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2012_Breast Cancer and Coronary Artery Disease

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  • This is a general concept, but recall that there are also some normal variations that can be present
    Ie. Type of dominance
    The posterior descending artery (PDA) may be supplied by the right coronary artery (RCA); this is referred to as RCA dominance.
    The PDA may be supplied by the circumflex (CX); this is referred to as left coronary dominance.
    - When both arteries supply the PDA, it is described as co-dominance
    Ie. Early branching of coronaries
    - The ramus intermedius (RI) is an artery arising between the left anterior descending artery (LAD) and the CX. Some call it a high diagonal (D) or a high obtuse marginal (OM) artery
    … there are several other variants in coronary anatomy, but this is beyond the scope of this presentation
  • Radiation damage to the myocardium is caused primarily by inflammatory changes in the microvasculature, leading to microthrombi and occlusion of vessels, reduced vascular density, perfusion defects and focal ischemia. This is followed by progressive myocardial cell death and fibrosis.
    Clinical studies also demonstrate regional perfusion defects in non-symptomatic breast cancer patients after radiotherapy. The incidence and extent of perfusion defects are related to the volume of left ventricle included in the radiation field.
    Irradiation of endothelial cells lining large vessels also increases expression of inflammatory molecules, leading to adhesion and transmigration of circulating monocytes. In the presence of elevated cholesterol, invading monocytes transform into activated macrophages and form fatty streaks in the intima, thereby
    initiating the process of atherosclerosis. Experimental studies have shown that radiation predisposes to the formation of inflammatory plaque, which is more likely to rupture and cause a fatal heart attack or stroke.
    ______________________________________________________________
    From JCO 2011 Editorial Accompanying Key Paper: “RT causes a loss of capillary density and a loss of collateral flow reserve in the
    territory of myocardium within the radiation portal. A subsequent coronary stenosis might be more likely to lead to a clinical cardiac event
    because of the reduced collateral flow. Furthermore, one might expect that the degree of myocardium that is affected by a coronary lesion of a given location/severity might be larger in a patient who has had previous RT compared with a patient with a similar coronary lesion who has not received RT”.
  • Atomic bomb survivors exposed to single doses of up to 4 Gy had dose-related excess risks decades later of about 17% per Gy for heart disease and 90% per Gy for lung cancer.14,15 Likewise, in patients given fractionated radiotherapy for peptic ulcer disease with mean cardiac doses of up to 4 Gy there was a
    dose-related increase in late cardiac mortality.
    In atomic bomb survivors and in patients with peptic ulcers, the excess risks did not become clear until more than 10 years after exposure.
    Note: The SEER public-use data set subdivides cardiac mortality during 1973–2000 (but not 2001) according to whether the certified cause involved acute myocardial infarction (ICD-9 410), other ischaemic heart disease (ICD-9 411–414), or other heart disease. A study of patients with breast cancer in Sweden suggested that all three of these categories of heart disease might be affected by radiotherapy.
  • Non-irradiated Women:
    -- Cardiac Mortality in Left vs Right sided breast cancer patients:
    - Cardiac Mortality Ratio was close to one (1·03 [95% CI 0·99–1·07]), and there was no significant
    trend in this ratio with time since diagnosis (p=0·83).
    Irradiated Women: By contrast, among irradiated women the cardiac mortality ratio, left versus right tumour laterality, was significantly greater than one (1·16 [1·08–1·24], 2=0·00004).
    The ratio increased steeply with time since diagnosis of breast cancer, which is effectively time since irradiation (trend: p=0·0001), and was highly significantly greater than one during the periods 10–14 years and 15 years or more after diagnosis.
    When different categories of heart disease were analysed separately, the mortality ratios, left versus right
    tumour laterality, among irradiated women during the period 10 years or more after diagnosis of breast cancer for acute myocardial infarction, for other ischaemic heart disease, and for other heart disease (table 2) did not differ significantly from each other. Furthermore, the distinction between these different types of heart disease on death certificates is often somewhat arbitrary, so subsequent analyses are of overall cardiac mortality.
  • Even if radiotherapy after mastectomy and after BCS are considered separately, there are substantial differences between the US radiotherapy regimens of the 1970s and those of the 1990s. Hence the relevance of time since radiotherapy must be studied separately among women treated in different time periods.
    For women diagnosed during 1973–82 and irradiated, the cardiac mortality ratio, left versus right tumour laterality, was:
    1st decade: 1·20 (1·04–1·38, 2p=0·01)
    10-15 years: 1·42 (1·11–1·82, 2p=0·005)
    15+ years: 1·58 (1·29–1·95, 2p0·0001)
    (trend: 2p=0·03, figure 2).
    Thus there is clear evidence of substantial hazard, particularly in the second decade after irradiation.
    For women diagnosed during 1983–92 or 1993–2001, and irradiated, the cardiac mortality ratios, left versus right tumour laterality:
    1983-1992 first decade: 1·04 (0·91–1·18)
    1993-2001 first decade: 0·96 (0·82–1·12)
    This indicated a reduction in any early cardiac hazard compared with women diagnosed during 1973–82 (trend across three periods of diagnosis (2p=0·04).
    For women diagnosed during 1983–92 and irradiated, however, there was only a limited amount of follow-up during the second decade after diagnosis, and the cardiac mortality ratio, left versus right tumour laterality, during this second decade was 1·27 (0·99–1·63). This ratio is based mainly on deaths 10–14 years after diagnosis, and its confidence limits are so wide that it is uninformative. Therefore, it is not yet possible to determine directly just from these data how much excess cardiac mortality will eventually occur among women irradiated during 1983–92, a period when much of the radiotherapy given was after BCS and when improvements in radiotherapy planning would have tended to result in progressively lower cardiac doses.
    The women diagnosed during 1993–2001 have not yet been followed for 10 years, so no direct information on their late cardiac mortality is yet available, although there is other evidence that mean cardiac doses had been continuing to decrease.
  • Interestingly, in this same paper, they found …
    Among women irradiated for breast cancer who subsequently developed an ipsilateral or contralateral lung cancer, the lung cancer mortality ratio (ipsilateral versus contralateral) for women diagnosed during 1973–82 and irradiated was 1·17 (0·62–2·19), 2·00 (1·00–4·00), and 2·71 (1·65–4·48), respectively, less than 10 years, 10–14 years, and 15 or more years afterwards (trend: 2p=0·04). For women irradiated after 1982 there is, as yet, little information on lung cancer risks more than 10 years afterwards.
