This prospective randomized study of early BC patients is the first, according to our best knowledge, to evaluate the efficacy and side effects of five-fractions ABPI (30Gy in 5 fractions) compared to accelerated, currently most used, WBI regimen (40Gy in 15 fractions). Furthermore, in contrast to the other trials[6, 24], a dose of 30 Gy was administered in 5 consecutive daily fractions and also given the accuracy and fast rate of dose application (IGRT, CBCT, DIBH, FFF), a 3mm PTV margin could be used. Another difference from previous studies is the use of the VMAT technique for dose application. Based on our findings, APBI is highly tolerable in regards to both toxicity and cosmetic effects, ultimately providing definite benefits to patients. As a result, the technique of external APBI may be used more often in clinical practice in the future.
Other randomized trials dealing with external APBI compared this technique with standard fractionated WBI (50Gy in 25 fractions)[24, 33]. In addition, thanks to more precise irradiation using available modern technologies used in targeted RT in our settings, it was possible to reduce the volume of the PTV and thereby avoid the increased toxicity described in the oldest external APBI studies[13–15]. Comparing different fractionation schedules is also crucial. Studies involving twice-daily irradiation of patients reported increased toxicity and more adverse cosmetic effects [7, 8, 15]. Furthermore, our study demonstrated that consecutive irradiation yields favorable cosmetic outcomes with minimal toxicity, so irradiating every other day may not be necessary[34–36].
Adjuvant RT after primary surgery aims to eliminate the potential microscopic residual disease in the surgery bed and/or surrounding satellites[37, 38]. Recurrences occur most often at the site of the primary lesion[39, 40]. The randomized trials[6, 11, 24, 34, 41–46] have shown noninferiority in LC and OS after the tumor bed irradiation as opposed to WBI in patients with early BC after BCT[10–12, 47]. Based on these results, ASTRO and ESTRO recommend APBI instead of WBI to selected patients with early BC.
Published reputable studies [6, 45, 46] using external beam RT show better toxicity profiles and cosmetic effects in APBI arms. Livi et al.[24, 34, 41] compared the same APBI fractionation scheme (30Gy in 5 fractions, every other day) with standard WBI (50Gy in 25 fractions + boost). There was a significant difference in both any grade and grade ≥2 acute toxicity in favor of the APBI arm. The most frequently observed event was skin erythema (19.9% and 66.5% in APBI and WBI arms, respectively). Concerning late side effects, no grade ≥2 toxicity was observed in the APBI group. The most represented event was skin fibrosis in both arms (4.5% and 11.2% in APBI and WBI arms, respectively). The trial showed not only a significantly better toxicity profile but also the functional status and Qol after treatment and after 2 years were better in the APBI group, which is consistent with our study findings.
Some studies used 10 fractions in 5 days, i.e., twice daily irradiation,[7, 8, 15] for external APBI. Data on patient preferences are limited, but both patients and physicians consider twice-daily radiation to be complicated and not optimal[48, 49]. The Canadian phase III RAPID study demonstrated the noninferiority of APBI in LC and acute toxicity. However, late toxicity and cosmetic results favored WBI. The authors concluded that the six-hour interval between fractions is too short for reparation. The APBI dose regimen used in our study (30 Gy in 5 fractions) is satisfactory for adjuvant irradiation. Qi et al.[50] described the α/β ratio (basic radiobiological parameter) of breast tumors to be relatively low (α/β = 2.88), and therefore high-dose RT can be very beneficial in the same way. Using a linear quadratic model and assuming an α/β ratio of 3 or 2.5, the prescribed dose used in our APBI study is equivalent to 54 Gy or 56.7 Gy when using standard fractionation.
Since ASTRO and ESTRO recommendations were strictly followed 10–12, 47], only low-risk patients were included in APBI studies. Treatment results may be impaired if patients with a higher risk of recurrence (larger tumors, smaller surgical margins, hormone non-dependency, or lymph node involvement) are included. The NSABP B-39/RTOG 0413[8] study criteria for noninferiority of the APBI were not reached in the number of ipsilateral recurrences (although the absolute difference was 0.7%). Including patients with nodal disease (pN1mic or pN1) could affect the results of this trial.
The crucial factor affecting toxicity is the size of the target volume. Clinical trials using the 3D-CRT technique were associated with higher skin reactions and worse cosmetic results, particularly because of the need to accommodate extra safety margins to compensate for all inaccuracies during irradiation, including breast movements during breathing. The median PTV volumes in the published 3D-CRT studies were 269 cc, 296 cc, and 185 cc, respectively[51]. Livi et al.[24], as also mentioned above, used intensity modulated radiation therapy (IMRT) and showed no significant difference between PBI and WBI in ipsilateral breast tumor recurrence and survival rates at ten years, with significantly improved outcomes in treatment-related toxic effects and cosmetic results in favor of the APBI arm. The mean PTV volume in their trial was 139 cc (range 55–259). In our APBI trial, the VMAT technique was used for its accuracy and fast rate of dose application.[19] The median PTV volume in the APBI arm was 86.5 cc (range 40.9–189.9). The data presented from all the mentioned studies indicates that PTV volumes up to 150–180 cc are safe for applying the dose of 30Gy in 5 fractions.
A growing interest in ultra-hypofractionated regimens emerged during the COVID-19 pandemic. A one-week hypofractionated WBI regimen has become standard in the UK. For local disease control, the WBI schedule of 26 Gy in 5 fractions over one week is non-inferior to 40 Gy in 15 fractions over three weeks.[52] Although it seems safe in terms of normal tissue effects for up to 5 years, this regimen has not been tested within a PBI phase 3 trial. In this context, the schedule of 30 Gy in 5 fractions represents an appealing treatment option that is both safe and effective.[24, 33, 34, 36]
We are aware of the study's limitations. The first is the relatively small number of patients, although sufficient for the statistical power of the considered objective. During the interim follow-up, there was no recurrence, regional or distant dissemination, or death of patients, but a longer follow-up for secondary objectives analysis is necessary. Second, WBI with a boost was used as part of the treatment protocols at our institution and applied in the published studies. In recent years, a 1-week hypofractionated[53] WBI regimen has become standard in the UK. We can hypothesize that hypofractionation leads to lower acute toxicity; therefore, the difference against APBI could be less pronounced. Two studies[6] and the Danish Breast Cancer Group[54] used the same dose fractionation for WBI and APBI and showed that reducing the irradiated volume alone reduced late toxicity. Given current knowledge and recommendations, WBI with a boost can mean certain overtreatment[55], and accordingly, a boost may not be indicated in older patients with sufficient resection margins.
Finally, several patients with a low-risk BC treated in the APBI trials may have been suitable candidates for the complete omission of adjuvant RT. Published meta-analyses established that forgoing WBI does not impact overall survival in selected patients but is associated with a significantly higher rate of LR.[56–58] This procedure is chosen mainly for patients with worse clinical conditions or comorbidities when a significant benefit from reducing the risk of ipsilateral disease recurrence using RT is not expected. On the other hand, the second pillar of early BC patient care is ET, which may negatively influence Qol of patients[59] due to its detrimental action on the cardiovascular system, bone density, sexuality, and cognition. Therefore, the oncological community is investigating[60] whether APBI could safely replace ET in very low-risk early BC (i.e., older age, luminal-A disease). In such a case, the double advantage of partial breast irradiation – a significant shortening of the total radiation time and less toxicity compared with WBI and the abolition of long-term toxicity of ET if omitted - would favorably affect QoL.