This document discusses radiation therapy for breast cancer and its potential effects on the heart and coronary arteries. It provides an overview of the pathophysiology of radiation-induced cardiac toxicity, including microangiopathy of small vessels, macroangiopathy of coronary arteries, and fibrosis. It also summarizes several studies that found increased risks of ischemic heart disease, pericarditis, and valvular disease in patients receiving left-sided breast radiation compared to right-sided radiation. Newer radiation techniques using methods like deep inspiration breath hold and intensity-modulated radiation therapy can help reduce radiation doses to the heart.

1. Breast Cancer Radiation
Treatment & Coronary Disease
Diandra N Ayala-Peacock, MD

2. A Review: Your Coronaries

3. Pathophysiology of RT-induced
cardiac toxicity
• Microangiopathy of
small vessels
• Macroangiopathy
of coronary arteries
• Fibrosis
S. Schultz-Hector & K.R. Trott, 2007, IJROBP.

4. RT-Related Cardiac Toxicity
• Increased death from IHD in
patients treated for left
breast cancers when
compared to right breast
cancers
• Documented Perfusion
Defects consistent with
microvascular injury soon
after RT (6mo-5yrs)
• Serum biomarker changes
[troponins, CK-MB,
proBNP]
• Increased risk of CV disease:
– Pericarditis
– coronary artery disease
(CAD)
– conduction abnormalities
– congestive heart failure
– valvular disease

5. • 308,861 US women
– Early Breast CA (known
laterality)
– 1973-2001SEER cancer
registries + prospective
f/u for cause-specific
mortality until 1/1/02
– Age 20-79 yrs with no
previous cancers
– Bilateral breast Dx or
autopsy diagnosis
excluded
(Lancet onc, 2005)

8. • Conclusions:
– Mortality from heart disease was increased among
women treated with L > R sided tumors (also seen
with ipsilateral vs contralateral lung CA-related
mortality)
– Substantial hazard seen in second decade
– A reduction in any early cardiac hazard seen in
later decades compared with women diagnosed
during 1973–82 (trend across three periods of
diagnosis (2p=0·04)).

9. • 72,134 women in
Denmark or Sweden
during 1976-2006
• Left vs Rt sided tumors
• No CT-based planning;
Dose estimates derived
from retrospective method
of dose reconstruction on
representative patient

10. • L sided breast CA: mean dose to WH > 5Gy, mean dose
to LAD > 15Gy
– In both countries, the mean dose to the LAD was greater than
the mean dose to the whole heart
• R sided breast CA: 2-4Gy WH, 1-2Gy mean dose to
LAD

11. • No RT: Little evidence of association between
laterality & heart disease incidence
• RT:
– Incidence of all heart disease (based on first Heart Disease
Dx after Breast CA Dx) was increased in L sided RT vs R
sided (1.08 [95% CI 1.02–1.15], p = 0.01)
• IHD (incidence ratio, L versus R-sided, 1.18 [1.07–1.30], p =
0.001)
• Pericarditis (1.61 [1.06–2.43], p = 0.03),
• Valvular Disease (1.54 [1.11–2.13], p = 0.009)

12. • For acute MI: the proportional
increase in the incidence ratio,
left-sided versus right-sided,
was greatest at 15+ years after
irradiation
• For Angina the increase in
incidence was greatest at 0- 4
years
• For Pericarditis and valvular
heart disease it was greatest at
5–9 years
• The variability between
incidence ratios in the different
5 year periods did not reach SS
for all heart disease or any of
the specific types

13. • A prior dx of IHD conferred a
substantial increase in
subsequent heart disease risk
in RT women for both R & L
laterality:
– Left-sided cancer a prior
diagnosis of IHD was
associated with a further
1.58-fold increase in risk
– Incidence ratio, right-
sided cancers with prior
IHD versus right-sided
cancer no prior IHD, 3.37
(2.82–4.01)

14. • Conclusions:
– Main risk of Acute MI occurs more than 15 years after
exposure
– Also risks for angina, pericarditis and valvular disease as
well as some risk of AMI in first decade after exposure
– Women with ischemic heart disease before breast cancer
diagnosis may have incurred higher risks than others
– Even with modern RT may still have risk of RT-induced
heart disease dependent on techniques,
favorable/unfavorable thoracic geometry etc.