    We have shown that, in women recorded in the US SEER cancer registries as having been diagnosed with
    breast cancer during 1973–82 and irradiated, mortality from heart disease was increased among women with left-sided breast tumours compared with women with right-sided breast tumours. In these same women, mortality from cancer of the ipsilateral lung was increased compared with mortality from cancer of the contralateral lung.
  • Danish Breast Cooperative Group
    72,134 women diagnosed with breast cancer in Denmark or Sweden during 1976– 2006 and followed prospectively. Radiation-related risk was studied by comparing women with leftsided and right-sided tumours
    Note: Only for the few women known to have had ischaemic heart disease diagnosed prior to breast cancer was there any evidence that the percentage of women irradiated was lower for left-sided than for
    right-sided breast cancer (p for difference = 0.06).
    Dose estimates were derived for a representative sample of women in the study areas. Radiotherapy charts were copied and each woman’s radiotherapy regimen was reconstructed on a representative
    patient with typical anatomy using a technique based on computerized tomography (CT) treatment planning; further details are given elsewhere [13]. The women in the study were all irradiated7
    prior to the advent of routine breast CT planning in Sweden and Denmark and, therefore, individual patient anatomical information was not available. The patient-to-patient variability in doses calculated
    using this retrospective method of dose reconstruction has been studied and it has been shown that the method accurately estimates the mean radiation dose to the whole heart
  • For left-sided tumours, meandose to the whole heart was close to 6 Gy and mean biologically effective dose to the whole heart was close to 10 Gy2 throughout the study period in Denmark, while in
    Sweden doses were higher than in Denmark before 1990 and similar during 1990–2001 (Table 2), and in both countries the mean dose tothe left anterior descending (LAD) coronary artery was higher than
    the mean dose to the whole heart throughout. For right-sided tumours cardiac exposures were lower.
    For both countries combined, mean dose to the whole heart for all time-periods combined was
    6.3 Gy for left-sided tumours and 2.7 Gy for right-sided tumours and mean dose to the LAD coronary artery for all time-periods combined was 18.8 Gy for left-sided and 1.5 Gy for right-sided tumours
  • Ischemic heart disease increase was due both to acute myocardial infarction and to angina.
    The pericarditis increase was due to acute pericarditis
    The valvular heart disease increase was due to aortic valve disease (incidence ratios, left-sided versus right-sided: acute myocardial infarction 1.22 [1.06–1.42], angina 1.25 [1.05–1.49], acute pericarditis 2.16 1.10–4.26], aortic valve disease 1.70 [1.14–2.53]).
    Likewise, there was no significant difference between the incidence ratios for all heart disease or for any specific type of heart disease when the data for irradiated women were subdivided by year of diagnosis of breast cancer (<1990 versus 1990+).
    For acute myocardial infarction, angina, and valvular heart disease the increases, left-sided versus right-sided, remained significant when women diagnosed after 1 January 1990 were considered separately.
    Among irradiated women there was no significant difference in the incidence ratio, left-sided versus right-sided, of all heart disease according to :
    country (Denmark/Sweden)
    age at diagnosis of breast cancer (<60/60+ years)
    whether or not breast-conserving surgery, hormonal therapy or chemotherapy was given
  • - For acute myocardial infarction, 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
    Also no SS when looked at in terms of country, age, therapy (BCS, hormonal, chemotherapy)
    The incidence ratio was, however, significantly higher for irradiated women who were known to have been diagnosed with ischemic heart disease more than 30 days prior to their diagnosis of
    breast cancer than for other irradiated women (incidence ratios, left-sided versus right-sided: 1.58 [1.19–2.10] versus 1.08 [1.01– 1.15], p for difference 0.01
  • As would be expected, a prior diagnosis of ischaemic heart disease conferred a substantial increase in subsequent heart disease risk even among irradiated women with right-sided cancer (incidence
    ratio, right-sided cancers with prior IHD versus right-sided cancer no prior IHD, 3.37 (2.82–4.01) (see Fig. 3). For irradiated women with left-sided cancer a prior diagnosis of IHD was associated with a further 1.58-fold increase in risk so that, compared with women with right-sided cancers and no prior diagnosis of IHD, women with left-sided cancers and a prior diagnosis of IHD, had
    incidence ratio 4.80 (4.05–5.68) (see Fig. 3).
  • The present study is consistent with previous studies indicating that the main risk of acute myocardial infarction occurs more than 15 years after exposure .
    However, it suggests that there are also risks of angina, pericarditis and valvular disease, as well as some risk of acute myocardial infarction, in the first decade after exposure.
    No previous studies have found evidence of a risk in patients diagnosed with breast cancer after 1990, or in patients given breast conserving surgery, but the cardiac doses received by such women were not much lower than those for women treated in the late 1970s and 1980s. Therefore, it is to be expected that risks will start to emerge as follow-up lengthens.
    For women being treated today, the extent to which they will be at risk of radiation-related heart disease in the future depends on their cardiac exposure. Recent estimates, calculated with all slices of a 3D planning scan representative sample of patients treated with tangential radiation, and without irradiation of the internal mammary chain, found that for approximately half of left-sided patients part of the heart still received >20 Gy .
    Furthermore, for patients with unfavourable thoracic geometry the mean heart dose has recently been reported in one centre to be 7 Gy for 3DCRTand 8.5 Gy for IMRT . These dose estimates suggest that contemporary techniques may still increase the risk of heart disease for a proportion of patients unless compromise coverage of the target tissue.
    “RT techniques to spare the heart, such as respiratory gating or breathing-adapted radiotherapy, are available. However, such techniques can be costly and time-consuming to implement, and may be unnecessary for the majority of patients. Therefore, further research is needed to characterise the consequences of radiation exposure of specific regions and structures of the heart in terms of increased risk of heart disease many years later. Only when such information is available will it be possible to formulate appropriate, evidence-based, limits on cardiac dose”.
  • All patients who underwent cardiac testing were treated with radiation techniques including 6MV or 15 MV tangential photons in 1.8-2.0 Gy fractions to 46-50 Gy. All pts also received either electron boosts or Iridium implants to tumor bed of 12.6 -21.2 Gy. Total radiation dose ranged from 60 to 66 Gy.
    For comparison purposes, a random group of n = 21 left-sided irradiated age and stage matched women who did not undergo any cardiac testing, had no cardiovascular disease or symptoms, and who had long-term follow-up (median follow-up. 12 years) were identified. All of these patients were treated with similar tangential beam technique and tumor bed boost.
    The Framingham model was used to estimate each patient’s absolute risk of developing coronary artery disease over the 10 years after RT.
