Conventional Care Versus Radioablation (Stereotactic Body Radiotherapy) for Extracranial Oligometastases

NCT ID: NCT02759783

Last Updated: 2019-08-21

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 245 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-11-30
• Study Completion Date: 2024-10-31

Brief Summary

Metastatic spread of cancer from its primary site to distant organs is the commonest cause of death from cancer. The term oligometastases describes an intermediate metastatic state, in which cancer exists as a limited number of metastases at first, before cells acquire the ability to metastasise more widely. For the large majority of solid cancers, once metastatic disease has been diagnosed the chances of cure are small. There are several situations where this is not the case, but it is not known if stereotactic body radiotherapy (SBRT) for oligometastatic disease will alter outcomes or whether the toxicity burden of this treatment is justified. SBRT is targeted radiotherapy which destroys cancer cells in the area of the body it is aimed at however low dose radiation may be received by surrounding tissue.

It is difficult to quantify incidence of patients with multiple primary cancers developing at intervals that are representative of oligometastatic stage IV disease, (defined for the purposes of this trial as ≤ 3 metastatic sites). However an increase in the use of surveillance imaging, together with improved diagnostic sensitivity has led to the diagnosis of patients with asymptomatic oligometastatic relapse becoming a more common clinical occurrence. The CORE study is a randomized controlled trial that will be conducted in patients with cancer in one of three primary sites where oligometastatic disease relapse is a common clinical scenario: breast, prostate and non-small cell lung cancer (NSCLC). The study will evaluate the use of SBRT in this patient population.

Eligible patients who consent to participate in this clinical trial will be randomized to receive standard care or standard care plus SBRT we hope to recruit approximately 206 patients to the study and the primary outcome measure is progression free survival.

Detailed Description

CORE is a phase II/III, multi-centre, non-blinded, parallel group randomised controlled trial in patients with breast, prostate or NSCLC primary cancer comparing standard of care (SOC) with or without SBRT for extra-cranial metastases. The aim of the phase II study is to demonstrate 1) feasibility of recruitment, 2) deliverability of the study in a multi-centre setting and 3) activity of SBRT, based on progression free survival, across the three tumour types. If all three aims are achieved the trial will be amended to roll into parallel tumour-site specific phase III trials.

Eligible patients are those with either primary breast, prostate or NSCLC who have presented with ≤3 extra-cranial, metachronous, oligometastases, all suitable for SBRT. Patients will be randomised in a 1:1 ratio to either SOC or SOC with the addition of SBRT. Choice of SOC treatment is at the discretion of the local oncologist and defined per patient prior to randomisation (see section 8). Patients randomised to SBRT+SOC will receive a dose and fractionation regimen dependent on the metastatic site and proximity to dose limiting organs and normal tissues. Treatment will take place within 6 weeks of randomisation. The average scheme would be 3 treatments over 5 days but the maximum period of SBRT duration could be 8 treatments over 19 days.

All patients will be reviewed every 3 months with a clinical examination and tumour markers (where applicable) during years 1 and 2, and 6 monthly thereafter to 5 years. Staging and follow up imaging protocols will be tumour type dependent:

• Breast: 3 monthly CT scans for years 1 and 2, and 6 monthly thereafter to 5 years.
• NSCLC: 3 monthly CT scans for years 1 and 2, 6 monthly to year 3, then annually to 5 years.
• Prostate: CT scans will be performed at 6, 12 and 24 months with imaging triggered by appropriate PSA rises. A rising PSA defined as 2 successive PSA rises from nadir, measured a minimum of 4 weeks apart. If the overall PSA rise has a doubling time of ≥ 3 months or the PSA level has doubled the original PSA value at trial entry or if clinically indicated, then restaging should be considered.

All patients will have a toxicity assessment at each clinic visit and patient reported quality of life (QOL) assessment at 3, 6, 12, 18 and 24 months.

Conditions

Prostate Cancer; Breast Cancer; Carcinoma, Non-Small-Cell Lung

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Standard of Care

Standard of care (SOC) is at the discretion of the local oncologist.

Group Type: ACTIVE_COMPARATOR

Standard of Care

Intervention Type: OTHER

Choice of standard of care treatment at the discretion of the local oncologist. This may include: Chemotherapy, Endocrine therapy, surgery, palliative radiotherapy

Standard of Care + SBRT

Patients randomised to SBRT will receive a dose and fractionation regimen dependent on the metastatic site and proximity to normal tissues. If allocated to SBRT, SBRT will precede SOC.

