OPTIMISE Lung SABR

OPTIMISation of pEripheral Lung Stereotactic Ablative Body Radiotherapy, a Prospective Independent Evaluation of 3 Fraction and 5 Fraction SABR Regimens (OPTIMISE Lung SABR)

This study is a phase II multi-centre, randomised study independently evaluating five fraction Image-Guided Stereotactic Ablative Radiotherapy (IG-SABR) and three fraction IG-SABR for patients with a peripherally located T1-T2 and selected T3 and T4 lung tumours, or a peripherally located single pulmonary oligometastatic lesion.

This study is for patients who have a lung tumour located near the ribs or chest wall, and who are not suitable for surgery. Currently, these patients are usually treated with Stereotactic Ablative Radiotherapy (SABR). SABR is a precise form of radiotherapy that delivers high doses of radiation to the tumour while protecting surrounding healthy tissue. The standard treatment for these patients currently is 60 Gray (Gy) in 5 treatments (12 Gy each), spread over about 2 weeks. This schedule is thought to reduce the risk of rib fractures and is currently adopted when a patient has a tumour located near the ribs or chest wall.

This study is testing whether an alternative investigational treatment schedule, 54 Gy in 3 treatments (18 Gy each) given over about 1 week, is just as safe and effective for these patients.

This new approach means patients would need to attend the hospital for two fewer visits. A new method of SABR planning for the alternative treatment schedule makes it possible to direct the radiation dose straight to the tumour while avoiding the ribs and chest wall as much as possible. Because of this planning method, the research team believes the investigational three-treatment schedule will not increase side effects such as rib fractures or chest wall pain compared with the standard five-treatment schedule.

SABR is already widely used in many types of cancer. It works by delivering higher doses of radiation over fewer treatment sessions. This can be more effective than conventional external beam radiotherapy where treatment is delivered over 4-6 weeks in some cases and is often more convenient for patients.

In this study, patients will be randomly assigned to receive either: Arm 1: Regimen of 60 Gy in 5 treatments over approximately two weeks, or Arm 2: Investigational regimen of 54 Gy in 3 treatments over approximately 1 week. Treatments in both groups are given on weekdays only, with at least forty hours between each session.

The technology used in SABR allows very precise targeting of the tumour while protecting nearby healthy organs such as the heart, spinal cord and normal lung tissue. The planning process also accounts for the natural movement of the lungs during breathing. Before each treatment, a cone beam CT scan is used to ensure the patient is in the correct position. The purpose of the study is to see how well each treatment schedule controls lung tumours and what side effects patients experience. It will also explore what factors might influence whether side effects such as rib fractures or chest wall pain occur. The enrolment period is expected to be approximately 3.5 years. Toxicity assessments will be carried out weekly during radiotherapy (RT), at 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: (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:

1. Predict response based on individual radiation sensitivity
2. Monitor response based on individual radiation sensitivity

Inclusion Criteria:

1. Written informed consent obtained prior to any study-specific procedures.

2. ≥ 18 years of age.

3. Life expectancy >6 months.

4. ECOG (Eastern Cooperative Oncology Group) performance status of 0-2.

5. Histological diagnosis (biopsy or cytology) or radiological diagnosis (tumour which meets definition of 'measurable' per RECIST criteria and eligible for local ablative therapy per multi-disciplinary team (MDT) recommendations) of either:

   (i) Primary Non-Small Cell Lung Cancer (squamous cell carcinoma, adenocarcinoma, large cell): T1-T2 N0 M0 tumour (AJCC 8th edition) and selected T3 and T4 N0M0 which has only one lesion (a co-existing lesion unlikely to interfere with treatment or assessment of outcomes is permitted) to be treated for the purpose of the study OR (ii) Single pulmonary oligometastatic lesion to be treated for the purpose of the study.

   (Note: for (i) and (ii), a co-existing lesion(s) unlikely to interfere with treatment or assessment of outcomes is (are) permitted).

6. Patients with peripherally located tumours, defined as tumours not fulfilling the UK 2022 SABR Consortium Consensus optimal 3 fraction constraints for Chest wall (0.1 cc <36.9 Gy) or (30 cc < 30 Gy), with standard Planning Target Volume (PTV) coverage due to the proximity of their tumour to the chest wall , but which are predicted to meet the CTRIAL-IE 24-15 OPTIMISE Lung SABR Study dose volume constraints with dose escalation optimised to the Gross Tumour Volume (GTV).

7. Inoperable (as per MDT) or patient refuses surgery.

8. People of childbearing potential must not be pregnant or lactating and must be prepared to take adequate contraception methods during treatment. People whose partners are of child-bearing potential must be prepared to take adequate contraception methods during treatment.

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 which is likely to interfere with treatment or assessment of outcomes.
2. Evidence of regional (nodal) or distant metastases or metastatic pleural effusion for patients with primary NSCLC.
3. Malignant spinal canal involvement.
4. Patients with syndromes or conditions associated with increased radiosensitivity.
5. Idiopathic pulmonary fibrosis / usual interstitial pneumonia.
6. Chemotherapy and/or other targeted therapy administered within 3 months prior to study radiotherapy (RT) or planned for <6 weeks following RT for patients with primary NSCLC, or within 1 week prior to study RT or planned within 1 week following RT for patients with an oligometastatic lesion.
7. Any previous RT to the thorax or mediastinum (excluding previous breast or Chest Wall RT) which is likely to interfere with treatment or assessment of outcomes.
8. Any tumour not clinically definable on the treatment planning CT scan (e.g. surrounding consolidation or atelectasis).
9. Patients unable to undergo 4-Dimensional Computed Tomography (4DCT scan).
10. Uncontrolled intercurrent illness that is likely to interfere with treatment or assessment of outcomes.
11. 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.