    Despite the low predicted baseline cardiac risk, there was a high incidence of cardiac test abnormalities (24 of 62, 39% actual vs. 6 of 62, 9% predicted, p = 0.001). The majority (21 of 24, 88%) of cardiac diagnostic test abnormalities were in the left anterior descending coronary artery territory; there was one abnormality each in the left circumflex, right coronary, and left circumflex plus right coronary artery territories.
    The following treatment parameters have been previously correlated with irradiated heart volume: central lung distance, and maximum heart width and length
    Coronary artery disease developed in 25 of 62 (40%), myocardial infarction in 16 of 62 (26%), and congestive heart failure in 14 of 62 (23%) of the 62 total tested patients.
    - The median central lung distance was larger in the 14 patients with CHF than in the 48 patients without congestive heart failure (2.8 cm [range, 2.1 – 3.5 cm] vs. 2.3 cm [range, 1.3 – 3.2 cm], with and without congestive heart failure, respectively, p = 0.008).
    Patients with CAD had a larger median central lung distance than those without coronary artery disease (2.6 cm vs. 2.2 cm, p = 0.03). Also, the median maximum heart width and length was larger among patients with coronary artery disease (width = 1.9 cm vs. 1.8 cm, p = 0.03, and length = 7.1 vs. 6.2, p = 0.04, with vs. without coronary artery disease, respectively).
    Pts with MI had larger median central lung distance than those without MI (2.6 cm vs. 2.2 cm, p = 0.06), although this difference did not reach statistical significance. Maximum heart width and length were not associated with diagnoses of myocardial infarctions or congestive heart failure (all p > 0.45).
  • There was a higher incidence of cardiac diagnostic test abnormalities among early-stage breast cancer patients who received RT for left-sided disease than expected from the patients’ cardiovascular risk factor profiles alone.
    - The anterior location of the abnormalities correlated with the portion of the heart potentially irradiated with tangential beam RT. In addition, both the presence of abnormalities on cardiac diagnostic tests, and development of coronary artery disease and congestive heart failure were associated with potentially modifiable RT parameters.
    The current study found a large proportion (39%, 24 of 62) of abnormal cardiac diagnostic test findings among symptomatic patients with left-sided breast cancer who received RT. Previous investigators have reported a high proportion of cardiac diagnostic test abnormalities among asymptomatic left-sided irradiated breast cancer patients. Patients with a maximum heart distance greater than 3.0 cm seemed to have a higher risk of ischemic heart disease;
  • Muren LP, Maurstad G, Hafslund R, Ankler G, Dahl O. Cardiac and pulmonary doses and complication probabilities in standard pre- and postoperative radiation therapy versus surgery alone in primary breast cancer. Radiother Oncol 1998;48:185–190.
    Landau D, Adams EJ, Webb S, Ross G. Cardiac avoidance in breast radiotherapy: A comparison of simple shielding techniques with intensity-modulated radiotherapy. Radiother Oncol 2001;60:247–255
  • The pathophysiology of radiation-induced heart disease involves micro and macroangiography of vessels resulting in fibrosis of myocardium, CAD, and eventually ischemic heart disease.
    This raises the question of which cardiac structures must be critically protected from radiation: the myocardium (ie, whole heart) or coronary arteries? Earlier
    studies reported only the mean radiation dose to the whole heart, whereas some of the newer studies have reported dose to the coronary arteries as well.
    The aim of this study was to examine the distribution of coronary artery stenosis to assess whether there was any correlation between the RT delivered
    and the location of stenosis.
    STUDY DESIGN
    199 eligible women with BC for analysis from two registries: 103 women from Falun and 96 women from Uppsala
    Medical records were the source of information for breast tumor characteristics, according to the Union for International Cancer Control TNM
    classification sixth edition, and details of BC treatments.
    RT records were reviewed for classification of target areas: remaining breast tissue after breast-conserving surgery, chest wall after mastectomy, lymph nodes in the axilla, internal mammary chain (IMC), and supraclavicular area.
    Information about adjuvant endocrine treatment, chemotherapy, and recurrences was abstracted from the medical records.
    Controls: Reference patients were taken from coronary angiography registry: sampled at random at a one-to-one ratio matched reference women not treated for BC. They were matched for age at time of angiography in four categories (ie,60, 60 to 69, 70 to 79, and 80 years) at the time of angiography, calendar period of angiography (1990 to 1994, 1995 to 1999, and 2000 to 2004), and site of angiography (Uppsala or Falun). The angiograms of these 199womenwere reviewed by the radiologists. Eleven women were excluded because of earlier coronary angiography and revascularization of the coronary arteries, leaving in total 188 reference women for analysis.
  • Coronary Angiography
    The coronary angiographies from Uppsala and Falun were reviewed by one radiologist in each hospital, blinded for any detail regarding treatment of
    the BC.
    The segments were graded according to a five-grade scale of stenosis
    Grade 3 to 5 stenosis was considered clinically significant, occasionally referred to as significant stenosis.
    Note: Because of anatomic reasons, segment 15 was combined with segment four, segment 17 with 12, and segment 16 with 13.
  • They identified two hot spot areas in the most anterior portion of the heart that was felt to most likely to receive RT dose prior to any analysis.
    Segments 7,8, and 10 [the most anterior portion of the LAD], located to the left of the sternum and corresponding to the mid, distal and diagonal branches of the LAD
    2) Segments 1&2, located retrosternal, close to the midline in the superior part and then running inferiorly to the right of the sternum and corresponding to the proximal RCA
    Fig 2. (A) Coronary angiogram superimposed on computed tomography (CT) of heart illustrating anatomy of coronary arteries with branches of right coronary artery (orange) and left circumflex and left anterior descending (LAD) arteries (red); numbered arrows indicate segments. (B) CT dose-planned left tangential breast irradiation showing distal LAD (yellow circle) and radiation fields.
  • During the study period (1970 to 2003), several different RT regimens were used:
    The thoracic wall was treated with low-energy electrons during the whole period.
    The fraction schemes were 3 Gy x 15 = 45 Gy (1970-1985), 2.3 Gy x 20 =46 Gy (1986-1996), and 2 Gy x 25 = 50 Gy thereafter. The use of breast-conserving surgery started in 1982. The remaining breast tissue after breast-conserving surgery was treated with two opposed tangential photon fields 2 Gy x 27 = 54 Gy. From 1997 on, the fraction scheme was 2 Gy x 25= 50 Gy.
    The lymph nodes were treated with different techniques and fractionation during this period.
