title: Optimisation of radiotherapy for pancreatic cancer
Creators: name: Duffton, Aileen Anne
Publisher: name: University of Glasgow
Year: 2024

description: Background:
Pancreatic ductal adenocarcinoma (PDAC) remains a cancer of unmet need, with modest improvement in overall survival (OS) being realised over the past few decades. State of the art RT technology has advanced treatment protocols for PDAC, increasing the ability to deliver sophisticated RT that exploits the therapeutic ratio and overcomes the innate radioresistance. PDAC is a disease that requires optimised multi-modality protocols. This can facilitate delivery of dose escalated radiotherapy (RT) of high-quality that can be investigated in studies to determine if clear benefits can be established.

Uncertainties continue to be problematic in the planning and delivery of RT for PDAC, with many challenges present in the multi-factorial chain. By considering the relationship between pathway components and the impact they have on the delivery of safe, precise, and accurate treatment, RT can be improved. 

Background Pancreatic ductal adenocarcinoma (PDAC) remains a cancer of unmet need, with modest improvement in overall survival (OS) being realised over the past few decades. State of the art RT technology has advanced treatment protocols for PDAC, increasing the ability to deliver sophisticated RT that exploits the therapeutic ratio and overcomes the innate radioresistance. PDAC is a disease that requires optimised multi-modality protocols. This can facilitate delivery of dose escalated radiotherapy (RT) of high-quality that can be investigated in studies to determine if clear benefits can be established. 

Aim:
To optimise components of the RT planning and delivery pathway using a linear accelerator (linac)-based treatment platform to improve safety, accuracy, and precision of stereotactic ablative RT for PDAC.

Methods:

I. A retrospective study evaluated dosimetric and clinical outcomes for patients treated for PDAC with conventionally fractionated VMAT. This was to describe clinical outcomes with standard of care treatment, which would provide a baseline measurement. 

II. A survey methodology was used to understand the views of clinical oncologists (CO) and clinical oncology trainees (COtrain), to determine the importance and priorities of areas that required optimisation of PDAC RT.

III. The volumetric impact of introducing MR-CT fusion to RT planning for pancreatic cancer was evaluated for CO and COtrain delineations. Volumes were quantified with and with and without MR, and concordance of volumes were compared to gold standard (GS) volumes. 

IV. Image quality scoring criteria was developed and used to evaluate if breath-hold (BH) imaging could improve subjective image quality, visualisation of structures and confidence in decision making, using a comparison of CBCT images acquired in exhale breath-hold (CBCT_EBH) and free-breathing (CBCT_FB). This was carried out for expert (EXP) and clinical observers (OBS).

V. Planning and delivery of stereotactic ablative RT (SABR) to PDAC patients was compared using two methodologies. These were i) a motion encompassing technique which used 4DCT in free-breathing (4DCT_FB) to plan with an ITV approach, with CBCT_FB verification; and an individualised EBH technique using a 3D-contrast enhanced CT in EBH (3DCECT_EBH) data set and the exhale phase of the 4DCT acquired in freebreathing (FB) (4DCT_EXHALE) for planning, with CBCT_EBH verification. 

Results:
Thirty-six patients were evaluated with clinically acceptable plans being created and delivered successfully for all patients. The maximum acute toxicity experienced was a grade 2 for anorexia (3 patients), diarrhoea (1 patient), nausea (6 patients) and pain (2 patients). The median OS for potentially operable patients was 16 months (95%CI 11-27) and for inoperable was 14 months (95%CI 6-17). 

CO and COtrain respondents described PDAC delineation was challenging, and they agreed that optimisation of the pathway was important. Optimisation of planning images; peer review of volumes and plans with a multi-disciplinary team (MDT); and improving tumour delineation by reducing inter-observer variability (IOV) were ranked as the most important.

Volumes of GS structures were smaller than mean observer structures. Across the population, MR volumes were smaller than those created with CT only (GTV_3D). The highest magnitude of mean difference was observed directly between volumes with and without MR. Using MR and CT for delineation showed an increase in dice-similarity coefficient (DSC). 

Image quality scores were improved for EXP and OBS in CBCT_EBH images and was statistically significant. An improvement in mean standard deviation (SD) scores for celiac artery (CA), superior mesenteric artery (SMA) and superior mesenteric vessel (SMV), duodenum, GTV/ITV and PTV were shown for EXP and OBS. Increased confidence was observed for the EXP and OBS groups. 

Clinically acceptable plans were created using both methodologies. Similar planning target volume (PTV) coverage were achieved for PTV_FB and PTV_BH, with OAR dose reduction being shown in the PTV_BH plans. CBCT_EBH significantly improved image quality, visualisation of structures and confidence in decision making. The assessment of PTV_BH resulted in 97% of scores, there was confidence in verifying coverage, significantly more than in CBCT_FB at 26%. 

Conclusions:
In conclusion, the evaluation of thirty-six patients in the initial retrospective study showed that VMAT plans resulted in acceptable acute toxicity. No grade &gt;3 toxicity reported, and grade 2 symptoms being reported in a small percentage of cases. The median overall survival for both potentially operable and inoperable patients were reported. This formed a baseline for conducting the next stages of the thesis.

The survey carried out highlighted the challenges in delineating pancreatic cancer (PDAC) and emphasised the collective desire to optimise the pathway when developing SABR. Various strategies, including peer review, improved imaging, and reducing inter-observer variability, were identified as crucial in this context.

The delineation study demonstrated that IOV was high across volumes using MR alone, CT alone, and registered images. MR imaging alone resulted in smaller target volumes, but more agreement was shown in volumes delineated with an ITV approach which used MR and CT.

CBCT image quality scores assessed using scoring criteria developed within this thesis showed improvements with CBCT_EBH. This was shown for EXP and OBS groups when compared to CBCT_FB scores. This enhanced visualisation of structures and improved confidence in decision-making. 

A comparison of plans for PTV_FB and PTV_EBH showed both methodologies were effective in generating clinically acceptable plans, with BH resulting in similar PTV outcomes and reduced dose to normal tissue. A clear and important advantage of a BH SABR technique was that CBCT_EBH offered superior image quality and increased confidence in verifying target coverage. This demonstrated that CBCT_EBH is superior to CBCT_FB in delivering PDAC SABR and should be considered a necessary method for linac-based RT.

This thesis has investigated a number of processes within the PDAC SABR pathway, identifying uncertainties which can be minimised, allowing protocols to be optimised. These findings contribute to the ongoing effort to optimise techniques that can be implemented in clinical trials going forward, with an aim to improve outcomes for pancreatic cancer patients.