Early-stage breast cancer: falling risks and emerging options
Authors: Reshma Jagsi
Journal: The Lancet (2017)

Great improvements in the therapeutic ratio of cancer treatment can result from innovative approaches that maintain tumour control benefits while lowering treatment-associated morbidity. The IMPORT LOW trial by Charlotte Coles and colleagues1Coles CE Griffin CL Kirby AM et al.on behalf of the IMPORT TrialistsPartial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial.Lancet. 2017; (published online Aug 2.)http://dx.doi.org/10.1016/S0140-6736(17)31145-5Google Scholar in The Lancet is a high-quality randomised trial of treatment de-escalation in the multidisciplinary management of breast cancer. Numerous trials and their meta-analyses have established that after breast-conserving surgery, radiotherapy cuts the risk of recurrence by half and reduces breast cancer mortality.2Early Breast Cancer Trialists' Collaborative Group (EBCTCG)Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10 801 women in 17 randomised trials.Lancet. 2011; 378: 1707-1716Summary Full Text Full Text PDF PubMed Scopus (2508) Google Scholar However, this treatment can also result in serious morbidity due to the incidental irradiation of normal tissues, including the heart, lung, and normal breast.3Darby 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 (2417) Google Scholar, 4Taylor C Correa C Duane FK et al.for the Early Breast Cancer Trialists' Collaborative GroupEstimating the risks of breast cancer radiotherapy: evidence from modern radiation doses to the lungs and heart and from previous randomized trials.J Clin Oncol. 2017; 35: 1641-1649Crossref PubMed Scopus (415) Google Scholar Partial-breast irradiation reduces the dose to normal tissues by treating only the region surrounding the tumour bed (the site of most local failures) rather than the traditional radiotherapeutic target (the whole breast). By reducing the volume of tissue irradiated, particularly when using advanced techniques that allow highly conformal dose distributions, the number of treatments needed could be reduced by allowing higher doses per treatment fraction than conventionally administered to the whole breast. Indeed, many trials have investigated or are investigating the simultaneous reduction in the treatment field and increased radiation dose per fraction in an attempt to reduce not only toxicity but also the burden from multiple repeated treatments.5Olivotto IA Whelan TJ Parpia S et al.Interim cosmetic and toxicity results from RAPID: a randomized trial of accelerated partial breast irradiation using three-dimensional conformal external beam radiation therapy.J Clin Oncol. 2013; 31: 4038-4045Crossref PubMed Scopus (309) Google Scholar, 6NSABP B-39, RTOG 0413: a randomized phase III study of conventional whole breast irradiation versus partial breast irradiation for women with stage 0, I, or II breast cancer.Clin Adv Hematol Oncol. 2006; 4: 719-721PubMed Google Scholar, 7Livi L Meattini I Marrazzo L et al.Accelerated partial breast irradiation using intensity-modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial.Eur J Cancer. 2015; 51: 451-463Summary Full Text Full Text PDF PubMed Scopus (325) Google Scholar By contrast, IMPORT LOW used a relatively simple technique to reduce the volume of treatment, while holding radiation dose and fractionation constant. The control group received a whole-breast regimen of 40 Gy radiotherapy daily in 15 fractions. The experimental groups had treatment in the vicinity of the tumour bed with the same dose and fractionation (partial-breast group) and this treatment with the addition of 36 Gy on the remainder of the whole breast (reduced-dose group). Notably, their approach differs from the more highly conformal approach to partial-breast irradiation that is actively being investigated in other trials. Treatment in IMPORT LOW involved simple forward planning using standard medial and lateral tangential beams reduced in length. This design allows the trial to answer the pure question of whether a reduction in radiation field is safe, with findings that can be applied to many settings, including those with low availability of resources or lower technological capability. The trial shows non-inferiority, with remarkably low estimates of local relapse at 5 years (1·1% [95% CI 0·5–2·3] of patients in the control group, 0·2% [0·02–1·2] in the reduced-dose group, and 0·5% [0·2–1·4] in the partial-breast group). Serious consequences