    In 1970-1972, small frontal cobalt-60 photon fields were given to cover the supraclavicular lymph nodes (SCL) and internal mammary chain (IMC). One such small field of 7Gy was given each day, and in consecutive days, a chain of fields was given to cover the targets. The axilla was treated with photons (cobalt-60): 4 Gy x 7 =28 Gy in a frontal field and 4 Gy x 6 = 24 Gy in a dorsal field.
    In 1973-1976, the IMC, SCL, and axilla were treated with a frontal cobalt-60 photon field of 4 Gyx 10 = 40 Gy. The IMC was simultaneously treated with a frontal field of electrons 3 Gy x 5 =15 Gy, and the axilla was given 4 Gy x 4-5 =16-20 Gy in a dorsal photon field.
    In 1977-1985, the IMC, SCL, and axilla were treated with a frontal cobalt-60 photon field of 3.5 Gy x 9 = 31.5 Gy. The IMC and SCL were simultaneously treated with a frontal field of electrons 3 Gy x 5 =15 Gy, and the axilla was given 4 Gy x 6 = 24 Gy in a dorsal photon field.
    In 1986-1994, the IMC, SCL, and axilla were treated with a frontal cobalt-60 photon field of 2.5 Gy x 12 = 30 Gy. The IMC and SCL were simultaneously treated with a frontal field of electrons 2.5 Gy x 8 =20 Gy, and the axilla was given 3.2 Gy x 8 =25.6 Gy in a dorsal photon field.
    In 1994 and later, the treatment of the lymph nodes was computed tomography–dose planned, and lymph nodes in the target were given 2 Gy x 27=54 Gy.
    In 1997 and later, the lymph nodes were given 2 Gy x 25 =50 Gy
  • The different regimens imply varying risk of receiving radiation dose to the coronary arteries. Therefore, the authors categorized the RT targets and regimens as high or low risk, regarding radiation to the hotspot areas of prox RCA and mdLAD and distal LAD. Left-sided RT to the chest wall or breast was considered high risk for mdLAD/dD. RT to the left IMC before 1995 included a frontal photon field and was regarded as high risk for prox RCA and mdLAD/dD. In 1995 and afterward, the left IMC was treated with tangential RT, still implying high risk for mdLAD/dD but not prox RCA. RT to the right IMC was considered high risk for prox RCA. All the remaining RT targets—the right chest wall, right breast, axillas, and supraclavicular areas—along with no RT were considered low risk of receiving radiation to the hotspot areas.
  • Characteristics of Patients With BC
    Table 1 describes the characteristics of the women with BC.
    Left-sided BC was slightly more common than right sided (55% v 45%).
    No major differences regarding age, calendar period for BC, follow-up, stage, RT, adjuvant systemic therapy, and distant recurrences between women with left- and right-sided BC were noticed.
    Mean age at diagnosis of BC was 58.2 years (standard deviation, 10.0 years).
    Median follow-up period between BC and coronary angiography was 10.3 years (25th percentile 5.4 years; 75th percentile, 15.8 years).
    The majority of the women had low-risk BC with good prognosis.
    ----- Seven percent had distant metastasis diagnosed before coronary angiography.
    Sixty-two percent of the women received RT.
    Twenty-nine percent were irradiated to the IMC. Adjuvant chemotherapy, received by only 9% of the women in our study, was seldom used during the time period of the study. A minority of women with early BC, approximately 17%, underwent adjuvant endocrine therapy during the study. Most of the
    women undergoing endocrine therapy received tamoxifen; only four women received an adjuvant aromatase inhibitor.
  • LEFT VS RIGHT
    We first compared women with left-sided BC to those with right sided (Table 2). Women with left-sided BC had a trend of increased incidence of stenosis of all segments and all grades of stenosis. In particular, women with left-sided BC more often had stenosis in mdLADdD, and the OR increased with more severe stenosis.
    IRRADIATED VS NONIRRADIATED
    In the nonirradiated group, ORs were close to unity, whereas in the irradiated group, evident differences appeared. A statistically significant increase of stenosis in mdLAD dD emerged: grade 1 to 5 (OR, 2.04; 95% CI, 1.18 to 3.55), grade 3 to 5 (OR, 4.38; 95%CI, 1.64 to 11.7), and grade 4 to 5 (OR, 7.22;95%CI, 1.64 to 31.8).
    In prox RCA, no statistically significant differences of stenosis were observed between irradiated left- and right-sided BC, although Odds Ratios were numerically below unity in all grades of stenosis.
  • Coronary Artery Stenosis in High- Versus Low-Risk RT/No RT
    Because the LSMEANS estimate depends on the segments included in the analyses, two different analyses were performed: one with all segments and one with hotspot areas only. All ORs were above unity. In the analyses of women with BC and hotspot areas:
    The Odds Ratios for grade 1 to 5 stenosis was 1.85 (95% CI, 1.17 to 2.93)
    The Odds Ratio for grade 2 to 5 stenosis was 1.33 (95% CI, 0.83 to 2.13)
    The Odds Ratio for grade 3 to 5 stenosis was 1.90 (95% CI, 1.11 to 3.24)
    for grade 4 to 5 stenosis was 1.87 (95% CI, 1.14 to 3.09).
  • Distribution of Coronary Artery Stenosis in Patients With BC and References
    We further investigated whether the distribution of coronary artery stenosis in women with BC was markedly different from that in reference women, indicating different types of coronary artery disease or different indications for angiography between the groups.
    segments were grouped according to the anatomy of the coronary arteries.
    No major differences of the distribution or occurrence of stenoses between the two groups could be found (Appendix Table A1, online only).
    For women with BC with at least one segment with significant stenosis, distribution is shown in Figures 3A to 3D. The pattern is similar in the groups of reference women and women with low-risk RT or no RT but seems to differ in the high-risk RT groups, with an increase of stenosis in prox RCA and mdLADdD in right and left-sided BC, respectively.
    No major difference in occurrence of stenoses was noticed between women with BC and reference women, probably because of the equivalent indication of performing an angiography in the two
    groups. When separating the women with BC into defined groups according to type of RT delivered, as shown in Figure 3, differences in distribution of coronary stenoses emerged.
    A possible confounder would be that disease stage in the irradiated women also prompted other treatments that could have led to damage of the coronary arteries. However, it is difficult to conceive
    How this would have been responsible for the specifically increased risk in women with left-sided irradiated BC and for the stenosis to occur in the hotspot areas. Furthermore, in the time period studied, chemotherapy and endocrine therapy were recommended for few women, and if these factors were confounders, they would have had to confer strong risk. They are not known to do so.
