Hypofractionated Whole Breast Irradiation and Simultaneous Integrated Boost in Large-breasted Patients: Long-term Toxicity and Cosmesis

doi:10.1016/j.clbc.2020.06.005

Clinical Breast Cancer

Volume 20, Issue 6, December 2020, Pages 527-533

https://doi.org/10.1016/j.clbc.2020.06.005 Get rights and content

Abstract

Introduction

The purpose of this study was to evaluate the impact of breast size on long-term toxicity and cosmesis in patients with breast cancer treated with hypofractionated simultaneous integrated boost (SIB) using volumetric modulated arc therapy (VMAT).

Patients and Methods

Patients with early stage breast cancer were treated with 3-week hypofractionated SIB-VMAT to the whole breast (40.5 Gy) and tumor bed (48 Gy). Two cohorts were identified: small/medium- (< 1000 cm³) and large- (> 1000 cm³) breasted patients. Acute and late (at 2 and 5 years) skin toxicity and cosmetic data were analyzed. Univariate and multivariate analysis evaluated associations between toxicity and dosimetric/anatomical variables.

Results

From August 2010 to March 2017, a total of 1160 patients were treated; 831 had at least 2 years of follow-up and were analyzed. Treated skin area (TSA) receiving at least 20 Gy > 400 cm² and V_{105% of Boost} > 5 cm³ were significant predictors for acute skin toxicity. Multivariate analysis at 2 years was significant for boost volume > 70 cm³, TSA > 400 cm², and breast size > 1500 cm³. At 5 year analysis (352 patients), none of the analyzed variables was significant. For cosmetic outcome, only the breast size (> 1000 cm³) and the boost size > 70 cm³ at 2 and 5 years, respectively, confirmed significance.

Conclusions

The TSA > 400 cm² resulted as a significant predictor of both acute and late skin toxicity at 2 years; however, at 5 years, no breast size or dosimetric parameter suggested indications for increased toxicity. A worse cosmetic outcome was recorded at the 2-year follow up for large breasts, but was not confirmed at the 5-year follow-up. These long-term data suggest that hypofractionated SIB-VMAT is a viable modality also in large-breasted patients.

Introduction

Results from large randomized trials confirmed that hypofractionated whole-breast irradiation (HF-WBI) provides equivalent outcomes in comparison to conventional fractionation in terms of efficacy and safety for women with early stage breast cancer.1, 2, 3

Moreover, the recent update of the American Society of Radiation Oncology evidence-based guidelines on radiation therapy for the whole breast confirmed that HF-WBI represents the preferred option for patients with early stage breast cancer, regardless of age, chemotherapy administration, and breast size, recommending to minimize the volume of breast tissue receiving > 105% of the prescription dose.⁴

There is retrospective evidence that large-breasted patients undergoing breast conserving surgery (BCS) and adjuvant radiotherapy using standard fractionation have an increased risk of late toxicity and poor cosmesis5, 6, 7 that might be linked to the difficulty in achieving a certain degree of dose homogeneity.

Larger breasts (in terms of breast volume, or thickness) could increase dose inhomogeneity, and the use of HF-WBI in this subset of patients remains a clinical concern for possible increased toxicity.⁸ In the Canadian Trial,³ large breast size was an exclusion criterion, whereas the results of the other trials on HF-WBI¹^,² have not been stratified for this feature.

The lack of a consensus to define uniformly the breast size as “large”⁹ represents a further variable. Different parameters were used to define the breast size, ranging from clothing and bra size, or the distance between the lateral and medial field edge or the measurement of volumes that could be the planning or the clinical target volume, or the volume included in an isodose (50% or 90%).¹⁰^,¹¹

The advent of intensity-modulated radiotherapy (IMRT) techniques proved to improve both the dosimetric and toxicity profiles in all the treatments. In particular, for breast, the improved dosimetric results obtained with those techniques regardless of the breast size might translate as an improved toxicity profile.12, 13, 14, 15

Based on this background, we evaluated the impact of breast size on long-term toxicity and cosmesis in our series of patients with breast cancer treated with hypofractionation and simultaneous integrated boost (SIB) using volumetric modulated arc therapy (VMAT).

Section snippets

Patients and Treatment

Since 2010, at our institution, patients with early stage breast cancer are treated with adjuvant radiotherapy delivered in 15 fractions using VMAT and SIB after BCS, according to an institutional phase II trial on hypofractionated breast irradiation (internal number 708). All patients are treated in compliance with the Helsinki declaration, and informed consent is obtained from all individual patients at the time of admission, for data analysis also in retrospective studies. Patient selection

Patient Characteristics

From August 2010 to March 2017, a total cohort of 1160 patients was treated with VMAT and SIB in a 3-week treatment. Of those, 831 patients had at least a 2-year follow-up and were included in the analysis. A summary of the patients’ characteristics is reported in Table 1 for the entire cohort of 831 patients, and for the 2 groups, A and B (breast size < 1000 and ≥ 1000 cm³, respectively).

