Published Ahead of Print on May 23, 2016 as 10.1200/JCO.2016.67.
4531
The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2016.67.4531
JOURNAL OF CLINICAL ONCOLOGY
Internal Mammary Node Irradiation in
Breast Cancer: The Issue of Patient
Selection
The article by Thorsen et al1 in Journal of Clinical Oncology
demonstrates that internal mammary node irradiation (IMNI)
increases overall survival in patients with early-stage axillary node-
positive breast cancer. These findings further define the role of
radiotherapy in node-positive patients.2-6 In a meta-analysis by the
Early Breast Cancer Trialists’ Collaborative Group, postmastectomy
radiotherapy to the chest wall and regional lymph nodes, including
internal mammary nodes, yielded a similar reduction in breast cancer
mortality in patients with one to three positive axillary nodes
(7.9% absolute reduction at 20 years) and in those with four or
more positive nodes (9.3% reduction).2 There was no benefit for
patients with node-negative axilla.2 Two large, randomized trials,
which included patients with conservative breast surgery3 or any
surgery,4 underscored the specific role of regional node irradi-
ation—to undissected levels II to III axilla, supraclavicular and
internal mammary nodes. In either trial, addition of regional
node irradiation to whole-breast or chest wall irradiation im-
proved the distant metastasis–free survival at 10 years.3,4 Aggregated
data from both trials showed a benefit from regional node therapy
not only for 10-year distant metastasis–free survival (hazard ratio,
0.84; P 5 .002), but also for 10-year overall survival (hazard ratio,
0.88; P 5 .034)5; however, the specific impact of IMNI could not be
assessed. This would be important information as IMNI delivers
a significant dose to the heart, especially in patients who are treated
for cancer in the left breast.7 The only trial that tackled this specific
question concluded a nonsignificant benefit from using IMNI:
10-year overall survival was 62.6% in the group that received
IMNI versus 59.3% in the group that did not receive IMNI.6
These negative results, however, may be explained by the fact
that the study was underpowered.
In the population-based cohort study by Thorsen et al,1 node-
positive patients with cancer in the right breast received IMNI treat-
ment, whereas patients with left-sided breast cancer did not. The 8-year
overall survival rates were 75.9% with IMNI and 72.2% without IMNI
(adjusted hazard ratio, 0.82; P 5.005). IMNI was beneficial for patients
with four or more positive nodes, whatever the tumor site (ie, medial or
lateral). For patients with one to three positive nodes, an exploratory
analysis suggested only a trend toward benefit in that case of medial and
central tumors and no benefit for tumors in the lateral quadrants.1
Thus, it is still unclear whether patients with one to three positive
nodes should be treated with IMNI and how to manage patients with
cancer of the left breast. A better selection than one that is simply on
the basis of on medial versus lateral tumor location is most likely
needed so that benefit from IMNI would outweigh the potential
cardiotoxicity, including in patients with left-sided breast cancer.
Two parameters define the risk of internal mammary (IM)
node involvement: the invasive power of the tumor—a higher risk
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Copyright 2016 by American Society of Clinical Oncology
C O R R E S P O N D E N C E
is associated with high tumor grade, extensive lymphovascular
invasion, large tumor size, or unfavorable molecular subtypes; and
the anatomic and physiologic probability for tumor cells to reach
IM nodes. This depends on the lymphatic flow toward the IM
lymphatic basin and can be visualized with lymphoscintigraphy.8,9
Today, the majority of patients with early node-positive disease are
diagnosed after axillary sentinel node biopsy, which is the standard
practice in patients with T1 to T2 and clinical N0 breast cancer. When
the radiotracer is injected peritumorally, the lymphoscintigraphy not
only identifies axillary sentinel nodes but also depicts a physiologic
drainage from the tumor site to the IM basin in approximately 20% of
patients.8 The risk of having IM involvement is higher in younger
patients and also depends on the location of the tumor.8,9 Contrary to
common belief, the probability of IM drainage for tumors of the lower
outer quadrant is as high as for tumors in the medial or central breast
(approximately 30%). Only tumors from the upper outer quadrant
have a smaller risk (approximately 10%).8,9 Of importance, some
large studies in which IM node biopsy was performed in case of
IM drainage showed that when IM drainage is present and an
axillary sentinel node is found positive, the risk of concomitant
IM invasion exceeds 40% (75 of 183 patients).10
Thus, information on physiologic lymphatic drainage from
the tumor site can be combined with tumor characteristics and the
individual cardiac risk factor from irradiation to weigh the benefit-
to-risk ratio from IMNI.
Elif Hindié
Bordeaux University Hospital, Bordeaux, France
David Groheux
Saint-Louis Hospital, Paris, France
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at
www.jco.org.
REFERENCES
1. Thorsen LB, Offersen BV, Danø 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 34:314-320, 2016
2. McGale P, Taylor C, Correa C, et al: Effect of radiotherapy after mastectomy
and axillary surgery on 10-year recurrence and 20-year breast cancer mortality:
Meta-analysis of individual patient data for 8135 women in 22 randomised trials.
Lancet 383:2127-2135, 2014
3. Whelan TJ, Olivotto IA, Parulekar WR, et al: Regional nodal irradiation in
early-stage breast cancer. N Engl J Med 373:307-316, 2015
4. Poortmans PM, Collette S, Kirkove C, et al: Internal mammary and medial
supraclavicular irradiation in breast cancer. N Engl J Med 373:317-327, 2015
5. Budach W, Bölke E, Kammers K, et al: Adjuvant radiation therapy of regional
lymph nodes in breast cancer: A meta-analysis of randomized trials—An update.
Radiat Oncol 10:258, 2015
6. 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 86:860-866, 2013; [Erratum: Int J Radiat Oncol Biol Phys 89:1145, 2014]
7. Taylor CW, Wang Z, Macaulay E, et al: Exposure of the heart in breast
cancer radiation therapy: A systematic review of heart doses published during
2003 to 2013. Int J Radiat Oncol Biol Phys 93:845-853, 2015
© 2016 by American Society of Clinical Oncology 1
 Correspondence

8. Hindié E, Groheux D, Brenot-Rossi I, et al: The sentinel node procedure in
breast cancer: Nuclear medicine as the starting point. J Nucl Med 52:405-414,
2011
9. Byrd DR, Dunnwald LK, Mankoff DA, et al: Internal mammary lymph node
drainage patterns in patients with breast cancer documented by breast lympho-
scintigraphy. Ann Surg Oncol 8:234-240, 2001
10. Hindié E, Groheux D, Hennequin C, et al: Lymphoscintigraphy can select
breast cancer patients for internal mammary chain radiotherapy. Int J Radiat Oncol
Biol Phys 83:1081-1088, 2012
DOI: 10.1200/JCO.2016.67.4531; published online ahead of print at
www.jco.org on May 23, 2016.

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 Correspondence

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Internal Mammary Node Irradiation in Breast Cancer: The Issue of Patient Selection
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Elif Hindié David Groheux
No relationship to disclose No relationship to disclose

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