Why 25 Gy/5 Fractions Is Not Widely Used Despite Promising Results
The 25 Gy in 5 fractions regimen is not used because it was never tested—the actual regimen studied and proven effective was 26 Gy in 5 fractions, which IS now recommended by current guidelines and is being adopted into clinical practice. 1
The Evidence Base: What Was Actually Studied
The confusion stems from misidentifying the dose. The FAST-Forward trial, which provided the breakthrough evidence for ultra-hypofractionation, tested 26 Gy in 5 fractions (not 25 Gy) and demonstrated non-inferiority to the standard 40 Gy in 15 fractions regimen. 2, 3
Key Trial Results
FAST-Forward trial (2020,5-year results): With 71.5 months median follow-up, 26 Gy/5 fractions showed a 5-year ipsilateral breast tumor relapse rate of 1.4% compared to 2.1% for 40 Gy/15 fractions, with a hazard ratio of 0.67 (95% CI 0.38-1.16), meeting non-inferiority criteria (p=0.00019). 2
Normal tissue effects were comparable: 5-year prevalence of moderate/marked clinician-assessed breast effects was 11.9% for 26 Gy versus 9.9% for 40 Gy, with an odds ratio of 1.12 (95% CI 0.94-1.34, p=0.20)—not statistically significant. 2, 3
The trial also tested 27 Gy/5 fractions, which showed significantly worse cosmetic outcomes (OR 1.55, p<0.0001) and was therefore rejected. 2
Current Guideline Adoption
The 26 Gy/5 fractions regimen IS now endorsed by major guidelines:
ESMO 2024 guidelines explicitly state: "The FAST-Forward trial demonstrated that after 6 years' median follow-up, ultra-hypofractionation of 26 Gy in five fractions in 1 week results in the same oncological and safety outcomes for breast and chest wall irradiation." 1
The ESTRO Advisory Committee recommends shorter regimens whenever indicated. 1
Important Limitations on Use
The critical caveat is that this regimen is validated specifically for breast and chest wall irradiation, NOT for comprehensive locoregional radiotherapy:
Awaiting data: The ESMO guidelines explicitly note that "in terms of outcomes after ultra-hypofractionation for locoregional RT, data from a prospective sub-study are awaited." 1
Current restriction: The 26 Gy/5 fractions schedule should be used for whole breast or chest wall radiation only, not when treating regional lymph nodes comprehensively. 1
For patients requiring regional nodal irradiation (axillary levels, supraclavicular, internal mammary nodes), moderate hypofractionation (15-16 fractions) remains the standard until further evidence emerges. 1
Why Adoption Takes Time
Even with strong evidence, clinical practice changes gradually due to:
Infrastructure requirements: Implementing ultra-hypofractionation requires updated treatment planning systems, quality assurance protocols, and staff training. 3
Physician comfort: Many radiation oncologists are waiting for 10-year follow-up data before fully adopting the regimen, despite 5-year data showing non-inferiority. 2, 4
Regional variations: The FAST-Forward trial was conducted in predominantly Caucasian UK populations; validation in other populations (particularly node-positive disease requiring regional nodal radiation) is ongoing through trials like HYPORT-Adjuvant in India. 5
Clinical Algorithm for Implementation
For whole breast radiation after breast-conserving surgery (without regional nodal irradiation):
- Use 26 Gy in 5 fractions over 1 week as a standard option, equivalent to 40 Gy in 15 fractions. 1, 2
- Add boost doses as needed (typically 10-16 Gy) for high-risk features. 1
For post-mastectomy chest wall radiation (without regional nodes):
For locoregional radiation including regional lymph nodes:
- Continue using moderate hypofractionation (40 Gy in 15 fractions) until prospective sub-study data become available. 1
- Conventional fractionation (45-50 Gy in 25-28 fractions) remains an alternative. 1
For frail patients with transportation difficulties:
- An alternative ultra-hypofractionation regimen of 5.7-6.0 Gy once weekly over 5 weeks can be used. 1