Evaluation of Image Guided Radiotherapy (IGRT) for more accurate Partial Breast Intensity-Modulated Radiotherapy: comparison with standard imaging technique

Radiotherapy is an effective treatment which kills any remaining cancer cells left after surgery and improves the cure rate for women with early breast cancer. Studies have shown that a subgroup of mainly younger women have a higher than average risk of the cancer returning after treatment and have poorer chances of survival. Since most of these tumour recurrences occur close to the site of original cancer, we call this area the tumour bed, a boost dose of radiotherapy is given to this area for the higher risk group of women. Radiotherapy is normally given daily for 3 or more weeks and in order to ensure that the tumour bed is always in the area targeted by the radiotherapy machine, a safety margin is added around the known tumour bed position. This safety margin accounts for daily variations in patient and breast position, including breathing motion during treatment. Checks on treatment accuracy are currently limited to images of the lung and bones. Because we cannot see the tumour bed directly, the added safety margin means that we have to boost (give a high dose to) up to twice as much healthy breast tissue than we really need to. The UK IMPORT HIGH trial tests a more efficient and effective way of delivering a boost using advanced radiotherapy techniques. An important innovation is a national agreement with breast cancer surgeons to mark the walls of the surgical excision cavity with small titanium clips that can be imaged during radiotherapy. We can now directly image the tumour bed before each treatment (this is called image guided radiotherapy, or IGRT). Our pilot studies suggest that safety margins around the tumour bed can be greatly reduced, leading us to expect a lower rate of long-term complications (breast shrinkage, hardness, pain and rib fracture). The IMPORT HIGH trial offers a unique opportunity to compare standard imaging and IGRT within the same patient. The main outcome measure is accuracy of radiotherapy with IGRT compared with standard imaging. It will be possible to calculate the margin of healthy tissue that would need to have been added around the tumour bed if standard imaging had been used. The study team consists of oncology, physics, radiography, statistics and radiobiology specialists. The study will cost £312,082 for a full time researcher and a physicist for 2.5 years.

RESEARCH DESIGN: Multi-centre observational study embedded within a national phase III randomised controlled trial: IMPORT (Intensity Modulated Partial Organ Radiotherapy) HIGH. STUDY POPULATION: Patients receiving breast radiotherapy as part of IMPORT HIGH. Eligibility criteria for IMPORT HIGH includes any patient where a high dose boost to the tumour bed is deemed beneficial. PLANNED INTERVENTIONS: There will be no direct intervention in the patients’ treatment. Experimental intervention is image guided radiotherapy (IGRT) and the control intervention is standard imaging. IMPORT HIGH patients receive IGRT as routine. OUTCOME MEASURES, ASSESSMENT AND TIMETABLE: Project duration is 30 months. The main project tasks are the evaluation of the outcome measures. Primary outcome measure: positional accuracy of IGRT versus standard imaging. This will be assessed using the mean absolute difference between the set-up errors measured using IGRT and standard imaging for all patients (months 1 -12). Secondary outcome measures: (1) Volume of normal tissue spared using IGRT compared to standard imaging: From the positional accuracy of IGRT versus standard imaging we can determine the required safety margins and tumour bed boost volume required for standard imaging. We will re-plan patients using this volume and determine the difference in the treated volume of tissue (volume that receives 95% of the prescribed dose to the tumour bed) for standard imaging and for IGRT (months 12 -24). (2) Differences in modelled risk of adverse effects, expressed in terms of normal tissue complication probability: Using existing trial data we will determine the relationship between volume of tissue treated and the risk of fibrosis. For each patient, the percentage reduction in rate of fibrosis achieved by the use of IGRT in preference to standard imaging will be estimated (months 21-27). (3) The time required to perform IGRT and standard imaging: This will be recorded during the study (months 1-12). STATISTICAL ANALYSIS: Each patient acts as their own control, paired analyses will be done comparing accuracy of the two techniques using either the t-test or the Wilcoxon rank-sum test. Distributions of random and systematic positional errors will be compared between centres using parametric or non-parametric analysis of variance (as appropriate). SAMPLE SIZE AND RECRUITMENT: Sample size calculation is based on the aim to compare techniques in terms of the measured overall set-up errors. We estimate the maximum sample size is 250 patients (see attached project protocol for details). We have arranged for an Independent Data Monitoring Committee to confidentially review the data after the first 100 patients, and give advice on the final sample size. IMPORT HIGH accural is predicted to have reached 400 patients by the end of the first year of the proposed study.