Hypofractionated radiotherapy after conservative surgery may increase low–intermediate grade late fibrosis in breast cancer patients

Figures & data

Figure 1 Example of the used IMRT technique (forward-planned).

Notes: The two tangential beams were divided into two different segments: one segment (A) was designed to include the WB without filters (6 MV photons) and a second segment (B) was directed to the area of under dosage to compensate for dose loss (15 MV photons).
Abbreviations: IMRT, intensity-modulated radiotherapy; WB, whole breast.

Table 1 RTOG/EORTC scale for late toxicity

Organ tissue	Grade 1	Grade 2	Grade 3	Grade 4
Skin	Slight atrophy; pigmentation change; some hair loss	Patch atrophy; moderate telangiectasia; total hair loss	Marked atrophy; gross telangiectasia	Ulceration
Subcutaneous tissue	Slight induration (fibrosis) and loss of subcutaneous fat	Moderate fibrosis but asymptomatic; slight field contracture <10% linear reduction	Severe induration and loss of subcutaneous tissue; field contracture >10% linear measurement	Necrosis

Abbreviation: RTOG/EORTC, Radiation Therapy Oncology Group/European Organization for Research and Treatment Cancer.

Table 2 Patients’ characteristics

Characteristics	Fractionation schedule		Total, N=447
	50.4 Gray in 28 fx, N=130	40 Gy in 16 fx, N=317
Average age, median (IQR)	55 (46–65)	65 (60–71)	63 (56–70)
Cancer site, N (%)
Right	61 (46.9)	146 (46.1)	207 (46.3)
Left	69 (53.1)	171 (53.9)	240 (53.7)
Histologic type, N (%)
Invasive ductal	75 (57.7)	201 (63.4)	276 (61.7)
Invasive lobular	14 (10.7)	39 (12.3)	53 (11.9)
Mixed	21 (16.2)	37 (11.7)	58 (13.0)
Ductal in situ	10 (7.7)	17 (5.4)	27 (6.0)
Lobular in situ	0 (0)	1 (0.3)	1 (0.2)
Other	10 (7.7)	22 (6.9)	32 (7.2)
T stage, N (%)
T1	77 (59.2)	235 (74.1)	312 (69.8)
T2	41 (31.6)	67 (21.1)	108 (24.2)
T3	3 (2.3)	2 (0.6)	5 (1.1)
T4	4 (3.1)	0 (0.0)	4 (0.9)
Not known	5 (3.8)	13 (4.2)	18 (4.0)
Tumor grade, N (%)
1	19 (14.6)	73 (23.0)	92 (20.6)
2	59 (45.4)	162 (51.1)	221 (49.4)
3	48 (36.9)	76 (24.0)	124 (27.7)
Not known	4 (3.1)	6 (1.9)	10 (2.3)
Pathological nodal status, N (%)
Positive	41 (31.6)	53 (16.7)	94 (21.0)
Negative	89 (68.4)	264 (83.3)	353 (79.0)
Not known	0 (0.0)	0 (0.0)	0 (0.0)

Abbreviations: fx, fractions; IQR, interquartile range; N, number of patients.

Table 3 Treatment characteristics

Characteristics	Fractionation schedule		Total, N=447
	50.4 Gy in 28 fx, N=130	40 Gy in 16 fx, N=317
Regional node irradiation, N (%)
No	109 (83.8)	317 (100)	42 (95.3)
Yes	21 (16.2)	0 (0)	21 (4.7)
Adjuvant chemotherapy, N (%)
No	46 (35.4)	212 (66.9)	258 (57.7)
Yes	84 (64.6)	105 (33.1)	189 (42.3)
Chemotherapy schedule, N (%)
No	45 (34.6)	213 (67.1)	258 (57.7)
CMF	28 (21.6)	23 (7.3)	51 (11.4)
Anthracycline	55 (42.3)	69 (21.8)	124 (27.7)
Anthracycline + docetaxel	2 (1.5)	12 (3.8)	14 (3.2)
Adjuvant hormonotherapy, N (%)
No	46 (35.4)	34 (10.7)	80 (17.9)
Yes	84 (64.6)	283 (89.3)	367 (82.1)

Abbreviations: CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; fx, fractions; N, number of patients.

Figure 2 Actuarial grade 1 late subcutaneous toxicity-free survival vs treatment technique.

Notes: The y axis indicates survival probability; the red colour shows the control group curve; the blue colour shows the MARA-1 curve.

Figure 3 Actuarial grade 2 late subcutaneous toxicity-free survival vs treatment technique.

Notes: The y axis indicates survival probability; the red colour shows the control group curve; the blue colour shows the MARA-1 curve.

Table 4 Univariate analysis of late skin toxicity

Variable	5-year late skin toxicity-free survival
	G1	P	G2	P	G3	P
Technique
CG	61.1	0.49	93.3	0.99	98.2	0.16
MARA-1	56.1		92.9		100
Hypertension
No	54.7	0.20	93.5	0.60	100	0.07
Yes	64.3		92.7		97.7
Diabetes
No	54.7	0.16	93.5	0.69	100	0.74
Yes	64.3		92.7		97.7
Tobacco smoking
No	60.4	0.007	93.1	0.95	99	0.64
Yes	43.4		93.7		100
Alcohol
No	56.8	0.22	92.1	0.16	98.8	0.40
Yes	61.6		95.6		100
Chemotherapy
No	60.0	0.77	93.5	0.72	100	0.17
Yes	57.2		92.6		98.3
Hormone therapy
No	59.2	0.98	95	0.45	100	0.41
Yes	58.1		92.8		98.8
PTV volume
1	64.4	0.002	98.5	<0.001	100	0.21
2	55.3		90.4		97.7
3	36.1		74.7		100

Abbreviations: CG, control group; G, grade; MARA-1, Modulated Accelerated Radiotherapy; PTV, planning target volume.