  • There may have been biases with respect to which patients were sent for an angiogram, on the basis of their Previous RT exposure.
    Patients with potential cardiac symptoms and a previous history of RT might have been more likely to be sent for an angiogram than those who had not received previous RT. This effect might be influenced by the laterality of the RT as well. Furthermore, patients with severe coronary disease who succumbed to a sudden cardiac event were obviously not included in the study and potentially could have suffered from RT-induced stenosis.
  • An example of the volume-time tracing display on the computer monitor outside the treatment console is shown.
    Once a stable breathing pattern was observed, we advised this pt. to take 2 deep breaths prior to triggering a breath hold at end exhale.
  • Fifteen breast cancer patients (9 left-sided and 6 right-sided lesions) with Stages 0–III breast cancer underwent standard FB and ABC (49) computed tomographic (CT) scans in the treatment position. Thirteen patients were treated with breast conservative surgery and 2 patients with mastectomy. All patients received adjuvant radiotherapy FB.
    A dosimetric planning study was performed in the context of an in-house Institutional Review Board–approved protocol. The patients were accrued between August 1999 and February 2002.
    Patient immobilization, CT scanning, and ABC procedure
    Before February 2000, the treatment setup position was supine with the ipsilateral arm stretched above the head (9 patients, 3 left and 6 right). After February 2000 (6 patients, all left-sided), the patients were immobilized in a personally customized expanded foam support (-cradle), supporting the thorax, the upper abdomen, the shoulders, and the elbows, with both arms stretched symmetrically above the head. Radiopaque skin markers were placed clinically on the field edges (medial, lateral, cranial, and caudal) by the treating physician, as is our practice for defining the target with standard whole breast tangential treatment. Helical CT scans (Philips SR7000) were acquired sequentially in 5-mm slices, and included cervical, thoracic, and upper abdominal regions. Breath-hold CT scans were acquired with the aid of an ABC apparatus. This device consists of an air-flow meter and a valve to suspend breathing at a user-defined lung volume. mDIBH was set at 75% of the maximum inspiration capacity and was chosen to reduce heart volume in the tangent fields, immobilize respiratory motion, and also to minimize patient fatigue. This 75% level was empirically derived from our initial clinical experience with multiple patients undergoing chest and abdominal CT scans under ABC. In addition to increased comfort at that level, it was easier for patients to repeat the procedure when another CT was performed to assess interfraction reproducibility. This choice was subsequently confirmed to be appropriate when ABC was clinically implemented for treatment (manuscripts in preparation).
    RT: during breath hold; durations ranging 18-26 seconds; 2-3 per beam. Step-and-shoot IMRT. 45 Gy or 50.4 Gy. Interfraction setup max 3.2mm, intrafraction max 2mm
  • Technique A (reproduction of the SWOG S9927 technique A) combines shallow tangential 6-MV photon beams clinically matched with two oblique electron fields to treat the IMNs. For the tangents, gantry and collimator rotations were designed to conform to the delineated breast while sparing as much heart and lung as possible. Transverse CT slices and digitally reconstructed radiographs (DRR) from the BEV were used to optimize field placement border was shifted into the ipsilateral chest wall and kept straight to match the electron fields. When wedges were used, the superior corners of the tangent beams were blocked with the MLC to compensate for collimator rotation and to match with the inferior border of the supraclavicular beam. With the mono-isocentric technique, the tangents employed roughly one-quarter of open beam and were matched in depth. For the electron field, the gantry was angled in the same direction as the medial tangent with a correction to match the field borders at the skin. A 5° angulation divergence in deep was used to reduce the hot spots at the photon–electron beam junction. Irradiation of the IMNs with electrons usually employed two fields with different electron energies to better cover the changing depth of the IMNs superiorly (higher energy) and inferiorly (lower energy). The SWOG protocol allowed the use of an IM photon field for up to five treatments “if skin sparing is needed.” Because this planning study was intended to compare the toxicity to the deep organs, the photon component of the IM field was not used.
  • . When wedges were used, the superior corners of the tangent beams were blocked with the MLC to compensate for collimator rotation and to match with the inferior border of the supraclavicular beam. With the mono-isocentric technique, the tangents employed roughly one-quarter of open beam and were matched in depth. For the electron field, the gantry was angled in the same direction as the medial tangent with a correction to match the field borders at the skin
  • Technique B (reproduction of the SWOG technique B) is a three-dimensional (3D) technique, which incorporates the IMNs in the tangent fields (DT). The MLC fields were designed with a 7-mm expansion around the PTV to account for the penumbra. Priority
    was given to the PTV coverage, with organ-sparing as the end point of the comparison.
  • Figure 1
    Beam’s Eye View of the medial field (open field) for a sample patient planned with deep tangents and IMRT compensation in Free Breathing Conditions.
    IMNs = green
    SCV = blue
    (b) Beam’s eye view of the medial field for a sample patinet planned with deep tangents and IMRT compensation in deep inspiration hold conditions
    … CAN SEE THAT THE ANTERIOR PORTION OF THE HEART IS SHIELDED WITH DEEP INSPIRATION HOLD CONDITIONS
  • (c) Shallow tangents matched with electrons during free breathing visible on transversal CT slice
    (d) Deep tangents during free breathing on transversal CT slices
    (e) Deep tangents during deep inspiration breath hold … due to the deep inspiration, the heart was displaced caudally by the diaphragmatic contractions and the visible structure at that level is now the large vessels
  • For the 9 left-sided patients, the mean percentage of heart receiving more than 30 Gy (heart V30) under free-breathing conditions was lower with the 5-field wedged technique than with the DT wedged technique, with values of 6.8% (range 0.2% to 15.1%) and 19.1% (0.6% to 35.9%) respectively. The mean difference was 12.3% (p = 0.004).
    When compared with the same DT-IMRT technique in free-breathing (FB), mDIBH systematically and significantly reduced the volume of heart receiving more than 30 Gy to a mean of 3.1% (0 to 10.2%), mean difference 13.2% (p 0.0004). This represents an 81% reduction in the mean heart V30. Compared with the 5-field technique, the benefit of mDIBH becomes dependent on patient anatomy and the difference loses statistical significance. In general, the contralateral breast position limited the choice of gantry angles in patients with large and/or anterior breasts. In this situation, an acceptable compromise between heart or contralateral breast sparing tended to favor more plans using shallow tangents matched with electrons than deep tangents. However, compared with the 5-field technique, DT with mDIBH reduced the percentage of heart V30 in 6 of the 9 patients; 2 of these 6 patients received zero or insignificant dose to the heart. For the 3 others, there was only a slight increase in heart dose. The same trend was observed for the percentage of heart receiving more than 40 Gy. Heart NTCP analyses produced similar trends (Fig. 3, bottom). When compared with the same 3-field IMRT technique in FB conditions, mDIBH systematically and significantly reduced the heart NTCP from a mean of 5.86% (0 to 9.5%) to a mean of 0.88% (0 to 3.1%), mean difference 4.98% (p 0.0002), or an 85% relative reduction. Compared with the 5-field technique, DT with mDIBH reduced the heart NTCP from a mean of 2.2% (0 to 6.2%) to a mean of 0.88% (0 to 3.1%), mean difference 1.32% (p 0.11).
