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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

Authors:
  • St. Bartholomews Hospital

Abstract and Figures

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% significance 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.
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ConibearJ, etal. 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: ConibearJ, ChiaB,
NgaiY, etal. 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 afliations 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% signicance 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 2year
Rusthovenetal,200925 38/63 Multiple colorectal Ca
24%; sarcoma 18%;
renal cell Ca 18%; lung
13%
Lung 48–60Gy/3# 7% 100% 96%
Ernst-Steckenetal,
200626
21/39 Multiple lung* 43% Lung 35–40Gy/5# 5%
Siva20108
Review of 19 papers8 19
334/564 Multiple Lung 2.6%
4%
78%
Herfarthetal, 200127 37/60 Multiple Liver 14–26Gy/1# 0% 71%
Mendez Romero200612 17/34 Multiple
colorectal Ca 82%
Liver 36–60Gy/3# 24% 100% 86%
Rusthovenetal,200928 47/63 Multiple colorectal Ca
32%; lung 21%
Liver 36–60Gy/3# 2% 95% 92%
Leeetal,200910 70/143 Multiple
CRC 57%
Liver 54–60Gy/6# 10% 71%
Holyetal,201116 18/18 NSCLC Adrenal 20–40Gy/5# 77%†
Chawlaetal,200929 30/35 Multiple
NSCLC 67%
Adrenal 16–50Gy/4–16#
Hoyeretal,200630 64/142 Colorectal Ca Multiple liver 69%;
lung 19%
45Gy/3# 79%
Milanoetal, 200831 121/293 Multiple breast 32%;
colorectal Ca 26%
Multiple liver 45%;
lung 41%;
thoracic nodes
20%; bone 12%
50Gy/5# <1% 67%
Salamaetal, 201120 61/113 Multiple NSCLC 18%;
breast 11%;
renal cell Ca 13%;
colorectal Ca 10%
Multiple lung 36%;
nodes 19%; liver
19%; bone 13%
24–48Gy/3# 13% 67% 53%
Gersztenetal, 2006977/87 Lung Spine 15–25Gy/1# 0%
Gersztenetal, 2005928/36 Melanoma Spine 17.5–25Gy/1# 0%
Stinaueretal, 201132 17/28
13/25
Melanoma
Renal cell Ca
Multiple lung 74%;
liver 21%
40–50Gy/5# or
42–60Gy/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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ConibearJ, etal. 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 afliations
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 renement 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 satised 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.
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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
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... Remarkable advances in systemic agents have aroused more aggressive local therapy for various types of cancers [1][2][3][4][5][6][7]. Previous phase-II randomized clinical trials have shown that aggressive local consolidative high-dose radiotherapy to all lesions improves local control rates with acceptable treatment-related complications in patients with localized metastatic non-small cell lung cancer (NSCLC) [8][9][10][11][12][13][14]. ...
... Therapeutic decisions were made on an individual patient basis at a multidisciplinary lung cancer conference. In the current study, we defined localized metastatic disease as the presence of one to three metastatic sites at the time of diagnosis [10][11][12][13]. And patients who showed favorable tumor response after systemic treatment, including oligo-progressive disease at the thoracic site which was amenable to curative high-dose local radiotherapy, were included. ...
Article
Full-text available
Our study has aimed to assess the effects of consolidative high-dose radiotherapy on clinical outcomes in patients with localized metastatic non-small cell lung cancer (NSCLC) who showed favorable tumor response after systemic treatment. We retrospectively reviewed the medical records of 83 patients with localized metastatic NSCLC, who received systemic therapy followed by consolidative local radiotherapy at the Korea University Guro Hospital between March 2017 and June 2022. In the current study, we defined localized metastatic disease as the presence of one to three metastatic sites at the time of diagnosis. And patients who showed favorable tumor response after systemic treatment, including oligo-progressive disease at the thoracic site which was amenable to curative high-dose local radiotherapy, were included. The planned total dose and fraction size mainly depended on the location of lesions. The median follow-up time after consolidative radiotherapy was 16 months (range: 5–52 months). The overall 2-year progression-free survival rates were 81.4%. Of 83 patients, only four (4.3%), treated with intensity-modulated radiation therapy, showed an in-field local recurrence. Interestingly, only one patient experienced a local failure among the 20 patients who showed an oligo-progressive disease at the thoracic site on the tumor response evaluation after systemic treatment. Regarding treatment-related pulmonary toxicity, three patients with grade-3 and one patient with grade-4 radiation pneumonitis were presented. If the disease is sufficiently controlled and localized by systemic therapy, local consolidative radiotherapy is thought to improves local control rates with acceptable treatment-related toxicities in patients with localized metastatic NSCLC, especially those with oligo-progressive disease.
