Title: VIdeo assisted thoracoscopic lobectomy versus conventional Open LobEcTomy for lung cancer, a multi-centre randomised controlled trial with an internal pilot. The VIOLET Study
Funder: Department of Health and Social Care

Abstract: DESIGN: Parallel group randomised controlled trial (RCT) with an internal pilot phase. Progression to phase 2 will depend on meeting defined success criteria in Phase 1. Phase 1 is necessary to establish processes for recruitment and to develop a study manual and measure of surgical expertise for participation in phase 2. The full RCT will evaluate the effectiveness, cost effectiveness and acceptability of minimal access VATS vs. conventional open lobectomy for lung cancer. Study participants will be randomised in a 1:1 ratio to VATS or open surgery and followed to 1-year. SETTING: Phase 1 will be conducted in 5 centres; Brompton, Bristol, Liverpool, Harefield & Middlesbrough. Qualitative research will be applied to both phases of the study to optimise recruitment. In-depth interviews with recruiters (surgeons and nurses) will discuss the study design, views about the procedures, and approaches to recruitment. Audio-recorded recruitment consultations and patient interviews will be conducted and analysed to identify communication difficulties, optimise information provision and ensure fully informed consent. Phase 2 will extend the study to a further 5 centres. TARGET POPULATION: Adults with early stage lung cancer suitable for both minimal access and open surgery. INCLUSION / EXCLUSION CRITERIA: Eligible patient with be adults, able to provide written informed consent, undergoing lobectomy for the treatment of known or suspected primary lung cancer with a peripheral tumour beyond a lobar orifice in TNM8 stage cT1-3 (by size criteria, equivalent to TNM7 stage cT1a-2b) or cT3 (by virtue of 2 nodules in the same lobe), N0-1 and M0 or undergoing frozen section biopsy with the intention to proceed with lobectomy or bilobectomy if primary lung cancer with a peripheral tumour beyond a lobar orifice in TNM8 stage cT1-3 (by size criteria, equivalent to TNM7 stage cT1a-2b) or cT3 (by virtue of 2 nodules in the same lobe), N0-1 and M0 is confirmed. Patients must have disease suitable for both VATS & open surgery, to be considered eligible. Patients who have a previous malignancy that influences life expectancy, in whom robotic surgery is planned or those having pneumonectomy or non-anatomic resection (e.g. wedge dissection) are not eligible to participate. HEALTH TECHNOLOGIES BEING ASSESSED: Video assisted thoracoscopic surgery (VATS) lobectomy and conventional open lobectomy. MEASUREMENT OF COST & OUTCOMES: Primary outcome is the physical function at 5 weeks measured using EORTC QLQ-C30 quality-of-life questionnaire, chosen because it is a patient-centred outcome that will reflect the anticipated earlier recovery with VATS lobectomy and has been used in other minimal access surgery trials (nephrectomy, colorectal, oesophageal). The 5 week timing was chosen to capture the early benefits of minimal access surgery on recovery. Secondary outcomes will include generic and disease specific patient-reported outcomes (EORTC QLQ-C30, QLQ-LC-13, EQ5D), overall and disease-free survival, adverse events, economic evaluation and utility, uptake of adjuvant treatment, pathologic up-staging, the proportion of patients who undergo complete resection during the procedure and the proportion of patients who experience prolonged incision pain. SAMPLE SIZE: 498 patients will provide 90% power to test the hypothesis that minimal access surgery leads to greater physical function than open surgery (5% sig. level), assuming an improvement of 0.25 standard deviations is clinically important and allowing for 20% dropout at 1 year. We will recruit about 162 participants in phase 1 and 498 by the end of phase 2. Project timetable including recruitment rate: Study will run over 69 months: 6m set-up; 45m recruitment (phase 1: 21m; phase 2: 24m), 12m follow-up on all participants; 6m analysis and report. We anticipate an average 20 eligible patients/m in phase 1 and that 30% will be recruited initially, increasing to 50% within 6m of study start at each centre. EXPERTISE IN THE TEAM: The team has surgeons, trialists, health economists and patients. MRC Trials Methodology Hub members provide qualitative expertise and expertise in RCTs in surgery.

Lay abstract: Lung cancer is the leading cause of cancer death worldwide and survival in the UK remains amongst the lowest in Europe. Surgery remains the main method of managing the disease, although it is associated with serious complications, mostly related to the chest and wound sites. Recently minimal access video assisted thoracoscopic surgery (VATS) for lung cancer has been introduced and 14% of UK procedures were undertaken with this approach in 2010. Research suggests that VATS leads to less tissue trauma than open surgery and there are several studies showing it is safe. However, it is unknown whether it improves patient outcome in a pragmatic trial. To generate high quality evidence to support (or refute) the provision of VATS, we intend to conduct a randomised controlled trial in patients with known or suspected lung cancer. We hypothesise that VATS will lead to less tissue trauma and therefore better recovery of several aspects of health-related quality of life in the early post-operative period than open surgery, but that surrogate clinical outcomes of survival will be similar to those of open surgery. The VIOLET study has been designed to include an internal pilot phase, which is necessary to establish the optimum processes for recruitment and to develop a measure of surgical expertise for participation in phase 2. The full RCT (covering both phases) will evaluate the effectiveness, cost effectiveness and acceptability of VATS vs. open surgery for early stage lung cancer. In total 498 participants (162 in phase 1; 336 in phase 2) will be recruited, with equal numbers recruited to the two groups. All study participants will be followed to 1-year after surgery. Adults with early stage lung cancer with a peripheral tumour suitable for both VATS and open lobectomy (surgical removal of a lung lobe) will be eligible to take part. The primary outcome for the full trial will be patient-reported physical function, measured at 5 weeks post-operatively using the EORTC QLQ C-30 quality-of-life questionnaire. Physical function has been chosen because it will reflect the anticipated earlier recovery with VATS and has been used in other minimal access surgery trials. We have chosen 5 weeks as the timing our primary endpoint to capture the early benefits of minimal access approaches on recovery. Secondary outcomes will include generic and disease specific patient-reported outcomes, overall and disease-free survival, adverse events, uptake of chemotherapy, pathological results of the lung tissue removed and an economic evaluation. It is anticipated that the results of this study will inform national and international guidelines on surgery for lung cancer.

Research activity codes: 6.4 SURGERY
Health categories: CANCER AND NEOPLASMS