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Stereotactic Ablative Radiotherapy for Comprehensive Treatment of Oligometastatic (1-3 Metastases) Cancer (SABR-COMET-3)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03862911
Recruitment Status : Not yet recruiting
First Posted : March 5, 2019
Last Update Posted : March 5, 2019
Sponsor:
Collaborators:
London Regional Cancer Program, Canada
Beatson Institute for Cancer Research, Scotland
The Alfred
Beacon Hospital, Ireland
Information provided by (Responsible Party):
Robert Olson, British Columbia Cancer Agency

Brief Summary:
Stereotactic Ablative Radiotherapy (SABR) is a modern RT technique that delivers high doses of radiation to small tumor targets using highly conformal techniques. SABR is non-invasive and delivered on an outpatient basis. The purpose of this study is to compare the effect of SABR, relative to standard of care (SOC) alone, on overall survival, progression-free survival, toxicity, and quality of life. An integrated economic evaluation will determine the cost per quality of life year gained using SABR (vs. SOC) and a translational component will enable identification of predictive/prognostic biomarkers of the oligometastatic state.

Condition or disease Intervention/treatment Phase
Metastatic Tumors Radiation: palliative radiotherapy Radiation: Stereotactic ablative radiotherapy Not Applicable

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Detailed Description:

TREATMENT PLAN

6.1 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. Patients in this arm should not receive stereotactic doses or radiotherapy boosts. Recommended dose fractionations in this arm will include 8 Gy in 1 fractions, 20 Gy in 5 fractions, and 30 Gy in 10 fractions.

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.

6.2 Experimental Arm (Arm 2)

6.2.1 Dose/Fractionation

Treatment recommendations are as follows:

Lung: Tumors 5 cm or less surrounded by lung parenchyma: 48 Gy in 4 fractions (12 Gy/#), 54 Gy in 3 fractions (18 Gy/#), every second day

Lung: Within 2 cm of mediastinum or brachial plexus 60 Gy in 8 fractions (7.5 Gy/#) daily

Bone: Any bone 35 Gy in 5 fractions (7 Gy/#), 24 Gy in 2 fractions (12 Gy/#), daily

Brain: Stereotactic lesions (no whole brain RT):

<2cm 24 Gy in 1 fraction (24 Gy/#) Once

2-3 cm 18 Gy in 1 fraction (18 Gy/#) Once

3-4cm 15 Gy in 1 fraction (15 Gy/#) Once

If whole brain treated, then simultaneous boost to each lesion:

35 Gy in 5 fractions (7 Gy to PTV) to metastases, daily

20 Gy in 5 fractions (4 Gy WBRT) to whole brain (optional), daily

Liver: 54 Gy in 3 fractions (18 Gy/#), every second day

Adrenal: 60 Gy in 8 fractions (7.5 Gy/#), daily

Lymph Node: 40 Gy in 5 fractions (8 Gy/#), daily

6.2.2 Immobilization Treatment will be setup using reproducible positioning and verified using an on-line protocol for all patients in this study. Immobilization may include a custom immobilization device, such as thermoplastic shell or vacuum bag, as per individual institutional practice when delivering SABR. Some centers do not use immobilization devices and have demonstrated high degrees of accuracy; this is acceptable in this study.

6.2.3 Imaging/Localization/Registration All patients in Arm 2 will undergo planning CT simulation. 4-dimensional CT will be used for tumors in the lungs, liver, or adrenals. Axial CT images will be obtained throughout the region of interest. For centres using stereotactic radiosurgery platforms, real-time tumor tracking and orthogonal imaging systems are permitted.

6.2.4 4D-CT Procedures

For patients undergoing 4D-CT, physics will review the 4D-CT images and will perform the following quality assurance procedures indicated on the 4D-CT template designed specifically for SABR:

i) Ensure all end inspiration (0%) tags exist and are in the right place. This ensures image integrity.

ii) If the quality of the 4D-CT images is not sufficient (determined by Physics), then standard 3D-CT will be performed on the fast helical CT or Untagged Average CT.

iii) Motion measurements in all 3 directions are performed:

  1. If the motion is less than or equal to 7 mm and the good quality images exist, then treatment planning may be performed on the Untagged Average CT with the 50% or 60% phase (End Expiration) and the 0% phase being fused to it. This will define the IGTV.
  2. If the motion is greater than 7 mm in any one direction, then respiratory-gated radiotherapy can be considered. In this case, treatment planning will be performed on a subset average CT dataset (usually labeled either 30%-60% Avg CT or 40%-70% Avg CT) generated by Physics. This is an average CT over the intended gated interval. Therefore, the GTV that is delineated on this scan will incorporate residual motion in the intended gated interval. The 0% phase will also be fused to this dataset. The PTV for planning will include the GTV delineated on the subset average CT plus margins for microscopic extension (Physician's discretion) and setup uncertainty. The GTV_0% should also be delineated and combined with the GTV delineated on the subset average CT to define an additional volume labeled IGTV_CBCT. This contour may be used for image registration with CBCT only.

