Predictors of poor cosmesis in breast cancer patients treated with adjuvant whole breast radiation therapy plus high-dose-rate interstitial brachytherapy boost after breast conservation surgery

Purpose

With recent advances in breast cancer loco-regional and systemic therapies, which resulted in high survival rates, cosmetic outcomes became more important [1, 2]. In addition, better recognition of risk factors contributing to poor cosmetic results may improve the quality of life of these patients [2].

Breast conservation surgery (BCS) plus whole breast irradiation (WBI) is the standard of care in early-stage breast cancer [3]. Also, there is evidence that a tumor bed boost enhances local control, especially in young patients, and in the presence of lympho-vascular space invasion or positive or close surgical margins [4, 5].

Low-energy electrons (range, 9-12 MeV) are widely used for delivering the boost dose. However, considering their limited therapeutic range, only superficial regions of the breast can be effectively irradiated. Using higher energy electrons to treat deeper areas of the breast results in overdosing of skin, normal breast, lungs, and heart, and also may have a negative impact on breast cosmesis. In this context, the EORTC boost trial showed that high energy electrons were linked to a higher 10-year risk of severe breast fibrosis.

Other techniques for tumor bed boosting, especially deep-seated tumor beds, are external beam radiation therapy (EBRT) and multicatheter interstitial brachytherapy (MIBT). Data regarding the pros and cons of these boost techniques in terms of effectiveness, toxicity, and cosmetic results are limited, and the most published data on MIBT boost comes from time before the widespread availability of high-dose-rate (HDR) sources, computerized remote after loaders, stepping source technology, cross-sectional image-based treatment planning, and inverse optimization algorithms. The advantage of each boost modality depends on breast anatomy and lumpectomy cavity location. For a shallow target, if the breast contour is roughly flat and beam obliquity can be avoided, en-face low energy electron beam is the preferred technique, as electron beam obliquity reduces its’ therapeutic range and increases the skin absorbed dose [6]. In deep-seated tumor beds (depth ≥ 4 cm), modern image-guided multicatheter interstitial brachytherapy boost in comparison with other boost modalities, such as high energy electron beams or advanced external beam photon techniques (e.g., intensity modulated radiation therapy [IMRT] or volumetric modulated arc therapy [VMAT]), can better protect nearby healthy organs from high doses of radiation, and therefore are an excellent modality for dose escalation [6-8].

In electron and external beam photon boosts, even if accompanied by modern treatment verification techniques, a larger volume (compared to brachytherapy) need to be irradiated to account for inter- and intra-fractional organ motions, and accelerator and patient’s setup uncertainties (planning target volume concept). These problems are irrelevant for MIBT. Multicatheter interstitial brachytherapy, as a minimally invasive procedure, has its’ limitations, including relative patient discomfort and the necessity of significant learning curve [6].

Several patient, tumor, and treatment-related factors have been connected to sub-optimal cosmetic outcomes after breast conservation therapy, but the results are not consistent across studies (many of them lack objective assessment of breast cosmesis). These factors include high body mass index (BMI), age (both younger and older patients), breast volume, inner quadrant tumor location, tumor size, extent of breast surgery (volume of tissue removed from the breast at lumpectomy), type of surgical incision, complete axillary dissection (versus sentinel node biopsy), receiving chemotherapy, regional nodal irradiation, higher total radiation doses (to the breast’s skin and tissue), conventionally fractionated regimens (versus hypofractionated schedules), receiving a boost, boost technique, and higher boost volumes [2, 9-13]. Additionally, in patients treated with an interstitial brachytherapy boost, the number of implanted catheters and automatic optimization technique (vs. manual optimization) have been reported to be inversely correlated with breast cosmesis [10].

This study was designed to measure breast cosmesis in breast cancer patients treated with adjuvant WBI plus high-dose-rate MIBT boost after BCS, both objectively by BCCT.core software (using front view digital photographs) and subjectively with Harvard’s score. Also, to identify patient, tumor, and treatment factors, including dosimetric parameters of external beam and brachytherapy plans, which predict poor cosmetic scores.

Material and methods

Results

Patient, tumor, and treatment characteristics are summarized in Table 2. The median time from completion of radiation therapy to cosmesis scoring was 18 months. In cosmesis evaluation with BCCT.core software, no patient was scored as excellent. Cosmesis was good in 5 (18%), fair in 14 (50%), and poor in 9 (32%) patients. According to the Harvard’s scale, 3 (10.5%) patients had excellent cosmesis. Moreover, 12 (43%), 8 (28.5%), and 5 (18%) patients had good, fair, and poor Harvard’s scores, respectively (Figure 1). There was a statistically significant strong direct correlation between BCCT.core and Harvard’s scores (p = 0.002) (Spearman’s coefficient = 0.54) (Figure 2).

Fig. 1

BCCT.core and Harvard’s scores bar plot

Fig. 2

This scatter plot illustrates the strong positive correlation between BCCT.core and Harvard’s scores

Absolute values of ipsilateral breast and skin biologically effective V parameters in WBI and MIBT plans are summarized in Table 3. WBI and MIBT relative dose-volume histograms are shown in Figures 3 and 4. In WBI, the median breast and skin biologically effective maximum doses (BED_max) (25-75^th percentile) were 114 Gy (range, 109-118 Gy) and 108 Gy (range, 104-113 Gy), respectively. Skin D parameters in MIBT plans are presented in Table 4.