Group Type: EXPERIMENTAL

SBRT

Intervention Type: RADIATION

Patients will receive a dose and fractionation regimen dependent on the metastatic site and proximity to normal tissues. If allocated to SBRT, SBRT will precede SOC. All patients should commence SOC therapy within 4 weeks of completing SBRT treatment.

Standard of Care

Intervention Type: OTHER

Choice of standard of care treatment at the discretion of the local oncologist. This may include: Chemotherapy, Endocrine therapy, surgery, palliative radiotherapy

Interventions

SBRT

Patients will receive a dose and fractionation regimen dependent on the metastatic site and proximity to normal tissues. If allocated to SBRT, SBRT will precede SOC. All patients should commence SOC therapy within 4 weeks of completing SBRT treatment.

Intervention Type: RADIATION

Standard of Care

Choice of standard of care treatment at the discretion of the local oncologist. This may include: Chemotherapy, Endocrine therapy, surgery, palliative radiotherapy

Intervention Type: OTHER

Other Intervention Names

Stereotactic body Radiotherapy; SABR

Eligibility Criteria

Inclusion Criteria

1. Age ≥ 18 years

2. WHO performance status 0-2

3. Histological confirmation of primary malignancy (histological confirmation of metastasis is not mandatory but should be performed in any situation where there is diagnostic uncertainty). Patients with breast, NSCLC or prostate primary malignancies are eligible.

4. Predicted life expectancy > 6 months

5. ≤ 3 metastatic lesions (total). A maximum of 2 different organ systems (e.g. liver, lung, bone, nodal) may contain metastases but the total number of lesions must not exceed 3. For example, a patient with 3 liver metastases or 1 liver metastasis and 2 lung metastases would be eligible. A patient with 1 lung metastasis, 1 liver metastasis and an adrenal metastasis is ineligible.

6. All metastases must be visible, imaging defined targets and be suitable for treatment with SBRT in accordance with the dose fractionation options specified in the protocol. (See the associated CORE trial radiotherapy delivery guidelines for detailed SBRT guidance by metastatic site)

7. Patients who have received prior ablative therapy (e.g. surgery, RFA or SBRT) for metastatic disease are eligible, as long as this site is controlled on imaging at the point of trial entry and the total number of metastases over time since diagnosis of metastatic disease does not exceed 3. Patients with 2 or 3 metastases in which ablative therapy (e.g. surgery/RFA) to 1 site is deemed appropriate as part of standard therapy may be entered into the trial following successful delivery of the ablative treatment. Ablative therapy (e.g. surgery, RFA, cryoablation, SBRT) is not permissible as a standard of care option following randomisation for patients as part of the trial.

8. Only patients with metachronous metastatic disease presentation are eligible. Primary site must be controlled.

NSCLC patients with synchronous presentation of a single brain metastasis with the primary lung malignancy are eligible as long as both sites of disease have received radical treatment. Both primary lung site and solitary synchronous brain metastasis must be controlled at trial entry, and the total number of metastases over time including the brain metastasis must not exceed 3.

Permissible disease-free intervals are:

Breast: ≥ 6 months from completion of radical treatment including any adjuvant therapy to diagnosis of metastases. Patients who have relapsed whilst on adjuvant endocrine therapy are eligible.

NSCLC: ≥ 4 months from completion of radical treatment (not including any adjuvant chemotherapy) to diagnosis of metastases.

Prostate: ≥ 6 months from completion of radical treatment including any adjuvant therapy to diagnosis of metastases. Patients who have relapsed whilst on adjuvant endocrine therapy are eligible.

9. Only patients who are systemic therapy naïve in the metastatic setting are eligible. Prior systemic therapy in the adjuvant setting is permitted. Patients who have had a change in endocrine therapy due to the diagnosis of oligometastatic disease can be entered into the CORE trial as long as entry is within 8 weeks of this change in therapy for prostate cancer patients and within 10 weeks of this change in therapy for breast cancer patients.

