Toxicity at three years with and without irradiation of the internal mammary and medial supraclavicular lymph node chain in stage I to III breast cancer (EORTC trial 22922/10925)

Figures & data

Table I. Patient characteristics

Per protocol population
	Treatment
	No IM-MS (N=1944)	IM-MS (N=1922)
Age (years)
Median	54.0	54.0
Range	22.0 - 75.0	19.0 - 75.0
< 45	346 (17.8)	354 (18.4)
45-<55	680 (35.0)	661 (34.4)
55-<65	582 (29.9)	579 (30.1)
>=65	336 (17.3)	328 (17.1)
Performance Status (PS)
PS 0	1733 (89.1)	1725 (89.8)
PS 1	198 (10.2)	181 (9.4)
PS 2	7 (0.4)	5 (0.3)
Missing	6 (0.3)	11 (0.6)
Menopausal status
Pre-menopausal	650 (33.4)	657 (34.2)
Peri-menopausal	151 (7.8)	133 (6.9)
Post menopausal	1080 (55.6)	1071 (55.7)
Artificial menopause	63 (3.2)	61 (3.2)
Type of breast surgery
Mastectomy	447 (23.0)	454 (23.6)
Breast conserving	1497 (77.0)	1468 (76.4)
Pathological T *
pT1	1180 (60.7)	1160 (60.4)
pT2	689 (35.4)	685 (35.6)
pT3	65 (3.3)	70 (3.6)
Missing	10 (0.5)	7 (0.4)
Pathological N (axilla) *
pN0	877 (45.1)	855 (44.5)
pN1	848 (43.6)	822 (42.8)
pN2	182 (9.4)	188 (9.8)
pN3	37 (1.9)	57 (3.0)
Tumour stage *
Stage I	658 (33.8)	654 (34.0)
Stage IIa	647 (33.3)	612 (31.8)
Stage IIb	376 (19.3)	374 (19.5)
Stage III	253 (13.0)	276 (14.4)
Missing	10 (0.5)	6 (0.3)
Combination of ER/PR status
ER+,PR+	1066 (54.8)	1055 (54.9)
ER+,PR-/unknown	359 (18.5)	380 (19.8)
PG+,ER-/unknown	82 (4.2)	66 (3.4)
ER-,PR-	320 (16.5)	295 (15.3)
Missing	117 (6.0)	126 (6.6)
Adjuvant hormonal therapy
None reported	775 (39.9)	786(40.9)
yes	1169 (60.1)	1136 (59.1)
Adjvuant chemotherapy
No chemotherapy	886 (45.6)	871 (45.3)
Adjuvant	243 (12.5)	242 (12.6)
Neo-adjuvant	815 (41.9)	809 (42.1)
Adjuvant treatment
None	294 (15.1)	316 (16.4)
Chemotherapy	481 (24.7)	470 (24.5)
Hormonal therapy	592 (30.5)	555 (28.9)
Both	577 (29.7)	581 (30.2)

