A comprehensive search of the PubMed database (https://pubmed.ncbi.nlm.nih.gov/) was performed to identify clinical trials on hypofractionated and ultrahypofractionated radiotherapy for breast cancer (Fig. 1). The following search query was used: ((‘breast neoplasms’[MeSH Terms] OR ‘breast cancer’[Title/Abstract]) AND (‘hypofractionation’[Title/Abstract] OR ‘hypofractionated’[Title/Abstract] OR ‘ultrahypofractionation’[Title/Abstract]) AND (‘randomized controlled trial’[Publication Type] OR ‘clinical trial’[Publication Type])) AND (‘2010’[Date-Publication]: ‘2024’[Date-Publication]).

Inclusion criteria. The inclusion criteria were as follows: i) Clinical trials published after 2010 involving patients with breast cancer receiving adjuvant radiotherapy. ii) Studies examining hypofractionated or ultra-hypofractionated radiotherapy. iii) Study design should be a clinical trial. iv) Trials reporting local or locoregional control as outcomes.

Exclusion criteria. The exclusion criteria were as follows: i) Studies with designs other than clinical trials. ii) Studies investigating fractionation regimens with a concomitant boost to the tumor bed. iii) Studies focusing on partial breast irradiation instead of whole breast irradiation. iv) Studies reporting only toxicity outcomes without local or locoregional control. For eligible studies, data were collected on total dose, number of fractions and fraction size.

An additional search was conducted in PubMed to identify studies discussing or proposing α/β ratios for breast cancer cells (Fig. 2). The studies identified in the earlier search were included in this phase, as they typically mention α/β ratios to justify the hypofractionated regimens used. Also, a previous study that discussed possible α/β ratios for breast cancer cells was also reviewed (12). The following search query was applied: ((‘breast neoplasms’[MeSH Terms] OR ‘breast cancer’[Title/Abstract] OR ‘breast carcinoma’[Title/Abstract]) AND (‘alpha-beta ratio’[Title/Abstract] OR ‘alpha beta ratio’[Title/Abstract] OR ‘α/β ratio’[Title/Abstract] OR ‘radiobiological parameters’[Title/Abstract]) AND (‘dose-response relationship’[Title/Abstract] OR ‘radiotherapy’[Title/Abstract] OR ‘radiation therapy’[Title/Abstract])).

Inclusion criteria. Studies investigating, adopting, or suggesting an α/β ratio for breast cancer cells (in vivo or in vitro) were included.

Exclusion criteria. The exclusion criteria were as follows: i) Studies not reporting any discussion about α/β ratio for breast cancer cells. ii) Studies examining α/β ratio of normal cells only. iii) Studies discussing α/β ratios for cancers other than breast cancer. Data on the α/β ratios adopted, utilized, or proposed by the included studies were collected.

The study selection process was conducted as follows: First, titles and abstracts were screened to identify studies that potentially met the inclusion criteria. Full-text review was then carried out for selected articles to confirm their eligibility for inclusion in the scoping review.

Subsequently, BED was analyzed for different fractionation schedules based on the different α/β ratios.

Analysis was conducted via GraphPad Prism 10.2.2. The BED and EQD2 were calculated using various α/β ratios extracted from the literature. Calculated values were rounded for clarity and ease of interpretation. To evaluate the variability of BED across fractionation regimens, the coefficient of variation (CV) was computed for both BED and BED adjusted for tumor repopulation (BED-kT). The Brown-Forsythe ANOVA test was employed to assess differences in variances across various α/β ratios. Lastly, a discussion of different practice-changing hypofractionation trials and elaboration of the doses used to yield equivalent tumor control probabilities were provided.

Starting with the data from clinical trials, from an analysis of 158 cases of ipsilateral local tumor recurrence, breast cancer α/β ratio was estimated at ~4.0 Gy (11). Yet, the estimation of this value has been evolving with the cumulative evidence of other altered fractionation trials and studies.

