR/SRS outside the trial
if randomised to the chemotherapy only Arm.
Thoracic SABR safety substudy
Primary endpoint
►Grade 3–5 radiation-induced pneumonitis (per
CTCAE V.4.03) up until 3 months’ post-thoracic
SABR.
Secondary endpoint
►Other grade 3–5 RT-related toxicities (per CTCAE
V.4.03).
PARTICIPANT RECRUITMENT AND TIMELINE
Sample size and study duration
In total, 340 patients are required (170 per arm) to
detect an improvement in median survival from 9.9
to 14.3 months, that is, a HR of at least 0.69, with a
two-sided 5% alpha and 85% power and a 10% dropout
rate.
Prior to study initiation, a survey was sent to all UK
radiotherapy centres on their SABR/SRS practices. At
least 26 centres replied with an average of 4.6 suitable
study patients in the previous 6 months. Assuming only
half of this amount would satisfy the eligibility criteria,
this would equate to around 120 patients. We thus expect
that the trial will take around 3 years to accrue. We hope
to include more than 30 centres in our study in improve
on trial participation. Nevertheless, an early feasibility
study will be conducted after the first 50 patients. The
study opened August 2016.
Recruitment and consent
Patients will be identified through MDT meetings and
clinic appointments. At the first consult, if all eligibility
criteria are fulfilled, the team will introduce the trial and
provide the patient information sheet (detailing ratio-
nale, trial design and risks involved) along with the rele-
vant contact information. Participants will have at least
24 hours to consider participation. Consent will have to
be obtained before collection of baseline tumour and
demographic data and the QoL survey. Patients can with-
draw at any stage of the trial.
After the second chemotherapy cycle, a CT scan will
be performed. If prerandomisation eligibility criteria are
fulfilled, the patient will be randomised. At this stage,
patients who are unable to fulfil the criteria will be with-
drawn from the study and only progression and OS data
will be collected.
Timeline
During the treatment, all recruitment patients will be
followed up with a blood test and physical examination
before each chemotherapy treatment cycle. Patients in
the interventional arm will have fortnightly reviews if they
need conventional RT and weekly reviews when they have
SABR/SRS.
On completion of fourth cycle of chemotherapy, an
assessment will be done by the treating physician every
month for the first 3 months, then 3 monthly until 2
years, then 6 monthly until 3 years postchemotherapy.
During each scheduled visit, the patient will be assessed
for disease status, performance status, adverse events and
QoL questionnaire. A CT scan will be required at 3, 6,
12, 18, 24 and 36 months postchemotherapy (follow-up
schedule in online supplementary appendix 2).
Patients in the Thoracic SABR Safety substudy will
need lung function test at 12 and 24 months follow-up
visits. Additionally, they will have fortnightly reviews for
the 1st month after radiotherapy and an additional visit 3
months after radiotherapy.
Patient participation will be completed at death, study
withdrawal or after 3 years of follow-up.
DATA MANAGEMENT AND ANALYSIS
Data management
Each participant is assigned a trial number by UCL CTC.
The patient data including CRFs, supporting documents
(eg, CT scan images, pathology reports) will be submitted
to UCL CTC without any patient-specific identifiers to
maintain confidentiality. To avoid missing data, forms
are checked onsite before submission to UCL CTC. UCL
CTC will check data for legibility, completeness, accuracy
and consistency. Query reports will be sent to the data
contact at site for checks and rectification.
Patients, who discontinue treatment for any reason,
should be kept on trial for purpose of follow-up and data
analysis. In patients lost to follow-up, every effort should
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ConibearJ, etal. BMJ Open 2018;8:e020690. doi:10.1136/bmjopen-2017-020690
Open Access
be made by the site to contact the GP for information on
patient status.
All trial-related documents will be archived centrally in
a secure place for a minimum of 5 years at the end of the
trial.
Analysis
The data will be analysed on completion of the study.
Analysis of primary and secondary endpoints will be
performed on an intention-to-treat population. The OS
will also be conducted on per-protocol basis. Survival
endpoints will be assessed using Cox proportional
hazards models to estimate HRs and Cox regression anal-
ysis to adjust for effect on stratification factors. Missing
data will be censored at the date they were last known
to be alive. For all tests, we will use two-sided p values
with 5% level of significance. QoL data will be analysed
using mixed effects repeated measured measures model
and reported by each domain. Adverse events (grade 3–5
CTCAE V.4.03 events) will be compared between groups
using χ² of Fisher’s exact test for all patients who received
any trial treatment.
