Title: Multi-modality local consolidative treatment versus conventional care of advanced lung cancer after first line systemic anti-cancer treatment: a multi-centre randomised controlled trial with an internal pilot. RAdical Management Of Advanced Non-small cell lung cancer (RAMON)
Funder: Department of Health and Social Care

Abstract: Lung cancer is the most common cause of cancer death worldwide, and the majority of patients in the UK present with advanced disease. One-year survival is improving but remains low at 37% despite new treatments which now form the current standard of care for advanced lung cancer. _x000D_ _x000D_ Although these new therapies are very good, some cancer persists (termed 'residual cancer') in most patients after treatment and little is known on how best to deal with it. As such the management of residual advanced lung cancer is highly variable across the UK, with some patients receiving only symptom management treatment while others go on aggressive treatment in the form of surgery, radiotherapy and/or ablation (an image-guided technique that uses heat to destroy cancer cells) to remove all remaining cancer within the lung and throughout the body. Collectively, these treatments are known as ‘local consolidative treatment’ (LCT). _x000D_ _x000D_ LCT is intensive, impacts quality of life and is expensive (we do not have accurate healthcare costs to the NHS) but most importantly, we do not know if it results in a better outcome for patients. The RAMON study will find out whether LCT is worthwhile (or not) for patients with residual advanced lung cancer. Over 3 years we will aim to recruit 244 patients who have completed initial treatment of their cancer with medicines. Patients who agree to join the study will be divided into two equal sized groups. One group will receive LCT and the other group will not. Everything else will be the same for all patients (all patients will have treatment for symptoms as necessary). The groups will be chosen by a process called randomisation to ensure that groups have similar patients in terms of general health, age, sex etc. to allow a fair comparison to be made between the two groups. Both groups will be followed up after 6 weeks and then every 6 months to the end of the study (minimum of 2 years). Information about survival, disease progression, quality of life, complications of treatment and costs to the NHS and patients will be collected. _x000D_ _x000D_ The number of patients agreeing to take part and being followed up successfully will be checked in each hospital and, after 12 months, the information will be reviewed to make sure that it is possible to complete the full trial. _x000D_ _x000D_ This study will be carried out by an experienced multi-disciplinary team of oncologists, surgeons, researchers and patient representatives with experience of lung cancer treatments, who will have input to all stages of the project, from the design of patient materials to dissemination of results. It will take 6 years to complete. An independent group of oncologists, surgeons, researchers and lay members/patients will review the study regularly and provide advice. The results will be made publicly available to inform future care of patients with advanced lung cancer. _x000D_ _x000D_ It is hoped that the study will enable us to determine the survival benefits (if any) and quality of life due to LCT and evaluate the complications and costs of LCT in order to make a decision on whether this treatment is necessary for future advanced lung cancer patients.

Lay abstract: Research question: For patients with advanced lung cancer, after initial systemic anti-cancer treatment, does local consolidative treatment (LCT), compared to no LCT, improve survival? _x000D_ _x000D_ Background: Residual cancer persists in most patients after anti-cancer treatment. Management of residual disease is highly variable. Some receive symptom management only while others surgery, radiotherapy and ablation (LCT). LCT is intensive and expensive but we do not know if it results in better outcomes._x000D_ _x000D_ Aims and objectives: To compare the clinical, cost effectiveness and resource use of LCT after initial systematic anti-cancer treatment of advanced lung cancer versus symptom management alone (conventional care)._x000D_ _x000D_ Methods: Multi-centre, pragmatic, parallel group, superiority randomised controlled trial (RCT) with an internal pilot phase to determine feasibility of recruitment and adherence to the protocol, a QuinteT Recruitment Intervention (QRI) and active patient follow-up to the end of trial (maximum 5 yrs, minimum 2 yrs). Progression to Phase 2 depends on meeting progression criteria set for Phase 1. Participants randomised in a 1:1 ratio to LCT or no LCT. Randomisation will be via a secure website to ensure allocation concealment. Setting: Secondary and tertiary care NHS hospitals. The study will recruit from 40 centres. Population: Adults, 18 years or older who have received systemic anti-cancer treatment for advanced non-small cell lung cancer with known or suspected residual disease. Exclusion criteria: inability to treat all sites of residual disease, any serious concomitant disorder that would compromise patient safety during LCT or complications that precludes maintenance anti-cancer treatment. Intervention: surgery, radiotherapy and / or ablation to all sites of residual disease. Comparator: symptom management (conventional care) without surgery, radiotherapy, or ablation to any residual site of disease (unless for palliation of symptoms). Measurement of costs and outcomes: Primary outcome will be overall survival (minimum follow-up 2 yrs). Secondary outcomes include disease progression free survival, serious adverse health events and patient-reported health related quality of life (HRQoL) measured using EORTC QLQ-C30, EORTC QLQ-LC13 and EuroQol EQ-5D-5L (up to 2 years). Resource use will be captured, costed and combined with quality-adjusted life years in a cost effectiveness analysis. Sample size: We aim to recruit 244 participants in total (122 per group). This will provide 90% power to detect an 18% improvement in survival with LCT assuming survival rate of 52% at 2 years without LCT, 5% two-tailed statistical significance. This target was chosen by our PPI group. We expect to recruit about 45 participants in Phase 1 and the remainder by the end of Phase 2. Criteria for progression from Phase 1 to 2: 25 centres open, 45 participants randomised, and at least 95% of randomised participants adhere to the allocated treatment pathway. _x000D_ _x000D_ Timelines for delivery: 72 months: 8m set-up; 34m recruitment (Phase 1: 12m; Phase 2: 22m); minimum 2 years follow-up on all participants; 6m analysis and report._x000D_ _x000D_ Anticipated impact and dissemination: Results will impact patients, clinicians, and healthcare providers whether LCT should be offered. If negative all stakeholders stand to benefit by stopping an intensive and expensive treatment regimen. We will submit to high impact medical journals, international meetings and ensure public access using social media and advocacy groups.

Research activity codes: 6.4 SURGERY;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS