Accelerated Partial Breast Irradiation: Florence Phase 3 Trial Experience and Future Perspectives

A phase 3 trial comparing accelerated partial breast irradiation (PBI, 30 Gy in 5 fractions given every other day) and conventionally-fractionated whole breast irradiation (WBI, 50 Gy in 25 fractions) followed by a tumor bed boost (10 Gy in 5 fractions) was conducted at the Department of Radiation Oncology, University of Florence (Florence, Italy).1 The trial design is reported in Fig. 1.

F1FIGURE 1: APBI-IMRT-Florence phase 3 trial design. Adapted from Meattini et al.3 Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

The eligible patients were women aged older than 40 years with a tumor size ≤25 mm suitable for breast-conserving surgery (BCS). The presence of extensive intraductal component, multiple foci tumors, final surgical margins <5 mm, or the absence of surgical clips in the tumor bed were exclusion criteria, while other risk factors, including lymph vascular space invasion or axillary lymph node involvement, were not considered as such. Between March 2005 and June 2013, 520 patients were enrolled and randomized into PBI and WBI arms with a 1:1 ratio, and 14 patients in the PBI arm refused to receive the assigned treatment.1 Patient and tumor characteristics according to the treatment groups are summarized in Table 1.

TABLE 1 - Patient, Tumor, and Treatment Characteristics According to the Treatment Arms of the APBI-IMRT-Florence Trial (adapted from Meattini et al3) Feature PBI Arm n=260 No. (%) WBI Arm n=260 No. (%) Age, year  ≤50 41 (15.8) 45 (17.3)  51-59 61 (23.5) 76 (29.2)  60-69 99 (38.1) 81 (31.2)  ≥70 59 (22.6) 58 (22.3) Tumor grade  G1-2 234 (90) 227 (87.3)  G3 26 (10) 33 (12.7) Postoperative T stage  Tis 23 (8.8) 32 (12.3)  T1 223 (85.8) 213 (81.9)  T2 14 (5.4) 15 (5.8) No. positive nodes  None 232 (89.2) 213 (81.9)  1-3 19 (7.3) 33 (12.7)  No ALDN 9 (3.5) 14 (5.4) ER status  Positive 248 (95.4) 249 (95.8)  Negative 12 (4.6) 11 (4.2) Ki67 index  <20% 193 (72.2) 174 (72.2)  ≥20% 50 (20.6) 67 (27.8) Molecular subtype*  Luminal A-like 169 (79.3) 151 (72.6)  Luminal B-like 33 (15.6) 42 (20.2)  HER2 positive (non-luminal) 6 (2.8) 13 (6.2)  Triple negative 5 (2.3) 2 (1) Systemic treatment  None 93 (35.8) 75 (28.8)  Endocrine therapy only 155 (59.6) 162 (62.3)  Chemotherapy only 5 (1.9) 3 (1.2)  Chemotherapy and endocrine therapy 7 (2.7) 20 (7.7) Risk Class  ASTRO suitable 133 (51.2) 113 (43.5)  ASTRO cautionary-unsuitable 127 (48.8) 147 (56.5)  ESTRO low 190 (73.1) 166 (63.8)  ESTRO intermediate-high 70 (26.9) 94 (36.2)

*Assessed by immunohistochemistry on primary tumor specimen.

Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

ALDN indicates axillary lymph nodes dissections; ASTRO, American Society for Radiation Oncology; ESTRO, European Society for Radiotherapy and Oncology; HER2, human epidermal growth factor receptor 2; PBI, partial breast irradiation; WBI, whole breast irradiation.

Accelerated PBI planning was performed using a step-and-shoot intensity-modulated radiation therapy technique with coplanar fields, while conventional radiation therapy (RT) technique with wedged photon tangential fields was employed for WBI.2 The dosimetric analysis of the PBI arm showed that the mean value of the uninvolved breast volume receiving ≥15Gy (ie, 50% of the prescription dose) was 32.3%. Doses to the heart and both the lungs were low: the mean value of the heart volume receiving ≥3 Gy was 7.4%, and the mean value of ipsilateral lung receiving ≥10 Gy was 10.3%. The planning constraints were fully satisfied except for 1 patient.3

Health-related quality of life (HRQoL) was measured using the European Organization for Research and Treatment of Cancer (EORTC) C30 and BR23 modules before RT, at the end of RT, and at 2-year follow-up visits. Two hundred five patients completed all the given questionnaires, and PBI was associated with an improved HRQoL in several domains as compared with WBI at the end of RT and at 2-year follow-up visits.4

The 5-year ipsilateral breast tumor recurrence (IBTR) rates, the primary endpoint, were 2.3% in the PBI arm and 1.2% in the WBI arm (P=0.31). When the median follow-up was 10.7 years, the 10-year IBTR rates were 3.7% and 2.5% in the PBI and WBI arms, respectively (P=0.40) (Fig. 2). Other survival outcomes, such as the overall and breast cancer-specific survival rates, were not different between the 2 arms either (Fig. 3).3

F2FIGURE 2: IBTR curves at 10 years median follow-up update. Adapted from Meattini et al.3 Adaptations are themselves works protected by copyright. So to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.F3FIGURE 3: Survival outcomes curves at 10 years median follow-up update. Adapted from Meattini et al.3 Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.

