Toxicity of internal mammary irradiation in breast cancer. Are concerns still justified in times of modern treatment techniques?

Figures & data

Table 1. Definition of risk groups, overview of the risk models used for calculation of absolute risks attributed to IMNI, and references to approaches based on alternative dose metrics.

	Definition of risk groups		Baseline risk model	Radiation risk model	Alternative dose metrics
	Low risk	High risk
Cardiac mortality	Non smoker RRsys 120 mmHg Cholesterol 200 mg/dl	Smoker RRsys 160 mmHg Cholesterol 300mg/dl	SCORE [19], coronary heart disease in low-risk European countries	ERR = Heart_Dmean × 0.074/Gy, [20]	LAD_Dmean [20], LV_V5 [21]
Radiation pneumonitis	Smoker No pulmonary comorbidities No sequential chemotherapy	Non-smoker Pulmonary comorbidities Sequential chemotherapy	Not applicable	Lyman-Kutcher-Burman model [22], adjusted for clicinal risk factors according to Appelt et al. [23] based on total mean lung dose	TotalLung_ V20 [24]
Lung cancer	Non-smoker	10 cigarettes/d since age 20	– Smokers: Bach [25] – Nonsmokers: Thun [26], correcting for incidence by factor 1.3 [27]	ERR = Total_Lung_Dmean × 0.11/Gy [28]	Lung_OEDPlat [29]
Contralateral breast cancer	No family history of breast cancer First child born before age of 30 years No history of high-risk neoplasia Negative hormone receptor status	Breast cancer in first degree relatives First child born at age 30–40 years History of high-risk neoplasia Positive estrogen receptor status and anti-estrogen therapy	CBCRisk [30]	– Age 40: ERR = CB_Dmean × 0.20/Gy [31,32] - 40% reduction per 10 years increase in age [29]	CB_OEDPlat [29]

Figure 1. Dose distribution of an exemplary patient in free breathing without (A) and with (C) IMNI and in DIBH without (B) and with (D) IMNI. Level: sternocostal joint of the third rip.

Figure 2. Box-plot diagrams delineating the dose difference between DIBH and FB ± IMNI. Comparison of dose to the heart (a), total lung (c, d) and the contralateral breast (b) during RNI with (+) and without (−) IMNI in free breathing (FB) and deep inspiration breath hold (DIBH). (a–c) Mean dose in gray (Gy); (d) volume fraction receiving at least 20 Gy in % (V20Gy). First and second box: positive dose difference means that OAR dose is lower for − IMNI. Third and fourth box: negative dose difference means that OAR dose is lower in DIBH.

Figure 3. Box-plot diagrams delineating the estimated additional risk of IMNI Estimated 10-year increase of cardiac mortality attributed to IMNI for different age and risk levels compared to the published (8-year or 10 year) overall survival (OS) benefit of IMNI [4,6]. Estimated increase of absolute 10-year contralateral breast cancer risk (b) additional 10-year absolute risks for pneumonitis (c) or secondary lung cancer (d) due to IMNI for different age and risk levels. Baseline risks in parentheses.

Table 2. Estimated toxicity after RNI ± IMNI.