Possible correlations between breast and boost size, and between breast size and TSA were evaluated. The

Discussion

Large breast size represents a patient-related factor that may negatively influence toxicity profile and cosmesis in women with early stage breast cancer who have undergone BCS and adjuvant radiotherapy.5, 6, 7

The use of HF-WBI as a recommended option in the clinical practice led to a widespread concern related to a possible increase of dose inhomogeneity, and consequently, of side effects, in women with large breasts.

Unfortunately, regarding this issue, there are no available data from large

Conclusions

The current study shows that the TSA receiving at least 20 Gy larger than 400 cm² resulted as a significant predictor of both acute and late skin toxicity at 2 years; however, at 5 years, no breast size or dosimetric parameter suggested indications for increased toxicity. A worse cosmetic outcome was recorded at the 2-year follow-up for large breasts, but not confirmed at 5 years. These long-term data suggest that hypofractionation is a viable therapeutic modality also in large-breasted

Disclosure

L. Cozzi acts as a Scientific Advisor to Varian Medical Systems and is a Clinical Research Scientist at Humanitas Cancer Center. The remaining authors have stated that they have no conflicts of interest.

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Cited by (11)

Skin dose-volume predictors of moderate-severe late side effects after whole breast radiotherapy
2024, Radiotherapy and Oncology
Toxicity after whole breast Radiotherapy is a relevant issue, impacting the quality-of-life of a not negligible number of patients. We aimed to develop a Normal Tissue Complication Probability (NTCP) model predicting late toxicities by combining dosimetric parameters of the breast dermis and clinical factors.
The skin structure was defined as the outer CT body contour's 5 mm inner isotropic expansion. It was retrospectively segmented on a large mono-institutional cohort of early-stage breast cancer patients enrolled between 2009 and 2017 (n = 1066). Patients were treated with tangential-field RT, delivering 40 Gy in 15 fractions to the whole breast. Toxicity was reported during Follow-Up (FU) using SOMA/LENT scoring. The study endpoint was moderate-severe late side effects consisting of Fibrosis-Atrophy-Telangiectasia-Pain (FATP G ≥ 2) developed within 42 months after RT completion. A machine learning pipeline was designed with a logistic model combining clinical factors and absolute skin DVH (cc) parameters as output.
The FATP G2 + rate was 3.8 %, with 40/1066 patients experiencing side effects. After the preprocessing of variables, a cross-validation was applied to define the best-performing model. We selected a 4-variable model with Post-Surgery Cosmetic alterations (Odds Ratio, OR = 7.3), Aromatase Inhibitors (as a protective factor with OR = 0.45), V20 Gy (50 % of the prescribed dose, OR = 1.02), and V42 Gy (105 %, OR = 1.09). Factors were also converted into an adjusted V20Gy.
The association between late reactions and skin DVH when delivering 40 Gy/15 fr was quantified, suggesting an independent role of V20 and V42. Few clinical factors heavily modulate the risk.
Volume matters: Breast induration is associated with irradiated breast volume in the Danish Breast Cancer Group phase III randomized Partial Breast Irradiation trial
2022, Radiotherapy and Oncology
Citation Excerpt :
The strict dose constraint of V42Gy_breast ≤ 2 mL in the study, resulted in a violation of this constraint in only 9% (PBI) and 20% (WBI) of the treatment plans, respectively (Table 2 and Supplementary Fig. 2), and therefore it was not possible to obtain a model with sufficient statistical basis for V42Gy. Irrespectively of treated volume, the treatment plans in this trial have a homogeneity comparable with inverse planned whole breast plans (IMRT or VMAT) [13,14]. The doses to lung and heart were low and a high compliance with the protocol-specified constraints was found.
The relation between breast induration grade 2–3 at 3 years after radiation therapy and irradiated breast volume was investigated for patients in the Danish Breast Cancer Group (DBCG) Partial Breast Irradiation (PBI) trial. METHODS Treatment plan data was obtained from the Danish radiotherapy plan database. Dosimetric parameters for breast and organs at risk were determined. Breast induration data was obtained from the DBCG database. The volume of the whole breast (CTVp_breast) treated to various dose levels was determined for treatment plans in both arms. Logistic regression was used to assess the frequency of induration on breast volume irradiated to ≥40 Gy. RESULTS PBI and WBI was given to 433 and 432 patients, respectively. Median and interquartile ranges (IQR) for CTVp_breast were 710 mL (467–963 mL; PBI) and 666 mL (443–1012 mL; WBI) (p = 0.98). Median and IQR for CTVp_breast treated to ≥40 Gy was 24.9% (18.6–32.6%; PBI) and 59.8% (53.6–68.5%; WBI). Grade 2–3 induration was observed in 5% (PBI) and 10% (WBI) of the patients. A dose–response relationship was established between irradiated breast volume and frequency of breast induration. From the model, 5% and 10% risks of breast induration were observed for ≥40 Gy delivered to CTVp_breast volumes of 177 mL (95%CI, 94–260 mL) and 426 mL (95%CI, 286–567 mL), respectively. CONCLUSION The frequency of breast induration increased significantly with increasing irradiated breast volume, strongly favouring small volumes and PBI. Thus, treated breast volume – not the breast size itself - is the risk factor for induration. This is the first report directly linking the 40 Gy irradiated breast volume to breast induration.
