Personalising radiotherapy in non-small cell lung cancer

Abstract

Background. Despite the development of new systemic drugs, targeted agents and technological advances in radiotherapy the outcome remains poor and there has been little improvement in overall survival rates over the last two decades. The clinical trials in this thesis aim to evaluate methods of personalising radical radiotherapy in Non-Small Cell Lung Cancer (NSCLC). Methods. Different approaches to personalising NSCLC treatment will be evaluated through two separate clinical studies. First, the Isotoxic Intensity Modulated Radiotherapy (IMRT) trial in inoperable stage III NSCLC is a multicentre feasibility study combining a number of intensification strategies; dose escalation, acceleration and hyperfractionation. The dose of radiation was increased until one or more of the organs at risk (OAR) met predefined constraints or the maximum dose of 79.2 Gy was reached. The primary objective was the delivery of isotoxic IMRT to a dose > 60 Gy EQD2. The second study is a single-arm, single-centre, open label phase I trial combining the MEK inhibitor selumetinib (AZD6244) with concomitant thoracic radiotherapy in NSCLC (MEKRT trial). The primary objective was to determine the recommended Phase 2 dose of selumetinib. The exploratory objective was to correlate [18F]FLT PET-CT imaging parameters with response to selumetinib and radiotherapy. Results. The Isotoxic radiotherapy schedule was found to be a feasible method of dose-escalation. In contrast, the outcome from concomitant radiotherapy and selumetinib was inferior to standard treatment. Based on the uptake of [18F]FLT uptake suggests the MEK inhibitor selumetinib did not effect the uptake of [18F]FLT. There was no association with baseline SUVmax of the primary tumour and survival. Conclusion. The studies in this thesis have evaluated ways of personalising radiotherapy treatment in non-small cell lung cancer. The isotoxic radiotherapy schedule is currently being tested alongside other dose escalated accelerated schedules in the randomised phase II ADSCaN trial (ISRCTN47674500). The combination of thoracic radiotherapy and selumetinib is not being pursued, but attention is turning to combination with immunotherapy. The future of personalized treatment and better outcomes in NSCLC will require the integration of immunotherapy and thoracic radiotherapy, the integration of targeted agents in the presence of driver mutations, personalised dose escalation and an improvement in the management of co-morbidities so patients can have the best treatment available.

Date of Award	1 Aug 2019
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Alan Jackson (Supervisor), Marie-Claude Asselin (Supervisor) & Corinne Faivre-Finn (Supervisor)