The START-P and START-A trials, spanning nearly two decades, have been pivotal in this journey. These trials were designed to directly assess the α/β ratio for tumor control and normal tissue effects (NTE) while standardizing overall treatment time (5-7). By comparing a standard 25-fraction regimen with two experimental 13-fraction hypofractionated regimens, all administered over 5 weeks, these trials provided valuable insights into the α/β ratios for both late toxicity endpoints and tumor control without the influence of varying overall treatment time.

START-P showed an estimated α/β value of 3.6 Gy [95% confidence interval (CI), 1.8-5.4] for any change in breast appearance, and an α/β value for palpable breast induration of 3.1 Gy (95% CI, 1.8-4.4) (5). Collectively, an α/β value of ~3 Gy for late normal tissue changes in the breast is inferred from the equivalence observed between 41.6 Gy delivered in 13 fractions and 50 Gy in 25 fractions over 5 weeks (5).

START-A trial randomized 2,236 patients to 50 Gy/25 Fx vs. 41.6 Gy or 39 Gy in 13 Fx every other day. With a median follow up of 9.3 years, no difference in 10-year locoregional control was found between the hypofractionated regimens and standard fractionation (41.6 Gy vs. 50 Gy: 6.3 vs. 7.4%; P=0.65 and 39 Gy vs. 50 Gy: 8.8 vs. 7.4%; P=0.41) (6).

The α/β ratio estimated for breast cancer based on local-regional relapse data in START Trial A is 4.8 Gy (95% CI, 0-16.3 Gy), bolstered by a meta-analysis including results from the pilot trial, yielding an α/β ratio estimate of 4.6 Gy (95% CI, 1.1-8.1) (7). This estimate aligns closely with the α/β ratio for NTE estimated at 3.4 Gy (95% CI, 2.3-4.5) from photographic assessments (6).

While uncertainties remain in precise fractionation sensitivity estimation, it was evident that breast cancer appears to differ from other cancers with higher α/β values, indicating potential variability in response to fraction size. As the story unfolded, START-B emerged as the next chapter, exploring how time influences treatment outcomes.

In START B trial, 1,105 women were allocated to the 50 Gy group and 1,110 to the 40 Gy group, with a median follow-up of 6.0 years (interquartile range, 5.0-6.2), the 5-year local-regional tumor relapse rate was 2.2 (95% CI, 1.3-3.1) in the 40 Gy group and 3.3% (95% CI 2.2-4.5) in the 50 Gy group (13). This represents an absolute difference of -0.7% (95% CI, -1.7 to 0.9%), suggesting that local-regional relapse could potentially be up to 1.7% lower or at most 0.9% higher after 40 Gy compared with 50 Gy. Both photographic assessments and patient-reported evaluations indicated fewer late adverse effects following treatment with 40 Gy than with 50 Gy (side effects, including telangiectasia, breast shrinkage and edema were significantly less frequent in the hypofractionated regimen) (13).

Traditionally, it was anticipated that local-regional relapse rates would be higher with 40 Gy in 15 fractions than with 50 Gy in 25 fractions, based on an α/β point estimate of 3.5 Gy for local-regional tumor control derived from the START-P and START-A trials. Adjusting for the EQD2 (Table II), the 40 Gy regimen in START-B approximates closer to 45 Gy rather than 50 Gy, assuming no impact of treatment time.

In a Canadian randomized trial involving 1,234 patients, no significant difference in ipsilateral tumor recurrence was observed between schedules of 50 Gy in 25 fractions of 2.0 Gy over 35 days and 42.5 Gy in 16 fractions of 2.66 Gy over 22 days to the whole breast (11). While the comparison based on 44 events lacks precision, if both schedules are equally effective for tumor control, the α/β value for tumor response could potentially be as low as 3.0 Gy, aligning with the fractionation sensitivity observed in healthy tissues that develop adverse effects years later.

Following these pivotal trials, the American Society of Radiation Oncology recommends 15- or 16-fraction schedules as preferred options for whole-breast radiotherapy (14). These trials have not only reshaped the landscape of breast radiotherapy but also catalyzed a renaissance in altered fractionation strategies, paving the way for subsequent ultra-hypofractionation trials.