of radiotherapy were uncommon; establishing the effect of irradiating reduced volumes of tissues on endpoints such as cardiac events or second malignancy will probably ultimately require observational comparative effectiveness analyses or individual patient-level meta-analyses of the multiple trials investigating partial-breast irradiation. Still, because the trial laudably included assessment of patient-reported outcomes, it was possible for IMPORT LOW to show that partial-breast treatment reduced patient-reported changes in breast appearance, providing support for the idea that treatment de-escalation in some women is not only safe, but might reduce toxicity. The findings of the trial should, however, only be generalised to women similar to those actually enrolled: women aged 50 years or older with small, unifocal, non-lobular invasive carcinoma resected with non-cancerous tissue margins of 2 mm or more. Most of the women had received endocrine therapy whereas few had received chemotherapy. Most patients enrolled were node negative, and the authors themselves caution against generalising the results of this trial to node-positive patients. Ongoing research regarding radiotherapy de-escalation is still crucial. Even 15 fractions of partial-breast radiotherapy is burdensome and has toxicity risks. Mature data from trials investigating partial-breast regimens that can be administered more efficiently are therefore important, as are trials seeking to identify patients who might safely forego radiotherapy altogether. Indeed, perhaps the most striking finding of IMPORT LOW is not simply that of non-inferiority but rather the extremely low absolute recurrence rates observed across all groups, which were markedly lower than in historical trials.2Early Breast Cancer Trialists' Collaborative Group (EBCTCG)Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10 801 women in 17 randomised trials.Lancet. 2011; 378: 1707-1716Summary Full Text Full Text PDF PubMed Scopus (2508) Google Scholar Although previous trials have not identified a subgroup of women in whom adjuvant radiotherapy might safely be omitted altogether, with the exception of older women with small hormone-sensitive tumours,8Hughes KS Schnaper LA Berry D et al.for the Cancer and Leukemia Group BRadiation Therapy Oncology GroupEastern Cooperative Oncology GroupLumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer.N Engl J Med. 2004; 351: 971-977Crossref PubMed Scopus (850) Google Scholar, 9Kunkler IH Williams LJ Jack WJ Cameron DA Dixon JM on behalf of the PRIME II investigatorsBreast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.Lancet Oncol. 2015; 16: 266-273Summary Full Text Full Text PDF PubMed Scopus (567) Google Scholar the remarkably low recurrence rates observed in this trial prompt yet again the question of whether some other patients might also reasonably omit radiotherapy. Although longer follow-up is needed, particularly in patients with favourable disease whose recurrences might develop late, the findings of IMPORT LOW support ongoing efforts in the UK, the USA, and beyond that aim to establish whether improvements in other disciplines (eg, imaging, pathology, surgery, and systemic therapy) might now render adjuvant radiotherapy immediately after breast-conserving surgery to be optional for an even larger, identifiable subgroup of patients who are not currently given this option.10Gradishar WJ Anderson BO Balassanian R et al.NCCN guidelines insights: breast cancer, version 1·2017.J Natl Compr Canc Netw. 2017; 15: 433-451Crossref PubMed Scopus (281) Google Scholar In summary, efforts to minimise toxicity and burden of treatment are increasingly important in an era of falling recurrence risks. Future generations of women diagnosed with breast cancer will benefit not only from the findings of the IMPORT LOW trial itself but also from the advances that will build on its foundational efforts. I have received grants from the National Institutes of Health (R01 and P01), the Doris Duke Foundation, and the Greenwall Foundation. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trialWe showed non-inferiority of partial-breast and reduced-dose radiotherapy compared with the standard whole-breast radiotherapy in terms of local relapse in a cohort of patients with early breast cancer, and equivalent or fewer late normal-tissue adverse effects were seen. This simple radiotherapy technique is implementable in radiotherapy centres worldwide. Full-Text PDF Open Access