15. • 416 pts treated between 1977-1995 with RT for primary L sided
breast CA
• 62 pts (15%) underwent diagnostic tests
for CV symptoms
– Median central lung distance greater for 24
pts with cardiac test abnormalities than
38 pts with normal results (p = 0.07)
– When compared to stage-matched
controls treated with similar RT techniques,
the 24 pts with significantly larger median
max heart width (p = 0.07) but not
heart length (p =0.17)

16. • Conclusions:
– Larger central lung distances were associated with
• increased likelihood of cardiac diagnostic test abnormalities and
therefore likely represented larger irradiated cardiac volumes.
• associated with the development of coronary artery disease and
congestive heart failure
– Patients with a maximum heart distance greater than 3.0cm seemed to
have a higher risk of ischemic heart disease
• Shortcomings:
– Small sample size; underpowered to detect differences
– RT parameters, CAD, MI and CHF were not assessed in all patients,
but rather in patients who had cardiac symptoms requiring further
evaluation
– Additive or synergistic effects of RT and cardiotoxic chemo not studied
(n = 4) The present study has several limitations.
– 2D planning only

17. RT: Old and New
• One study estimated an average 64% reduction in the volume
of heart receiving 50% of the prescribed treatment dose with
3D CT-based as compared with conventional treatment
planning (Muren et al, Radiother Oncol, 1998)
• Treatment planning studies have shown that IMRT and partial
cardiac shielding can reduce the average percentage of the
heart receiving > 60% of the prescribed dose from
4.4%(conventional tangents) to 2.3% (intensity-modulated
radiation therapy) or 1.5% (partial heart block) without
compromise of target coverage (Landau et al, Radiother
Oncol, 2001)

18. • 199 women with invasive BC or DCIS
– Dx 1970-2003
– Coronary Angiography 1990-2004
• 188 reference women
– Random sample of one-to-one match
– Matched on age at time of angiography, year of
angiography and site of angiography
• Angiographies were reviewed by blinded (to treatment)
radiologist in each of two hospitals

19. • RCA, L main, LAD and L
Cx arteries divided into 18
segments
• Five grade scale of stenosis
– 0: Normal
– 1: Light atheromatosis
– 2 – 4: Increasing frade of
stenosis
– 5: Occlusion of segment

20. Coronary “Hot Spots”

21. Breast Tissue Thoracic Wall
Lymph Nodes
Axilla
IMC
SCV
1973-1976 (‘70-85): 3 Gy x 15
(‘86-96)
2.3 Gy x 20 =46
Low energy
electrons
(‘96 and after)
2 Gy x 25 = 50 Gy
4Gy x10
3e x5 (fr)
4Gy x10
4x10/ 4x5
(dorsal)
1977-1985
2.5Gy x 12 = 30 (fr)
2.5e-x 8 = 20Gy (fr)
3.5Gy x 9 = 31.5 (fr)
& 3e- x 5 (frontal)
All LNs: 2Gy x 25 = 50 Gy
3.5Gy x 9
4Gy x 6 (d)
1986-1994
1994 +
1997 +
1982 BC surgery
Then …
2Gy x27 = 54Gy
2Gy x 25 = 50Gy
CT planned: 2Gy x27 = 54 Gy
2.5Gy x 12
(fr)
3.2e-x8 (d)

22. “High & Low Risk RT”
• Relative to the identified “hot spots”
• High Risk RT
– Mid LAD/dD with Left sided RT to Chest Wall/Breast
– Prox RCA & mid LAD/dD with RT to L IMC before
1995
• Low Risk RT
– All remaining RT targets [R chest wall, R breast,
Axillas, and SCV areas] along with no RT

23. • Patient Characteristics
– Lft Side BC > Rt Side BC
– Mean age at Dx: 58.2 yrs
– Median f/u between Tx &
Angiography: 10.3 yrs
– Majority had low risk BC
with good prognosis
– 62% of women received
RT
– 17% underwent endocrine
therapy [tamoxifen]

24. • Women with L sided BC had a trend of increased incidence of
stenosis of all segments and all grades of stenosis
• When comparing RT vs No RT, A SS increase in stenosis of
midLAD/distal LAD emerged.

25. • Significant stenosis was found in hotspot areas in BC pts
irradiated to the left breast/chest wall or IMC, as compared
with BC pts who had not received RT to these target areas

27. • Conclusions:
– An increase of stenosis in mdLAD /dD in irradiated
left-sided BC and an association between high-risk
RT and stenosis in hotspot areas for radiation indicate
a direct link between radiation and location of
coronary stenoses
• Criticisms:
– Selection biases in angiograms?
– Sudden cardiac events from RT stenosis?