6.2.5 Volume Definitions (Arm 2) For all lesions, the gross tumor volume (GTV) will be defined as the visible tumor on CT and/or MRI imaging +/- PET. No additional margin will be added for microscopic spread of disease (i.e. Clinical Target Volume [CTV]=GTV). For bone lesions, CTV of 3-5mm will be allowed. For vertebral lesions, anatomic approach will be taken as per International Spinal consortium guideline (Cox 2012)

An anatomic approach is taken to the CTV based on where the disease within the spinal segment is located. The rules for CTV are as follows:

  1. If the vertebral body is involved with GTV then the entire vertebral body is taken as CTV.
  2. If the ipsilateral pedicle and/or transverse process has GTV then the entire ipsilateral posterior segment (pedicle, lamina and transverse process) ±the spinous process is taken into the CTV. The inclusion of the spinous process is per the discretion of the radiation oncologist.
  3. If the ipsilateral pedicle, lamina, and/or transverse process has GTV, then the entire ipsilateral posterior segment (pedicle, lamina, and transverse process) plus the spinous process is taken into the CTV
  4. If bilateral involvement of the pedicle and/or transverse process with GTV, then the posterior segment anatomy ± the spinous process is taken into the CTV. The inclusion of the spinous process is per the discretion of the radiation oncologist.
  5. If bilateral involvement of the pedicles and lamina, and/or transverse process with GTV, then the entire posterior segment anatomy is taken into the CTV, including the spinous process.
  6. If the spinous process is involved with GTV alone then the bilateral lamina ± pedicles are to be taken into the CTV.

The International Spinal Consortium Guideline is a reference for CTV delineation (Cox 2012) and can be adhered to as described.

In the case of epidural disease, a 5 mm anatomic margin (excluding the spinal cord) beyond the GTV may be used within the epidural compartment including in the cranio-caudal direction. A circumferential CTV as per a donut based CTV is allowed and encouraged in the case of epidural disease at the discretion of the treating radiation oncologist. If paraspinal disease present, a minimum 5 mm CTV margin may be applied beyond the GTV.

A Planning Target Volume (PTV) margin of 2-5 mm will be added depending on site of disease, immobilization, and institutional set-up accuracy: 2-3 mm margins should be used for spinal stereotactic treatments, 0-2 mm for brain tumors, and 5 mm for other sites.

Targets should be named based on the organ involved, and numbered from cranially to caudally. For example, in a patient with 3 lung lesions, there would be: GTV_lung_1, GTV_lung_2, and GTV_lung_3, and corresponding PTV_lung_1, PTV_lung_2_, and PTV_lung_3, representing the lesions from superior to inferior.

For spinal lesions, a pre-treatment MRI is required to assess the extent of disease and position of the cord. This must be fused with the planning CT scan. A Planning Organ at Risk Volume (PRV) expansion of 2 mm will be added to the spinal cord, and dose constraints for the spinal cord apply to this PRV. Alternatively, the thecal sac may be used as the PRV. For radiosurgery platforms, a PRV margin of 1 mm is permitted for the spinal cord.

6.2.6. Organ At Risk (OAR) Doses OAR doses are listed in Appendix 1 of protocol. OAR doses may not be exceeded except in the case of chestwall / ribs. In cases where the PTV coverage cannot be achieved without exceeding OAR doses, the PTV coverage is to be compromised. All serial organised OARs within 5 cm of the PTV must be contoured (partial organ contours allowed); for parallel organised organs (liver, lung, etc.) within 5cm of PTV, the whole organs need to be contoured. This should be tested for each PTV by creating a 5 cm expansion to examine which OARs lie within that expansion.

6.2.7 Treatment Planning Treatment can be delivered using static beams (either 3D-conformal radiotherapy or intensity-modulated) or rotational therapy (volumetric modulated arc therapy, or tomotherapy).

Dose constraints may not be exceeded (except chestwall/ribs). If a dose constraint cannot be achieved due to overlap of the target with an organ at risk, the fractionation can be increased or the target coverage compromised in order to meet the constraint. In cases where the target coverage or dose must be reduced, the priority for dose coverage is the GTV (e.g. attempt to cover as much of the GTV as possible with the prescription dose). All such cases of dose reduction or target coverage compromise must be approved by the local PI prior to treatment. For vertebral tumors, note that the spinal cord constraints apply to the PRV (see section 6.2.5).

For all targets, doses should be prescribed to 60-90% isodose line surrounding the PTV, and all hotspots should fall within the GTV. 95% of the PTV should be covered by the prescription dose, and 99% of the PTV should be covered by 90% of the prescription dose.