... SARON is a randomized controlled phase III trial on OM-NSCLC without driver mutations, in which patients may have up to three sites of metastatic disease, at least one of which must be extracranial [23]. Participants are randomized to either standard platinum-doublet chemotherapy alone or chemotherapy with radical radiotherapy to the primary tumor and SBRT to all sites of metastatic disease. ...
Article
Full-text available
Non-small cell lung cancer (NSCLC) is a major cause of mortality in Canada, with many patients presenting with metastatic disease. The oligometastatic state (OM-NSCLC) may be amenable to cure using aggressive local consolidative therapies. Stereotactic body radiotherapy (SBRT), which entails the utilization of a high dose of radiation in one or few fractions, has many benefits in this setting, including its applicability in varied patient populations to ablate lesions in varied anatomical locations. It has also been demonstrated to prolong the time to next-line systemic therapy, to reduce financial burden, to improve quality-adjusted life years, and reduce adverse events caused by these lesions. This review outlines the published phase II and III trials that have already demonstrated the utility of SBRT in OM-NSCLC, as well as the many ongoing trials aiming to further define its role, including the largest phase II/III trial to date, NRG-LU002. Overall, SBRT appears to improve outcomes when combined with a broad range of standard-of-care therapies and is generally well tolerated; however, careful patient selection is necessary to maximize benefits while minimizing harm. Ongoing trials will help define the optimal patients for SBRT and the best timing for this intervention.
... Several randomized trials have reported that stereotactic body radiotherapy (SBRT) can be employed in the setting of oligometastatic disease to achieve improved survival and longer delays before the initiation of systemic therapy [1][2][3][4][5]. Additional trials further exploring the potential role of SBRT in this setting are ongoing [6][7][8][9]. A critical requirement, however, is the ability to deliver fractional doses of radiation to a conformal volume with biologic equivalent dose (BED) goals of >75Gy [10]. ...
Article
Full-text available
There is a growing interest in the application of stereotactic body radiotherapy (SBRT) for the treatment of oligometastatic cancers. This increasing appeal of SBRT has highlighted the need for more sophisticated radiotherapy techniques that allow high doses of radiation to be delivered to multiple sites while limiting the exposure of neighboring healthy tissue. A major obstacle to achieving this aim has been the occurrence of interfraction target variability: the tendency of both the tumor and the surrounding tissue to undergo day-to-day non-synchronous shifts in position. Such changes in the conformation of the tumor field often compromise the effectiveness of conventional SBRT prescribed for a fixed target. We report a case of oligometastatic pelvic disease where the challenge of an unusually mobile tumor was overcome with the use of a novel technique employing cone beam CT (CBCT)-based online adaptive radiotherapy (OART). The Phase I “Adaptive Radiation for Abdominopelvic Metastases (ARAM)” clinical trial was designed to determine if OART can achieve dosing targets superior to those attained using conventional radiotherapy techniques. In this case, CT adaptive planning enabled the treatment of a pelvic target prescribed per protocol to 45Gy that would otherwise have not been amenable to treatment with conventional SBRT planning. Adaptive plans showed significant improvements in target coverage while respecting critical organ constraints, resulting in a total treatment V35Gy of 89.3% and V45Gy of 52.8%, whereas the scheduled plan would have achieved V35Gy of 67.4% and V45Gy of 13.6%. Treatment times were variable (38.1-96.7 mins), and correlated with the magnitude of daily translation which ranged from 4 to 7 cm of total linear translation. The patient tolerated treatment without any adverse events. These results demonstrate a novel application of CBCT-guided OART that allowed for the administration of ablative treatment to an unexpectedly mobile target unamenable to conventional SBRT. CBCT-guided OART currently requires increased treatment time, a need which might be reduced by optimization of daily contouring. The phase 1 clinical trial NCT05880667 is ongoing and may provide further evidence that CBCT-guided OART can meet the technical challenges posed by radiotherapy for oligometastatic abdominal and pelvic disease.
... The significantly better OS and PFS in our oligometastatic cohort is therefore unsurprising. Of common primaries in our series, definitive treatment in oligometastatic lung cancers has demonstrated PFS benefit in randomized studies [7,35], with Phase III results awaited [38]. In kidney cancers, SBRT to all metastatic lesions with [39] and without [40] immunotherapy Fig. 4 Cumulative incidence of late toxicity grade 3 or higher. ...
