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Abstract

The aim of this study was to assess tissue computed tomography (CT) number changes and corresponding dosimetric shifts in repeatedly performed simulation CT (re-sim CT) scans after conventionally fractionated irradiation in breast cancer patients. A total of 28 breast cancer patients who underwent breast-conserving surgery were enrolled in this study. All the patients had received 50.4 Gy of conventional whole-breast irradiation (WBI) and underwent re-sim CT scans for tumor bed boost. For evaluation of dosimetric shifts between initial and re-sim CT scans, electron boost plans in the same field size with the same monitor unit with source-to-skin distance of 100 cm were conducted. Dosimetric parameters (V_105%, V_103%, V_100%, V_98%, V_95%, V_90%: V_x% indicates volumes which receive X% of prescribed doses) between initial and re-sim CT scans were compared. The CT number data (CT_mean, CT_max, CT_min) of the original and irradiated CT (re-sim CT) scans from each representative structure (lung, rib bone, soft tissue, muscle, etc.) were examined and recruited. CT numbers showed highly variable changes. Soft tissue CT_mean and muscle CT_max/CT_min showed statistically and significantly increased values in the CT (re-sim CT) compared to the original CT scans. Rib bone CT_mean/CT_min showed statistically and significantly decreased values in the re-sim CT compared to the original CT scans. Other CT number values showed no statistically significant changes. Among the dosimetric parameters, only V_105% (p = 0.015, mean = 3.07 cc versus 1.63 cc) and V_103% (p = 0.017, mean = 13.8 cc versus 11.9 cc) exhibited statistically increased values in the re-sim CT compared to the original CT scans. CT number changes after conventional WBI were different according to tissue component. For electron boost plans, the implementation of a re-sim CT might be helpfully considered because significant dosimetric factor changes were observed especially in the high-dose areas (hot spots: V_105% and V_103%).

Keywords

Breast cancer computed tomography Hausenfield unit whole-breast irradiation radiotherapy

Introduction

The beneficial effect of postoperative adjuvant radiotherapy (RT) following breast-conserving surgery (BCS) has been demonstrated in several randomized clinical trials.^1–4 In a long-term follow-up of meta-analysis in 17 randomized trials, the 10-year risk of any first recurrence decreased from 35% to 19.3% and the 15-year risk of breast cancer death diminished from 25.2% to 21.4% by RT after BCS.⁵

The most common pattern of failure of breast cancer is local, and the majority of local recurrences occur in tumor beds and adjacent areas.⁶ Therefore, novel breast RT techniques based on these concepts have been recently developed over the past few years.^6–9 In conventional fractionation whole-breast irradiation (WBI), the addition of boost on the primary tumor bed after BCS improved local control rates without a significant difference in overall survival (OS).¹⁰ In a 10-year follow-up of the European Organisation for Research and Treatment of Cancer (EORTC) 22881/10882 trial, improved local control after additional boost RT was also demonstrated in all the age groups.¹¹

WBI using the tangential field technique with physical wedges has been the standard postoperative adjuvant therapy for avoiding local recurrence after BCS in early-stage breast cancer.¹² However, the radiation dose homogeneity for WBI using this tangential field wedge technique is rarely achieved because of several physical factors. These factors include the complex 3-dimensional (3D) character of the breast, differences in distance between beam access and exit points, and the influence of the lower attenuation of lung tissue included in the RT field.¹² Therefore, the 3D field-in-field (FIF) WBI technique was recently introduced and popularly utilized in many institutions to improve the beam homogeneity of the treated breast.^12,13

In a conventional fractionation WBI schedule, boost RT begins following 5–6 weeks of initial WBI, whereas boost RT is planned based on the computed tomography (CT) scan performed before the initiation of RT. For the 5–6 weeks of treatment, several elements can affect the beam dosimetry. Therefore, the actual dose distribution on the boost plan can be different from the initial RT plan based on the original CT scan. We hypothesized that the CT numbers (Hausenfield units) of irradiated tissues can be altered through the absorption of 5–6 weeks of WBI, and these could be one of the issues attributable to the shifts of 3D beam dosimetry of the treated breast. In this study, we compared the CT numbers in the breast and adjacent tissues between the original and re-simulation CT (rCT; for boost plan) scans and reproduced the RT plans to investigate whether the actual beam dosimetry could be affected.

