Identification of dose constraints and evaluation of optimal planning technique for thoracic re-irradiation

Supervisors: Anthony Chalmers (University of Glasgow), Stephen Harrow (Beatson West of Scotland Cancer Centre)

Lung cancer is the most lethal cancer worldwide, and even after radical treatment, the rate of local treatment failure or a second lung cancer is between approximately 30%. Thoracic re-irradiation in observational studies has shown promise in controlling the disease with acceptable toxicity, but there are concerns that repeat irradiation may cause significant side effects. However, new radiotherapy techniques are available that may reduce the risk of severe toxicity. In this project, the clinical fellow will use clinical data from previously re-irradiated patients, radiobiological modelling and clinical consensus to derive re-irradiation dose constraints. Using these constraints, conventional and novel radiotherapy planning strategies will be evaluated to identify the optimal re-irradiation technique. This will subsequently be the basis for an early stage clinical trial assessing the safety of thoracic re-treatment. The project will be supervised by Prof Chalmers (UoG) and Dr Harrow (Beatson West of Scotland Cancer Centre) with assistance from Suzanne Currie (Radiotherapy Physics, Beatson) and Dr Fenwick (University of Liverpool).

Lung cancer remains the most lethal cancer in the UK, with over 45,000 new patients diagnosed each year and over 39,000 deaths [Cancer Research UK, accessed Sept 2018]. It is estimated that half of all lung cancer patients will have radiotherapy as part of their initial treatment [Tyldesley et al. 2001]. However, conventional or hyperfractionated radiotherapy as the sole treatment has poor 2 year loco-regional control rates of 50% [Mauguen et al., 2012]. Isolated intra-thoracic relapses are a significant clinical problem, occurring in approximately 30% of patients treated with concurrent chemoradiotherapy [Curran et al., 2011]. In addition, 14% of patients treated with radical radiotherapy will develop a second lung cancer in the 10 years after radical radiotherapy [Jeremic et al, 2001]. In patients who develop either intra-thoracic relapsed disease or a new lung cancer, clinicians have been reluctant to repeat radical radiotherapy to the thorax, fearing unacceptable toxicity, leaving patients with very limited treatment options. However, radiotherapy technology has improved significantly in the past decade, with the introduction of 4D-CT scanning, cone beam CT scans for image guidance, and new planning algorithms that better target the tumour and spare normal tissue. Combining these new technologies makes the concept of radical thoracic re-irradiation much more feasible.

Data from observational studies indicate that thoracic re-irradiation has promising efficacy, with median overall survival rates of 7 - 14 months, and 1 year local control rates of 51-67% [Rulach et al. 2018]. While the only phase 1 clinical trial performed in this patient group to date reported acceptable safety data, with no grade 3 or 4 toxicities, 96% of patients experienced grade 1/2 pneumonitis, and a 40% experienced grade 1/2 oesophagitis [Wu, 2003]. This study utilised out-dated radiotherapy techniques, however, so there is considerable scope to reduce both the incidence and the severity of toxicity. Of note, no robust published data is available regarding the cumulative maximum doses that organs in the thorax can tolerate; this information is critical when planning re-treatments. Hence there is significant interest across the international radiotherapy community in rigorously investigating the use of state-of-the-art radiotherapy techniques to optimise thoracic re-irradiation, and to properly assess its safety and efficacy.

The Radiotherapy Department at the Beatson West of Scotland Cancer Centre and the Institute of Cancer Sciences at the University of Glasgow are uniquely placed to undertake this work. We have a large population of patients with non-small cell lung cancer (NSCLC) who have received radical radiotherapy or chemoradiotherapy, and we are the first clinical department in the world to use a novel radiotherapy planning technique called multi-criteria optimisation (MCO) which has the potential to significantly reduce doses to organs at risk. Our lung cancer multidisciplinary team comprises experienced researchers in the three main disciplines: Stephen Harrow (Consultant Clinical Oncologist, NRS Research Fellow), Suzanne Currie (Radiotherapy Physics), Karen Moore and Aileen Duffton (Therapy Radiographers). Clinical supervisor Stephen Harrow and potential candidate Robert Rulach have recently published a definitive review on this topic (Rulach et al, 2018) and have assembled a strong team of collaborators and advisors from across the UK, including John Fenwick, a leading expert in radiobiological modelling. Anthony Chalmers will provide academic supervision and facilitate further collaborations with UK and international researchers through existing CTRad and ESTRO relationships. The project harmonises perfectly with the Glasgow Radiotherapy Research Strategy, the main theme of which is the use of advanced radiotherapy technologies to improve outcomes for patients with 'difficult to treat' cancers, and within which lung cancer is a major focus.

Radical dose thoracic re-irradiation can be delivered with acceptable toxicity and has the potential to extend progression-free survival for patients with locally recurrent NSCLC.

(1) Define theoretical and clinical re-irradiation dose constraints for organs at risk in the thorax.
(2) Evaluate a range of re-irradiation planning solutions for both initial and re-treatment of NSCLC, and define the utility of multi-criteria optimisation (MCO) in reducing normal tissue toxicity and facilitating dose escalation.
(3) Develop a clinical trial protocol that utilises the dose constraints and optimised radiotherapy planning methods identified in aims (1) and (2) to robustly evaluate, for the first time, the safety, toxicity and efficacy of re-irradiation for NSCLC.

It is not possible to use animal models to identify re-irradiation dose constraints because dose, fractionation, scheduling and toxicity parameters are not directly transferable to humans. Therefore, in Aim 1, we will interrogate the existing literature to identify grade 3/4 toxicity events from which to establish dose limits, and will extract clinical and radiotherapy dosimetric data from patients previously re-irradiated at the Beatson and five additional UK centres to build a radiobiological model for each organ at risk. This part of the project will be supervised by radiobiological modelling expert John Fenwick (University of Liverpool) and will provide a sound theoretical basis for re-irradiation dose constraints. Results will be validated clinically by a consensus approach using the Delphi method [Nguyen et al., 2018]. The clinical applicability of our findings will be strengthened by engaging with patients who have previously had thoracic radiotherapy and finding out what level of toxicity they would accept if they were to be offered re-irradiation at the time of recurrence. Output: clinically applicable, validated re-irradiation dose constraints. Aim 2 will evaluate the ability of a range of different planning solutions to achieve those constraints while delivering a meaningful dose to the recurrent tumour. Initially, we will evaluate how best to record the details of primary irradiation and how to utilise this information when planning re-irradiation. We will evaluate different methods for superimposing primary dosimetry on re-irradiation CT planning scans (the shape of the patient is likely to have changed over time) before comparing four different planning techniques (conventional 3-field, 2-field hybrid, volumetric arc therapy, and MCO) to find the optimal planning solution. These comparative studies will be performed using the CT planning scans of patients who have already undergone re-irradiation at the Beatson, and will be evaluated in terms of the lowest dose that can be given to the organs at risk, whilst delivering a radical dose to the recurrent tumour. Output: identify the optimal planning and delivery technique for re-irradiation. Aim 3 will integrate the dose constraints and planning information to produce a phase 1 clinical trial protocol, incorporating biopsy samples for translational research. This trial will test the safety of conventional radical dose re-irradiation in the first part, and, if no adverse toxicities are encountered, escalate the re-treatment dose until a dose constraint is unable to be met. Output: a modern re-irradiation clinical trial protocol ready for use.


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