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Full-text available
Purpose To report clinical outcomes for patients with metastatic disease to the head and neck (HN) treated with stereotactic body radiation therapy (SBRT). Methods A retrospective review of patients treated with SBRT to HN sites from 2012 to 2020 was conducted. Treatment indications included the following: oligometastases, oligoprogression, and control a dominant area of progression (DAP). Kaplan–Meier method was used to estimate local control (LC), regional control (RC), overall survival (OS), and progression-free survival (PFS). Univariable (UVA) and multivariable analyses (MVA) were performed. Grade 3–4 acute and late toxicities were reported by the Common Terminology Criteria for Adverse Events v5.0. Results Fifty-six patients (58 lesions) were analysed with a median follow-up of 16 months. Primary sites included lung (25.0%), kidney (19.6%), breast (19.6%) and other (35.8%). SBRT indications were as follows: oligometastases (42.9%), oligoprogression (19.6%) and local control of a dominant area of progression (37.5%). Most patients received SBRT to a single neck node (n = 47, 81.0%). Median SBRT dose was 40 Gy (range 25–50 Gy) in five fractions, with a median biologically effective dose (BED10) of 72 Gy (range 37.5–100 Gy). One- and 2-year LC and RC rates were 97.6% and 72.7% as well as 100% and 86.7%, respectively. Median OS was 19.2 months (95% [CI] 14.8–69.4), and median PFS was 7.4 months (95% [CI] 5.2–11.9). The 1-year OS and PFS rates for oligometastases, oligoprogression and DAP were 95.8%, 63.6% and 38.1% (p = 0.0039) as well as 56.5%, 27.3% and 19.1% (p = 0.0004), respectively. On MVA, treatment indication and histology were predictive for OS, while indication and prior systemic therapy were predictive for PFS. Cumulative late grade 3 + toxicity rate was 11.3%, without grade 5 events. Conclusion The use of SBRT for metastatic disease to the HN provided excellent LC rates with low rates of regional failure and an acceptable toxicity profile, highlighting its utility in these patients. Patients with oligometastatic disease had better OS and PFS than others.
... The SARON trial, a UK-based randomized trial comparing SBRT to chemotherapy in oligometastatic NSCLC, allows for a prescription dose for adrenal metastases between 30 to 45Gy in 3 fractions with at least 95% PTV coverage. 11 This spectrum of dose corresponds to a wide range of BED 10 (60-100Gy). Regarding our patient, SBRT was given to the metastatic left adrenal gland, to a total dose of 35Gy in 5 fractions (BED=59.50Gy), in order to respect organs at risk constraints, namely the kidney and small bowel. ...
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Neuroendocrine tumors comprise a rare but increasing heterogeneous group of malignancies arising from neuroendocrine cells, most commonly from the lung and gastrointestinal tract. Due to the vast histopathological differentiation of each subtype and the scarce clinical data published, choosing the most effective therapy can be challenging. Radiotherapy can play a significant role in the treatment of locally advanced metastatic tumors, however there is a lack of randomized clinical trials in this setting. This article reviews the current knowledge on the classification and treatment of unresectable lung atypical carcinoids. We present a clinical case of a ULAC treated with systemic therapy and RT in different settings of the disease. The subject is a 48 years old male, diagnosed with a well differentiated pulmonary NET, classified as cT4N3M1b (supraclavicular and mediastinal adenopathies and an adrenal metastatic lesion) with disease progression after systemic treatment, and with superior vena cava compression. The primary tumor and involved nodal areas were treated to 54Gy/30 fractions using VMAT. SBRT was given to the metastatic left adrenal gland. Five months after RT, CT showed a volumetric reduction of <25% of the thoracic disease and adrenal gland’s lesion stability. The disease remained stable for the next year and a half, when local and distant progression occurred, starting systemic treatment. A year and a half later, the patient presented with brain metastasis and underwent radiosurgery. At last follow-up, 5 years after diagnosis, the patient maintains treatment with capecitabine and temozolomide and is clinically stable. Definitive RT should be considered in the management of ULAC to improve local control.
