Lung cancer is the third most common cancer in the UK with around 48,500 people diagnosed
with the condition each year. Unfortunately, despite significant progress in treatment
options and their delivery, improvements in survival remain elusive. Radiotherapy (RT) is
a cornerstone of both radical and palliative treatment in non-small cell lung cancer
(NSCLC). Radiation pneumonitis (RP) is the key dose-limiting constraint and a morbid,
potentially even life-threatening, toxicity associated with RT to the thorax. Newer
combinations of chemo-radiotherapy and adjuvant immunotherapy demonstrate improved
survival but are associated with higher risk of RP.
Current management of RP is very limited consisting of supportive measures and steroids;
the latter of which are often ineffective and come with their own risks. The typical
triad of symptoms (exertional dyspnoea, a non-productive cough and hypoxia) can be
directly fatal for some whilst for others represent a devastating and permanent decline
in their lung function and quality of life. Although modest understanding of the patient
and treatment related risk factors for RP development have been identified the underlying
mechanisms remain poorly understood and has been challenging to investigate. A cascade of
inflammatory changes with hypoxia lead to endovascular damage, cytokine release and
ultimately endothelial cell death and irreversible fibrosis. Single-cell RNA sequencing
(scRNA-seq) is a relatively novel technique that allows access to an understanding of
this process. It can allow the identification of what genetics, cell types and functional
heterogeneity are up/down-regulated in association with irradiated lung tissue in humans.
It is known that Stereotactic-Ablative Radiotherapy (SABR) is a well-tolerated highly
conformal form of RT. It has been safely delivered to patients before radical surgery
without significant toxicity or increase in complication rate. If a targetable mechanism
behind this condition could be identified it has the potential to change the landscape of
lung cancer RT management and in doing so save lives.
A literature search revealed no investigation like this has been conducted in humans. A
Chinese study has been done in murine models and demonstrated several signals which, if
demonstrated in humans, could be of interest. SPITFIRE proposes to obtain inflamed lung
tissue from patients who have developed pneumonitis following radiation for their lung
cancer to find these answers.
1.2 RATIONALE FOR STUDY Both patients who have potentially been cured of their lung
cancer and those being treated to alleviate symptoms in their last months-to-years of
life are diagnosed with RP. Potentially treatable disease can be refused due to an
unacceptable combination of risk factors for developing RP. Hospitalisation for RP is
common and yet often frustratingly unhelpful. RP is a major contributor to patient
morbidity, mortality and healthcare cost. Although clearly a constant concern in lung
cancer any radiation delivered through the chest (including oesophageal, breast and
pulmonary metastatic RT) carries a risk of RP.
Pulmonary fibrosis treatment is starting to improve with novel agents such as Nintedanib
and Pirfenidone demonstrating some promise. There is likely, though yet unproven,
crossover between the molecular and genetic processes involved in these conditions.
Should a better understanding of the mechanisms behind RP reveal a targetable signal, and
subsequent treatment, it has the potential to completely change not only the management
of this toxicity but that of thoracic malignancies.
Obtaining tissue from human lung affected by RP is a challenge. These patients are often
too unstable to safely proceed with such intervention. There is, however, a population of
patients who have clinical and radiological features diagnostic of the condition but
maintain oxygen saturations (SpO2) adequate to proceed to bronchoscopy. Some of these
patients will be referred for a bronchoscopy to exclude super-added infection. As part of
this process they may be enrolled in the ELFMAN (Edinburgh Lung Fibrosis Molecular
Endotyping) Study - to better characterise suspected inflammatory and fibrotic
interstitial lung disease, as it may have shared molecular pathways to interstitial
pneumonias including idiopathic pulmonary fibrosis (IPF). Standard bronchoscopy may not
reach the effect area of lung but deep bronchial brushings obtains a good cellular yield
which should be adequate for scRNA-seq whilst minimising risk to the patient. This study
proposes to utilise a brushing from these patients to process using a novel laboratory
technique to help identify the cellular processes that may be involved in radiation
pneumonitis.