Cosmesis and treatment-related toxic effects were also assessed. The cosmesis evaluated both by the patients and physicians were significantly in favor of the PBI arm (P=0.0001 and 0.0001, respectively). Overall, patients’ grading on their cosmesis was poorer than those of physicians, and the fair rates assessed by patients were 14.6% in the WBI arm compared with 0.8% in the PBI arm (P=0.0001). Both acute and late toxicities assessed according to the Radiation Therapy Oncology Group and EORTC criteria were significantly fewer in the PBI arm compared with the WBI arm (P=0.0001 and 0.0001, respectively). Specifically, grade 2 or greater acute toxicity was observed in 37.7% of the WBI arm and 2.0% of the PBI arm (P=0.0001) (Table 2).3

TABLE 2 - Acute and Late Toxic Effects and Cosmesis Assessment at 10 years Median Follow-up Update (adapted from Meattini et al3) Assessment PBI n=246 No. (%) WBI n=260 No. (%) P Acute toxic effects*  None 194 (78.9) 87 (33.5) 0.0001  Yes, any Grade 52 (21.1) 173 (66.5) 0.0001  Grade 0-1 241 (98) 162 (62.3) —  Grade ≥2 5 (2) 98 (37.7) — Late toxic effects*  None 235 (95.5) 182 (70) 0.0001  Yes, any Grade 11 (4.5) 78 (30) 0.015  Grade 0-1 246 (100) 253 (97.3) —  Grade ≥2 - 7 (2.7) — Physician-rated cosmesis  Excellent 233 (94.7) 189 (72.7) 0.0001  Good 13 (5.3) 66 (25.4) —  Fair - 5 (1.9) —  Poor - - — Patient-rated cosmesis  Excellent 44 (17.9) 13 (5.1) 0.0001  Good 200 (81.3) 209 (80.3) —  Fair 2 (0.8) 38 (14.6) —  Poor - - —

*Worst grade experienced by patients in the acute (within 6 months from start of radiation therapy) and in the late period (beyond 6 months).

†Worst grade experienced by patients in the follow-up period. Global cosmetic outcome assessed by the physician and the patient using the Harvard Cosmetic Scale.

PBI indicates partial breast irradiation; WBI, whole breast irradiation.

Few specific sub-groups of patients’ analyses were performed and published over time, including ductal carcinoma in situ (DCIS)5,6 and patients aged 70 years or older.7 Also, a planning study was performed to compare the manual with automated planning, and the automated planning achieved superior dosimetric results and less planning time, which might facilitate the application of accelerated PBI with reduced time and resource requirements.8 Recently, the treatment regimen was amended as a continuous schedule within 1 week using the volumetric modulated arc therapy technique. A detailed technique and planning delivery approach update was published together with the first encouraging results on safety for patients treated with 30 Gy in 5 fractions on a consecutive-day schedule.9

FUTURE PERSPECTIVES

A plateau has been probably reached concerning the reduction of the number of fractions in the postoperative PBI setting. A 5-fraction schedule is the standard regimen and probably the appropriate compromise in terms of efficacy, safety, and HRQoL,10 also considering the negative results of most intraoperative single-fraction PBI trials.11–16 A new frontier is now open on the potential benefit of preoperative PBI delivery,17 although concerns remain on the optimal dose, fractionation, and technique.18–23 Therefore, postoperative PBI still represents the gold-standard of treatment.

One of the most exciting perspectives is based on trials evaluating the optimization of all adjuvant treatments for low-risk breast cancer, including but not limited to RT.24 The omission of postoperative radiation after BCS in elderly patients has been tested in several randomized trials. At present, based on the results of the CALGB 9343 and PRIME II trials,25,26 WBI omission might be considered in patients 70 years or older, with a hormonal receptor-positive, pT1 N0 breast cancer who is planned to receive adjuvant endocrine therapy. However, both trials showed a significant and not negligible improved IBTR rate in favor of arms receiving both endocrine and irradiation.