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PURPOSE Local ablative therapy, such as radiotherapy or surgery, plays a key role in treatment of patients with oligometastatic disease. Stereotactic ablative body radiotherapy (SABR) comes to the fore as a safe and effective treatment for patients with a limited number of metastases, even those located in hard-to-reach body sites. Many researchers have suggested that metastatsis-directed therapy could improve long-term progression-free survival (PFS) and overall survival (OS) in patients with oligometastases. PATIENTS AND METHODS This was a retrospective, single-arm, observational study conducted between July 2015 and February 2022. In our institute, 60 patients with controlled primary tumors and one to five metastases were treated with SABR. Prescribed radiation doses ranged from 12 to 60 Gy administered in one to seven fractions. We aimed to determine whether metastatic-directed therapy using SABR for all oligometastases affects OS and PFS and whether the primary tumor or metastatic site influences OS/PFS. RESULTS The most common primary malignancy types were prostate (n = 14), colorectal (n = 10), lung (n = 7), and breast cancers (n = 6). The median follow-up was 30 months, ranging from 9 to 79. The 1-, 3-, and 5-year PFS and OS rates were 54.9%, 37.0%, and 37.0% and 98.3%, 84.4%, and 73.8%, respectively, and the median time to first progression was 15 (range, 2-32) months. Twenty-four (40%) patients had no recurrence. In our analysis, primary tumor site was not an independent prognostic factor. The metastatic site may influence on patient outcome in cases of localized bone and liver metastases. CONCLUSION In our retrospective analysis, SABR was associated with favorable levels of PFS and OS in patients with oligometastases. The limitations of our study were lacking high-level evidence, and randomized studies to compare SABR and palliative standard of care are mandatory.
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Background: Evidence from retrospective studies suggests that disease progression after first-line chemotherapy for metastatic non-small-cell lung cancer (NSCLC) occurs most often at sites of disease known to exist at baseline. However, the potential effect of aggressive local consolidative therapy for patients with oligometastatic NSCLC is unknown. We aimed to assess the effect of local consolidative therapy on progression-free survival. Methods: In this multicentre, randomised, controlled, phase 2 study, eligible patients from three hospitals had histological confirmation of stage IV NSCLC, three or fewer metastatic disease lesions after first-line systemic therapy, an Eastern Cooperative Oncology Group performance status score of 2 or less, had received standard first-line systemic therapy, and had no disease progression before randomisation. First-line therapy was four or more cycles of platinum doublet therapy or 3 or more months of EGFR or ALK inhibitors for patients with EGFR mutations or ALK rearrangements, respectively. Patients were randomly assigned (1:1) to either local consolidative therapy ([chemo]radiotherapy or resection of all lesions) with or without subsequent maintenance treatment or to maintenance treatment alone, which could be observation only. Maintenance treatment was recommended based on a list of approved regimens, and observation was defined as close surveillance without cytotoxic treatment. Randomisation was not masked and was balanced dynamically on five factors: number of metastases, response to initial therapy, CNS metastases, intrathoracic nodal status, and EGFR and ALK status. The primary endpoint was progression-free survival analysed in all patients who were treated and had at least one post-baseline imaging assessment. The study is ongoing but not recruiting participants. This study is registered with ClinicalTrials.gov, number NCT01725165. Findings: Between Nov 28, 2012, and Jan 19, 2016, 74 patients were enrolled either during or at the completion of first-line systemic therapy. The study was terminated early after randomisation of 49 patients (25 in the local consolidative therapy group and 24 in the maintenance treatment group) as part of the annual analyses done by the Data Safety Monitoring Committee of all randomised trials at MD Anderson Cancer Center, and before a planned interim analysis of 44 events. At a median follow-up time for all randomised patients of 12·39 months (IQR 5·52-20·30), the median progression-free survival in the local consolidative therapy group was 11·9 months (90% CI 5·7-20·9) versus 3·9 months (2·3-6·6) in the maintenance treatment group (hazard ratio 0·35 [90% CI 0·18-0·66], log-rank p=0·0054). Adverse events were similar between groups, with no grade 4 adverse events or deaths due to treatment. Grade 3 adverse events in the maintenance therapy group were fatigue (n=1) and anaemia (n=1) and in the local consolidative therapy group were oesophagitis (n=2), anaemia (n=1), pneumothorax (n=1), and abdominal pain (n=1, unlikely related). Interpretation: Local consolidative therapy with or without maintenance therapy for patients with three or fewer metastases from NSCLC that did not progress after initial systemic therapy improved progression-free survival compared with maintenance therapy alone. These findings suggest that aggressive local therapy should be further explored in phase 3 trials as a standard treatment option in this clinical scenario. Funding: MD Anderson Lung Cancer Priority Fund, MD Anderson Cancer Center Moon Shot Initiative, and Cancer Center Support (Core), National Cancer Institute, National Institutes of Health.