Risk Group	Cardiac risk (%)
	Baseline risk	FB		DIBH
		−IMNI	+IMNI	−IMNI	+IMNI
40 year low risk	0.0	0 (0–0)	0 (0–0)*	0 (0–0)	0 (0–0)*
40 year high risk	0.2	0.2 (0.2–0.3)	0.3 (0.2–0.3)*	0.2 (0.2–0.3)	0.2 (0.2–0.3)*
50 year low risk	0.1	0.1 (0.1–0.2)	0.1 (0.1–0.2)*	0.1 (0.1–0.1)	0.1 (0.1–0.1)*
50 year high risk	0.9	1.1 (1.1–1.3)	1.3 (1.1–1.4)*	1.1 (1.1–1.2)	1.1 (1.1–1.3)*
60 year low risk	0.5	0.6 (0.6–0.7)	0.7 (0.6–0.7)*	0.6 (0.6–0.7)	0.6 (0.6–0.7)*
60 year high risk	3.5	4.4 (4.2–5.1)	4.9 (4.4–5.4)*	4.2 (4.1–4.7)	4.4 (4.1–4.8)*
70 year low risk	1.3	1.6 (1.5–1.9)	1.8 (1.6–2)*	1.6 (1.5–1.8)	1.6 (1.5–1.8)*
70 year high risk	9.7	12.3 (11.5–14)	13.6 (12.1–15)*	11.6 (11.3–13.1)	12.1 (11.4–13.3)*
	Pneumonitits risk (%)
	Baseline risk	FB		DIBH
		−IMNI	+IMNI	−IMNI	+IMNI
50 year low risk	n.a.	1.4 (1.2–1.7)	1.8 (1.6–2.1)*	1.4 (1.2–1.6)	1.6 (1.4–1.8)*
50 year high risk	n.a.	4.9 (4.4–5.8)	6.1 (5.5–7.1)*	5 (4.2–5.7)	5.6 (4.9–6.2)*
70 year low risk	n.a.	2.3 (2–2.7)	2.9 (2.6–3.4)*	2.3 (1.9–2.7)	2.6 (2.3–2.9)*
70 year high risk	n.a.	7.9 (7.1–9.3)	9.7 (8.7–11.3)*	8 (6.7–9)	8.9 (7.8–9.9)*
	Secondary cancer lung (%)
	Baseline risk	FB		DIBH
		−IMNI	+IMNI	−IMNI	+IMNI
40 year low risk	0.05	0.1 (0.1–0.1)	0.1 (0.1–0.1)*	0.1 (0.1–0.1)	0.1 (0.1–0.1)*
40 year high risk	0.2	0.2 (0.2–0.2)	0.2 (0.2–0.2)*	0.2 (0.2–0.2)	0.2 (0.2–0.2)*
50 year low risk	0.1	0.1 (0.1–0.1)	0.1 (0.1–0.1)*	0.1 (0.1–0.1)	0.1 (0.1–0.1)*
50 year high risk	0.9	1.2 (1.2–1.3)	1.4 (1.3–1.4)*	1.2 (1.2–1.3)	1.3 (1.2–1.4)*
60 year low risk	0.2	0.3 (0.3–0.3)	0.3 (0.3–0.3)*	0.3 (0.3–0.3)	0.3 (0.3–0.3)*
60 year high risk	3.2	4.4 (4.2–4.7)	4.8 (4.6–5)*	4.4 (4.1–4.6)	4.6 (4.4–4.8)*
70 year low risk	0.4	0.6 (0.5–0.6)	0.6 (0.6–0.6)*	0.6 (0.5–0.6)	0.6 (0.6–0.6)*
70 year high risk	6.5	8.9 (8.5–9.5)	9.7 (9.3–10.2)*	8.9 (8.3–9.4)	9.3 (8.8–9.7)*
	Secondary cancer contralateral breast (%)
	Baseline risk	FB		DIBH
		−IMNI	+IMNI	−IMNI	+IMNI
40 year low risk	3.3	5.4 (4.1–6.9)	5.9 (4.9–7.6)*	5.1 (4.3–6)	5.4 (4.9–6.4)*
40 year high risk	7.1	11.6 (8.9–14.8)	12.7 (10.4–16.4)*	11.1 (9.3–12.9)	11.5 (10.5–13.8)*
50 year low risk	3.7	5.1 (4.3–6.1)	5.5 (4.7–6.6)*	4.9 (4.4–5.5)	5.1 (4.8–5.8)*
50 year high risk	7.9	10.9 (9.1–13)	11.7 (10.1–14.1)*	10.6 (9.4–11.8)	10.9 (10.2–12.4)*
60 year low risk	4.3	5.3 (4.7–6)	5.5 (5–6.3)*	5.2 (4.8–5.6)	5.3 (5–5.8)*
60 year high risk	9.2	11.3 (10–12.8)	11.8 (10.8–13.5)*	11.1 (10.2–11.9)	11.3 (10.8–12.3)*
70 year low risk	4.4	5 (4.6–5.4)	5.2 (4.8–5.6)*	4.9 (4.7–5.2)	5 (4.9–5.3)*
70 year high risk	9.4	10.7 (9.9–11.6)	11 (10.4–12)*	10.5 (10–11.1)	10.7 (10.4–11.3)*

Risk for cardiac mortality, pneumonitis and secondary breast and lung cancer for different risk groups compared to the baseline risk. Median values and range based on dose distribution in 20 patients and risk scenarios are specified in Table 1.