Materials and methods

CT number measurement

In this study, we evaluated CT number changes between initial CT (iCT) and rCT scans (performed for boost RT) in 28 patients who received BCS followed by WBI. Initial CT scans were acquired for WBI, and rCT scans were performed for tumor bed boost plans after 5.5 weeks (28 fractions of RT) of WBI. Each CT scan was obtained in 3 mm thickness without contrast enhancement using a CT scanner (SOMATOM Definition AS+, Siemens Medical Solutions USA, Inc).

For CT number analyses, we measured maximum (CT_max), minimum (CT_min), and mean CT number (CT_mean) values of the soft tissue, muscle, rib, and lung tissue from iCT and rCT scans. We contoured the abovementioned organs and measured CT number values from CT scans using freeware imageJ (http://rsb.info.nih.gov/ij/).

Dosimetric evaluation

For evaluation of dosimetric shifts, electron boost plans were reproduced with the same field size and same monitor unit with source-to-skin distance (SSD) of 100 cm in iCT and rCT scans. Dosimetric parameters (V_105%, V_103%, V_100%, V_98%, V_95%, V_90%: V_x% indicates volumes receiving X% of the prescribed dose) were measured in each boost plan on the iCT and rCT scans.

All the patients planned to receive 50.4 Gy in 28 fractions of WBI using 6–10 MV photons, followed by a tumor bed boost of 10 Gy in five fractions. Every treatment plan was generated using the Eclipse treatment planning system (ECLIPSE™, Varian Medical Systems).

Follow-up and toxicity evaluation

Acute and late RT-related toxicities were measured using Radiation Therapy Oncology Group (RTOG) common toxicity criteria.

Statistical analyses

Statistical analysis was conducted using SPSS statistics, version 12.0 (SPSS Inc, Chicago, IL). Descriptive statistics and patient demographics were generated to present the characteristics of the variables. The changes of CT numbers in the organs of interest (soft tissue, muscle, rib, and lung) and dosimetric volume parameters were assessed using the two-tailed paired t-test. Local control (LC), disease-free survival (DFS), and OS rates were estimated using the Kaplan–Meier method. A p-value less than 0.05 was considered to be statistically significant.

Results

The study population

The patient and tumor characteristics are summarized in Table 1. The entire study population was female, and the median age was 54 (range, 40–75) years. The involved sites were the right breast in 12 patients (42.9%) and the left breast in the 16 remaining patients (57.1%). The upper outer quadrant (UOQ) was the most commonly affected area (n = 16, 57.1%), followed by the upper inner quadrant (UIQ; n = 4, 14.3%).

Table 1.

The patient and tumor characteristics.

Characteristic		N (%)
Age (years), median (range)	54 (40–75)	–
Site	Right	12 (42.9)
	Left	16 (57.1)
Quadrant	UOQ	16 (57.1)
	UIQ	4 (14.3)
	LOQ	3 (10.7)
	LIQ	0 (0.0)
	Central	3 (10.7)
Surgery	Lumpectomy	26 (92.9)
	Quadrantectomy	2 (7.1)
T-stage	T_is	2 (7.1)
	T1	17 (60.7)
	T1a	3 (10.7)
	T1b	4 (14.3)
	T1c	10 (35.7)
	T2	9 (32.1)
N-stage	N0	22 (78.6)
	N1	5 (17.9)
	No staging	1 (3.6)
Histology	Ductal	25 (89.3)
	Lobular	1 (3.6)
	Papillary	2 (7.1)
Histologic grade	WD	7 (25)
	MD	10 (35.7)
	PD	11 (39.3)
Resection margin	Wide (>1 mm)	25 (89.3)
	Close (≤1 mm)	3 (10.7)
Lymphatic invasion	Negative	20 (71.4)
	Positive	7 (25)
	Unknown	1 (3.6)
Vascular invasion	Negative	21 (75)
	Positive	5 (17.9)
	Unknown	2 (7.1)
Estrogen receptor	Negative	7 (25)
	Positive	21 (75)
Progesterone receptor	Negative	12 (42.9)
	Positive	16 (57.1)
HER-2 receptor (including FISH analysis)	Negative	23 (82.1)
	Positive	5 (17.9)
Ki-67 index (%), median (range)	25 (0–80)

UOQ: upper outer quadrant; UIQ: upper inner quadrant; LOQ: lower outer quadrant; LIQ: lower inner quadrant; WD: well differentiated; MD: moderately differentiated; PD: poorly differentiated; HER-2: human epidermal growth factor receptor type 2; FISH: fluorescent in situ hybridization.

