Pneumonitis and fibrosis after breast cancer radiotherapy: occurrence and treatment-related predictors

Figures & data

Table 3. Predictors for pneumonitis and fibrosis by univariate and multivariable logistic regression analysis.

	Univariable			Multivariable
	OR	CI	p	OR	CI	p
rRP 3 months
Smoking	0.29	0.10–0.64	0.01	0.28	1.31–2.34	.001
cRP 3 months
Mastectomy	2.50	1.25–5.00	0.01	2.48	1.15–5.34	.02
rRP 6 months
V20	1.05	1.01–1.09	0.01	1.06	1.02–1.10	.003
V30	1.08	1.03–1.13	0.003	1.10	1.04–1.16	.001
MLD	1.10	1.01–1.20	0.03	1.12	1.03–1.23	.01
D25	1.03	0.99–1.05	0.06	1.03	1.00–1.06	.03
Age	1.03	0.99–1.06	0.08	1.03	0.99–1.06	.12
BMI	1.06	0.99–1.13	0.11	1.05	0.98–1.13	.19
cRF 6 months
Smoking	0.50	0.22–1.14	0.10	0.50	0.21–1.16	.10
Mastectomy	2.43	1.13–5.46	0.02	2.73	1.14–6.55	.03
cRF 12 months
Endocrine treatment	2.32	1.09–4.96	0.03	2.31	1.07–4.97	.03
Tamoxifen	1.87	1.04–3.40	0.04	2.12	1.13–3.97	.02
Comorbidity	1.78	0.82–3.87	0.14	0.81	0.34–1.89	.62

RP: radiation pneumonitis; cRF : symptomatic radiation pneumonitis; RF: radiation fibrosis; cRF: symptomatic radiation fibrosis; OR: odds ratio; p :  p-value; CI: confidence interval; V20 :  percent of ipsilateral lung given 20 Gy or more; V30 :  percent of ipsilateral lung given 30 Gy or more; MLD: mean lung dose. Note. Only significant predictors are presented, while complete models (with all variables) are available in the supplementary materials.

Figure 1. Consort diagram. Clinical visit by physician, CT, CTCAE, and EORTC registration at baseline and at 3, 6, and 12 months after radiotherapy. Excluded patients at the right.

Table 1. Patient and treatment characteristics.

	n (%)	Mean (SD)
Age (year)		58.1 (9.9)
Age, range (year)		28–89
BMI		26.1 (4.5)
BMI, range		16.7–44.8
Comorbidity	59 (24)
Cardiovascular disease	35 (14)
Lung disease	10 (4)
Other (kidney, rheumatoid arthritis diabetes, depression)	14 (6)
Smoking	47 (19)
pT1	165 (66)
pT2	49 (20)
pT3/4	16 (6)
Tis	20 (8)
Axillary node positive	73 (29)
Grade 1	51 (21)
Grade 2	107 (44)
Grade 3	83 (34)
ER positive	191 (83)
PR positive	133 (58)
HER-2 positive	49 (22)
IDC / ILC	216 (86)
DCIS	34 (14)
Chemotherapy	103 (41)
FEC 60 × 6	57 (23)
FEC 100 × 6	27 (11)
FEC 60 × 6 + Docetaxel × 4	19 (8)
Endocrine therapy	137 (56)
Tamoxifen	114 (46)
Aromataseinhibitor	23 (9)
Tratuzumab^1	34 (146)
Surgery
Mastectomy	69 (28)
Breast conserving surgery	181 (72)
Radiation therapy
Local RT	168 (67)
Locoregional RT	82 (33)
RT to axilla	38 (15)
Boost	28 (11)
Dosemetric values
V20 (%)		9.6 ± 8.5
V30 (%)		15.7 ± 6.4
Mean lung dose (MLD (Gy)		10.7 ± 8.5
D25 (Gy)		12.6 ± 11.1
Local RT (Gy)		8.1 ± 2.44
Loco-regional RT (Gy)		14.0 ± 2.33

T: tumor size according to AJCC staging 7^th edition; ER: estrogen receptor> =10%; PR: progesterone receptor; HER-2: human epidermal growth factor receptor by FISH; IDC: invasive ductal carcinoma; ILC: invasive lobular carcinoma; DCIS: ductal carcinoma in situ. FEC 60:  5-Fu 600 mg/m², Epirubicin 60 mg/m² and Cyclofosfamide 600 mg/m². FEC 100: Epirubicin100mg/m². EC: Epirubicin 60 mg/m² Cyclofosfamide 600 mg/m². Docetaxel: Docetaxel 100 mg/m². Tratuzumab¹: four doses trastuzumab given concomitant with docetaxel and thereafter for totally one year. Local: the whole breast. Loco-regional: the whole breast or the chestwall and fossa supraclav/axillaregion.

Table 2. Radiological and symptomatic radiation pneumonitis and fibrosis reported by CTCAE.

	Before RT n (%)		3 months n (%)	6 months n (%)	12 months n (%)
rP	3 (1)	rRP	179 (78)	52 (23)	4 (2)
crP	1 (0.4)	cRP	42 (19)	9 (4)	0
rF	15 (6)	rRF	42 (18)	189 (84)	200 (89)
crF	3 (1)	cRF	11 (5)	35 (16)	38 (17)

rP: radiological pneumonitis; crP: clinical rP (rP and symptoms); rF: radiological fibrosis; crF: clinical rF ; rRP: radiological radiation pneumonitis; cRP: clinical radiation pneumonitis; rRF: radiological radiation fibrosis; cRF: clinical radiation fibrosis. All symptoms were reported as grade 1 except for two grade 2 at baseline (one dyspnea and one coughing), and one grade 2 (coughing) at 3, 6, and 12 months, respectively.

Table 4. Physician-reported dyspnea and coughing by CTCAE.

Symptom	Baseline (n = 243) n (%)	3 months (n = 218) n (%)	6 months (n = 223) n (%)	12 months (n = 225) n (%)
Dyspnea	21 (9)	36 (17)^a	23 (11)	26 (12)^a
Coughing	27 (11)	30 (14)	21 (9)	22 (10)
Dyspnea and coughing	15 (6)	15 (7)	9 (4)	6 (3)

CTCAE: common terminology criteria for adverse events. All symptoms reported as grade 1 except one dyspnea grade 2 at baseline and one coughing grade 2 at baseline, one at 6 months, and one at 3 and 12 months respectively.

^aSignificant more frequent reported dyspnea compared to baseline.

Figure 2. Physician- and patient-reported dyspnea during the first year after radiotherapy. Columns represent the proportions of patients. Physician-reported no dyspnea (blue), physician-reported dyspnea (orange), patient-reported no dyspnea (gray), patient-reported a little dyspnea (yellow), and patient-reported quite a bit/very much dyspnea (light blue).