28. RT Techniques to Reduce Dose to the
Heart

29. Active Breathing Control (ABC)

30. Breath Hold at Normal Exhale
Pressure
Volume
Flow
Valve closed,
Breath held
Valve open

31. End-Inspiration Gating

32. • 15 Stage 0-III Breast CA pts
– 9 L sided; 6 R sided breast pts
• Standard FB and ABC CT scans
• Plans:
– Technique A: 5 field technique + matching e- field
for IMNs
– Technique B: Deep Tangents

33. Technique A
– Shallow 6mV tangents
– Matched oblique e- fields
for IMNs
– Gantry and Collimator
rotation to minimize
RT to heart and lung

34. Technique A
– With wedges: superior
corners of tangents
blocked with MLCs to
compensate for
collimator rotation
and for SCV
inferior match
border

35. Technique B
– IMNs covered with deep
tangent fields

36. Deep Tangents & IMRT (Free Breath) Deep Tangents/IMRT (Inspiration Hold)
(Heart)
(Heart)
IMNs
IMNs
SCV
SCV

37. Shallow Tangents (Free Breath) Deep Tangents (Free Breath)
Deep Tangents (Inspiration Hold)

38. • The mean percentage of heart V30 under FB was less
with 5-field wedged plan (6.8%) than DT wedged plan
(19%) (mean difference 12.3%)
• When DT IMRT (FB) was compared to mDIBH:
reduction in heart V30 to mean 3.1% (mean difference
13.2%, p < 0.0004).
13.2%

39. • mDIBH systematically and significantly
reduced the heart NTCP from a mean of 5.86%
to mean 0.88%, a mean difference of 4.98% (p
< 0.0002; an 85% relative reduction)

40. • mDIBH systematically and
significantly reduced lung V20
(bilateral lung) to a mean of 15.7%:
mean difference 3.3% (p < 0.004).
• The use of mDIBH as compared with
FB reduced the mean lung dose (both
lungs) significantly with values
ranging 9.9 Gy vs 8.1 Gy. Mean diff
1.8 Gy (p < 0.0008)
• Reduction in NTCP values
(ipsilateral lung) with mDIBH versus
FB (10.9% vs 31.7%). Mean diff
20.8% (p <0.02)

41. • The use of IMRT (DT-IMRT) was associated with slight reduction in dose to
contralateral breast (11.5%)
• mDIBH with DT-IMRT reduced this contralateral breast dose percentage to
6.8% (p <0.4)
– > 5% of contralateral breast received > 10Gy for 6 of 9 pts in FB
– > 5% of contralateral breast received >10Gy for 3 of 9 in DT-IMRT mDIBH

42. • Conclusions:
– mDIBH significantly reduces heart and lung doses when
DT are used for LR breast irradiation including the IMNs.
Compared with shallow tangents matched with electrons,
DT with mDIBH reduces the heart dose (in most patients)
and results in comparable lung toxicity parameters, but
may increase the dose to the contralateral breast.
– IMRT improves dose homogeneity, slightly reduces the
dose to the heart, and diminishes the number of MUs
required

43. • 21 pts with L breast CA s/p PORT for BCS
– 65 yrs or younger. ECOG 0-1.
– Stage 0-IIA
• Respiratory Gating System during CT scanning
– Three respiratory phase scans obtained: (1) Free Breathing,
(2) End-inspiration gating with audio prompting, (3) Deep
Inspiration Breath Hold
– DVH of heart, lung, & breast of each respiratory phase
were compared
– Opposed Tangents, 6mV photons c EDW
(Japanese Rad Society, 2009)

44. • Patterns for breathing
modes:
•  Free Breathing &
Gaiting
•  DIBH

45. • The distance between front of
heart and inner CW was
measured for FB, IG, and DIBH
– FB: median 0.7cm (range 0.1–1.1
cm)
– IG: median 1.0 cm (range 0.2–1.9
cm)
– DIBH: median 1.7cm (range 0.4–
2.5 cm)

46. • Craniocaudal
displacement of Apex
on Inspiration:
– FB-IG: median
distance1.5cm (0-2.0cm)
– FB-DIBH: median
distance 2.0cm (0.5-3cm)
• Irradiated Lung Vol:
Note: No significant differences
between each respiratory
phase appreciated when
evaluating DVH.

47. Free Breathing Inspiratory Gaiting DIBH

49. • Conclusions:
– Breast RT during DIBH is better able to reduce the
irradiated heart volume than FB or IG. (This may lead to
a reduction in the incidence of delayed cardiac toxicity).
– No observed advantage of BART [Breath-Adapted RT]
in reducing the irradiated lung volume.