All the patients underwent BCS: 26 (92.9%) lumpectomies and 2 (7.1%) quadrantectomies. The most common T-stage was T1 (n = 17, 60.7%), followed by T2 (n = 9, 32.1%) and Tis (n = 2, 7.1%).

CT number changes

In the radiologic evaluation, the CT numbers exhibited highly variable changes. The CT_mean of soft tissue increased from −72.9 in iCT to −68.8 in rCT (p = 0.001; Figure 1(a)). The CT_mean and CT_min of rib bone decreased from 267.4 to 253.3 (p = 0.050) and from 50.8 to 16.3 (p < 0.001), respectively (Figure 1(b) and (c)). With regard to muscle tissue, CT_mean did not show a statistically significant change, whereas CT_max and CT_min values increased from 66.8 to 75.8 (p < 0.001) and from −70.5 to −59.7 (p = 0.015), respectively (Figure 1(d) and (e)). In the lung, none of the CT numbers exhibited statistically significant changes (CT_mean, CT_max, and CT_min). The results are summarized in Table 2.

Figure 1.

Computed tomography (CT) number changes after whole-breast irradiation. CT_mean of the soft tissue (a), CT_mean and CT_min of the rib bone (b and c), and CT_max and CT_min of muscle (d and e).

Table 2.

CT number changes of soft tissue, rib, muscle, and lung in iCT and rCT.

	Mean			Max			Min
	iCT	rCT	p-value	iCT	rCT	p-value	iCT	rCT	p-value
Soft tissue	−72.9	−68.8	0.001	47.5	53.3	0.096	−152.4	−151.3	0.511
Rib	267.4	253.3	0.050	579.1	597.5	0.272	50.8	16.3	0.000
Muscle	15.7	17.4	0.682	66.8	75.8	0.000	−70.5	−59.7	0.015
Lung	−784.8	−763.4	0.110	−441.8	−438.9	0.889	−879.7	−866.4	0.055

iCT: initial computed tomography; rCT: re-simulation computed tomography.

Dosimetric changes

In the dosimetric comparison of volume parameters, V_105% (p = 0.015, mean 3.1 cc versus 1.6 cc) and V_103% (p = 0.017, mean 13.8 cc versus 11.9 cc) showed statistically increased values in rCT compared to iCT scans. Other parameters (V_100%, V_98%, V_95%, and V_90%) did not show any statistically significant change (Table 3).

Table 3.

Dosimetric comparison of measured volume parameters in iCT and rCT.

	iCT (cc)	rCT (cc)	p-value
V_105%	1.6	3.1	0.015
V_103%	11.9	13.8	0.017
V_100%	37.8	38.6	0.15
V_98%	51.1	50.4	0.45
V_95%	64.7	64.8	0.607
V_90%	81.3	81.1	0.339

Adjuvant treatment other than RT

Adjuvant chemotherapy was administered in 24 (85.7%) patients. Adjuvant endocrine therapy and human epidermal growth factor receptor type 2 (HER-2) targeted therapy with trastuzumab were employed in 21 (75%) and 5 (17.9%) patients, respectively.

LC, DFS, and OS outcomes

The median follow-up duration after RT was 34 (range, 25.6–51.5) months. During the follow-up period, no local or regional recurrences developed. No evident (pathologically confirmed) distant metastasis was observed. Therefore, the 3-year LC, DFS, and OS rates were all 100%.

Toxicity

Acute grade 2 and 3 skin toxicities were detected in 11 (39.3%) and 1 (3.6%) patient, respectively. However, the skin injuries recovered after several weeks and were not linked to late toxicities. Symptomatic radiation pneumonitis was not noted, and only mild fibrotic radiation changes were observed in 7 (25%) patients. No other late toxicities (≥grade 2) were observed.

Discussion

In this study, we assessed the CT number changes caused by absorption of radiation after a 5.5-week course of conventional WBI. Late radiation-induced fibrotic transformation after long-term periods particularly in the lung after WBI was well-reported in earlier publications.^14,15 However, this study specifically focused on the radiation-induced tissue changes in early periods (during radiation treatment), which has not been addressed previously.

