Current role of modern radiotherapy techniques in the management of breast cancer

Table 1 Randomized phase III trials of intensity modulated radiation therapy for breast cancer

Ref.	N		FU (mo)	End-points	IMRT	Non IMRT	P value	Outcomes reported
	IMRT	2D RT
Donovan et al[32], 2007	150	156	N/A	Distribution of any change in breast appearance between the presence or absence of doses > 105%	OR, 2.6; 95%CI: 1.1-6		0.03	DC, LAE, QOL
				Photographic assessment of any change in breast appearance at 1, 2 and 5 yr	OR, 1.7; 95%CI; 1.2-2.5		0.008
				Physician assessment of breast induration at 5-yr, %
				Centre of the breast	21	32	0.02
				Pectoral fold	22	29	0.006
				İnframammary fold	17	24	0.009
				Boost site	37	61	< 0.001
Pignol et al[30], 2008	170	161	N/A	Acute skin toxicity (Gr 3-4), %	27.1	36.7	0.06	DC, AAE, QOL
				Moist desquamation (all breast), %	31.2	47.8	0.002
				Moist desquamation (inframammary crease), %	26.5	43.5	0.001
				Pain (Gr 2-4), %
Barnett et al[31], 2012	411	404	241	Photographic assessment of breast shrinkage at 2 yr	OR, 1.51; 95%CI: 0.83-1.58		0.41	AAE, LAE, QOL
				Acute toxicity (Gr ≥ 2)	OR, 1.00; 95%CI: 0.76-1.34		0.97
				Telangiectasia	OR, 1.68; 95%CI: 1.13-2.50		0.009
				Moderate or poor overall cosmesis (good baseline surgical cosmesis)	OR, 0.63; 95%CI: 0.39-1.03		0.061
				Patient reported
				Breast pain, %	46.7	37.3	0.98
				Oversensitivity, %	47.1	35	0.43
Mukesh et al[33], 2013	228	237	601	Photographic assessment of breast shrinkage at 5 yr	OR, 0.79; 95%CI: 0.55-1.14		0.21	LAE, TRO
				Teleangiectasia	OR, 0.58; 95%CI: 0.36-0.92		0.021
				Overall cosmesis	OR, 0.68; 95%CI: 0.48-0.96		0.027
				Breast edema	OR, 0.74; 95%CI: 0.48-1.15		0.18
				Tumor bed induration	OR, 0.76; 95%CI: 0.54-1.06		0.11
				Pigmentation	OR, 0.80; 95%CI: 0.46-1.38		0.42
				5-yr overall survival, %	91.7	92.5	0.88
				5-yr locoregional recurrence, %	1.35	2.56	0.36

¹Minimum average follow-up. IMRT: Intensity modulated radiotherapy; 2D RT: Two dimensional radiotherapy; N: Number of patients; FU: Follow-up; DC: Dosimetry characteristics; AAE: Acute adverse effects; LAE: Late adverse effects; TRO: Treatment related outcomes; QOL: Quality of life; Gr: Grade; N/A: Not available; NS: Not significant.

Table 2 American Society for Radiation Oncology and GEC-ESTRO recommendations on patient selection criteria for Accelerated Partial Breast Irradiation

	ASTRO	GEC-ESTRO	ASTRO	GEC-ESTRO	ASTRO	GEC-ESTRO
Factor	Suitable	Low-risk	Cautionary	Intermediate-risk	Unsuitable	High-risk
Patient factors
Age (yr)	≥ 60	> 50	50-59	40-50	< 50	< 40
BRCA1/2 mutation	Not present	Not defined	Not present	Not defined	Present	Not defined
Pathologic factors
Tumor size (cm)	≤ 2	≤ 3	2.1-3.0	≤ 3	> 3	> 3
T stage	T1	T1-2	T0 or T2	T1-2	T3-4	T2 (> 3 cm), T3-4
Histology	IDC or other favorable subtypes	IDC, mucinous, tubular, medullary and colloid carcinoma	ILC allowed	ILC allowed	Any	Any
Grade	Any	Any	Any	Any	Any	Any
Pure DCIS	Not allowed	Not allowed	≤ 3 cm	Allowed	> 3 cm	Any
EIC	Not allowed	Not allowed	≤ 3 cm	Not allowed	> 3 cm	Allowed
Associated LCIS	Allowed	Allowed	Allowed	Allowed	Allowed	Allowed
Multicentricity	Unicentric	Unicentric	Unicentric	Unicentric	Multicentric	Multicentric
Multifocality	Clinically unifocal ≤ 2 cm	Unifocal	Clinically unifocal 2.1-3 cm	Multifocal (limited within 2 cm of the index lesion)	Clinically multifocal, > 3 cm	Multifocal (> 2 cm from the index lesion)
LVSI	No	Not allowed	Limited/focal	Not allowed	Extensive	Allowed
ER status	Positive	Any	Negative	Any	Any	Any
Surgical margins	≥ 2 mm	≥ 2 mm	< 2 mm	< 2 mm	Positive	Positive
Nodal factors
N stage	pN0 (i-, i+)	pN0	pN0 (i-, i+)	pN1mi, pN1a	≥ pN1	pNx, ≥ pN2a
Nodal surgery	SN biopsy or ALND				None performed
Neoadjuvant therapy	Not allowed	Not allowed	Not allowed	Not allowed	If used	If used

