Challenges for breast radiotherapy with SIB: the IMPORT HIGH trial – Authors' reply
Authors: Charlotte E Coles, Joanne S Haviland, Anna M Kirby, Clare Griffin, Mark Sydenham, Judith M Bliss
Journal: The Lancet (2024)

We thank the authors for their positive comments regarding the IMPORT HIGH trial.1Coles CE Haviland JS Kirby AM et al.Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer (IMPORT HIGH): a multicentre, phase 3, non-inferiority, open-label, randomised controlled trial.Lancet. 2023; 401: 2124-2137Summary Full Text Full Text PDF PubMed Google Scholar The main points raised are addressed as follows. We agree with Yongkai Lu and colleagues that deep-inspiratory breath-hold is an important technique to reduce mean heart and lung dose. However, this technique was only becoming UK standard of care in the last months of the trial, so the number of people receiving it would have been small. Despite this, more than 99% and more than 97% of radiotherapy plans achieved the stringent mandatory dose constraints for heart and ipsilateral lung, respectively (appendix of the Article p 22).1Coles CE Haviland JS Kirby AM et al.Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer (IMPORT HIGH): a multicentre, phase 3, non-inferiority, open-label, randomised controlled trial.Lancet. 2023; 401: 2124-2137Summary Full Text Full Text PDF PubMed Google Scholar The median mean heart dose was less than 3 Gy with an IQR of 1·7–3·7 Gy across all groups. Using the Darby Tables,2Darby SC Ewertz M McGale P et al.Risk of ischemic heart disease in women after radiotherapy for breast cancer.N Engl J Med. 2013; 368: 987-998Crossref PubMed Scopus (2848) Google Scholar the estimated absolute risk of radiation-related disease by age 80 years for a woman receiving a mean heart dose of 3 Gy is 1% and this increases to 1·7% with at least one cardiac risk factor. There were ten instances of ischaemic heart disease reported in IMPORT HIGH and confirmed by investigation; 8 and 2 from people with left-sided and right-sided breast cancer, respectively. We have no concerns regarding the long-term cardiopulmonary risks with IMPORT HIGH and do not accept that a few patients receiving deep-inspiratory breath-hold would introduce bias, given the low mean heart doses already achieved and the very small absolute risk of late toxicity. Masashi Mizumoto and colleagues raise the possibility of increased risk of second malignancies due to doses to organs at risk from rotational intensity modulated radiotherapy (IMRT). We are confident that IMPORT HIGH will not have increased risk compared with sequential boost, as the whole breast dose was delivered using tangential techniques to reduce the dose to organs at risk and only the small boost dose volume was delivered with rotational IMRT. The median mean lung doses across groups were 5·20–5·60 Gy and 0·34–0·52 Gy for ipsilateral and contralateral lung, respectively. 99% of all plans achieved a contralateral mean breast dose of less than 1·5 Gy (appendix of the Article p 23).1Coles CE Haviland JS Kirby AM et al.Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer (IMPORT HIGH): a multicentre, phase 3, non-inferiority, open-label, randomised controlled trial.Lancet. 2023; 401: 2124-2137Summary Full Text Full Text PDF PubMed Google Scholar We agree with Jose Luis Guinot and colleagues that many patients older than 50 years do not require a boost and can be treated in 5 days: this is UK practice. The median age in IMPORT HIGH was 48·9 years and those older than 50 years typically had biologically high-risk breast cancers. Subgroup analysis by age was not planned because the event rate for local recurrence is very low, making these data unreliable, especially as there were only 322 participants younger than 40 years within our trial. Continued follow-up and reporting of 10-year results in IMPORT HIGH are planned. We thank Thomas Mulliez and Mark De Ridder for highlighting that IMPORT HIGH achieved very low local recurrence events despite much smaller than traditional boost volumes. We feel that these small boost volumes contribute to the low late toxicity reported. 