Doses must be corrected for tissue inhomogeneities. Several non-overlapping 6/10 MV beams (on the order of 7-11 beams) or 1-2 VMAT arcs combined possibly with a few non-coplanar beams should be utilized. Non-coplanar beams can be used to reduce 50% isodose volume.

The number of isocentres is at the discretion of the treating physician, physicists, and dosimetrists. Generally, metastases can be treated with separate isocenters if they are well-separated.

The scheduling and sequence of treating each metastasis is at the discretion of individual physicians, but in general should begin with the brain, due to risks associated with progression. All SABR must be completed within 2 weeks.

6.2.8 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, each patient must be discussed at quality assurance (QA) rounds or be peer reviewed by a radiation oncologist with SABR expertise.
  • All radiotherapy plans must meet target dose levels for organs at risk (except chestwall/ribs) (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.

6.3 Systemic Therapy Patients treated with prior systemic therapy are eligible for this study, however, no chemotherapy agents (cytotoxic, or molecularly targeted agents) are allowed within the period of time commencing 2 weeks prior to radiation lasting until 1 week after the last fraction. Hormonal therapy is allowed. Use of chemotherapy schemes containing potent enhancers of radiation damage (e.g. gemcitabine, adriamycin) are discouraged within the first month after radiation.

6.4 Further radiotherapy for progressive disease at new metastatic sites Patients in Arm 1 who develop new, untreated metastatic deposits should be treated with standard-of-care approaches. SABR to those sites is not permitted, except for unique scenarios where it would be considered standard of care (e.g. all disease controlled on systemic therapy with a newly developed brain metastasis). Apart from brain metastases, treatment of 'oligo-progression' with SABR is not permitted.

Patients in Arm 2 who develop new, untreated metastatic deposits should be considered for SABR at those sites, if such deposits can be treated safely with SABR, and if the treating institution offers SABR for that body site. If SABR is not possible, then palliative RT can be delivered if indicated.

6.5 Quality Assurance for Centres Joining Study Prior to opening the study, each participating research centre will be required to send to one of the Principal Investigators a mock treatment plan for the anatomic sites that will be treated (e.g. Lung, brain, liver, adrenal), to ensure that the treatment plans are designed in compliance with the protocol. The principal investigators will provide pertinent CT datasets. Each participating research centre can choose which tumor sites will be treated at their individual centre (i.e. some centres may only choose to treat a subset of the eligible metastatic sites). Sites that have prior accreditation for SABR through a clinical trial (e.g. SABR-COMET, or organ-specific SABR trials) are exempt from this requirement for the organ sites that have been accredited in those trials.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 201 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

This study is a phase III multicentre randomized trial. Subjects 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.

Subjects will be stratified by two of the strongest prognostic factors, based on a large multi-institutional analysis: histology (Group 1: prostate, breast, or renal; Group 2: all others), and disease-free interval (defined as time from diagnosis of primary tumor until first detection of the metastases being treated on this trial; divided as ≤2 years vs >2 years).

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase III Randomized Controlled Trial and Economic Evaluation of Stereotactic Ablative Radiotherapy for Comprehensive Treatment of Oligometastatic (1-3 Metastases) Cancer (SABR-COMET-3)
Estimated Study Start Date : April 2019
Estimated Primary Completion Date : December 2026
Estimated Study Completion Date : December 2026

Arm Intervention/treatment
Active Comparator: Standard of Care Treatment (Arm 1)
Standard of care, palliative radiotherapy, and chemotherapy at the discretion of the treating medical oncologist
Radiation: palliative radiotherapy
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. Patients in this arm should not receive stereotactic doses or radiotherapy boosts. Recommended dose fractionations in this arm will include 8 Gy in 1 fractions, 20 Gy in 5 fractions, and 30 Gy in 10 fractions.

Experimental: Stereotactic Arm (Arm 2)
Stereotactic ablative radiotherapy, and chemotherapy at the discretion of the treating medical oncologist
Radiation: Stereotactic ablative radiotherapy

Lung:

Tumors 5 cm or less surrounded by lung parenchyma 48 Gy/4# 12, or 54 Gy/3# 18, every second day Within 2 cm of mediastinum or brachial plexus 60 Gy/8# 7.5, daily Bone: Any bone 35 Gy/5# 7, or 24 Gy/2# 12, daily Brain: Stereotactic lesions (no whole brain RT) <2cm 24 Gy/1# 24, once 2-3 cm 18 Gy/1# 18, once 3-4cm 15 Gy/1# 15, once

If whole brain treated, then simultaneous boost to each lesion:

35Gy/5# to metastases 7 Gy to PTV, daily 20 Gy/5# whole brain (optional) 4 Gy WBRT, daily Liver: 54 Gy/3# 18, every second day Adrenal: 60 Gy/8# 7.5, daily Lymph Node: 40 Gy/5# 8, daily





Primary Outcome Measures :
  1. Overall survival [ Time Frame: At approximately end of year 5 (study completion) ]
    Time from randomization to death from any cause


Secondary Outcome Measures :
  1. Side effects [ Time Frame: At approximately end of years 1, 2, 3, 4, and 5 (study completion) ]
    Occurrences of grade 2 or higher adverse events

  2. Progression-free survival (PFS) [ Time Frame: At approximately end of years 1, 2, 3, 4, and 5 (study completion) ]
    Time from randomization to disease progression at any site or death.

