A Randomized Phase III Trial of Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of 4-10 Oligometastatic Tumors (SABR-COMET 10)

The oligometastatic state refers to a stage of disease where a cancer has
spread beyond the site of the primary tumor, but is not yet widely metastatic.1
In patients with a limited oligometastatic burden, emerging evidence suggests
that treatment of all sites of disease with ablative therapies (such as surgery
or stereotactic radiation) can improve patient outcomes, including overall- and
progression-free survival.

Historically, evidence to support the oligometastatic state has consisted of
single-arm, non-randomized studies without controls. One classic study reported
on over 5000 patients with lung metastases from a variety of primary tumors. In
patients who achieved a complete resection of their lung metastases, 5-year
overall survival (OS) was 36%, better than might be expected for a cohort of
patients with metastatic disease.2 Similarly, after radiation, a recent pooled
analysis of 361 patients with oligometastatic lesions treated with radiation
demonstrated a 3-year OS of 56%.3

It has been suggested the long-term survivals achieved in patients with
oligometastases after ablative therapies is merely due to the selection of very
fit patients with slow growing tumors, since randomized evidence to support the
oligometastatic paradigm has been lacking.4,5 However, at least four recent
randomized phase II trials now provide some supporting evidence of an
oligometastatic state.

1.1 Randomized Evidence Supporting the Oligometastatic State

Two of these four randomized trials were done in the setting of oligometastatic
non-small cell lung cancer (NSCLC). In both, patients presented with a primary
lung tumor and a limited number of metastatic lesions (1-3 in one trial, 1-5 in
the other), and after initial systemic therapy, patients were randomly assigned
to standard palliative treatments vs. consolidative ablative treatments to all
sites of disease. Both trials were stopped early due to evidence of efficacy,
with the ablative treatments achieving a ~3-fold improvement in
progression-free survival (PFS).6,7 Based on these results, the phase III NRG
LU-002 trial is assessing the impact of consolidative ablative therapies on
OS.

A third trial, EORTC 40004, examined the impact of an ablative therapy
(radiofrequency ablation [RFA]) in patients with colorectal cancer metastatic
to the liver. In this trial, patients with a controlled primary tumor and fewer
than 10 hepatic metastases not amenable to resection, and with no extra-hepatic
disease, were randomized to systemic therapy +/- RFA to all sites of disease.8
When initially reported,9 the trial showed no difference in OS between arms,
but with long-term follow-up (median 9.7 years), a significant difference in OS
emerged, with an 8-year OS of 36% in the RFA arm and only 9% in the systemic
therapy arm.8

The fourth trial, Stereotactic Ablative Radiotherapy for the Comprehensive
Treatment of Oligometastatic Disease (SABR-COMET) enrolled 99 patients who had
controlled primary solid tumors and up to 5 metastatic lesions. Patients were
randomized in a 1:2 ratio between standard of care (SOC) palliative treatments
(Arm 1) vs. SOC + SABR to all sites of disease (Arm 2). The primary endpoint
was OS, and the trial employed a randomized phase II screening design, with an
alpha of 0.20, in order to provide an initial comparison between arms. More
than 90% of patients enrolled had 1-3 metastases. OS was 28 months in Arm 1 and
41 months in Arm 2 (p=0.09), meeting the primary endpoint of the trial. PFS was
doubled: 6 months in Arm 1 and 12 months in Arm 2 (p=0.001). SABR was generally
well tolerated, with a 29% rate of grade 2 or higher toxicity, although the
rate of treatment-related grade 5 toxicity was 4.5%.

Despite this new evidence, many uncertainties remain regarding the
oligometastatic state.

1.2 Defining the Oligometastatic State

A major unanswered clinical question is the precise definition of the
oligometastatic state, namely, how many metastatic lesions are amenable to
ablative therapies that may benefit the patient.

Many studies have defined *oligometastatic* as 1-3, or 1-5, metastatic lesions,
although some have used broader definitions, including the EORTC 40004 trial
described above that allowed up to 9. For example, one single-arm phase II
trial in patients with NSCLC enrolled 24 patients with up to 6 active sites of
extracranial disease, and treated patients with SABR to all active sites along
with erlotinib. The treatment was well-tolerated, with only two grade 3
toxicities. Median OS was 20.4 months, and median PFS was 14.7 months. A second
study included NSCLC patients with up to 8 lesions, as long as all could be
treated within established dose constraints.10