* Staging is according to UICC 1992

ER=Estrogen receptor, PR=progesterone receptor

Table II. Toxicity up to year three according to treatment arm

	No IM-MS (N=1944)	IM-MS (N=1922)
	N (%)	N (%)	P-value
Lung Fibrosis (to year 3) *	17 (0.9)	54 (2.8)	<0.0001
Cough	5 (0.3)	10 (0.5)	0.19
Dyspnoea	1 (0.1)	14 (0.7)	0.0007
Pneumonitis	1 (0.1)	13 (0.7)	0.0012
Pleuritis	5 (0.3)	2 (0.1)	0.26
Other lung toxicity	2 (0.1)	4 (0.2)	0.41
Any lung toxicity	26 (1.3)	83 (4.3)	<0.0001
Dermatitis	38 (2.0)	26 (1.4)
Skin fibrosis
Yes, unspecified	160 (8.2)	152 (7.9)
Breast/chestwall	0 (0.0)	6 (0.3)
Matchline	1 (0.1)	5 (0.3)
Hyperpigmentation
Yes, unspecified	55 (2.8)	56 (2.9)
Parasternal	0 (0.0)	3 (0.2)
Teleangectasia
Yes, unspecified	27 (1.4)	41 (2.1)
Parasternal	0 (0.0)	1 (0.1)
Supraclavicular	1 (0.1)	2 (0.1)
Skin - other	7 (0.4)	11 (0.6)
Any (breast) skin toxicity	246 (12.7)	262 (13.6)	0.37
Cardiac fibrosis (to year 3) *	5 (0.3)	7 (0.4)	0.55
Evidence of cardiac disease (to year 3) *	28 (1.4)	31 (1.6)	0.64
Mastitis	7 (0.4)	6 (0.3)
Breast Infection	4 (0.2)	3 (0.2)
Radionecrosis	2 (0.1)	1 (0.1)
Osteonecrosis	22 (1.1)	27 (1.4)
Oedema
Yes, unspecified	81 (4.2)	81 (4.2)
Presternal	0 (0.0)	1 (0.1)
Arm/hand	70 (3.6)	73 (3.8)
Breast/chestwall pain	45 (2.3)	35 (1.8)
Retrosternal pain	1 (0.1)	2 (0.1)
Other pain	15 (0.8)	26 (1.4)
Dysphagia	0 (0.0)	4 (0.2)
Fatigue	20 (1.0)	22 (1.1)
Arm or shoulder function impairment	8 (0.4)	1 (0.1)
Other - unspecified	8 (0.4)	8 (0.4)
Any toxicity (to year 3)	424 (21.8)	491 (25.5)	0.006

pre printed item on case report forms

Table III. WHO performance status at baseline and at year for the non-progressive patients

Performance status at year 3	Baseline Performance status
No IM-MS Group	Missing	Performance status 0	Performance status 1	Performance status 2	Total
Missing	1	223	29	2	255
Performance status 0	5	1370	135	3	1513
Performance status 1	0	133	33	1	167
Performance status 2	0	4	0	1	5
Performance status 3	0	1	1	0	2
Performance status 4	0	2	0	0	2
Total	6	1733	198	7	1944
IM-MS Group	Missing	Performance status 0	Performance status 1	Performance status 2
Missing	4	224	30	0	258
Performance status 0	4	1361	114	4	1483
Performance status 1	3	134	33	1	171
Performance status 2	0	4	4	0	8
Performance status 3	0	1	0	0	1
Performance status 4	0	1	0	0	1
Total	11	1725	181	5	1922

(Missing: patients with missing performance status or with progression before the assessment time point

Blue=deterioration, orange=improvement

Table IV. Influence of various parameters on WHO performance status deterioration