  • The normal tissue complication probabilities were significantly reduced with DIBH versus FB.
    Compared with the 5-field technique, Deep Tangents with DIBH reduced the heart NTCP from a mean of 2.2% to a mean of 0.88% (mean difference of 1.32%, p < 0.11).
    Compensation with IMRT in FB reduced the heart NTCP as well: Compared with DT wedges, DR-IMRT reduced the heart NTCP from a mean of 8.33% to a mean of 5.86%, mean difference 2.47% (p < 0.08)
  • Note: V20 lower with 5-field wedge than DT plans: mean difference 3.9% (p< 0.02)
    For the deep tangent technique, the replacement of wedges with IMRT diminished slightly the lung V20 to 19% (with a mean difference of 0.6%, p = 0.6). The impact of IMRT was negligible for the 5-field technique.
    When compared with the same 3-field IMRT technique in FB conditions, mDIBH systematically and significantly reduced the lung V20 (both lungs) to a mean of 15.7% (13.5% to 18.3%), mean difference 3.3% (p 0.004). This represents a 79% absolute reduction in the mean lung V20 with mDIBH ((15.7% 3.3%)/15.7%). This mean lung V20 of 15.7% is similar to that obtained with the 5-field technique.
    Considering the 9 left-sided patients planned with DT-IMRT compensation, the use of mDIBH as compared with FB reduced the mean lung dose (both lungs) significantly and systematically with values of 9.9 Gy (range 8.8–11.2 Gy) vs. 8.1 Gy (range 7–9.3 Gy), respectively. The mean difference was 1.8 Gy (p 0.0008). This mean lung dose of 8.1% is comparable to the 8.7% (6.6–12.4) value obtained with the 5-field technique.
    The NTCP values (ipsilateral lung) for those patients planned with DT-IMRT were significantly and systematically reduced when FB was replaced by mDIBH, with mean
    values of 31.7% (range 10% to 67%) and 10.9% (range 3% to 33%), respectively. The mean difference was 20.8% (p 0.02). The NTCP value of 10.9% with mDIBH was lower than the 18.7% (range 1% to 82%) value obtained with the 5-field technique.
  • For the 9 left-sided patients, the percentage of the contralateral breast receiving more than 10 Gy was lower for the 5-field wedge than the DT-wedge technique.
    The mean percentages were 0.9% (range 0 to 6.1%) vs. 12.2% (range 0.1% to 28.7%) (p = 0.01), respectively.
    The use of IMRT (DT-IMRT) was associated with a slight reduction to 11.5% (range 0 to 29.1%), p 0.9), while the association of mDIBH with DT-IMRT reduced this percentage
    to 6.8% (range 0 to 26.3%), (p 0.4). With DT-IMRT, more than 5% of the contralateral breast received more than 10 Gy for 6 of the 9 patients in FB, 3 of 9 patients in
    DT-IMRT-mDIBH, and only 1 patient planned with 5 fields.
    CONCLUSION: Although mDIBH significantly reduced heart and lung doses and even when DTs were used even when compared to shallow tangents, the mDIBH had better heart dose, NTCP with comaprable mean lugn dose, lung V20 and NTCP values, BUT it may also increase the dose to the other breast
  • 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
  • Purpose. The aim of this study was to evaluate the effect of decreasing the irradiated cardiac volume in breastconserving therapy (BCT) using breath-adapted radiation therapy (BART).
    Materials and methods. The radiation therapy (RT)– computed tomography (CT) of 21 patients with left breast cancer during free breathing (FB), end-inspiration gating (IG) with audio-prompting, and deep inspiration breath-hold (DIBH) were subjected to BART [Breath adaptive RT] planning analysis. Respiratory movement was monitored during CT scanning with the respiratory-gating system. The opposing tangential fields were planned for each respiratory- gated CT. The dose–volume histograms (DVHs) of the heart, lung, and breast of each respiratory phase were compared.
    Results. The median respiratory movement of the right chest wall was 5.6 mm with FB CT, 10.9 mm with audio-prompting CT, and 21.3 mm from end-inspiration to DIBH. The median left ventricular volume receiving >50% of the prescribed dose was 2.9% for FB, 0.2% for IG, and 0% for DIBH. DIBH led to signifi cant cardiac spattering effect compared with FB or IG (P < 0.01). The median lung volume receiving 20 Gy or more was 5.0% for FB, 4.7% for IG, and 4.3% for DIBH. There were no signifi cant differences between each respiratory phase.
    Conclusion. We concluded that radiotherapy on the DIBH facilitates a reduction of the irradiated heart volume compared to FB and IG.
  • Figure 1: Patterns for the breathing modes in the study.
    During deep inspiration breath-holding (DIBH), the position of the right chest wall gradually decreased. This slow movement of the R chest wall during one seesion of DIBH eas 3.6mm (median) and the median rate of deviation during DIBH was 20%.
    A free-breathing pattern and inspiration gaiting
    Deep inspiration breath holding
  • The distance between the front of the heart and inner chest wall shown on digitally reconstructed radiographs (DRRs) was measured with the FB phase, IG phase, and DIBH phase. The median distance was 0.7 cm (range 0.1–1.1 cm) for FB, 1.0 cm (range 0.2–1.9 cm) for IG, and 1.7 cm (range 0.4–2.5 cm) for DIBH.
  • The craniocaudal displacement of the apex of heart was measured on inspiration phase CT images and FB phase CT images to evaluate respiratory cardiac movement.
    The heart moved in the posterior caudal direction with inspiration. The irradiated lung volume was also dependent on the respiratory phase, although the relation was more complex than that of the cardiac volume.
    DVH values of each respiratory phase were evaluated, resulting in a median V20 of 5.0% for FB, 4.7% for IG, and 4.3% for DIBH (Table 4). There were no significant differences between each respiratory phase.