In the setting of brain metastases, recent non-randomized evidence suggests
that patients may benefit from stereotactic radiotherapy to 4-10 metastatic
lesions. The prospective JLGK0901 trial treated 1194 patients who had 1-10
metastatic lesions, with a total cumulative volume of <=15 mL, and treated all
with stereotactic radiosurgery. The study used a non-inferiority design with a
primary endpoint was OS, comparing patients with 5-10 lesions vs. those with
2-4. Median OS in both groups was 10.8 months, meeting the primary endpoint of
non-inferiority (p<0.0001). Treatment was well-tolerated, with only 9% of
patients in either group experiencing adverse events of any grade. A separate
retrospective study examined stereotactic radiation in patients with more than
10 brain metastases (where 64% had received prior brain radiotherapy), and
concluded that it could be delivered safely, with no episodes of symptomatic
necrosis and a 13% rate of radiographic necrosis.11

The toxicity of SABR may not depend on the overall number of lesions, but
moreso the doses delivered to organs at risk. For serial organs, such as the
spinal cord, bronchi, and great vessels, reduction of the maximum dose of
radiation is expected to reduce the risk of toxicity. For parallel organs, such
as the lung, liver and renal cortex, the risk of toxicity may be mitigated by
ensuring that a critical volume of the organ is spared from substantial doses
of radiation.12 The typical critical volume to be spared is about 1/3 of the
volume of the organ. Therefore, this trial will employ dose constraints for
serial structures that ensure minimization of high-dose volumes, constraints
for parallel structures that ensure critical volume sparing, and constraints
for dose spillage, to ensure that all SABR plans are highly conformal.

The application of ablative therapies for patients with 4-10 metastatic
deposits appears promising, based on the encouraging results from randomized
trials mostly enrolling patients with 1-3 lesions and the single-arm studies
evaluating ablative therapies patients with a larger burden of disease.
However, it is likely that as the number of metastases increases, the risk of
further distant failure (i.e. development of additional metastases after SABR)
will increase, and the risk of toxicity from SABR will likely increase. As a
result, the use of SABR in such patients might be best in a scenario where the
doses of SABR are lowered to reduce the risk of toxicity, pre-planning of SABR
is required before enrollment, and SABR is given immediately prior to systemic
therapy that will help to address the risk of occult micrometastases.

To assess the impact of SABR, compared to standard of care treatment, on
overall survival, oncologic outcomes, and quality of life in patients with a
controlled primary tumor and 4-10 metastatic lesions.

This study is a phase III multicentre randomized trial. Patients will be
randomized in a 1:2 ratio between current standard of care treatment (Arm 1)
vs. standard of care treatment + SABR (Arm 2) to sites of known disease.

Patients will be stratified by two of the strongest prognostic factors, based
on a large multi-institutional analysis3: histology (Group 1: prostate, breast,
or renal; Group 2: all others), and type of pre-specified systemic therapy
(Group 1: immunotherapy/targeted/hormones; Group 2: cytotoxic; Group 3:
observation)

Standard Arm (Arm 1)

Radiotherapy for patients in the standard arm should follow the principles of
palliative radiotherapy as per the individual institution, with the goal of
alleviating symptoms or preventing imminent complications. Recommended dose
fractionations in this arm will include 8 Gy in 1 fractions, 20 Gy in 5
fractions, and 30 Gy in 10 fractions. Patients in this arm should not receive
stereotactic doses or radiotherapy boosts, unless there is a clearly known
clinical benefit (e.g. stereotactic radiation to a new brain metastases when
all disease is controlled on systemic therapy).

Systemic therapy will be pre-specified based on the standard of care approach
for that patient, and it may include systemic therapy (cytotoxic, targeted,
hormonal, or immunotherapy) or observation. See section 6.3 for the timing of
systemic therapy.

Experimental Arm (Arm 2)

Stereotactic radiation in Arm 2 will be delivered with three major guiding
principles:

• Minimization of Toxicity: The SABR doses used herein are lower than those
used for radical treatments, and normal tissue tolerance doses will never be
exceeded. Concurrent chemotherapy or targeted therapy at the time of
radiotherapy is not permitted

• Minimization of Treatment Time. To avoid delays in proceeding to systemic
therapy, all SABR will be delivered over the course of two weeks.

• Pre-planning required before enrollment: To ensure safety, all patients
require a pre-plan of their SABR treatments before enrollment. If a patient
undergoes pre-planning but cannot be randomized due to failure to generate an
acceptable plan, the centre will receive modest compensation to cover
pre-planning costs. The baseline information of such patients will be captured
(i.e. the Eligibility Checklist and Baseline Form), but they will not be
followed for outcomes.

Quality Assurance (Arm 2)

In order to ensure patient safety and effective treatment delivery, a robust
quality assurance protocol is incorporated. The following requirements must be
completed for each patient:

• Prior to treatment, plans for each patient must be peer-reviewed, either by
discussion at quality assurance (QA) rounds or by another individual radiation
oncologist.

• All radiotherapy plans must meet target dose levels for organs at risk
(Appendix 1). Prior to plan approval, the dose to each organ at risk must be
verified by the physicist or treating physician.

• All dose delivery for intensity-modulated plans (including arc-based
treatments) will be confirmed before treatment by physics staff.