Recently, the LUMINA trial, a prospective multicenter cohort study, also showed that endocrine therapy alone achieved very low rates of local recurrence without postoperative irradiation (5-year rate, 2.3%) in patients 55 years or older affected by a luminal-like, grade 1-2, pT1 N0 breast cancer.27 However, it should be strongly considered that adjuvant endocrine therapy might significantly compromise patients’ HRQoL.28 Moreover, compliance and adherence to planned endocrine therapy are well known to decrease over time.29,30 In this context, the phase 3 EUROPA trial (NCT04134598) is underway to compare irradiation alone (both PBI and WBI) versus endocrine therapy alone in patients 70 years or older with a luminal A-like, pT1 N0 breast cancer; co-primary endpoints of the study are local relapse rate and HRQoL.31

Waiting for robust findings and ongoing trials’ results, personalized treatments based on genomic data are becoming a standard strategy in the decision-making process on the optimal systemic treatment for patients affected by hormonal receptor-positive breast cancer.32 In stage I low-risk breast cancer patients of the EORTC 10041/BIG 3-04 MINDACT trial who received no adjuvant systemic treatments, the effect of endocrine therapy on distant metastases-free interval was limited after a relatively short follow-up of 8 years.33 However, the integration of genomics into the RT practice is not yet come. Historically, Danish Breast Cancer Group (DBCG) evaluated the gene expression profiling of the tumor specimens of those patients enrolled in the DBCG 82 b&c trials and reported the 7-gene expression could differentiate patients who can benefit from post-mastectomy radiotherapy (PMRT) from those not.34 Recently, the ARTIC score has also been suggested to select the subgroup of patients who may need more intensified treatment, such as tumor bed boost or regional nodal irradiation (RNI), compared with the subgroup whose loco-regional recurrence was much lower when only WBI was given.35 In addition, MA.39 trial is testing the benefit of RNI/PMRT in pN1 intermediate-risk breast cancer patients with an Oncotype DX recurrence score ≤18 (NCT03488693).

Regarding low-risk early breast cancers, several prospective trials are testing the omission of radiation after BCS, where low-risk is defined using multigene panels such as Oncotype DX or PAM 50. However, these trials are also based on the backbone of endocrine therapy. Ongoing trials testing the optimization of treatments for low-risk early-stage breast cancer are summarized in Table 3. A potential, genomic data-based personalized RT algorithm for low-risk early breast cancer is presented in Fig. 4. International recommendations in favor of PBI over WBI are currently based on clinic-pathologic risk factors.36,37 Since genomic-based predictive recurrence scores provide both the risk for local and distant recurrence, their integration with the clinic-pathologic risk factors could further refine the optimal local therapy. In the context of treatment optimization, de-escalation or intensification of RT could be tested based on genomic score regardless of clinic-pathologic features. Clinical trials to test these hypotheses are urgently needed. More personalized RT and selective administration of endocrine therapy might improve cost-effectiveness and patients’ HRQoL without compromising oncologic outcomes.

TABLE 3 - Ongoing Optimization Trials for Patients Affected by Low-risk Breast Cancer (Adapted from Meattini I, et al31) Name EUROPA Expert Natural Precision Primetime Idea LUMINA Study Randomized Randomized Randomized Single Arm Single Arm Single Arm Single Arm Age, years ≥70 ≥50 ≥60 ≥50 and ≤75 ≥60 ≥50 and ≤69 ≥55 Stage pT1 N0 pT1 N0 pT1 N0 pT1 N0 pT1 N0 pT1 N0 pT1 N0 Grade and histology Any grade (pT ≤10 mm) Grade 1-2 (pT=11-19 mm) Grade 1-2 Grade 1-2 Nonlobular Grade 1-2 Grade 1-2 Any Grade 1-2 Nonlobular Subtype Luminal A-like Luminal A-like Luminal A-like Luminal A-like Very low risk (IHC4+C) RS ≤18 Luminal A-like Assessment IHC PAM 50 IHC PAM 50 IHC4+C Oncotype DX IHC Biology ER/PgR ≥10% HER2 negative Ki67 ≤20 ER/PgR ≥10% HER2 negative ROR ≤60 ER ≥10% HER2 negative ER/PgR ≥10% HER2 negative ER/PgR positive HER2 negative ER/PgR positive HER2 negative ER ≥1%/PgR >20% HER2 negative Surgical margins Negative Negative ≥2 mm Negative ≥1 mm ≥2 mm ≥1 mm Interventions RT vs ET ET+RT vs ET ET+RT vs ET ET only ET only ET only ET only Primary endpoint(s) 2-year HRQoL 5-year LR 5-year LR 5-year LR 5-year LRR 5-year LR 5-year LRR 5-year LR No. patients 926 1167 926 690 2400 202 500

ER indicates estrogen receptor; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HRQoL, health-related quality of life; IHC, immunohistochemistry; IHC4+C, immunohistochemical biomarkers plus clinical information; LR, local recurrence; LRR, loco-regional recurrence; PgR, progesterone receptor; ROR, risk of recurrence score; RS, recurrence score; RT, radiation therapy.


F4FIGURE 4:

Proposed genomic data-based personalized radiation therapy algorithm for low-risk early breast cancer. G-high indicates genomic-high; G-low, genomic-low; LVI, lymph vascular invasion; PBI, partial breast irradiation; ST, systemic therapy; WBI, whole breast irradiation.

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