  • The beam’s eye view of each respiratory phase is shown (Fig. 2). Of the 21 cases, 3 required magnification of the treatment fields initially planned with anatomical landmarks because the PTV was not fully included. The LV volume within each radiation field of each respiratory mode was calculated. For 16 of 21 patients, RT on FB facilitated excellent cardiac spattering. However, for other 5 patients, breathing adaptation techniques should be considered.
    The median LV volume receiving 25 Gy or more (>50% of the prescribed dose) was:
    -- 2.9% for FB,
    -- 0.2% for IG
    -- 0% for DIBH (Table 2).
    DIBH provided a significantly greater cardiac spattering effect than either FB or IG (P < 0.01) (Table 3).
  • The advantage of RT during DIBH is not only to minimize the irradiated heart volume but also to shorten the RT time. The disadvantages involve larger movement during RT and poorer reproducibility than FB or IG. We think it is important to improve the reproducibility of the chest wall during DIBH. Patients’ understanding and cooperation can improve the reproducibility of chest wall movement and reduce the internal margin as well as the irradiated critical organ volume.
    Symptomatic RT-induced pneumonitis of postoperative RT after breast-conserving surgery (BCS) was reported in only ≤1% of cases without chemotherapy. This incidence was related to the irradiated lung volume and dose
  • MRI-based volumetric assessment of cardiac anatomy and dose reduction via active breathing control during irradiation for left-sided breast cancer.
    Krauss DJ, Kestin LL, Raff G, Yan D, Wong J, Gentry R, Letts N, Vargas CE, Martinez AA, Vicini FA.
    Source
    Department of Radiation Oncology, William Beaumont Hospital, 3601 W. Thirteen Mile Rd., Royal Oak, MI 48073, USA.
    Abstract
    PURPOSE:
    Heart dose-volume analysis using computed tomography (CT) is limited because of motion artifact and poor delineation between myocardium and ventricular space. We used dedicated cardiac magnetic resonance imaging (MRI) to quantify exclusion of left ventricular (LV) myocardium via active breathing control (ABC) during left breast irradiation and to determine the correlation between irradiated whole heart and LV volumes.
    METHODS AND MATERIALS:
    Fifteen patients who completed adjuvant irradiation for early-stage left breast cancer participated. Treatment consisted of 45 Gy to the entire breast using ABC followed by a 16-Gy electron boost to the lumpectomy cavity. Patients underwent planning CT scans in free breathing (FB) and moderate deep inspiration breath hold (mDIBH). Electrocardiogram-gated cardiac MRI was performed in the treatment position using alpha-cradle immobilization. MRI scans were acquired in late diastole (LD), mid-diastole (MD), and systole (S) for both FB and mDIBH. After image fusion with the patients' radiation therapy planning CT scan, MRI LV volumes were defined for the three examined phases of the cardiac cycle, and comparative dose-volume analysis was performed.
    RESULTS:
    Cardiac volume definition was found to differ significantly because of combinations of respiratory and intrinsic heart motion. The fraction of LV myocardium receiving 50% (22.5 Gy) of the prescribed whole breast dose (V(22.5)) was reduced by 85.3%, 91.8%, and 94.6% via ABC for Late Diastole, Mid-Diastole, and Systole, respectively. Linear regression revealed strong correlation between MRI-defined whole heart and LV V(22.5) reduction via ABC, suggesting that LV myocardium accounts for up to approximately 50% of the excluded heart volume through this technique. Significant but weaker correlations were noted between CT-defined whole heart and LV V(22.5) reductions with marked variability in the measurements of patients with larger amounts of heart in the treatment field.
    CONCLUSIONS:
    Cardiac MRI demonstrated a significant reduction in LV myocardium irradiated with the use of ABC. The correlation between reduction in V(22.5) values for LV wall and CT-defined whole heart suggests that CT is adequate for determining which patients are likely to benefit from ABC treatment, but inaccuracies inherent to standard CT dictate that more detailed imaging studies such as MRI are required for accurate cardiotoxicity assessment.
  • RT is also associated with reductions in regional perfusion as assessed by single photon emission computed tomography (SPECT) scans, in a manner consistent with microvascular injury, relatively soon after RT (eg, 6 months to 5 years). These perfusion defects seem to largely persist with longer follow-up,
    but their clinical relevance is not yet known.
    ------------------------
    Single-photon emission computed tomography (SPECT, or less commonly, SPET) is a nuclear medicine tomographic[1] imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera. However, it is able to provide true 3D information. This information is typically presented as cross-sectional slices through the patient, but can be freely reformatted or manipulated as required.
  • The breast or chest wall was treated with tangential photon beams to a total dose of 46 to 50 Gy at 1.8 to 2 Gy per day The internal mammary nodes were included in the tangent fields in 53 patients.
    Patients with intact breasts typically received an additional 16-Gy to 18-Gy boost to the tumor bed in 2-Gy fractions via en face electrons. An electron energy was selected to provide adequate coverage of the tumor bed, as seen on the treatment-planning computed tomography (CT) scan.
    Postmastectomy RT, an additional 10-Gy boost was typically delivered to the mastectomy scar, with a 3-cm margin. An appropriate electron energy was selected to deliver a therapeutic dose to the tissues superficial to the ribs.
    3D radiation dose calculation
    A pre-RT treatment-planning CT scan was performed on each patient in the treatment position on a dedicated CT scanner Plan University North Carolina (PLUNC) 3D treatment-planning software: This calculation reflected tissue density correction and was used to compute the RT dose to each region of the heart. The volume of heart and left ventricle (LV) that received a dose from 0 to the maximum was calculated to create a dose–volume histogram (DVH). In general, the bin size used for DVH calculation was equal to the maximum RT dose/100. Only the tangent photon fields were considered in the DVH computation. The contribution of electrons to the tumor bed/chest wall and supraclavicular/ axillary fields was not considered.
    Quantitative assessments of cardiac function/endpoints
    - Resting-gated single-photon emission computed tomography (SPECT) cardiac perfusion scans were used to provide objective quantitative data on left ventricular regional myocardial perfusion, regional wall motion, and EF.
    - Details on imaging: Patients were imaged 30 to 60 minutes after the resting intravenous injection of 25 to 40 mCi technetium 99m (Tc-99m) sestamibi or Tc-99m tetrofosmin. Single-photon emission computed tomography projection data were acquired over a 180° rotation (3°/stop) by use of a fixed 90°
    dual-head detector gamma camera equipped with low-energy and high-resolution collimators (Elscint, Haifa, Israel). Projection data were acquired at 60 projections for 20 seconds per projection, each in a circular orbit. The camera was set for a 140-kev photopeak with a 20% energy window. Acquisition was obtained by use of a 64 x 64 x 8 matrix. During acquisition, projection images were gated for 8 frames per cardiac cycle with 100% beat acceptance.
