Protocol for the isotoxic intensity modulated radiotherapy (IMRT) in stage III non-small cell lung cancer (NSCLC): a feasibility study

Abstract

IntroductionThe majority of stage III patients with non-small cell lung cancer (NSCLC) are unsuitable for concurrent chemoradiotherapy, the non-surgical gold standard of care. As the alternative treatment options of sequential chemoradiotherapy and radiotherapy alone are associated with high local failure rates, various intensification strategies have been employed. There is evidence to suggest that altered fractionation using hyperfractionation, acceleration, dose escalation, and individualisation may be of benefit. The MAASTRO group have pioneered the concept of ‘isotoxic’ radiotherapy allowing for individualised dose escalation using hyperfractionated accelerated radiotherapy based on predefined normal tissue constraints. This study aims to evaluate whether delivering isotoxic radiotherapy using intensity modulated radiotherapy (IMRT) is achievable.Methods and analysisIsotoxic IMRT is a multicentre feasibility study. From June 2014, a total of 35 patients from 7 UK centres, with a proven histological or cytological diagnosis of inoperable NSCLC, unsuitable for concurrent chemoradiotherapy will be recruited. A minimum of 2 cycles of induction chemotherapy is mandated before starting isotoxic radiotherapy. The dose of radiation will be increased until one or more of the organs at risk tolerance or the maximum dose of 79.2 Gy is reached. The primary end point is feasibility, with accrual rates, local control and overall survival our secondary end points. Patients will be followed up for 5 years.Ethics and disseminationThe study has received ethical approval (REC reference: 13/NW/0480) from the National Research Ethics Service (NRES) Committee North West—Greater Manchester South. The trial is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP). The trial results will be published in a peer-reviewed journal and presented internationally.Trial registration numberNCT01836692; Pre-results.

Is heterogeneity in stage 3 non-small cell lung cancer obscuring the potential benefits of dose-escalated concurrent chemo-radiotherapy in clinical trials?

“…An early phase feasibility study showed accelerated individualised dose prescriptions allowed escalated doses to be safely delivered to the tumour (no excess toxicity and comparable survival) [54] [55]. The original study used 3DCRT so 2 further studies have been conducted in the UK (ClinicalTrials.gov:NCT01836692) and the Netherlands (ClinicalTrials.gov:NCT01166204) using IMRT alongside 4DCT planning and image guided radiotherapy techniques with the hypothesis that these technologies will allow safe dose-escalation to the tumour without breaching OAR tolerances [56].…”

An overview on personalisation of radiotherapy prescriptions in locally advanced non-small cell lung cancer: Are we there yet?

“…In these trials, a number of 3DCRT planning approaches were reported. It is possible that the use of isotoxic planning techniques which require the increased conformity that comes with IMRT or VMAT, could translate to reduced clinical toxicity and the published outcomes of the Isotoxic IMRT are eagerly awaited [13]. However, two studies that reported Grade 5 haemoptysis utilised modulated techniques but studies observed this toxicity in patients with centrally located tumours [21,23].…”

“…Isotoxic treatment planning has been suggested as a method of personalising radiotherapy for each patient based on their individual treatment plan [13]. In isotoxic RT planning, the prescribed dose is increased incrementally until an organ at risk (OAR) maximum tolerated dose is reached.…”

The Challenges Faced in Developing Novel Drug Radiation Combinations in Non-small Cell Lung Cancer

“…In spite of significant technical developments in the radiotherapy, local recurrence rates following curative intent radiotherapy in the treatment of non-small cell lung cancer (NSCLC) remain high [3]. Radiation dose escalation is one potential avenue of optimisation, but is limited by adjacent normal tissue tolerances [4]. Another strategy to optimise the biological effectiveness of radiotherapy is by co-administration of therapeutic agents that preferentially sensitize malignant cells to radiotherapy.…”

“…Another approach to improving outcomes for patients with locally advanced NSCLC is to alter radiotherapy fractionation, either by increasing the number of fractions delivered each day, delivering the radiation over a shorter period of time (acceleration), or a combination of the two [4,16].…”