Thoracic SABR safety substudy analysis
After the initial 20 patients with thoracic metastases
have been treated and monitored for adverse events. If
the data show evidence that the true rate of grade 3–5
pneumonitis related to RT is above 30%, the IDMC may
consider suspending the treatment of thoracic metastases
with SABR. If incidence is below 30%, the treatment is
safe to continue. If inconclusive (ie, 95% the CI of events
crosses 30%) the substudy will continue for another 10
patients until a conclusion can be drawn (figure 4).
ETHICS AND DISSEMINATION
Version 1.0 of the protocol was approved by West
Midlands, Coventry & Warwickshire Research Ethics
Committee (Registration 15/WM/0392) on 7 December
2015. All participants will be given a SARON trial patient
information sheet and will be required to give written
informed consent. The SARON trial is supported by
Cancer Research UK (C13530/A18015) and sponsored
by UCL and coordinated by UCL CTC. Results will be
submitted for presentation at local and international
medical conference and expected to be published in a
peer-reviewed journal.
DISCUSSION
There is growing evidence supporting the safety of
SABR/SRS, its effect on LC and a possible impact on OS
to warrant a randomised phase III trial. The key ques-
tion regarding the successful completion of such a trial
relates to its feasibility, which will be governed by patient
numbers and access to appropriate SABR/SRS treatment.
There are also no definitive data yet on the toxicity of
SABR/SRS in the specific context of thoracic SABR with
radical RT to the primary tumour and mediastinal lymph
nodes. SARON is an important study, as it will test the
impact of radical RT and SABR/SRS on OS in oligometa-
static NSCLC with an early evaluation of overall feasibility
and toxicity for thoracic metastases. The study is currently
recruiting; the study opened to recruitment in the UK
on 11 August 2016 and the first patient was enrolled 19
August 2016.
Author afliations
1St Bartholomew's Hospital, London, UK
2Cancer Research UK & UCL Cancer Trials Centre, London, UK
3University Hospital Southampton NHS Foundation Trust, Southampton, UK
4National Radiotherapy Trials QA Group (RTTQA), Mount Vernon Hospital, Northwood,
UK
5The University of Manchester and The Christie NHS Foundation Trust, Manchester,
UK
6Department of Oncology, University of Oxford, Oxford, UK
7University College London Hospital, London, UK
8Centre for Cancer Research and Cell Biology, Queen’s University of Belfast, Belfast,
UK
9Addenbrooke's Hospital, Cambridge, UK
10The Clatterbridge Cancer Centre, Liverpool, UK
11Guys & St Thomas NHS Trust, London, UK
12Department of Oncology, University College London, London, UK
Contributors DL conceived of the study and is the grant holder. DL, JC, ATB, CF-F,
JF, MF, GGH, PM, SM, SH, NC, YN, DE, RP and BC initiated, developed and planned
the study design. NC also provided statistical expertise in clinical trial design. RP
and DE also developed the radiotherapy quality assurance programme for the trial.
All the authors contributed to renement of the study protocol and approved the
nal manuscript. All contributors have been heavily involved in the design of the
trial and have been involved in the drafting and review of the article to be published.
Funding This research is funded by Cancer Research UK’s (CR UK) Clinical Trials
Awards and Advisory Committee (CTAAC). Grant reference number C13530/
A18015.
Competing interests None declared.
Patient consent Detail has been removed from this case description/these case
descriptions to ensure anonymity. The editors and reviewers have seen the detailed
information available and are satised that the information backs up the case the
authors are making.
Ethics approval West Midlands, Coventry & Warwickshire Research Ethics
Committee (15/WM/0392).
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Results/data not yet generated.
Open Access This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
properly cited and the use is non-commercial. See: http:// creativecommons. org/
licenses/ by- nc/ 4. 0/
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2018. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
REFERENCES
1. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing
cisplatin plus gemcitabine with cisplatin plus pemetrexed in
chemotherapy-naive patients with advanced-stage non-small-cell
lung cancer. J Clin Oncol 2008;26:3543–51.