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Background: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. Methods: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. Results: The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. Conclusions: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.).
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Importance Patterns-of-failure studies suggest that in metastatic non–small-cell lung cancer (NSCLC) sites of gross disease at presentation are the first to progress when treated with chemotherapy. This knowledge has led to increased adoption of local ablative radiation therapy in patients with stage IV NSCLC, though prospective randomized evidence is limited. Objective To determine if intervening with noninvasive stereotactic ablative radiotherapy (SAbR) prior to maintenance chemotherapy in patients with non–progressive limited metastatic NSCLC after induction therapy led to significant improvements in progression-free survival (PFS). Design, Setting, and Participants This is a single-institution randomized phase 2 study of maintenance chemotherapy alone vs SAbR followed by maintenance chemotherapy for patients with limited metastatic NSCLC (primary plus up to 5 metastatic sites) whose tumors did not possess EGFR-targetable or ALK-targetable mutations but did achieve a partial response or stable disease after induction chemotherapy. Interventions Maintenance chemotherapy or SAbR to all sites of gross disease (including SAbR or hypofractionated radiation to the primary) followed by maintenance chemotherapy. Main Outcomes and Measures The primary end point was PFS; secondary end points included toxic effects, local and distant tumor control, patterns of failure, and overall survival. Results A total of 29 patients (9 women and 20 men) were enrolled; 14 patients (median [range] age, 63.5 [51.0-78.0] years) were allocated to the SAbR-plus-maintenance chemotherapy arm, and 15 patients (median [range] age, 70.0 [51.0-79.0] years) were allocated to the maintenance chemotherapy–alone arm. The trial was stopped to accrual early after an interim analysis found a significant improvement in PFS in the SAbR-plus-maintenance chemotherapy arm of 9.7 months vs 3.5 months in the maintenance chemotherapy–alone arm (P = .01). Toxic effects were similar in both arms. There were no in-field failures with fewer overall recurrences in the SAbR arm while those patients receiving maintenance therapy alone had progression at existing sites of disease and distantly. Conclusions and Relevance Consolidative SAbR prior to maintenance chemotherapy appeared beneficial, nearly tripling PFS in patients with limited metastatic NSCLC compared with maintenance chemotherapy alone, with no difference in toxic effects. The irradiation prevented local failures in original disease, the most likely sites of first recurrence. Furthermore, PFS for patients with limited metastatic disease appeared similar to those patients with a greater metastatic burden, further arguing for the potential benefits of local therapy in limited metastatic settings. Trial Registration clinicaltrials.gov Identifier: NCT02045446
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Stereotactic body radiotherapy (SBRT) is now an established therapy in stage I lung cancer with comparable local control rates to surgical resection. Owing to the conformity of treatment dose delivery and with appropriate fractionation considerations, minimal side-effects to surrounding normal tissues are observed in most patients. SBRT is now being used in the treatment of oligometastatic disease, alone or alongside systemic therapy. At present there is a paucity of evidence available showing a clinical benefit, but several international studies are being set-up or have started recruitment. This overview considers the clinical entity of an oligometastatic state, discusses the role of SBRT in the management of oligometastatic disease and discusses potential novel therapy combinations with SBRT. Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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Stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS) have been demonstrated to be highly effective for a variety of tumors. However, the radiobiological principles of SBRT and SRS have not yet been clearly defined. It is well known that newly formed tumor blood vessels are fragile and extremely sensitive to ionizing radiation. Various lines of evidence indicate that irradiation of tumors with high dose per fraction, i.e. >10 Gy per fraction, not only kills tumor cells but also causes significant damage in tumor vasculatures. Such vascular damage and ensuing deterioration of the intratumor environment then cause ischemic or indirect/secondary tumor cell death within a few days after radiation exposure, indicating that vascular damage plays an important role in the response of tumors to SBRT and SRS. Indications are that the extensive tumor cell death due to the direct effect of radiation on tumor cells and the secondary effect through vascular damage may lead to massive release of tumor-associated antigens and various pro-inflammatory cytokines, thereby triggering an anti-tumor immune response. However, the precise role of immune assault on tumor cells in SBRT and SRS has not yet been clearly defined. The "4 Rs" for conventional fractionated radiotherapy do not include indirect cell death and thus 4 Rs cannot account for the effective tumor control by SBRT and SRS. The linear-quadratic model is for cell death caused by DNA breaks and thus the usefulness of this model for ablative high-dose SBRT and SRS is limited.
