IMPORT HIGH is the first phase III randomised study with published 5-year outcome data using hypofractionated simultaneous integrated boost and is substantially larger than any other reported simultaneous integrated boost studies. It is the first breast boost study to use smaller, more targeted boost volumes with intensity modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) in all groups, including the control group. These measures ensured consistent boost volumes across the treatment groups, leaving timing of boost, synchronous versus sequential, as the main variable in the study. At 5 years, hypofractionated simultaneous integrated boost (48 Gy) showed non-inferiority in terms of ipsilateral breast tumour relapse (IBTR) compared with sequential boost with incidence of relapse much lower than anticipated, and with low late side effect rates in all groups.
There was no advantage for escalating to 53 Gy simultaneous integrated boost, which was associated with increased breast induration. By contrast, 48 Gy simultaneous integrated boost showed similar or reduced normal tissue toxicity compared with control. Follow-up is ongoing and reporting of 10-year results is envisaged. The findings are reported by Prof. Charlotte E Coles of the Department of Oncology, University of Cambridge in Cambridge, UK, and colleagues on 8 June 2023 in The Lancet.
The authors wrote in the background that data from pathological breast specimens and clinical studies suggest that most IBTRs occur close to the original site of resection. Randomised studies of breast conserving surgery followed by whole breast radiotherapy with or without a tumour bed boost have showed that a boost roughly halves the risk of breast tumour relapse. Although individual boost studies have not shown an overall survival advantage over whole breast radiotherapy alone, breast tumour relapse should be minimised as it often requires mastectomy and systemic therapy. Independent prognostic factors for local relapse include young age and high tumour grade.
The potential local control gain with boost is offset by an increased risk of late normal tissue toxicity, including an approximate doubling of breast fibrosis, which increases with irradiated volume. A tumour bed boost is traditionally delivered sequentially after whole breast radiotherapy in 5-8 fractions. It increases local cancer control rates, but requires more patient visits and can increase breast hardness. IMPORT HIGH is the largest randomised study to date testing dose-escalated simultaneous integrated boost against standard sequential boost. It builds on the results of previous UK breast radiotherapy studies and uses newer radiation techniques to address the challenges of boost radiotherapy.
IMPORT HIGH is a phase III, non-inferiority, open-label, randomised controlled study that recruited women after breast conserving surgery for pT1–3pN0–3aM0 invasive carcinoma from radiotherapy and referral centres in the UK. Patients were randomly allocated to receive one of 3 treatments in a 1:1:1 ratio, with computer-generated random permuted blocks used to stratify patients by centre.
The control group received 40 Gy in 15 fractions to the whole breast and 16 Gy in 8 fractions sequential photon tumour bed boost. Test group 1 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 48 Gy in 15 fractions concomitant photon boost to the tumour bed volume. Test group 2 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 53 Gy in 15 fractions concomitant photon boost to the tumour bed volume. The boost clinical target volume was the clip-defined tumour bed.
The primary endpoint was IBTR analysed by intention to treat; assuming 5% 5-year incidence with the control group, non-inferiority was predefined as 3% or less absolute excess in the test groups (upper limit of two-sided 95% confidence interval [CI]). Adverse events were assessed by clinicians, patients, and photographs. The study is closed to new participants.
Between 4 March 2009 and 16 September 2015, a total 2617 patients were recruited of whom 871 were assigned to the control group, 874 to test group 1, and 872 to test group 2. Median boost clinical target volume was 13 cm3. At a median follow-up of 74 months there were 76 IBTR events: 20 for the control group, 21 for test group 1, and 35 for test group 2.
5-year IBTR incidence was 1.9% (95% CI 1.2 to 3.1) for the control group, 2.0% (1.2 to 3.2) for test group 1, and 3.2% (2.2 to 4.7) for test group 2. The estimated absolute differences versus the control group were 0.1% (–0.8 to 1.7) for test group 1 and 1.4% (0.03 to 3.8) for test group 2. The upper confidence limit for test group 1 versus the control group indicated non-inferiority for 48 Gy.
Cumulative 5-year incidence of clinician-reported moderate or marked breast induration was 11.5% for the control group, 10.6% for test group 1 (p = 0.40 versus control group), and 15.5% for test group 2 (p = 0.015 versus control group).
The authors commented that observing lower than anticipated event rates adds complexity to interpretation of non-inferiority studies given that the relative effect threshold is defined according to the original absolute risk estimates. Therefore, the predefined critical hazard ratio translates to a smaller absolute difference, leading to dialogue around the importance of absolute versus relative treatment differences.
In IMPORT HIGH, the study management group, including patient advocates, discussed this specific dilemma while still masked to the observed results. It was agreed that the absolute 3% difference between groups and confirmation that event rates were low compared with the anticipated 5% IBTR were of importance. There was no evidence of a difference in efficacy endpoints between groups. Within the two simultaneous integrated boost test groups there was no evidence of benefit in escalating boost dose beyond current biologically equivalent standard of care doses. Prevalence of moderate or marked late normal tissue adverse events was low in all groups for clinician-reported, patient-reported, and photographic assessments, with no statistically significant differences in rates between study groups.
The authors concluded that IBTR rates are low in this higher risk breast cancer group treated with small boosts, whether boost is delivered sequentially or simultaneously, with the upper limit of the 95% CI excluding the 5-year 5% rate originally predicted for the control group. Non-inferiority for IBTR was achieved in absolute terms according to the prespecified difference of 3% for test group 1 versus control, but not for test group 2. This study highlights the challenges of assessing non-inferiority when primary outcome event rates become very low. Rates of 5-year moderate or marked adverse events are low and 48 Gy simultaneous integrated boost showed similar or reduced toxicity compared with the control group. Simultaneous integrated boost is a safe treatment that requires fewer patient visits and further escalation of boost dose does not appear advantageous.
The study was funded by Cancer Research UK.
Reference
Coles CE, Haviland JS, Kirby AM, et al. on behalf of the IMPORT Trial Management Group. Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer (IMPORT HIGH): a multicentre, phase 3, non-inferiority, open-label, randomised controlled trial. The Lancet; Published online 8 June 2023. DOI: https://doi.org/10.1016/S0140-6736(23)00619-0