50. • Heart dose volume analysis with CT is limited
because of motion artifact and poor delineation
between myocardium and ventricular space
• EKG-gated Cardiac MRI to quantify exclusion
of LV myocardium with ABC
• 15 pts (45Gy/16Gy boost lump cavity)
• CT adequate for identifying patients who can
benefit from ABC, MRI required for
cardiotoxicity assessment

51. Modalities for Assessing Cardiac
Toxicity in Breast CA Pts

52. CT Spect: Observed Regional
Perfusion Abnormalities
• Single institution [Duke] prospective trial
• 114 Lt sided breast CA pts
• Comparison of post-RT perfusion scans with
pre-RT studies to assess perfusion defects and
functional changes
(2005, IJROBP)

53. • CT-planned RT Tx:
– Tangential photon beams: 46-50Gy
– Intact breast: additional 16-18Gy e- boost to
tumor bed
– Post-Mastectomy: additional 10Gy e- to scar
• CT Planning DVH
• Endpoints:
– Perfusion eval by SPECT [LV perfusion, wall
motion, EF] & t = 6, 12, 18, 24 mo
– Comparison with pre-RT images [control]

54. • Reduction in perfusion in
RT field seen on SPECT
• SS increase in proportion of
patients with new defects
over time when compared
to t = 0. (p = 0.003 - 0.05)

55. • SS trends towards higher
incidence of perfusion
defects seen at 6,12,18,
and 24 months with
increasing volumes of LV
having been irradiated.

56. • Rates of wall-motion defects appeared
greater in patients with perfusion
abnormalities than patients with normal
SPECT scans
• No correlation exists between the presence or
absence of perfusion defects and the rates of
declines in EF of 5 percentage points or more.

57. • Conclusions:
– RT causes regional cardiac perfusion defects of approximately
40% of patients 6 to 24 months after RT
– Perfusion defects are more prevalent in patients with larger
volumes of LV within the RT field; and are associated with
abnormalities in regional wall motion.
– Did not find any significant association between regional
cardiac perfusion defects and changes in ejection fraction.
• Criticisms:
– 2D echo versus SPECT for LV fxn evaluation
– Long term outcomes? No MI or CHF seen from these
perfusion defects at their 2 year time pt.

58. • 15 patients
– No Hx of Heart Disease
– Anatomy such that LV would be irradiated with at least
65-95% of total dose based on location in mediastinum
• Followed clinically q 3 months (based on data that signs of
RT-induced heart disease occurs most frequently 6-12
months after RT).
• Treatment techniques “A” or “B’
– A: Modified radical mastectomy: Target Volume
included CW, IM nodes, SCV fossa and Axilla
– B: Partial mastectomy; Target Volume was breast only.
No RNI.
• All received chemo or endocrine therapy
– 3: Anthracyclines
– 1: CMF [Cyclophosphamide, MTX, 5-FU]
– 7 Tamoxifen +/- megesterol acetate
• All rec’d (2- D), M-mode, pulsatile, and continuous wave
Doppler echo & Tc99 sestamibi scintigraphy stress test

59. • All defects were fixed and located in the
anterior, anteroseptal, anterolateral or apical LV
• Clinical Correlation?
– All pts with (+) scintography changes seen
in f/u were asymptomatic with (-) echo and
(-) stress

60. • 80 pts with DCIS or IBC s/p BCS
• Pre-RT Coronary Artery Calcium Scores compared with healthy
asymptomatic MESA cohort
– Questionnaire identifying RFs:
• Age, height, BMI, CAD RFs: Hx Heart/Vascular Dz, DM,
HTN, HLD, Smoking Hx.
– Radiologist grading of CACs:
• Sum of all calcium lesion present in LMain, LAD, LCx,
and RCA.
• Second blinded radiologist to confirm scores (No
interobserver variability appreciated p =0.3) (IJROBP, 2011)

61. • Significantly (p < 0.01) higher CAC
scores of RCWEST compared to
(female) Caucasian MESA cohort in 55-
64 age group.
• No SS differences were found for ages
45-54 (p = 0.84) or age category 65-74
(p=0.07).

62. • Conclusions:
– Breast cancer patients bear a higher risk of
developing CAD. Therefore, measures to decrease
cardiac dose further in breast cancer radiotherapy
are paramount.
• Criticisms:
– Low numbers: power
– Apples and Oranges: Dutch RCWEST cohort vs
health American MESA cohort
• Smoking, lifestyle, BMI

63. Conclusions
• Evidence of prior RT techniques resulting in
IHD.
• Modern techniques available: cost/benefit
• Identifying evidenced-based limits on cardiac
dose
• Diagnostic evaluations and Clinical correlations