Long term results of a phase II trial of hypofractionated adjuvant radiotherapy for early-stage breast cancer with volumetric modulated arc therapy and simultaneous integrated boost
2021, Radiotherapy and Oncology
Citation Excerpt :
The size of the breast is a factor that could affect the side effects. A study was published in 2020 from our group, looking for skin toxicity predictors in relation to the size of the breast [25]. On a cohort of 831 patients treated according to the same protocol here described, the treated skin area (correlated with the breast size) resulted in a significant predictor of skin toxicity.
to report toxicity and cosmetic outcome with a median follow-up of 6 years of a phase II trial of hypofractionated radiotherapy with volumetric modulated arc therapy (VMAT) and simultaneous integrated boost (SIB) for early-stage breast cancer after conservative surgery.
From August 2010 to September 2014, patients requiring adjuvant radiotherapy for early-stage breast cancer were treated according to a phase I–II protocol with SIB to 40.5 and 48 Gy to the breast and the boost region, respectively, with VMAT technique. The primary endpoint evaluated the treatment feasibility regarding adherence to required dose constraints for target, heart and lungs. Acute and late toxicity, local and distant control were secondary endpoints.
450 patients were included in the trial and analysed after a median follow-up of 6 years. Acute toxicity was already presented in a previous paper. Regarding late toxicity, 93% of patients had no skin alteration at five years, while 5.3% and 1.3% did record G1 and G2 residual toxicity, respectively. Cosmetic outcome was scored good or excellent in almost all cases (97.2%), fair only in 2.3% of patients. Residual tenderness in the irradiated breast was reported by 10% of patients. Cosmesis and breast pain improved during follow-up. Two cases of G2 pneumonitis and two cases of ischemic cardiopathy were registered during follow-up.
Five cases presented local recurrence in the homolateral breast, four patients had a new primary cancer in the contralateral breast, while distant metastasis developed in 7 patients.
After more than six years, hypofractionated VMAT with SIB for adjuvant radiotherapy in early-stage breast cancer patients remains a safe and effective approach. Mature data on skin toxicity and cosmetic outcome are encouraging. However, longer follow-up is required to evaluate local control, cardiac toxicity and secondary carcinogenesis.
Two-year toxicity of simultaneous integrated boost in hypofractionated prone breast cancer irradiation: Comparison with sequential boost in a randomized trial
2021, Radiotherapy and Oncology
Citation Excerpt :
Five year locoregional control and survival data also seem excellent [9,11,18,20].
A simultaneous integrated boost (SIB) leads to less acute toxicity. Less is known for late toxicity due to SIB. In this first and only randomized trial, two-years toxicity is analysed.
Physician-assessed toxicity, using the LENT SOMA scale, and photographs, analysed with the BCCT.core software, was examined for 150 patients, randomized between SIB and sequential boost (SEB).
Differences in physician-assessed two-years toxicity and photographic analysis between SIB and SEB are very small and not significant.
There is no indication that a SIB leads to an excess in toxicity or worse cosmetic outcome at 2 years.
Decrease of radiation-induced skin reactions in breast cancer patients by preventive application of film dressings—a systematic review
2024, Strahlentherapie und Onkologie
10-Year Outcomes of Concomitant Boost Irradiation Following Breast-conserving Surgery versus Sequential Boost for Early-stage Breast Cancer treatment
2023, Research Square

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Original StudyHypofractionated Whole Breast Irradiation and Simultaneous Integrated Boost in Large-breasted Patients: Long-term Toxicity and Cosmesis

Abstract

Introduction

Patients and Methods

Results

Conclusions

Introduction

Section snippets

Patients and Treatment

Patient Characteristics

Discussion

Conclusions

Disclosure

Pract Radiat Oncol

Radiother Oncol

Clin Oncol (R Coll Radiol)

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Med Dosim

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Original Study
Hypofractionated Whole Breast Irradiation and Simultaneous Integrated Boost in Large-breasted Patients: Long-term Toxicity and Cosmesis