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

• Feasibility of recruitment [ Time Frame: 3 years from first patient ]
  Recruitment rate and proportion of patients receiving SBRT (if allocated) in the absence of new developing widespread disease
• Feasibility of SBRT delivery [ Time Frame: 3 years from first patient ]
  Recruitment of patients receiving SBRT within the dosimetric constraints
• Overall Survival [ Time Frame: 60 months post treatment ]
  Time from randomisation until time of death from any cause
• Local lesion control [ Time Frame: 60 months post treatment ]
  Time from randomisation until radiological evidence of progression at the treated site and be measured on a lesion based on analysis using RECIST criteria.
• Clinical reported acute and late toxicity [ Time Frame: 60 months post treatment ]
  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.
• Patient reported Quality of Life [ Time Frame: Pre-treatment and at 3,6,12,18 and 24 months post treatment ]
  Patient reported quality of life will be measured using EORTC QLQ C30

• Feasibility of recruitment [ Time Frame: 3 years from first patient ]
  Recruitment rate and proportion of patients receiving SBRT (if allocated) in the absence of new developing widespread disease
• Feasibility of SBRT delivery [ Time Frame: 3 years from first patient ]
  Recruitment of patients receiving SBRT within the dosimetric constraints
• Overall Survival [ Time Frame: 60 months post treatment ]
  Time from randomisation until time of death from any cause
• Local lesion control [ Time Frame: 60 months post treatment ]
  Time from randomisation until radiological evidence of progression at the treated site and be measured on a lesion based on analysis using RECIST criteria.
• Clinical reported acute and late toxicity [ Time Frame: 60 months post treatment ]
  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.
• Patient reported Quality of Life [ Time Frame: Pre-treatment and at 3,6,12,18 and 24 months post treatment ]
  Patient reported quality of life will be measured using EORTC QLQ C30
• Patient reported Quality of Life [ Time Frame: Pre-treatment and at 3,6,12,18 and 24 months post treatment ]
  Patient reported quality of life will be measured using EQ5D

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.

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.

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

• 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 Names:

  • Stereotactic body Radiotherapy
  • SABR
• 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

• Active Comparator: Standard of Care
  Standard of care (SOC) is at the discretion of the local oncologist.
  Intervention: Other: Standard of Care
• Experimental: 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.
  Interventions:

  • Radiation: SBRT
  • Other: Standard of Care

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, non-small cell lung 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 after ablative treatment, following successful delivery of clinical treatment.

8. Metachronous metastatic disease presentation only. Primary site must be controlled. Disease-free interval from completion of radical treatment (including any adjuvant therapy) to diagnosis of metastases:

   • Breast: ≥ 6 months. Patients who have relapsed whilst on adjuvant endocrine therapy are eligible.
   • NSCLC: ≥ 4 months
   • Prostate: ≥ 6 months. Patients who have relapsed whilst on adjuvant endocrine therapy are eligible.
9. Systemic therapy naïve in the metastatic setting. Prior systemic therapy is permitted but minimum time interval (as per primary site) from last dose of cytotoxic chemotherapy to first fraction of SBRT is allowed as per primary site listed in criterion 4 above. Concurrent endocrine therapy with SBRT is allowed.
10. Adequate baseline organ function to allow SBRT to all relevant targets (please see relevant appendix dependent on location of metastatic subsite for necessary baseline investigations).
11. Negative pregnancy test (for women of childbearing potential)
12. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
13. Written informed consent

Exclusion criteria

1. Intra-cranial metastases
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 or regional field radiotherapy is standard of care. Patients with supraclavicular, axillary and internal mammary nodal relapse from breast cancer are excluded.
8. Spinal cord compression.
9. Any condition or significant clinical co-morbidities that precludes the safe delivery of SBRT (eg history of clinically significant diffuse interstitial lung disease if SBRT to lung metastases or lesions adjacent to lungs are considered or clinically significant colitis ie ulcerative colitis /Crohn's disease if SBRT to the pelvis or abdomen is considered).
10. Prostate cancer patients previously relapsing on Androgen Deprivation Therapy (ADT) or CAB and receiving abiraterone, enzalutamide or docetaxel are ineligible.
11. Patients whose entry to the trial will cause unacceptable clinical delays in their planned management.

• Institute of Cancer Research, United Kingdom
• National Health Service, United Kingdom