Decades ago, the concept of 50 Gy/25 fractions to eradicate residual microscopical disease was calculated based on a 50% cell survival rate after 2 Gy. Moderately hypofractionated RT became introduced as the new standard based on solid data more than 10 years ago, but its broad adoption remains slowed down a.o. due to improper considerations such as inappropriate reimbursement based on the number of fractions. Nowadays, the only patients that might benefit from more protracted schedules are those for whom we combine it with systemic or other concomitant therapies to obtain radio-sensitisation.
Since the publication of the results of the FAST-Forward trial, with a median follow-up of 71.5 months, ultra-hypofractionated radiation therapy should be considered the new standard for whole breast irradiation. Whereas the COVID-related “pandemisery” facilitated rapid introduction in clinical practice, it should indeed not be considered as a “crisis-related schedule”. Quite like for the adaptation of moderate hypofractionation, considerable reluctance exists regarding the clinical introduction of ultra-hypofractionation, even for whole breast irradiation which formed the vast majority of the trial population of in total 4096 patients.
We saw that, similar to moderate hypofractionation studies in breast and prostate cancer, small differences in fractionation exert a measurable impact on endpoints, as seen in the 27 Gy in 5 fractions regimen. Noteworthy, with 40 Gy/15 fractions being more gentle for normal tissues compared to 50 Gy/25 fractions, we now see that the 26 Gy/5 fractions is iso-effective for normal tissue effects with 40 Gy/15 fractions, while 27 Gy/5 fractions equates the side effects seen with 50 Gy/25 fractions. Several large trials that evaluated e.g., the value of a boost to the primary tumourbed, clearly showed that the difference in development of fibrosis and the impact on cosmetic outcome with a (higher) boost dose is present after 3 to 5 years, with thereafter only little further changes in frequency and severity of side effects. Therefore, the follow-up of nearly 6 years of the FAST-Forward trial reliably provides evidence for long-term evolution of fibrosis and cosmesis. Moreover, the prevalence of moderate/marked late effects was low in all FAST-Forward schedules, the most frequent being breast shrinkage assessed by clinicians in merely 5.5% of patients after 40 Gy/15 fractions compared with 6.8% after 26 Gy/5 fractions.
Real life evidence, e.g., based on prospective cohorts and registration studies can assist in the broad introduction of ultra-hypofractionation. However, I strongly advocate that further randomised research in this field should focus on topics such as immediate breast reconstruction, simultaneous integrated boost, preoperative RT, combinations with other treatments and nodal irradiation, instead of spending the little money that is available for pure academic radiation oncology research to repeat was has already been demonstrated.