*p < .05.

Conroy RM, Pyorala K, Fitzgerald AP, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J. 2003;24(11):987–1003.

 PubMed Web of Science ®Google Scholar

Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987–998.

 PubMed Web of Science ®Google Scholar

van den Bogaard VA, Ta BD, van der Schaaf A, et al. Validation and modification of a prediction model for acute cardiac events in patients with breast cancer treated with radiotherapy based on three-dimensional dose distributions to cardiac substructures. J Clin Oncol. 2017;35(11):1171–1178.

 PubMed Web of Science ®Google Scholar

Semenenko VA, Li XA. Lyman-Kutcher-Burman NTCP model parameters for radiation pneumonitis and xerostomia based on combined analysis of published clinical data. Phys Med Biol. 2008;53(3):737–755.

 PubMed Web of Science ®Google Scholar

Appelt AL, Vogelius IR, Farr KP, et al. Towards individualized dose constraints: adjusting the QUANTEC radiation pneumonitis model for clinical risk factors. Acta Oncol. 2014;53(5):605–612.

 PubMed Web of Science ®Google Scholar

Marks LB, Bentzen SM, Deasy JO, et al. Radiation dose-volume effects in the lung. Int J Radiat Oncol Biol Phys. 2010;76(3):S70–S76.

 PubMed Web of Science ®Google Scholar

Bach PB, Kattan MW, Thornquist MD, et al. Variations in lung cancer risk among smokers. J Natl Cancer Inst. 2003;95(6):470–478.

 PubMedGoogle Scholar

Thun MJ, Henley SJ, Burns D, et al. Lung cancer death rates in lifelong nonsmokers. J Natl Cancer Inst. 2006;98(10):691–699.

 PubMedGoogle Scholar

Clement-Duchene C, Stock S, Xu X, et al. Survival among never-smokers with lung cancer in the Cancer Care Outcomes Research and Surveillance Study. Annals Ats. 2016;13(1):58–66.

 Web of Science ®Google Scholar

Taylor C, Correa C, Duane FK, et al. Estimating the risks of breast cancer radiotherapy: evidence from modern radiation doses to the lungs and heart and from previous randomized trials. JCO. 2017;35(15):1641–1649.

 PubMed Web of Science ®Google Scholar

Schneider U, Zwahlen D, Ross D, et al. Estimation of radiation-induced cancer from three-dimensional dose distributions: concept of organ equivalent dose. Int J Radiat Oncol Biol Phys. 2005;61(5):1510–1515.

 PubMed Web of Science ®Google Scholar

Chowdhury M, Euhus D, Arun B, et al. Validation of a personalized risk prediction model for contralateral breast cancer. Breast Cancer Res Treat. 2018;170(2):415–423.

 PubMed Web of Science ®Google Scholar

Stovall M, Smith SA, Langholz BM, et al. Dose to the contralateral breast from radiotherapy and risk of second primary breast cancer in the WECARE study. Int J Radiat Oncol Biol Phys. 2008;72(4):1021–1030.

 PubMed Web of Science ®Google Scholar

Boice JD, Jr., Harvey EB, Blettner M, et al. Cancer in the contralateral breast after radiotherapy for breast cancer. N Engl J Med. 1992;326(12):781–785.

 PubMed Web of Science ®Google Scholar

Thorsen LB, Offersen BV, Dano H, et al. DBCG-IMN: a population-based cohort study on the effect of internal mammary node irradiation in early node-positive breast cancer. J Clin Oncol. 2016;34(4):314–320.

 PubMed Web of Science ®Google Scholar

Hennequin C, Bossard N, Servagi-Vernat S, et al. Ten-year survival results of a randomized trial of irradiation of internal mammary nodes after mastectomy. Int J Radiat Oncol Biol Phys. 2013;86(5):860–866.

 PubMed Web of Science ®Google Scholar