Emerging evidence for de-escalation and hypofractionation of radiotherapy in early breast cancer
Authors: Professor Ian Kunkler
Institution: Institute of Cancer Genetics, University of Edinburgh
Introduction
Radiotherapy with surgery and systemic therapy remain the core treatments in the multidisciplinary treatment of early breast cancer. With breast screening and advances in diagnostic imaging and pathology, they have led to a dramatic fall in UK breast cancer mortality. Improved systemic therapy has almost certainly also made an important contribution to parallel falling loco-regional recurrence rates.
Methods
Historically virtually all patients underwent postoperative radiotherapy after breast-conserving surgery (BCS), and most with node-positive disease after mastectomy. We are moving away from a 'one size fits all' approach to a more nuanced one based on individual risk of recurrence. With the fixed risks of radiation toxicity (cardiac damage/second malignancies), non-essential radiotherapy should be avoided where possible. This concept is exemplified by the US Choosing Wisely policy. Over the last two decades randomised trials have shown that postoperative radiotherapy after breast-conserving surgery in lower-risk, older, hormone-receptor-positive women (CALGB, PRIME 2), receiving 5 years of adjuvant endocrine therapy, can be safely omitted. Other trials of selective radiotherapy de-escalation in biomarker-directed trials (LUMINA, IDEA) suggest this approach may be applicable in low-risk younger patients. Other trials testing this hypothesis are ongoing. Shorter hypofractionated (40 Gy in 15 daily fractions) or ultra-hypofractionated (26 Gy in 5 daily fractions (eg FAST-FORWARD) to the breast or chest wall or partial breast irradiation (IMPORT-LOW) have proved as effective and more convenient to patients but with lower acute and late morbidity. Further evidence is needed on 1 week of radiotherapy in patients undergoing immediate reconstruction. There is limited data on hypofractionated regional nodal irradiation.
Results
Suggested minimum standards for hypofractionation in low- and middle-income countries include a linear accelerator with the capability to provide 3DCRT with 5 mm collimators, CT treatment simulation, inverse planning, quality assurance protocols and a well-trained team of radiation/clinical oncologists, medical physicists, therapy radiographers/radiation therapists and dosimetrists. Hypofractionation may widen access to radiotherapy, reduce travelling time for patients and cause loss of income. Postoperative radiotherapy alone after BCS, avoiding the toxicity of adjuvant endocrine therapy in low-risk, older luminal A-like patients, is being explored in the EUROPA trial.
Conclusion
The MRC/EORTC SUPREMO has shown that in intermediate-risk breast cancer adjuvant chest wall irradiation does not improve 10-year overall survival and has a minimal effect on chest wall recurrence. There has been a paradigm shift in loco-regional radiotherapy from an anatomy-based approach to a biologically informed and adapted one. Response to neoadjuvant chemotherapy (e.g., the NSABP B51 trial) can guide the need for adjuvant irradiation. Identifying biomarkers which predict individual benefit from irradiation is an active field of investigation, but none is yet sufficiently validated for routine use in the clinic.