  3. Patient-reported quality of life (QoL) [ Time Frame: At approximately end of years 1, 2, 3, 4, and 5 (study completion) ]
    Functional Assessment of Cancer Therapy- General (FACT-G) questionnaire

  4. Health-related quality of life (HRQoL) questionnaire [ Time Frame: At approximately end of years 1, 2, 3, 4, and 5 (study completion) ]
    EuroQOL Group EQ-5D-5L

  5. Correlation between candidate biomarkers of oligometastatic disease (blood- or tissue-derived) and oncologic outcomes [ Time Frame: At approximately end of years 1, 2, 3, 4, and 5 (study completion) ]
    CTC and ctDNA Enumeration



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 18 or older
  • Willing to provide informed consent
  • ECOG score 0-2
  • Life expectancy >6 months
  • Histologically confirmed malignancy with metastatic disease detected on imaging. Biopsy of metastasis is preferred, but not required.
  • Controlled primary tumor (defined as: at least 3 months since original tumor treated definitively, with no progression at primary site)
  • Total number of metastases of 1-3

Exclusion Criteria:

  • Serious medical comorbidities precluding radiotherapy. These include interstitial lung disease in patients requiring thoracic radiation, Crohn's disease in patients where the GI tract will receive radiotherapy, and connective tissue disorders such as lupus or scleroderma.
  • Substantial overlap with a previously treated radiation volume. Prior radiotherapy in general is allowed, as long as the composite plan meets dose constraints herein. For patients treated with conventional radiation previously, biological effective dose calculations should be used to equate previous doses to the tolerance doses listed below. All such cases should be discussed with one of the study PIs.
  • Malignant pleural effusion
  • Inability to treat all sites of disease
  • Maximum size of 6 cm for lesions outside the brain, except:

    • Bone metastases over 5 cm may be included, if in the opinion of the local PI it can be treated safely (e.g. rib, scapula, pelvis)
    • Any brain metastasis >3 cm in size or a total volume of brain metastases greater than 30 cc.
  • Clinical or radiologic evidence of spinal cord compression, or epidural tumor within <2 mm of the spinal cord. Patients can be eligible if surgical resection has been performed, but the surgical site counts toward the total of up to 3 metastases.
  • Dominant brain metastasis requiring surgical decompression
  • Pregnant or breast feeding women

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03862911


Contacts
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Contact: Robert Olson, MD, MSc 250-645-7300 rolson2@bccancer.bc.ca
Contact: Lindsay Mathews 250-960-6511 mathews@unbc.ca

Locations
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Canada, British Columbia
BC Cancer Not yet recruiting
Surrey, British Columbia, Canada
Contact: Devin Schellenberg, MD    604-930-4085    dschellenberg@bccancer.bc.ca   
BC Cancer Not yet recruiting
Vancouver, British Columbia, Canada
Contact: Mitchell Liu, MD    250-645-7300    mliu@bccancer.bc.ca   
BC Cancer Not yet recruiting
Victoria, British Columbia, Canada
Contact: Tanya Berrang, MD    250-519-5577    TBerrang@bccancer.bc.ca   
Canada, Ontario
London Health Sciences Centre Not yet recruiting
London, Ontario, Canada
Contact: David Palma, MD, PhD    519-685-8600      
United Kingdom
Beatson West of Scotland Cancer Centre Not yet recruiting
Glasgow, United Kingdom
Contact: Stephen Harrow, MD, PhD         
Contact    +44-141-301-7000      
Sponsors and Collaborators
British Columbia Cancer Agency
London Regional Cancer Program, Canada
Beatson Institute for Cancer Research, Scotland
The Alfred
Beacon Hospital, Ireland

Publications:

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Responsible Party: Robert Olson, Radiation Oncologist & Department Head Radiation Oncology & Developmental Radiotherapeutics, British Columbia Cancer Agency
ClinicalTrials.gov Identifier: NCT03862911     History of Changes
Other Study ID Numbers: COMET-3
First Posted: March 5, 2019    Key Record Dates
Last Update Posted: March 5, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Neoplasm Metastasis
Neoplastic Processes
Neoplasms
Pathologic Processes