10% of patients in IMPORT HIGH received regional radiotherapy because axillary lymph node dissection was standard for node-positive breast cancer at that time and only patients with N2 disease received supraclavicular fossa radiotherapy (now called level 3 and 4 lymph node regions). We agree that more research is required to individualise boost treatment and we are exploring the molecular clonality and spatial mapping of original tumours and recurrences in a translational study. We thank Fabiana Gregucci and Antonella Ciabattoni for showcasing their cohort study of 91 patients treated with concurrent breast boost. We look forward to the published results of the NRG RTOG 1005 trial. JMB, CG, JSH, and MS report grants from Cancer Research UK during the conduct of the study. JMB reports grants and non-financial support from AstraZeneca, Clovis Oncology, Eli Lilly, Janssen-Cilag, Merck Sharp & Dohme, Novartis (previously GlaxoSmithKline), Pfizer, Puma Biotechnology, and Roche outside the submitted work. AMK is President of the European Society of Radiation Oncology. CEC reports grants from the National Institute for Health Research Efficacy and Mechanism Evaluation, Cancer Research UK RadNet, the Lancet Breast Cancer Commission, and Addenbrooke's Charitable Trust outside the submitted work; reports membership of five external independent monitoring committees; is Chair of the Lancet Breast Cancer Commission; and is funded by the National Institute for Health and Care Research (NIHR) and supported by the NIHR Cambridge Biomedical Research Centre. The views expressed are those of CEC and not necessarily those of the NIHR or the UK Department of Health and Social Care. Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer (IMPORT HIGH): a multicentre, phase 3, non-inferiority, open-label, randomised controlled trialIn all groups 5-year IBTR incidence was lower than the 5% originally expected regardless of boost sequencing. Dose-escalation is not advantageous. 5-year moderate or marked adverse event rates were low using small boost volumes. Simultaneous integrated boost in IMPORT HIGH was safe and reduced patient visits. Full-Text PDF Open AccessChallenges for breast radiotherapy with SIB: the IMPORT HIGH trialCharlotte E Coles and colleagues1 discuss the latest results from the IMPORT HIGH research, a phase 3 randomised trial that assessed three hypofractionated radiation treatments for efficacy and safety. Most patients were scanned while free breathing, with deep-inspiratory breath-hold techniques implemented only at the end of the trial. This may have biased experimental results. In ischaemic heart disease, pneumonia, and pulmonary fibrosis, considerable delayed unfavourable consequences show the possibility for variance. Full-Text PDF Challenges for breast radiotherapy with SIB: the IMPORT HIGH trialCharlotte E Coles and colleagues,1 on behalf of the IMPORT Trial Management Group, published the results of a phase 3, non-inferiority trial (IMPORT HIGH) comparing standard breast radiotherapy with a sequential (23 fractions) or concomitant (simultaneous integrated boost of 15 fractions) boost to the tumour bed. The trial randomly assigned 2617 patients with early breast cancer and showed comparable safety and efficacy (defined as incidence of ipsilateral breast recurrence) of the shorter regimens at a median follow-up of 74 months. Full-Text PDF Challenges for breast radiotherapy with SIB: the IMPORT HIGH trialThe excellent results of the IMPORT HIGH trial,1 published with more than 6 years of median follow-up, suggest that this treatment is adequate for all patients with breast cancer. In the boost versus no boost trial, the risk of relapse at 5 years of follow-up with 66 Gy to the tumour bed was around 3%, which increased to 6·2% at 10 years. But in young patients (aged 41–50 years) the risk of relapse reached 8·7% at 10 years,2 and for those younger than 41 years it was 13·5% at 10 years. These statistics rose to 13·5% and 24·4% at 20 years, respectively. Full-Text PDF Challenges for breast radiotherapy with SIB: the IMPORT HIGH trialWe thank the IMPORT HIGH trial1 authors for conducting a well designed randomised controlled trial comparing whole-breast radiotherapy with a sequential boost versus two simultaneous integrated boost (SIB) protocols, one with a normal and one with a dose-escalated boost dose. Oncological outcomes were comparable and late toxicity was low; however, more breast induration was detected in the dose-escalated SIB group. Full-Text PDF Challenges for breast radiotherapy with SIB: the IMPORT HIGH trialWe read the Article by Charlotte E Coles and colleagues1 with great interest. The use of hypofractionated simultaneous integrated boost (SIB) radiotherapy with a 48 Gy dose in 15 fractions to the tumour bed showed non-inferiority in ipsilateral local relapse compared with sequential boost. In addition, the lower number of treatments for SIB (15) versus sequential boost (23) have a positive effect on the patients themselves and on the health-care system. To achieve dose localisation, an intensity modulated radiotherapy (IMRT) technique was allowed in this study. Full-Text PDF