2. Lee SM, Rudd R, Woll PJ, et al. Randomized double-blind placebo-
controlled trial of thalidomide in combination with gemcitabine and
Carboplatin in advanced non-small-cell lung cancer. J Clin Oncol
2009;27:5248–54.
group.bmj.com on April 17, 2018 - Published by http://bmjopen.bmj.com/Downloaded from
10 ConibearJ, etal. BMJ Open 2018;8:e020690. doi:10.1136/bmjopen-2017-020690
Open Access
3. Oh Y, Taylor S, Bekele BN, et al. Number of metastatic sites is a
strong predictor of survival in patients with nonsmall cell lung cancer
with or without brain metastases. Cancer 2009;115:2930–8.
4. Pirker R, Pereira JR, Szczesna A, et al. Prognostic factors in patients
with advanced non-small cell lung cancer: data from the phase III
FLEX study. Lung Cancer 2012;77:376–82.
5. Albain KS, Crowley JJ, LeBlanc M, et al. Survival determinants in
extensive-stage non-small-cell lung cancer: the Southwest Oncology
Group experience. J Clin Oncol 1991;9:1618–26.
6. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol
1995;13:8–10.
7. Hanna GG, Landau D. Stereotactic body radiotherapy for
oligometastatic disease. Clin Oncol 2015;27:290–7.
8. Siva S, MacManus M, Ball D. Stereotactic radiotherapy for pulmonary
oligometastases: a systematic review. J Thorac Oncol 2010;5:1091–9.
9. Gerszten PC, Mendel E, Yamada Y. Radiotherapy and radiosurgery
for metastatic spine disease: what are the options, indications, and
outcomes? Spine 2009;34(22 Suppl):S78–92.
10. Lee MT, Kim JJ, Dinniwell R, et al. Phase I study of individualized
stereotactic body radiotherapy of liver metastases. J Clin Oncol
2009;27:1585–91.
11. Parikh RB, Cronin AM, Kozono DE, et al. Denitive primary therapy in
patients presenting with oligometastatic non-small cell lung cancer.
Int J Radiat Oncol Biol Phys 2014;89:880–7.
12. Méndez Romero A, Wunderink W, Hussain SM, et al. Stereotactic
body radiation therapy for primary and metastatic liver tumors: a
single institution phase i-ii study. Acta Oncol 2006;45:831–7.
13. Kim MS, Cho CK, Yang KM, et al. Stereotactic body radiotherapy for
isolated paraaortic lymph node recurrence from colorectal cancer.
World J Gastroenterol 2009;15:6091–5.
14. Bignardi M, Cozzi L, Fogliata A, et al. Critical appraisal of volumetric
modulated arc therapy in stereotactic body radiation therapy for
metastases to abdominal lymph nodes. Int J Radiat Oncol Biol Phys
2009;75:1570–7.
15. Jereczek-Fossa BA, Fariselli L, Beltramo G, et al. Linac-based or
robotic image-guided stereotactic radiotherapy for isolated lymph
node recurrent prostate cancer. Radiother Oncol 2009;93:14–17.
16. Holy R, Piroth M, Pinkawa M, et al. Stereotactic body radiation
therapy (SBRT) for treatment of adrenal gland metastases from non-
small cell lung cancer. Strahlenther Onkol 2011;187:245–51.
17. Torok J, Wegner RE, Burton SA, et al. Stereotactic body radiation
therapy for adrenal metastases: a retrospective review of a
noninvasive therapeutic strategy. Future Oncol 2011;7:145–51.
18. Kang JK, Kim MS, Kim JH, et al. Oligometastases conned one
organ from colorectal cancer treated by SBRT. Clin Exp Metastasis
2010;27:273–8.
19. Milano MT, Katz AW, Okunieff P. Patterns of recurrence after curative-
intent radiation for oligometastases conned to one organ. Am J Clin
Oncol 2010;33:157–63.
20. Salama JK, Hasselle MD, Chmura SJ, et al. Stereotactic body
radiotherapy for multisite extracranial oligometastases: nal report
of a dose escalation trial in patients with 1 to 5 sites of metastatic
disease. Cancer 2012;118:2962–70.