Table 5 HRs of G1 and G2 late skin toxicity estimates from Cox proportional-hazards regression models

Variable	Value	Late skin toxicity	Univariate analysisa			Multivariate analysisa
			HR	(95% CI)	P	HR	(95% CI)	P
Technique	MARA-1	G1	1.07	(0.77–1.50)	0.686
		G2	1.31	(0.54–3.17)	0.555
Hypertension		G1	0.80	(0.58–1.12)	0.191
		G2	1.03	(0.44–2.42)	0.939
Diabetes		G1	1.43	(0.85–2.39)	0.179
		G2	1.22	(0.29–5.23)	0.788
Tobacco smoking		G1	1.88	(1.22–2.91)	0.005	2.15	(1.38–3.34)	0.001
		G2	0.88	(0.21–3.79)	0.869
Alcohol		G1	0.77	(0.53–1.11)	0.156
		G2	0.38	(0.11–1.28)	0.117
Chemotherapy		G1	0.95	(0.69–1.30)	0.734
		G2	1.34	(0.58–3.12)	0.497
Hormone therapy		G1	0.85	(0.58–1.24)	0.399
		G2	1.81	(0.53–6.13)	0.342
PTV volume		G1	1.11	(1.06–1.17)	0.001	1.12	(1.07–1.18)	0.001
		G2	1.27	(1.15–1.41)	0.001	1.27	(1.15–1.41)	0.001

Notes: Analysis of 437 patients with complete information.

a Covariates to be included in multivariable models were selected with a stepwise backward elimination (P removal =0.10; P addition <0.10) based on likelihood ratio test.

Abbreviations: G, grade; P, probability; MARA-1, Modulated Accelerated Radiotherapy.

Table 6 Univariate analysis of late subcutaneous toxicity

Variable	5-year late subcutaneous toxicity-free survival
	G1	P	G2	P	G3	P
Technique	73.4	<0.001	96.5	0.03	99.2	0.67
CG	49.1		89.6		99.6
MARA-1
Hypertension
No	57	0.41	92.6	0.91	99.1	0.25
Yes	59.7		92.3		100
Diabetes No
No	59.7	0.02	93.8	0.05	99.4	0.68
Yes	31.5		82.2		100
Tobacco smoking
No	57.3	0.50	92.8	0.23	99.7	0.07
Yes	65.7		90		96.8
Alcohol
No	56.1	0.51	92.3	0.53	99.2	0.36
Yes	62.6		95.5		100
Chemotherapy
No	57.1	0.14	91.8	0.35	100	0.11
Yes	59.6		94.8		98.7
Hormone therapy
No	66.5	0.34	95.8	0.35	100	0.48
Yes	55.4		91.3		99.3
PTV volume
1	68.1	<0.001	95.2	0.24	99.4	0.91
2	50.2		89.4		99.4
3	27.3		91		100

Abbreviations: CG, control group; G, grade; MARA-1, Modulated Accelerated Radiotherapy; PTV, planning target volume; P, probability.

Table 7 HRs of G1 and G2 late subcutaneous toxicity estimates from Cox proportional-hazards regression models

Variable	Value	Late subcutaneous toxicity	Univariate analysisa			Multivariate analysisa
			HR	(95% CI)	P	HR	(95% CI)	P
Technique	MARA-1	G1	2.35	(1.61–3.41)	0.001	2.18	(1.50–3.18)	0.001
		G2	3.07	(1.11–8.53)	0.031	3.01	(1.08–8.42)	0.036
Hypertension		G1	0.88	(0.64–1.23)	0.458
		G2	1.15	(0.52–2.54)	0.725
Diabetes		G1	1.77	(1.08–2.90)	0.023	1.65	(1.01–2.71)	0.047
		G2	2.57	(0.87–7.54)	0.086
Tobacco smoking		G1	0.89	(0.52–1.53)	0.682
		G2	1.82	(0.62–5.33)	0.275
Alcohol		G1	0.82	(0.57–1.18)	0.295
		G2	0.79	(0.31–1.97)	0.606
Chemotherapy		G1	0.80	(0.58–1.10)	0.167
		G2	0.71	(0.32–1.60)	0.414
Hormone therapy		G1	2.34	(0.69–8.00)	0.174
		G2	1.20	(0.80–1.81)	0.371
PTV volume		G1	1.14	(1.09–1.20)	0.001	1.14	(1.08–1.20)	0.001
		G2	1.13	(1.01–1.27)	0.027	1.14	(1.01–1.28)	0.035

Notes: Analysis of 437 patients with complete information.

a Covariates to be included in multivariable models were selected with a stepwise backward elimination (P removal =0.10; P addition <0.10) based on likelihood ratio test.

Abbreviations: G, grade; MARA, Modulated Accelerated Radiotherapy.