Overview
This is a phase II, non-randomised study examining the safety of treating high risk centrally located non-small cell lung cancer (NSCLC) tumours and single pulmonary oligometastatic lesions using radiation therapy (RT), for patients whose disease is inoperable. The method of delivering the RT in this study is image guided stereotactic ablative radiation therapy (IG-SABR). This method involves using imaging to ensure the radiation is being delivered to the correct location within the body and using higher than normal doses per treatment (fraction) to treat the lung cancer (NSCLC)/oligometastatic lung lesion. This study aims to determine its safety by looking at the number and severity of side effects. This study will deliver 8 treatments/fractions of RT with 7.5 Gy delivered in each fraction. To be eligible for this study the initial treatment plan for the patient must be shown to not fulfil certain criteria relating to doses to the tumour and surrounding normal tissue. This study has its own study specific criteria which must be adhered to. Translational sub-studies (optional) are open to patients in participating centres only. Patients will have the option to consent to participating in both translational studies or to neither.
Description
This study is a phase II non-randomised, multi-centre, single arm trial of image-guided (IG)-SABR for high-risk centrally located T1-T4 lung tumours (NSCLC) and single pulmonary oligometastatic lesions. Treatment will consist of IG-SABR using a total of 8 fractions of 7.5 Gy per fraction adhering to organ at risk dose-volume histogram constraints allowing a minimum dose coverage of 75% to 95% of the planning target volume (PTV) coverage, and a minimum dose of 87% to 99% of the gross tumour volume (GTV), using dose intensity modulation.
The primary aim of the study is to determine the safety of the 8 x 7.5 Gy treatment regimen on the basis of the rate of ≥ Grade 3 treatment related toxicity using NCI CTCAE V5, in patients with medically inoperable early stage, ultracentrally located lung tumours. This is defined by central tumours which are not fulfilling the conservative hybrid DVCs of the LungTech (Adebahr et al., 2015), RTOG 0813 (Bezjak et al., 2015) studies and UK consortium guidelines (v6.1 2019) with full dose coverage, but which subsequently meet SOURCE DVC's with potentially reduced dose coverage. Toxicities occurring between start of treatment and one-year from the end of treatment, which are possibly, probably or definitely related to radiotherapy will be assessed.
A total of 60 evaluable patients will be required for the study. The sample size was calculated using continuous monitoring for toxicity, up to one year post RT, using a Pocock-type boundary. Accrual will be halted if excessive numbers of ≥ Grade 3 TxR-AEs are seen. The regime will not be considered to be safe if >25% of evaluable patients experience a ≥ Grade 3 treatment-related adverse event (TxR-AE) by the end of 1-year post-RT. This study will be considered adequately safe if ≤ 25% of evaluable patients experience ≥ Grade 3 TxR-AE by the end of 1 year post-RT.
The enrolment period is expected to be 3-3.5 years.
Toxicity assessments will be carried out weekly during radiotherapy (RT), at 2, 4 and 8-weeks post-treatment and at 3, 6, 9, 12, 18, 24 months post treatment and annually thereafter to 5 years post treatment.
Translational Sub-Study 1 (Raman spectroscopic analysis) - Primary aim is to undertake biomarker discovery using label-free Raman spectroscopy coupled with multivariate statistical methods to identify spectral biomarkers that could:
- Predict response based on individual radiation sensitivity
- Monitor response based on individual radiation sensitivity
Translational Sub-Study 2 (Proteomic analysis) - Primary aim is to use proteomic analysis of sequential blood samples before, during and after treatment to detect changes in protein expression profiles that may predict outcome and identify prognostic biochemical markers of early toxicity.
Eligibility
Inclusion Criteria:
- Written informed consent obtained prior to any study-specific procedures
- ≥ 18 years of age
- Life expectancy >6 months
- ECOG (Eastern Cooperative Oncology Group) performance status 0-2
- Histological diagnosis (biopsy or cytology) or radiological diagnosis (PET-positive
FDG-avid tumour which requires local ablative therapy per Multi-Disciplinary Team
(MDT) recommendations) of either:
(i) Primary NSCLC (Squamous Cell Carcinoma (SCC), Adenocarcinoma, Large Cell) OR (ii) Single pulmonary oligometastatic lesion
- Patients with central lung tumours whose radiotherapy plan meets the following
- criteria
(i) OAR eligibility constraints are initially exceeded when full PTV coverage is met;
(ii) subsequently meets the CTRIAL-IE 18-33 SOURCE OAR Lung constraints and meets
CTRIAL-IE 18-33 SOURCE Lung minimum constraints
7. Inoperable (as per MDT) or patient refuses surgery,
8. Females of childbearing potential must not be pregnant or lactating, must be prepared
to take adequate contraception methods during treatment. Males whose female partners
are of childbearing potential must be prepared to take adequate contraception methods
during treatment. Examples of effective contraception methods are a condom or a
diaphragm with spermicidal jelly, or oral, injectable or implanted birth control
9. Absence of psychological, familial, sociological or geographical condition, or
psychiatric illness/social situation potentially hampering compliance with the study
protocol and follow-up schedule
Exclusion Criteria:
1. Known co-existing or prior malignancy within the last 5 years (except for adequately
treated basal cell carcinoma (BCC) or Squamous Cell Carcinoma (SCC) of the skin))
which is likely to interfere with treatment or assessment of outcomes
2. Tumour/oligometastatic lesion that is abutting the oesophagus
3. Evidence of regional (nodal) or distant metastases or metastatic pleural effusion
4. Spinal canal involvement
5. Patients with syndromes or conditions associated with increased radiosensitivity
6. Idiopathic pulmonary fibrosis / usual interstitial pneumonia
7. Chemotherapy and/or other targeted treatment administered within 3 months prior to
study registration or planned for <6 weeks following radiotherapy
8. Any previous radiotherapy to the thorax or mediastinum (excluding previous breast or
chest wall radiotherapy) which is likely to interfere with treatment or assessment of
outcomes
9. Any tumour not clinically definable on the treatment planning CT scan (e.g.
surrounding consolidation or atelectasis)
10. Patients unable to undergo 4D-CT scan
11. Uncontrolled intercurrent illness that is likely to interfere with treatment or
assessment of outcomes
12. Evidence of any other significant clinical disorder or laboratory finding that makes
it undesirable for the patient to participate in the study, or if it is felt by the
research / medical team that the patient may not be able to comply with the protocol.