Hypofractionation Radiotherapy vs. Conventional Fractionation for Breast Cancer: A Comparative Review of Toxicity

The use of postoperative radiation therapy after breast-conserving surgery was longstanding standard practice. The treatment protocol used a standard fractionation of 50 Gy in 25 fractions plus a boost. Recently, the hypofractionation approach has gained support based on Canadian and English studies that claimed equal tumor control and similar toxicity to the standard protocol. We conducted a review of the literature of hypofractionation studies and compared the reported toxicity with the general literature. We placed special emphasis on breast fibrosis after hypofractionation versus standard fractionation. We found a striking difference in the breast toxicity reported by the hypofractionation literature regarding breast fibrosis as compared to standard fractionation. Breast fibrosis should be explored further via additional studies and discussed with potential breast-conserving surgery patients.


Introduction And Background
Recently, the American Society of Radiation Oncology released a task force guideline recommending hypofractionated radiotherapy for all women of any age whether they had received chemotherapy or not [1]. Their evidence-based recommendations were supported by studies from Canada and the United Kingdom [2][3][4][5][6]. This study is a review of the scientific and radiobiological basis for the two treatment protocols (hypofractionation and standard fractionation) and an evaluation of the short-term and long-term toxicity reported.

Review
According to Hall, "laboratory data proved that fewer and large dose fractions result in more severe late reactions, even though the early reactions are matched by an appropriate adjustment in total dose" [7]. Hall also reports that if "a fractionated scheme is changed in clinical practice from many small doses to a few large fractions and the total dose is titrated to produce equal early effects, the treatment protocol involving a few large fractions results in more severe late effects" [7]. Fraction size, according to Hall, "is the dominant factor in determining late effects, the overall treatment time has little influence" [7].
We calculated the biological effective dose (BED) for both protocols using α/β of 3 Gy for late 1 2 tissues and α/β of 10 Gy for early tissues.
In regards to the standard fractionation (50 Gy in 2-Gy fractions), the BED for late tissues was 83.3 Gy and 60 Gy for early tissues where: Comparatively, for hypofractionation (41.6 Gy in 3.2 Gy per fraction), the BED for late tissues was 86 Gy and 55 Gy for early tissues.   14 Gy in five to seven fractions). The cosmetic assessment was dependent on photographs and the patient's own assessment. There was no report of breast fibrosis. They reported similar or improved cosmetic outcomes with hypofractionation as compared to standard fractionation [9].
These studies showed a high rate of breast fibrosis with hypofractionation and a similarly high rate of breast fibrosis with standard fractionation.
Haviland reported more side effects with a fractionation schedule of 13 sessions at 3.3 Gy versus 50 sessions at 2 Gy or 39 sessions at 3 Gy. There was a statistically significantly increased rate of physician-assessed shoulder stiffness in the 42.9-Gy schedule compared to the 50-Gy treatment in the START pilot (hazard ratio, 3.07; 95% confidence interval, 1.62 to 5.83, p = 0.001). There was no such effect reported for the hypofractionated schedules in START-A and START-B [10]. Table 2 presents a comparison of the incidence of breast induration.   [11]. Yu et al. found 19% subcutaneous fibrosis after hypofractionation, yet "good" or "excellent" cosmesis was reported in 94% of the cases [12]. According to Pezner, a "course of external beam radiation therapy to the whole breast to a dose of 50 Gy in 25 fractions without local boost yields cosmetic results with little if any palpable fibrosis, even after 12 years of follow-up" [13]. Bartelink  breast fibrosis after 5000 cGy of breast radiation is rare. He also reported an increase in breast fibrosis after 6000 cGy [16].

Incidence of Breast Induration
De La Rochefordiere et al. found that using a dose of more than 2 Gy per fraction is associated with worse cosmesis [17]. Clark et al. concluded that daily fractionation with a dose of 2.5 Gy leads to greater fibrosis and breast retraction [18]. There were many reports stating that radiation oncologists in the United States are reluctant to adopt the hypofractionation regimen [19].

Conclusions
There is some discrepancy between hypofractionation studies and many other literature reports about the incidence of breast fibrosis reported for standard fractionation. Breast fibrosis can be a potential side effect of hypofractionated radiotherapy that needs to be further studied.