The α/β values derived from the FAST trial align closely with those observed in the 10-year analysis of the START-A trial, indicating estimates ranging from 3-4 Gy for late NTE in the breast (8). This consistency underscores the applicability of the linear-quadratic model for fraction sizes up to 5.0-6.0 Gy.

However, there appears to be a slightly heightened sensitivity (lower α/β value) than initially predicted (reduced rates of moist desquamation and subsequent late skin damage) when larger fractions are utilized. For instance, the FAST trial randomized 915 patients with early stage invasive ductal breast cancer (pT1-2 pN0; age ≥50) to 50 Gy/25 Fx, 30 Gy/5 Fx (once weekly), or 28.5 Gy/5 Fx (once weekly). After a median follow up of 9.9, findings showed that patchy/confluent moist desquamation rates were 11.7, 2.7 and 2.8% after doses of 50.0 Gy, 30.0 Gy and 28.5 Gy, respectively (8).

With an α/β value estimated at 2.7 Gy, the 15-fraction regimen equates to ~45.7 Gy in 2.0 Gy equivalents (Table II). The FAST trial identifies a 5-fraction schedule that appears radio-biologically equivalent to the standard 25-fraction regimen with respect to late NTE.

The FAST-Forward trial demonstrated the non-inferiority, as measured by ipsilateral breast tumor relapse rates at 5 years, of 27 Gy and 26 Gy schedules delivered in 5 fractions compared with 40 Gy in 15 fractions for patients with early breast cancer [5-year ipsilateral breast recurrence was similar among the three arms; 2.1 (40 Gy), 1.7 (27 Gy) and 1.4% (26 Gy)] (9). The NTE observed over 5 years with the 26 Gy regimen were comparable to those with the 40 Gy regimen.

Late NTE show a steep dose-response curve, allowing for clinically and statistically significant differences in event rates between the 26 Gy and 27 Gy schedules. While a 3-4 Gy difference in EQD2 between these regimens might appear small for detecting toxicity differences, understanding repair time can elucidate its significance. Repair time, typically measured in half-lives where 5 half-lives equate to ~95% repair, is crucial in late toxicity. Previous studies proposed a half-life of ~40 days for skin telangiectasia, suggesting a slow repair mechanism that mitigates toxicity over time (15,16).

The 26 Gy in 5 fractions schedule, which is equally effective with 40 Gy in 15 fractions, provides a direct estimation of α/β for late NTE, consistent with values observed in other trials. The α/β value of 3.7 Gy (95% CI, 0.3-7.1) for tumor control in FAST-Forward is similar to the 3.5 Gy (1.2-5.7) estimated from the START-P and START-A trials. Assuming no time effect, 26 Gy in 5 fractions corresponds to 46.8 Gy and 53.7 Gy in 2 Gy fractions, assuming α/β values of 2 Gy and 1 Gy, respectively (Table II).

The 26 Gy dose level exhibits similar NTE as the 40 Gy in 15 fractions regimen, supporting its adoption as a new standard for adjuvant breast radiotherapy. Based on the findings of these practice-changing studies, the ultra-hypofractionated dose of 26 Gy/5 Fx was adopted in the radiotherapy clinical guidelines of the European Society for Radiotherapy and Oncology Advisory Committee in Radiation Oncology Practice consensus (17) and the National Institute for Health and Care Excellence (18).

Although the LQ model has proven reliable for predicting late tissue toxicities, the present analysis reveals complexities when applying it to other critical endpoints, such as tumor control. These findings underscore the necessity for a more nuanced approach to radiobiological indices, particularly in the context of fractionation schedules. By rigorously examining BED variations across α/β ratios and incorporating considerations for tumor repopulation, it becomes clearer that further research is warranted to acquire stronger grasp on fundamental radiobiological properties of cancer cells.