10. Adequate baseline organ function to allow SBRT to all relevant targets dependent on location of metastatic subsite

11. Negative pregnancy test (for women of childbearing potential)

12. Written informed consent.

Exclusion Criteria

1. Intra-cranial metastases (not meeting above inclusion criterion 8).

2. Malignant pleural effusion

3. Malignant peritoneal disease

4. Any single metastasis >6cm,( >5cm for lung metastases)

5. Prior radiotherapy to a site that precludes safe delivery of SBRT

6. Co-morbidities precluding staging or follow up imaging, or precluding procedures required to facilitate SBRT

7. Loco-regional nodal relapse where surgery is considered the standard of care and is technically feasible. Patients with internal mammary chain or supraclavicular fossa lymph node relapses of breast cancer are eligible if SBRT dose constraints can be met. Patients with axillary nodal relapse from breast cancer are excluded

8. Spinal cord compression, or impingement of the cord or any other situation whereby the clinician feels that urgent radiotherapy to the spine is required (within 24 hours)

9. Any condition or significant clinical co-morbidities that preclude the safe delivery of SBRT (e.g. history of clinically significant diffuse interstitial lung disease if SBRT to lung metastases or lesions adjacent to lungs are considered or clinically significant colitis i.e. ulcerative colitis /Crohn's disease if SBRT to the pelvis or abdomen is considered).

10. Prostate cancer patients who have relapsed on Androgen Deprivation Therapy (ADT) which was started for biochemical relapse without staging investigations to define their relapse status, or who have relapsed on CAB which was started for biochemical relapse.

11. Prostate cancer patients receiving or have previously received abiraterone, enzalutamide or chemotherapy e.g. docetaxel.

12. Previous malignancy within the last 2 years (except basal cell carcinoma or squamous cell carcinoma of the skin), or if previous malignancy is expected to significantly compromise 5 year survival.

13. Patients whose entry to the trial will cause unacceptable clinical delays to their planned management.

14. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Institute of Cancer Research, United Kingdom

OTHER

Sponsor Role: collaborator

National Health Service, United Kingdom

OTHER_GOV

Sponsor Role: collaborator

Royal Marsden NHS Foundation Trust

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Vincent Khoo, MD

Role: PRINCIPAL_INVESTIGATOR

Royal Marsden NHS Foundation Trust

Locations

Liverpool Hospital

Liverpool, New South Wales, Australia

Calvary Mater Newcastle

Waratah, New South Wales, Australia

Princess Alexandra Hospital

Brisbane, Queensland, Australia

Royal Brisbane and Women's Hospital

Brisbane, Queensland, Australia

GenesisCare - Adelaide Radiotherapy Centre

Adelaide, South Australia, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Austin Health

Melbourne, Victoria, Australia

Peter MacCallum Cancer Centre

Melbourne, Victoria, Australia

Sir Charles Gairdner Hospital

Nedlands, Western Australia, Australia

Churchill Hospital

Oxford, Oxfordshire, United Kingdom

Mount Vernon Cancer Centre

London, Surrey, United Kingdom

Belfast City Hospital

Belfast, , United Kingdom

Queen Elizabeth Hospital

Birmingham, , United Kingdom

Bristol Haematology and Oncology Centre

Bristol, , United Kingdom

Addenbrooke's Hospital

Cambridge, , United Kingdom

The Beatson

Glasgow, , United Kingdom

Royal Surrey County Hospital

Guildford, , United Kingdom

St James's University Hospital

Leeds, , United Kingdom

Leicester Royal Infirmary

Leicester, , United Kingdom

Royal Marsden Hospital

London, , United Kingdom

Guy's Hospital

London, , United Kingdom

St Bartholomew's Hospital

London, , United Kingdom

University College Hospital

London, , United Kingdom

The Christie Hospital

Manchester, , United Kingdom

Clatterbridge Cancer Centre

Metropolitan Borough of Wirral, , United Kingdom

James Cook University Hospital

Middlesbrough, , United Kingdom

Freeman Hospital

Newcastle upon Tyne, , United Kingdom

Nottingham City Hospital

Nottingham, , United Kingdom

Weston Park Hospital

Sheffield, , United Kingdom

Royal Marsden Hospital

Sutton, , United Kingdom

Countries

Australia; United Kingdom

Other Identifiers

182152

Identifier Type: OTHER

Identifier Source: secondary_id

ISRCTN45961438

Identifier Type: REGISTRY

Identifier Source: secondary_id

CCR4323

Identifier Type: -

Identifier Source: org_study_id