		Without neo-adjuvant chemotherapy(N=2242)				With neo-adjuvant chemotherapy(N=1624)
Effect		OR	95%CI		P-value	OR	95% CI		P-value
Treatment	IM-MS vs. No IM-MS	1.02	0.77	1.35	0.89	1.12	0.68	1.86	0.66
Side	left vs. right	0.98	0.75	1.30	0.92	1.15	0.69	1.91	0.60
Adjuvant hormonal therapy	Yes vs. None reported	0.56*	0.44	0.76	<0.0001	0.99	0.59	1.67	0.97
Adjuvant chemotherapy	Yes vs. No	1.26	0.90	1.75	0.18	N.A.
Age	45-<55y vs. <45y	1.34	0.82	2.19	0.48	1.41	0.72	2.74	0.06
	55-<65 vs. <45 y	1.10	0.67	1.81	(df=3)	0.66	0.29	1.54	(df=3)
	≥65 vs. <45 y	1.34	0.80	2.23		2.13	0.91	4.99
Type of surgery	Breast conserving vs. Mastectomy	0.88	0.61	1.29	0.52	0.87	0.51	1.50	0.61
Tumour size (pathology)	> 1cm-2cm vs. <=1 cm	0.95	0.66	1.37	0.66	1.98	0.59	6.62	0.71
	> 2 cm-3cm vs. <=1 cm	1.20	0.79	1.82	(df=3)	1.70	0.49	5.89	(df=3)
	>3 cm vs. <=1 cm	108	0.60	1.94		1.98	0.55	7.17
pN	pN+ vs. pN0	1.15	0.86	1.53	0.34	0.65	0.37	1.13	0.13
Pathological Stage	Stage IIa vs. Stage I	0.98	0.70	1.37	0.41	1.19	0.54	2.64	0.60
	Stage IIb vs. Stage I	1.33	0.89	1.97	(df=3)	0.81	0.33	1.99	(df=3)
	Stage III vs. Stage I	1.35	0.71	2.56		0.81	0.32	2.06
Oestrogen receptor	positive vs. negative	1.06	0.69	1.63	0.005	0.89	0.50	1.58	0.79
	Unknown vs. negative	2.22	1.24	3.99	(df=2)	1.39	0.31	6.36	(df=2)
Progesterone receptor	positive vs. negative	0.81	0.58	1.12	0.025	1.10	0.64	1.92	0.77
	Unknown vs. negative	1.38	0.88	2.15	(df=2)	0.77	0.25	2.29	(df=2)
Combination of Receptors	ER+,PG-,unkn vs. ER+,PG+	1.32	0.92	1.88	0.50	0.63	0.29	1.38	0.66
	PG+,ER-,unkn vs. ER+,PG+	0.97	0.41	2.31	(df=3)	1.01	0.30	3.37	(df=2)
	ER-,PG- vs. ER+,PG+	1.09	0.67	1.77		1.07	0.57	2.02
Menopausal status	Post-Menopausal vs. Pre-menopausal	0.95	0.70	1.29	0.74	1.02	0.61	1.71	0.94

* Significant in multivariate model

Table V. Influence of various parameters in the multivariate analysis on WHO performance status deterioration

		Without neo-adjuvant chemotherapy
Effect		OR	95%CI		P-value
Neo-Adjuvant chemotherapy	Yes vs. No	0.30	0.18	0.52	<0.0001
Adjuvant hormonal therapy (if no neoadjuvant CT)	Yes vs. None reported	0.53	0.38	0.74	0.0002
Adjuvant hormonal therapy(if neoadjuvant CT)	Yes vs. None reported	0.90	0.50	1.61	0.72
Age	45-<55y vs. <45y	1.42	0.90	2.25	0.087
	55-<65 vs. <45 y	1.20	0.67	2.16	(df=3)
	≥65 vs. <45 y	1.77	0.96	3.24
Pathological Stage	Stage IIa vs. Stage I	1.22	0.89	1.68	0.44
	Stage IIb vs. Stage I	1.35	0.92	1.99	(df=3)
	Stage III vs. Stage I	1.20	0.71	2.04
Combination of Receptors	ER+,PG-,unkn vs. ER+,PG+	1.16	0.84	1.61	0.087
	PG+,ER-,unkn vs. ER+,PG+	0.87	0.43	1.35	(df=3)
	ER-,PG- vs. ER+,PG+	0.87	0.57	2.25
Menopausal status	Post-Menopausal vs. Pre-menopausal	0.95	0.62	1.44	0.79

Table VI. Correlation between toxicity and WHO performance status deterioration at three years

Deterioration by year 3	No Change/improvement (N=3056)	Deterioration (N=285)
	N (%)	N (%)	OR	95% CI	P-value
Any lung toxicity
No	2972 (91.5)	276 (8.5)
Yes	84 (90.3)	9 (9.7)	1.19	0.59-2.41	0.62
Lung Fibrosis (to year 3)
No	2996 (91.5)	280 (8.5)
Yes	56 (91.8)	5 (8.2)	1.02	0.40-2.59	0.96
Missing	4 (100.0)	0 (0.0)
Cardiac Fibrosis (to year 3)
No	3038 (91.4)	285 (8.6)			Too small
Yes	11 (100.0)	0 (0.0)			sample for
Missing	7 (100.0)	0 (0.0)			testing
Evidence of cardiac disease (to year 3)
No	2989 (91.9)	265 (8.1)
Yes	38 (76.0)	12 (24.0)	3.71	1.90-7.24	<0.0001
Missing	29 (78.4)	8 (21.6)