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

Breast Cancer Clinical Trial

— CORE  

Official title:

A Randomised Trial of Conventional Care Versus Radioablation (Stereotactic Body Radiotherapy) for Extracranial Oligometastases

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02759783
• Other study ID #: CCR4323
• Secondary ID: 182152ISRCTN4596
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: November 2016
• Est. completion date: October 2024

Study information

• Verified date: August 2019
• Source: Royal Marsden NHS Foundation Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 245
• Est. completion date: October 2024
• Est. primary completion date: October 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

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

Intervention

Radiation:
• 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.

Other:
• 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

Locations

Country	Name	City	State
Australia	GenesisCare - Adelaide Radiotherapy Centre	Adelaide	South Australia
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Princess Alexandra Hospital	Brisbane	Queensland
Australia	Royal Brisbane and Women's Hospital	Brisbane	Queensland
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	Austin Health	Melbourne	Victoria
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	Sir Charles Gairdner Hospital	Nedlands	Western Australia
Australia	Calvary Mater Newcastle	Waratah	New South Wales
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	Guy's Hospital	London
United Kingdom	Mount Vernon Cancer Centre	London	Surrey
United Kingdom	Royal Marsden Hospital	London
United Kingdom	St Bartholomew's Hospital	London
United Kingdom	University College Hospital	London
United Kingdom	The Christie Hospital	Manchester
United Kingdom	James Cook University Hospital	Middlesborough
United Kingdom	Freeman Hospital	Newcastle upon Tyne
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	Churchill Hospital	Oxford	Oxfordshire
United Kingdom	Weston Park Hospital	Sheffield
United Kingdom	Royal Marsden Hospital	Sutton
United Kingdom	Clatterbridge Cancer Centre	Wirral

Sponsors (3)

Lead Sponsor	Collaborator
Royal Marsden NHS Foundation Trust	Institute of Cancer Research, United Kingdom, National Health Service, United Kingdom

Countries where clinical trial is conducted

Australia,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Freedom from widespread metastatic disease (FFWMD)	FFWMD will be measured from the time of randomisation until radiological evidence of disease progression, which is not suitable for radical salvage therapy.	Pre-treatment and at 3,6,9,12,15,18,21,24,30,36,42,48,54 and 60 months post treatment
Primary	Progression Free Survival	Time from randomisation to evidence of progression of cancer at any site or death from any cause	60 months post treatment
Secondary	Feasibility of recruitment	Recruitment rate and proportion of patients receiving SBRT (if allocated) in the absence of new developing widespread disease	3 years from first patient
Secondary	Feasibility of SBRT delivery	Recruitment of patients receiving SBRT within the dosimetric constraints	3 years from first patient
Secondary	Overall Survival	Time from randomisation until time of death from any cause	60 months post treatment
Secondary	Local lesion control	Time from randomisation until radiological evidence of progression at the treated site and be measured on a lesion based on analysis using RECIST criteria.	60 months post treatment
Secondary	Clinical reported acute and late toxicity	Clinician reported acute and late toxicity will be graded using NCI CTCAE v4.0 / RTOG systems. Acute events are defined as those occurring up to 3 months follow-up; late events are reported from 6 months post randomisation.	60 months post treatment
Secondary	Patient reported Quality of Life	Patient reported quality of life will be measured using EORTC QLQ C30	Pre-treatment and at 3,6,12,18 and 24 months post treatment