DCIS: Ductal carcinoma in situ; EIC: Extensive intraductal component; LCIS: Lobular carcinoma in situ; ASTRO: American Society for Radiation Oncology.

Table 3 Prospective randomized phase III trials of Accelerated Partial Breast Irradiation

Institution/trial	Number of patients	Inclusion criteria	Control arm	Experimental arm
National Institute of Oncology, Budapest, Hungary[80]	258	Wide local excision, > 40 yr, Tm ≤ 20 mm, Invasive ductal carcinoma (non-lobular), Node negative, Margin negative	WBRT (50 Gy in 25 fx)	(1) MIB (36.4 Gy in 7 fx) (2)Electrons (50 Gy in 25 fx)
European Institute of Oncology ELIOT[63,82]	1305	Quadrantectomy, ≥ 48 yr, Tm ≤ 2.5 cm, Invasive carcinoma, Node negative	WBRT (50 Gy in 25 fx) ± 10 Gy boost	IORT (21 Gy in 1 fx, electrons up to 9 MeV)
TARGIT-A[69,81]	3451	Lumpectomy, ≥ 45 yr, Invasive ductal carcinoma (non-lobular), Node negative	WBRT 40–56 Gy ± 10–16 Gy boost	IORT (20 Gy in 1 fx, low-energy X-rays)

Tm: Tumor; WBRT: Whole breast radiotherapy; fx: Fraction; MIB: Multicatheter interstitial brachytherapy; IORT: Intraoperative radiotherapy; DCIS: Ductal carcinoma in situ; 3DCRT: Three dimensional conformal radiotherapy; Gy: Gray.

Table 4 Prospective randomized phase III trials of whole breast radiotherapy vs conventional fractionation radiotherapy

Institution/trial	N	MedianF/U	Eligibility criteria	Treatment arms	Primary endpoint	Secondary endpoint
Royal Marsden Hospital/Sutton and Gloucestershire Oncology Centre[90,91]	1410	5 yr1	Invasive breast cancer, T1-3N0-1M0, < 75 yr, BCS (complete macroscopic resection),Level II/III AD	50 Gy in 25 fx 39 Gy in 13 fx 42.9 Gy in 13 fx	Late changes in breast appearance	Palpable breast induration Ipsilateral tumor recurrence
UK START A[92,94]	2236	9.3 yr	Invasive breast cancer, T1-3aN0-1M0, > 18 yr, Clear tm margins (≥ 1 mm), No immediate surgical reconstruction, Available for follow-up	50 Gy in 25 fx 41.6 Gy in 13 fx 39 Gy in 13 fx	Loco-regional tumor recurrence	Late normal tissue effects QOL
UK START B[93,94]	2215	9.9 yr	Invasive breast cancer, T1-3aN0-1M0,> 18 yr, Clear tm margins (≥ 1 mm), No immediate surgical reconstruction, Available for follow-up	50 Gy in 25 fx 40 Gy in 15 fx	Loco-regional tumor recurrence	Late normal tissue effects QOL
Ontario Clinical Oncology Group[95]	1234	12 yr	Invasive breast cancer, BCS + Level I/II AD,Tm ≤ 5 cm, Negative axillary nodes, Maximum width of breast tissue ≤ 25 cm, No multicentric disease	50 Gy in 25 fx 42.5 Gy in 16 fx	Local recurrence	Regional and distant recurrence Second cancers Breast cosmesis Late toxic effects of radiation

¹Minimum follow-up. N: Number of patients; F/U: Follow-up; WBRT: Whole breast radiotherapy; RT: Radiotherapy; BCS: Breast conserving surgery; AD: Axillary dissection; fx: Fraction; Gy: Gray; UK START; United Kingdom Standardization of Breast Radiotherapy; QOL: Quality of life.