Internal Mammary Lymph Node Radiation: Pros and Cons of Inclusion In Radiation Fields

Jean Wright, MD

Johns Hopkins University

Department of Radiation Oncology

NCIC MA.20

• Randomized trial of 1832 woman with node-positive breast cancer or “high risk” node-negative breast cancer – High risk = T>5 cm or – High risk – T2-5 cm, fewer than 10 nodes removed, and

either LVI, ER-, or grade 3

• Randomization: – Whole breast irradiation (WBI) vs – Whole breast irradiation plus regional nodal irradiation

(WBI + RNI)

• Followup: 9.5 years; primary endpoint: overall survival

Whelan et al, NEJM July 2015

Survival Endpoints

Whelan et al, NEJM July 2015

EORTC 22922

• Randomized trial of 4004 woman with node-positive breast cancer or node-negative breast cancer with medially located tumors

• Randomization:

– Whole breast (or chest wall) irradiation (WBI) vs

– Whole breast irradiation plus regional nodal irradiation (WBI + RNI)

• Followup: 10.9 years; Primary endpoint: overall survival

Poortmans et al, NEJM July 2015

EORTC 22922 + MA.20

• Both studies suggest:

– Addition of RNI improved DFS and locoregional recurrence-free survival in a group of patients with primarily 1-3 positive nodes OR medially located tumors without positive nodes

• RNI in both studies specifically targets internal mammary nodes

EORTC 22922 + MA.20: IM Coverage

MA.20

1st-3rd intercostal spaces

EORTC 22922

1st-5th intercostal spaces

Hypotheses

• The addition of RNI impacts distant recurrence by treating microscopic nodal disease that may seed distant metastases, but never develop into clinically apparent regional recurrences

– This explains why treatment of the internal mammary nodes in medially located tumors impacts DFS even in axillary node-negative tumors

So why not treat the internal mammary nodes?

University of Michigan: Mean heart dose with internal mammary nodal radiation by treatment era

Mean Heart Dose (Left) “Early” 1997-2007

3D-CRT cohort

“Contemporary” 2014-2016

3D-CRT cohort

P-value

IMN RT 4.8 Gy 1.8 Gy <0.001

No IMN RT 2.6 Gy 1.1 Gy <0.001

Dess et al. Int J Radiat Oncol Biol Phys 2017

Mean heart dose with internal mammary nodal radiation by treatment era

Mean Heart Dose “Early” 1997-2007

cohort

“Contemporary” 2014-2016

cohort

P-value

IMN RT 4.8 Gy 1.8 Gy <0.001

No IMN RT 2.6 Gy 1.1 Gy <0.001

Dess et al. Int J Radiat Oncol Biol Phys 2017

Coverage of internal mammary nodes increases

mean cardiac dose

Radiation Impact On Cardiac Events is Dose Dependent

– Case-control study of 2168 women treated for breast cancer in Sweden and Denmark 1958-2001

• 963 with major coronary events (MCE)

• 1205 controls

– Radiation doses estimated based on “standard anatomy” as CT-based planning not done during this period

• Risk of MCE increases with cardiac dose

• No apparent threshold dose

Darby, NEJM 2013

• While differences in mortality are detected late, coronary events may begin to occur earlier- providing an endpoint that is easier to study

Darby, NEJM 2013

Impact of Radiation Dose on Coronary Events

Risk: 16.5% per Gy (almost identical to Darby et al within same

follow-up time)

Van den Bogaard J Clin Oncol 2017

No cardiac risk

factors

Diabetes

Hypertension Prior ischemic

cardiac event

Excess risk of an acute coronary event (ACE) depends on mean V5 of the LV

Van den Bogaard J Clin Oncol 2017

Why Not Treat IM?

• Benefit is likely to be small in most patients

• Generally confers increased cardiac exposure

• Must consider:

– Clinical benefit on case by case basis

– Ability to cover IM nodes while sparing the heart

Impact of Respiratory Motion on Heart

Jagsi et al IJROBP 2007

Deep Inspiration Breath Hold- Optimizing Anatomy

Matched Electron-Photon Field for IM Coverage-

Using Modality to Optimize Dosimetry

Partially Wide Photon Tangents for IM Coverage

Using Blocking to Shape Photon Field

Protons for IM Coverage: Using Modality to Optimize Dosimetry

• RADCOMP: ongoing randomized trial of photons vs protons

• Primary Endpoint: Major Coronary Events

• Protons generally recommended on protocol, use off protocol may be increasing

VMAT IMRT for Challenging Cardiac Anatomy

• The VMAT Trade-Off: – Improved dose

homogeneity

– Reduced high-dose volume outside contoured target

– At the cost of…

– Larger low-dose bath to heart and lung

• Offers dosimetric benefit in some challenging cases but not recommended routinely

Ho Radiat Oncol 2018

FDG-avid on PET-CT

Dose Constraints RTOG 1301

• Internal Mammary Nodes:

– Contour first 3 intercostal spaces, expand 5 mm in all dimensions except anterior and posterior

– 90% of the contoured IM should receive 45 Gy

• Heart (left sided)

– 20 Gy to <5% of the contoured heart

– 10 Gy to <30% of the contoured heart

– Mean dose <4 Gy

Real- World Target Coverage of RTOG Volumes

• 20 actual cases re-planned with RTOG contours

• The mean V45 values for the RTOG consensus volumes: – CW 74% (SD 9%) – Ax3 96% (7%) – SCV 85% (10%) – IM 80% (21%) – Ax1 84% (19%) – Ax2 88% (17%)

Fontanilla PRO 2011

Dosimetry

• Internal mammary node coverage goals on current protocols are higher than what has traditionally been achieved in the pre-contouring era

• Mean heart doses when the IM nodes are covered are often high enough to be clinically relevant

Conclusions

• Benefit of IM radiation likely varies with individual characteristics, and may be very low in some node-positive patients

• Cardiotoxicity is an important consideration in selection of patients for regional nodal radiation

–Cardiac risk factors and anatomy should be considered for each patient individually

Conclusions

• Judicious use of IM radiation in patients with established risk factors for recurrence with attention to cardiac risk may provide the best balance to reduce toxicity and improve disease-free survival outcomes

Thank you!