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Purpose: Although palliative chemotherapy is the standard of care for patients with diagnoses of stage IV non-small cell lung cancer (NSCLC), patients with a small metastatic burden, "oligometastatic" disease, may benefit from more aggressive local therapy. Methods and materials: We identified 186 patients (26% of stage IV patients) prospectively enrolled in our institutional database from 2002 to 2012 with oligometastatic disease, which we defined as 5 or fewer distant metastatic lesions at diagnosis. Univariate and multivariable Cox proportional hazards models were used to identify patient and disease factors associated with improved survival. Using propensity score methods, we investigated the effect of definitive local therapy to the primary tumor on overall survival. Results: Median age at diagnosis was 61 years of age; 51% of patients were female; 12% had squamous histology; and 33% had N0-1 disease. On multivariable analysis, Eastern Cooperate Oncology Group performance status ≥ 2 (hazard ratio [HR], 2.43), nodal status, N2-3 (HR, 2.16), squamous pathology, and metastases to multiple organs (HR, 2.11) were associated with a greater hazard of death (all P<.01). The number of metastatic lesions and radiologic size of the primary tumor were not significantly associated with overall survival. Definitive local therapy to the primary tumor was associated with prolonged survival (HR, 0.65, P=.043). Conclusions: Definitive local therapy to the primary tumor appears to be associated with improved survival in patients with oligometastatic NSCLC. Select patient and tumor characteristics, including good performance status, nonsquamous histology, and limited nodal disease, may predict for improved survival in these patients.
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Background: Stage IV non-small-cell lung cancer (NSCLC) patients with oligometastases (< 5 metastatic lesions) may experience long-term survival when all macroscopic tumor sites are treated radically, but no prospective data on NSCLCs with synchronous oligometastases are available. Methods: A prospective single-arm phase II trial was conducted. The main inclusion criteria were pathologically proven NSCLC stage IV with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). The study is listed in clinicaltrials.gov, number NCT01282450. Results: Forty patients were enrolled, 39 of whom were evaluable (18 men, 21 women); mean age was 62.1 ± 9.2 years (range, 44-81). Twenty-nine (74%) had local stage III; 17 (44%) brain, seven (18%) bone, and four (10%) adrenal gland metastases. Thirty-five (87%) had a single metastatic lesion. Thirty-seven (95%) of the patients received chemotherapy as part of their primary treatment. Median overall survival (OS) was 13.5 months (95% confidence interval 7.6-19.4); 1-, 2-, and 3-year OS was 56.4%, 23.3%, and 17.5%, respectively. Median progression-free survival (PFS) was 12.1 months (95% confidence interval 9.6-14.3); 1-year PFS was 51.3%, and both 2- and 3-year PFS was 13.6%. Only two patients (5%) had a local recurrence. No patient or tumor parameter, including volume and F-deoxyglucose uptake was significantly correlated with OS or PFS. The treatment was well tolerated. Conclusion: In this phase II study, long-term PFS was found in a subgroup of NSCLC patients with synchronous oligometastases when treated radically. Identification of this favorable subgroup before therapy is needed.
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The FLEX study demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). In the FLEX intention to treat (ITT) population, we investigated the prognostic significance of particular baseline characteristics. Individual patient data from the treatment arms of the ITT population of the FLEX study were combined. Univariable and multivariable Cox regression models were used to investigate variables with potential prognostic value. The ITT population comprised 1125 patients. In the univariable analysis, longer median survival times were apparent for females compared with males (12.7 vs 9.3 months); patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 compared with 1 compared with 2 (13.5 vs 10.6 vs 5.9 months); never smokers compared with former smokers compared with current smokers (14.6 vs 11.1 vs 9.0); Asians compared with Caucasians (19.5 vs 9.6 months); patients with adenocarcinoma compared with squamous cell carcinoma (12.4 vs 9.3 months) and those with metastases to one site compared with two sites compared with three or more sites (12.4 months vs 9.8 months vs 6.4 months). Age (<65 vs ≥65 years), tumor stage (IIIB with pleural effusion vs IV) and percentage of tumor cells expressing EGFR (<40% vs ≥40%) were not identified as possible prognostic factors in relation to survival time. In multivariable analysis, a stepwise selection procedure identified age (<65 vs ≥65 years), gender, ECOG PS, smoking status, region, tumor histology, and number of organs involved as independent factors of prognostic value. In summary, in patients with advanced NSCLC enrolled in the FLEX study, and consistent with previous analyses, particular patient and disease characteristics at baseline were shown to be independent factors of prognostic value. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798.