21. De Ruysscher D, Wanders R, van Baardwijk A, et al. Radical
treatment of non-small-cell lung cancer patients with synchronous
oligometastases: long-term results of a prospective phase II trial
(Nct01282450). J Thorac Oncol 2012;7:1547–55.
22. Song CW, Kim MS, Cho LC, et al. Radiobiological basis of SBRT and
SRS. Int J Clin Oncol 2014;19:570–8.
23. Gomez DR, Blumenschein GR, Lee JJ, et al. Local consolidative
therapy versus maintenance therapy or observation for patients with
oligometastatic non-small-cell lung cancer without progression after
rst-line systemic therapy: a multicentre, randomised, controlled,
phase 2 study. Lancet Oncol 2016;17:1672–82.
24. Iyengar P, Wardak Z, Gerber DE, et al. Consolidative Radiotherapy
for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2
Randomized Clinical Trial. JAMA Oncol 2018;4:e173501.
25. Rusthoven KE, Kavanagh BD, Burri SH, et al. Multi-institutional
phase I/II trial of stereotactic body radiation therapy for lung
metastases. J Clin Oncol 2009;27:1579–84.
26. Ernst-Stecken A, Lambrecht U, Mueller R, et al. Hypofractionated
stereotactic radiotherapy for primary and secondary intrapulmonary
tumors: rst results of a phase I/II study. Strahlenther Onkol
2006;182:696–702.
27. Herfarth KK, Debus J, Lohr F, et al. Stereotactic single-dose radiation
therapy of liver tumors: results of a phase I/II trial. J Clin Oncol
2001;19:164–70.
28. Rusthoven KE, Kavanagh BD, Cardenes H, et al. Multi-institutional
phase I/II trial of stereotactic body radiation therapy for liver
metastases. J Clin Oncol 2009;27:1572–8.
29. Chawla S, Chen Y, Katz AW, et al. Stereotactic body radiotherapy
for treatment of adrenal metastases. Int J Radiat Oncol Biol Phys
2009;75:71–5.
30. Hoyer M, Roed H, Traberg Hansen A, et al. Phase II study on
stereotactic body radiotherapy of colorectal metastases. Acta Oncol
2006;45:823–30.
31. Milano MT, Katz AW, Muhs AG, et al. A prospective pilot study of
curative-intent stereotactic body radiation therapy in patients with 5
or fewer oligometastatic lesions. Cancer 2008;112:650–8.
32. Stinauer MA, Kavanagh BD, Schefter TE, et al. Stereotactic body
radiation therapy for melanoma and renal cell carcinoma: impact
of single fraction equivalent dose on local control. Radiat Oncol
2011;6:34.
33. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus
chemotherapy in advanced ALK-positive lung cancer. N Engl J Med
2013;368:2385–94.
34. Aaronson NK, Ahmedzai S, Bergman B, et al. The European
Organization for Research and Treatment of Cancer QLQ-C30: a
quality-of-life instrument for use in international clinical trials in
oncology. J Natl Cancer Inst 1993;85:365–76.
35. Bergman B, Aaronson NK, Ahmedzai S, et al. The EORTC QLQ-
LC13: a modular supplement to the EORTC Core Quality of
Life Questionnaire (QLQ-C30) for use in lung cancer clinical
trials. EORTC Study Group on Quality of Life. Eur J Cancer
1994;30A:635–42.
group.bmj.com on April 17, 2018 - Published by http://bmjopen.bmj.com/Downloaded from
cancer
alone for oligometastatic non-small cell lung
radiotherapy with standard chemotherapy
ablative radiotherapy and radical
trial comparing the addition of stereotactic
multicentre, randomised controlled phase III
Study protocol for the SARON trial: a
Syed Moinuddin and David Landau
Fenwick, Martin Forster, Gerard G Hanna, Susan Harden, Philip Mayles,
Nicholas Counsell, Rushil Patel, David Eaton, Corinne Faivre-Finn, John
John Conibear, Brendan Chia, Yenting Ngai, Andrew Tom Bates,
doi: 10.1136/bmjopen-2017-020690
2018 8: BMJ Open
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