In the publication by Krengli et al.,¹⁵ the authors prospectively analyzed high-resolution CT (HRCT) scans and pulmonary function tests with a correlation with dosimetric data from RT in patients who had underwent BCS followed by adjuvant WBI. The radiologic changes were scored using the classification from Nishioka et al.,¹⁶ a scoring system that reflects alterations detectable by HRCT. Localized pulmonary fibrosis at 9 months was observed in 78% of patients, with a 24% rate of improvement and 7% rate of worsening between 3 and 9 months. Pulmonary changes in the irradiated volume were detected by HRCT at 3 months after RT in 78% of the patients in the study. Okonogi et al.¹⁷ investigated the changes in bone mineral density after pelvic RT in patients with uterine cervical cancer. They found decreased bone marrow density (BMD) in the irradiated region within 1 year after RT, regardless of the menopausal status of the patients. Furthermore, pelvic RT caused a decrease in systemic BMD within 1 year. The effect seemed to be mediated by a decrease in estrogen level due to exposure of the ovary to radiation. Carmona et al.¹⁸ observed increases in bone marrow fat composition within the RT field, particularly in the presence of concurrent myelotoxic chemotherapy. All of the aforementioned articles focused on late tissue changes following RT, and no reports examined the change of physical factors following RT in early periods during the treatment course. The late tissue alterations of lung, bone, and fat composition following RT in the abovementioned publications might have some fundamental connections to our results.

3D FIF WBI techniques adopt the same daily plans, which were designed initially during the 5.5 weeks of WBI treatment. We hypothesized that during these treatment periods, radiation-induced CT number changes as well as other daily variables could be attributed to the change of actual beam dosimetry in treated breasts. Our institutional experimental phantom studies also revealed that 3D beam dosimetry could be altered according to the media the radiation beam passes through. Whether re-simulation should be performed or not for tumor bed boost treatment is also a debatable concern. However, our study showed that volumes receiving high doses (V_105% and V_103%) were statistically significantly different between iCT and rCT scans, and these results support the implementation of rCT scans to reflect various changes during the 5–6 weeks of initial WBI treatment. We also strived to maintain consistency in the measurement of CT numbers and contouring the organs of interest in each CT scan despite the possibility of inter-observer variability.

The interpretation of CT number changes was somewhat complicated because the results exhibited highly variable changes. Soft tissue CT_mean, muscle CT_max, and CT_min showed statistically and significantly higher values in rCT compared with iCT scans. Rib bone CT_mean and CT_min showed statistically significantly lower values in rCT compared with iCT scans. Lung CT number values did not show any statistically significant change (only marginal significance in CT_min, p = 0.055). Thus, there is need to examine the underlying implications of these results after re-evaluation and comparison of late normal tissue changes in further follow-up CT scans.

The dosimetric evaluation specifically focused on the isodose volume changes after reproducing electron boost plans in iCT and rCT scans. The physical nature of the decreased intensity of electrons compared to photons might contribute to increased susceptibility to various factors; thus, the variation in electron beams could be increased. Additional studies are needed to inspect whether creating plans using photons in the same reproducing conditions would result in different consequences.

This study has the following limitations. There are several types of factors that could affect the changes of actual beam dosimetry. However, we focused on identifying CT number changes in organs of interest after absorption of WBI and tried to reduce inconsistency during the analysis of variables. We cannot be certain whether the change of CT numbers and isodose volumes in 3D planning would influence actual treatment outcomes (toxicities), since only the isodose volumes of high-dose regions (hot spots) were affected in our study.

However, this hypothesis-generating study investigated the new aspects of variables that could impact beam dosimetry after several weeks of WBI. We need to further explore detailed normal tissue changes after various dose-fractionation schedules and late tissue variations after a longer follow-up period.

In conclusion, CT number changes after conventional WBI varied according to tissue component. For electron boost plans, implementation of rCT scans might be helpfully utilized because significant dosimetric factor changes were observed, especially in high-dose areas (hot spots: V_105% and V_103%). More comprehensive normal tissue variations following different dose-fractionation WBI schedules and their impact on conformal beam dosimetry need to be further surveyed in future clinical studies.

Footnotes

Acknowledgements

This study was presented in part at the ESMO (European Society for Medical Oncology) Asia 2017 Congress.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research has been supported by grants from the Korean Breast Cancer Foundation.

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Evaluation of tissue computed tomography number changes and dosimetric shifts after conventional whole-breast irradiation in patients undergoing breast-conserving surgery