Breast SSG: SABR and Oligometastatic Disease Charlie Comins 22/1/2016

SABR - the basics Stereotactic Ablative Body Radiotherapy A misnomer? Extremely high dose Body As opposed to intracranial Radiotherapy

SABR - History Stereotactic radiotherapy is an old technique Developed at Karolinska Institute in 1960s for treatment of intracranial lesions Use of multiple radiotherapy fields (7 or more) delivering a high dose to the target but low dose to surrounding structures Taken up by Japanese to treat peripheral lung tumours

Why now? 2 main technical advances Compensation for tumour motion 4DCT ABC Respiratory gating Image guided radiotherapy Daily CT imaging of target to ensure accuracy

SABR platforms Tomotherapy Cyberknife

Linear Accelerator

Practicalities Patient attends for coaching session 4DCT scan (40 minutes) Voluming by clinician (1 hours) Planning by physicists Day 0: dry run to ensure patient can tolerate and iron out problems (now dropped) Day 1: first treatment

Practicalities 3 dose prescriptions: Toxicities 54Gy in 3 fractions Minimum of 48 hours between treatments Toxicities Fatigue, skin reaction, cough, dysphagia Chest wall pain, rib fracture, pneumonitis

No Fly Zone

Or this can happen…..

Oligometastatic disease What is this? The clinical state of oligometastatic disease was proposed in 1995 by Hellman and Weichselbaum.  They hypothesized that, in some patients with a limited number of clinically detectable metastatic tumors, the extent of disease exists in a transitional state between localized and widespread systemic disease. Is this a real entity? Even if it isn’t, could ablative treatment be worthwhile? Can we determine in which patients it might be beneficial?

Oligometastatic disease PuLMICC – resection of lung mets in colorectal cancer 2 potential radiotherapy trials: SARON for NSCLC patients CORE for Breast, Lung, and prostate cancer patients NHS England CtE Commissioning through Evaluation Bristol one of 17 centres to be selected to deliver SABR for oligometastatic disease 5 referrals; 1 patient treated to date

CORE Trial Assessing the impact of SABR in patients 1-3 metachronous mets from breast, lung and prostate cancer primaries Maximum 3 metastases and two different organs Randomised trial: standard of care +/- SABR Patients eligible for the CORE will not be able to receive SABR through CtE scheme

Background & Rationale Emerging concept Hellman and Weichselbaum 1995 No Level 1 evidence Current PRTs on-going SABR-COMET (CA & NL) Randomised ph II (N=99) for any tumour type Oligomets ≤ 5 including brain mets SBRT vs Pall RT or systemic Rx OS endpoint STEREO-SEIN (IGR) Randomised Ph III (N=280), Breast ca SBRT + systemic Rx vs Pall RT or systemic Rx PFS endpoint Oligomets ≤ 5 & ≤ 10 cm

Why lung, breast and prostate? Currently insufficient evidence to choose a single tumour site to investigate; no strong biological rationale why SBRT would be effective for some tumour sites and not others Decision to include lung, breast and prostate cancer made following wide consultation with clinicians across the UK, including the relevant Clinical Studies Groups and CTRad – common cancers, size of patient pool Increased heterogeneity with this approach is acknowledged; pragmatic design for phase II – signal finding

Phase II or phase III? General agreement amongst protocol development group that there were too many uncertainties to commit to a large phase III trial on the data and experience available Delivery of SBRT in this setting is novel across the UK A staged design will allow assessment of patient recruitment and feasibility of delivery in a multi-centre setting enable an efficacy signal to be detected across the three tumour sites If a positive signal is seen, expand to parallel phase III trials aiming to show superiority of SBRT over standard of care

Design Multistage Phase II/III, international, multi-centre, non-blinded, parallel group randomised controlled trial: N = 206 Breast, non-small cell lung (NSCLC) or prostate cancer Metachronous oligomets (≤ 3 lesions) Standard of care (SoC) ± SBRT / SABR SOC therapy is at the discretion of the local oncologist and will be defined (per patient) prior to randomisation. It may include any standard therapy that is clinically appropriate: chemotherapy, biological therapy, endocrine therapy, palliative radiotherapy or observation. Multistage aspect (Emma Hall)

CORE trial schema Randomise (1:1) SBRT + Standard of Care NSCLC, breast or prostate cancer patients Completed radical treatment ≤3 extra cranial metachronous oligometastases Suitable for SBRT Randomise (1:1) Standard of Care SBRT + Standard of Care Standard of Care defined prior to randomisation May include further chemotherapy, hormone therapy, palliative radiotherapy or observation at PI discretion

Aims/Objectives Primary Secondary To evaluate if the addition of SBRT to SoC improves PFS Secondary

Secondary Aims/Objectives To demonstrate feasibility of recruitment To demonstrate deliverability of SBRT within dosimetric constraints To evaluate if the addition of SBRT to SoC improves OS To evaluate the acute and late toxicity associated with the addition of SBRT to SoC To evaluate the lesion local control rates in those receiving SBRT To compare the quality of life (QoL) in patients receiving SBRT compared to those receiving SoC alone To investigate and evaluate resource use and costs of SBRT and SoC therapy within the trial setting.

Development of SABR in Bristol VMAT Flattening –filter free ?Abdominal compression Participation in trials

Conclusions Thank you for your support Techniques and service continue to be improved Will need continued support to recruit to current and future SABR trials Other ablative techniques available but proper evaluation required