Fig. 3

Whole breast irradiation relative ipsilateral breast and skin biologically effective dose-volume histogram

Fig. 4

Multicatheter interstitial brachytherapy relative ipsilateral breast and skin biologically effective dose-volume histogram

In univariate analysis, no patient (age, follow-up time, breast volume, and breast tumor location), tumor (pT stage, pN status, and tumor size), and treatment characteristics (lumpectomy specimen volume, hormone therapy regimen, WBI dose-fractionation schedule, before or after EBRT brachytherapy boost timing, and regional nodal irradiation), or dosimetric parameters were predictive of BCCT.core scores. Only there was a trend for higher BCCT.core scores in pN-positive cases, and patients who received regional nodal irradiation. In contrast, receiving regional nodal irradiation (p = 0.039), larger breast volumes (p = 0.037), higher WBI absolute breast V_86Gy (p = 0.038), and higher MIBT absolute breast V_29Gy (p = 0.037) were significant predictors of poorer Harvard’s scores. Also, there was a trend for higher Harvard’s scores in pN-positive cases, patients with higher WBI absolute breast V_90Gy, and higher MIBT absolute breast V_36Gy, V_43Gy, V_50Gy, and V_57Gy (Table 5).

On multivariate analysis, none of the demographic factors, tumor, and treatment characteristics, or dose-volume histogram parameters remained statistically significant for predicting Harvard’s score. Only there was a trend for higher Harvard’s score in patients with higher MIBT absolute breast V_29Gy (p = 0.066) (Table 5).

Discussion

In recent two decades, the widespread availability of electron beams combined with their relative comfort of use, has led to decreased use of interstitial brachytherapy for delivering boost dose. In fact, in superficial lumpectomy beds, if the breast contour is roughly flat and beam obliquity could be avoided, the preferred modality for breast boost is low energy electrons. However, in women with large breasts and centrally located deep-seated tumor bed, MIBT boost could be a great tool in radiation oncology armamentarium, since it can better protect nearby tissues from high doses of radiation in comparison with high energy electrons (> 12 MeV) due to increased skin dose, or sophisticated photon EBRT techniques. Additionally, with a MIBT boost, safer dose escalation is achievable in patients with a higher risk for local recurrence [6].

Recently, following the availability of highly effective systemic treatments for breast cancer, and as a consequence of longer survivals in these patients, long-term treatment toxicity and cosmetic outcomes have become more important. Therefore, the present study assessed the potential patient, tumor, and treatment-related factors, which could predict poor cosmesis in patients treated with WBI + MIBT boost [1,2].

In our study, 18% and 53.5% of patients had an excellent or good cosmesis according to BCCT.core and Harvard’s scores, respectively. Since baseline (pre-RT) cosmesis scoring was not performed, relative effects of surgery, chemotherapy, and radiation on cosmesis could not be distinguished. The Harvard score results are compatible with Polgár et al. [19] retrospective study showing 56% of excellent or good cosmesis, and contradictory to Rulli et al. [20] and Dolezel et al. [21] prospective studies, with 97% and 82.6% of excellent or good cosmesis, respectively. In our literature review, no study that used the BCCT.core objective scoring system for cosmesis evaluation was found (Table 6).

In the multivariate model, we did not find any statistically significant patient, tumor, or treatment-related factor for cosmesis prediction. There was a trend for poorer cosmesis in patients with higher absolute, but not relative, MIBT V_29Gy (volume of the breast tissue that received 100% of the prescribed dose in brachytherapy boost, if α/β = 3 Gy was assumed for normal breast late effects), with odds ratio = 1.01, meaning that every centimeter cube increase in MIBT breast V_100% (treated volume) increases the risk of poorer Harvard’s score by 1%. This finding is in line with Kulik et al. [10], Cambeiro et al. [22], Quéro et al. [23], and Morales et al. [24] studies (Table 6). In univariate analysis, patients treated with irradiation of regional lymphatics (odds ratio ≈ 5), and patients with larger breast volumes presented statistically significant poorer cosmesis scores. Wang et al. [2], in a prospective longitudinal study, found that larger breast volumes and supra-clavicular regional nodal irradiation are associated with worse breast asymmetry one year after EBRT. Larger breast volumes or using a supra-clavicular field is often accompanied by a heterogeneous dose distribution (more hot spots) in EBRT planning. Other proposed mechanisms are higher susceptibility of breast adipose tissue to radiation-induced atrophy and radiation damage to regional lymphatics [2].

The small sample size and short follow-up times are the main limitations of the current study that preclude reaching a statistical significance. Moreover, due to the retrospective nature of this study, baseline (pre-RT) cosmetic scores were not available, therefore the impact of surgery or chemotherapy on cosmesis could not be distinguished from radiation therapy. Another problem was that since different software was used for EBRT and brachytherapy plannings, cumulative DVH parameters (WBI + MIBT) could not be calculated.

One strength of our study was that biological equivalent dose-volume parameters were used instead of physical ones to eliminate the impact of dose-fractionation regimens used for WBI and MIBT; thus, the study results can become more generalizable. Also, observer-independent objective measures (BCCT.core) for cosmesis scoring in addition to traditional subjective methods (Harvard’s method) were applied.

Conclusions

Based on the findings of our study, higher absolute breast V_29Gy in multicatheter interstitial brachytherapy boost, regional nodal irradiation, and large breast volumes are the potential candidates that could have deleterious effects on cosmesis in breast cancer patients treated with whole breast radiotherapy plus HDR interstitial brachytherapy boost after breast conservation surgery. Larger-scale longitudinal prospective studies with longer follow-up durations are needed to confirm these results.

Ethical approval

The Ahvaz Jundishapur University of Medical Sciences ethics and scientific committees approved the study protocol according to the Helsinki Declaration (approval No.: ajums.REC. 1398.801).