Wong, Swee Ling; (2021) Improving clinical outcomes for patients with locally advanced non-small cell lung cancer treated with photon and proton radiotherapy. Doctoral thesis (M.D(Res)), UCL (University College London).

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Abstract

Objectives To identify mechanisms improving clinical outcomes for patients with unresectable locally advanced non-small-cell lung cancer (LA-NSCLC) treated with photon and proton radiotherapy. Strategies explored include 1. Investigating using routine healthcare datasets to estimate survival outcomes for patients with LA-NSCLC treated with definitive radiotherapy, in order to assess the effectiveness of current strategies; 2. Assessing the physical advantages of protons by conducting a retrospective planning study comparing volumetric modulated arc therapy (VMAT) and pencil beam scanning (PBS) proton plans of superior sulcus tumours (SSTs), a rare subset of LA-NSCLC; 3. Exploring potential biological advantages of protons by examining major cell death pathways following XRT, high and low linear energy transfer (LET) proton irradiation of NSCLC cells. Methods Workflow 1: LA-NSCLC patients receiving definitive radiotherapy were identified. For each, key time points (date of diagnosis, recurrence, death or last clinical encounter) were used to calculate overall survival (OS) and progression free survival (PFS) from manual-data (hospital notes) and compared to estimated OS and PFS from routine-data (electronic databases). Dataset correlations were then tested to establish if routine-data were a reliable proxy measure for manual-data. Workflow 2: Patients with SSTs treated with 4D radiotherapy were identified. Tumour motion was assessed and excluded if >5 mm. Comparative VMAT and PBS plans were generated retrospectively. Robustness analysis was assessed for both plans involving: 1. 5 mm geometric uncertainty scenarios, with an additional 3.5% range uncertainty for proton plans; 2. verification plans at breathing extremes. Comparative dosimetric and robustness analyses were carried out. Workflow 3: Human NSCLC cell lines were irradiated with single doses of 2-15 Gy photon radiotherapy, high- or low-linear energy transfer (LET) protons (12 keV/µm and 1 keV/µm, respectively) and analysed 24-144 hours post-irradiation. DNA damage foci and cell death mechanisms were investigated. Results Workflow 1: In forty-three patients, routine data underestimated PFS by 0.09 months (p=0.86; 95% CI -0.86-1.03) and OS by 1.02 months (p=0.00; 95% CI 0.34-1.69) but there was good correlation with a Pearson correlation coefficient of 0.94 (p=0.00, 95% CI 0.90-0.97) for PFS and 0.97 (p= 0.00, 95% CI 0.95-0.98) for OS. Workflow 2: In ten patients, both modalities achieved similar target coverage with mean clinical target volume D95 of 98.1% + 0.4 (97.5-98.8) and 98.4% + 0.2 (98.1-98.9) for PBS and VMAT plans, respectively. The same four PBS and VMAT plans failed robustness. Proton plans significantly reduced mean lung dose (by 21.9%), lung V5, V10, V20 (by 47.9%, 36.4%, 12.1%, respectively), mean heart dose (by 21.4%) and vertebra dose (by 29.2%) (p<0.05). Workflow 3: XRT predominantly induced mitotic catastrophe, autophagy and senescence. Senescence, established via the p53/p21 pathway, was the major cell death pathway by which protons more effectively reduce clonogenic potential compared to XRT in NSCLC cell lines. High LET protons at a dose of 10 Gy(RBE) resulted in the lowest cell survival. The mechanisms driving the LET- and dose-dependent senescence was unclear but did not appear to be related to differential DNA repair machineries. Conclusions Proton radiotherapy could be pivotal in improving outcomes in select cases of LA-NSCLC. These studies demonstrate that 1. survival-outcomes are reliably estimated by routine data and such a methodology could enable rapid outcomes analysis to keep pace with trial development; 2. robust PBS plans are achievable in carefully selected patients and considerable dose reductions to the lung, heart and thoracic vertebra are possible without compromising target coverage; 3. Identification of LET- and dose-dependent proton-induced cellular senescence may guide radiotherapy optimisation and drug-radiotherapy combinations, maximising tumour cell kill. This work contributes to important preliminary research required to understand the physical and biological strengths and weaknesses prior to trials.

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