The economic implications of hypofractionation and ultra-hypofractionation in breast cancer radiotherapy are substantial. Multiple studies have demonstrated the cost-effectiveness of these approaches (19-21). By reducing the number of treatment sessions, these fractionation schedules not only decrease the direct costs associated with fewer patient visits and less machine usage but also indirectly reduce expenses related to transportation and time off work for patients. These economic benefits make hypofractionated and ultra-hypofractionated regimens particularly appealing, especially in resource-limited settings. Resistance to adopting hypofractionation has even been revealed to add extra avoidable costs (22). Additionally, adding radiotherapy to hormonal therapy in older patients has been found to yield the highest clinical benefits and costs compared with hormonal therapy alone, indicating that radiotherapy combined with hormonal therapy is cost-effective in the US (23). Moreover, advancements in fractionation schedules have demonstrated that a 5-fraction regimen of radiotherapy is even more cost-effective than hormonal therapy in older patients (24). These findings suggested that future research should potentially shift practice towards this regimen, as omitting hormonal therapy might spare more side effects than omitting a 5-fraction schedule of radiotherapy, particularly for older patients.

Alongside advancements in fractionation schedules, the development of radiotherapy techniques such as three-dimensional conformal radiation therapy, intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) has transformed the landscape of breast cancer treatment. These technologies represent a significant leap forward in precision medicine, offering refined control over radiation dose distribution. IMRT and VMAT enable clinicians to achieve greater homogeneity in dose delivery within the target area while minimizing exposure to critical neighboring organs. Clinicians need to be mindful of the impact that such planning techniques can have on tumor and normal tissue radiation doses (25).

The equivalent uniform dose (EUD), pioneered by Niemierko (26), is a method used to address volume effects on normal tissue toxicity and tumor control by condensing dose distributions into a single dose level that yields equivalent biological effects. EUD is quantified as the uniform dose delivered in daily 1.8 Gy fractions, achieving an equivalent tumor control probability (TCP) compared with the original dose distribution, formulated as (26,27):

Where:

v_i is the fraction of the target volume irradiated with dose D_i

d_i is the fractional dose. In each dose bin, d_i can be calculated as .

γ is ln(2)/T_pot; T_pot is the potential doubling time; T_t is the treatment time.

The extent of irradiated normal tissue plays a critical role in predicting late toxicity. For example, IMRT has demonstrated potential improvements in the homogeneity index and EUD for targets (28). Addressing the challenges posed by non-uniform dose distributions is crucial for optimizing radiation plans, with methodologies including EUD and models such as normal tissue complication probability and TCP playing pivotal roles in plan evaluation.

Looking ahead, the incorporation of radiomics may show potential for customizing radiation plans and techniques according to the unique characteristics of each breast cancer patient, with the goal of improving treatment outcomes on a personalized basis (29-33). Progress in biomolecular markers, radio-genomics and radiomics is crucial in addressing individual patient vulnerability to late toxicity (34-38). Integrating these genomic and radiomic findings into comprehensive clinical and dosimetric predictive models offers the possibility of enhancing the accuracy of predictions for normal tissue toxicity. This integrated approach also empowers radiation oncologists to refine fractionation regimens more precisely, thereby optimizing treatment outcomes for their patients.

As the present scoping review focused on the radiobiology and clinical implications of whole-breast radiotherapy, the exploration of accelerated partial breast irradiation (APBI) is beyond its scope. APBI represents a significant shift in radiotherapy by targeting only the tumor bed rather than the entire breast. The rationale behind APBI is to achieve improved geometric sparing of healthy breast tissues using brachytherapy, external beam radiotherapy and intraoperative radiotherapy, thereby reducing treatment-related toxicity and improving cosmetic outcomes. The potential of APBI to further reduce the treatment burden and enhance patient quality of life underscores the ongoing evolution and personalization of breast cancer radiotherapy. The extensive and intriguing radiobiology, as well as the clinical and cost-effectiveness aspects of APBI, were not discussed in the present study.

Ultimately, this narrative of discovery and innovation in radiotherapy underscores a transformative era. It is a story where science and compassion converge, promising tailored treatments that not only combat cancer but also enhance patients' quality of life. As these developments are put behind, the future holds promise for personalized radiotherapy paradigms that redefine standards of care, offering renewed hope to those battling breast cancers.