    The projection data were prefiltered with a 2-dimensional Butterworth filter (order 5.0, 0.35 cycles per pixel with a pixel size of 0.64 cm).
    Images were reconstructed with filtered back projection and no attenuation correction. Attenuation artifacts may exist. However, in the study, multiple emission studies were obtained in each patient. All post-RT images were compared with pre-RT images, which allowed patients to serve as their own control.
    Therefore, if an attenuation was present on the baseline study, it should also be present on the subsequent follow-up studies.
    Blinded Nuc Med Radiologist scored SPECT scan using a 12-segment reporting system to quantify perfusion
    --- The relative perfusion to each segment was quantified in 4 gradations of perfusion defect with each assigned a numerical value:
    0 = no defect
    1 = mild defect
    2 = moderate defect
    3 = severe defect
    A cumulative SPECT summed-rest score (SRS) was obtained by summing the score for each of the 12 segments.
    --- Therefore:
    SRS 0 = Normal studies
    SRS 36 = Max score (severe perfusion defect in all 12 segments).
    The SRS has been previously shown to be highly predictive of cardiovascular outcomes in a 20-segment model in other papers.
    Wall-motion abnormalities were assessed in the same 12 segments. Wall-motion abnormalities were recorded as present or absent in each cardiac segment. When present, wall-motion abnormalities were classified as hypokinetic, akinetic, or dyskinetic.
    The extent of wall involvement (small or large portion) was described as mild or severe.
  • Follow-up
    Of the 114 patients enrolled …
    6 mo SPECT: 94 pts
    12 mo SPECT: 69 pts
    18 mo SPECT: 41 pts
    24 mo SPECT: 27 pts
    Seventeen patients with pre-RT perfusion defects and 7 without a pre-RT SPECT scans were excluded from the analysis.
    Not all patients were evaluable at all time intervals.
    Regional perfusion defects Anatomic location of defects. A representative example on the above slide … A clear reduction in perfusion seen in RT field on post-RT image. Almost all perfusion defects were located in the anterior region of the Left Ventricle (corresponding well wih RT fields)
    Defects as a function of time: A statistically significant increase in the proportion of patients with new defects is seen at each timepoint as compared with the incidence of defects seen at baseline (0 because patients with defects at baseline were excluded from this analysis) (p 0.003– 0.05), but no significant difference is seen in the proportion of patients with new defects at each follow-up assessment (p value is not significant).
  • Defects as a function of LV volume irradiated.
    The number of evaluable patients with less than 1%, 1% to 5%, 5% to 10%, and greater than 10% of their LV within the RT field were 29, 19, 17, and 13, respectively. Some patients were not evaluable for this portion of the analysis because their LV volume could not be computed for technical reasons.
    The incidence of new perfusion defects as a function of the volume of LV included within the RT field and time is shown in Table 3 and Fig. 2. Statistically significant trends toward higher incidence of perfusion defects with increasing volume of LV irradiated at 6, 12, 18, and 24 months were seen (p values shown in Table 3).
  • Regional cardiac function (cardiac wall motion)
    Wall-motion abnormalities were seen in 16% (12/73), 7% (4/55), 6% (2/34), and 12% (3/25) patients at 6, 12, 18, and 24 months after RT, respectively. Several patients at each interval were not evaluable for wall motion because of technical issues. Table 4 shows the rates of wall-motion abnormalities in the patients with and without new perfusion abnormalities. At all of the follow-up intervals, the rates of wall-motion defects appear greater in patients with perfusion abnormalities than in patients with normal SPECT scans. The location of wall-motion defects in the majority of patients was the anterior portions
    of the LV, which corresponds to the region of the heart within the RT field. The wall-motion defects in most of these patients were scored as hypokinetic and
    involved small portions of the wall.
    Global cardiac function (ejection fraction)
    The absolute decline in EF in patients with and without new perfusion defects 6 to 24 months after RT is shown in Fig. 3. No correlation exists between the presence or absence of perfusion defects and the rates of declines in EF of 5 percentage points or more.
    The relationship between the severity of the perfusion defect, measured by the SRS, and the changes in EF 6 months after RT, is shown in Fig. 4. Among patients with any new perfusion defects, those with more severe perfusion defects (i.e., SRS greater than the mean) were more likely to have a decline in EF than were patients with a lesser SRS (7/9 vs. 6/12, p 0.37). A similar finding exists at the later timepoints (data not shown). No patient has had a myocardial infarction or experienced congestive failure.
  • Global heart function has not been significantly affected.
    -- Not that surprising given the small volume of LV that is incidentally included within the tangent fields.
    -- Borges-Neto et al. (39) demonstrated a quantitative relationship between the extent of myocardial perfusion defects and EF among patients with ischemic heart disease.
    --- Reduced EFs were not consistently observed until approximately 30% or more of the left ventricle had abnormal perfusion.
    Because the percent of left ventricle in our cases is typically less than 5%, one would not expect to see
    dramatic changes in ejection fraction. In a separate analysis, we determined that patients with perfusion defects were more likely than those without perfusion defects to complain of chest pain (40). In no instance was myocardial infarction diagnosed. In 2 cases, diagnosis of pericarditis was made, but in the remaining 8 patients, no clear cause for the chest pain was found.
    (2) The perfusion defects in the current study are visible in patients with relatively small volumes of the LV within the radiation field. Approximately 5% of the LV corresponds to approximately 2% to 3% of the heart. The presence of such perfusion abnormalities after irradiation of such a small fraction of the myocardium suggests that these defects are caused by damage to the microvasculature of the myocardium, typically limited to the radiation field, and do not follow the distribution of major coronary
    Vessels.
  • Gyenes et al. (38) performed Tc-99m sestamibi scintigraphy before and approximately 1 year after left-breast/ chest-wall RT in 12 patients with Stage I to III left-sided breast cancer. Six of 12 patients (50%) with some LV within the radiation field exhibited new perfusion defects. Four patients were treated with tangential photons to an intact breast, and 8 patients received chest-wall irradiation with electrons after mastectomy. All 4 patients treated with tangential photons (no heart block) developed new defects. In
    contrast, only 2 of 8 patients who received chest-wall irradiation with electrons developed new defects. The authors concluded that the development of new perfusion defects was likely related to the volume of heart within the RT field and the dose to which the heart was irradiated, a conclusion consistent with our results
    Technique A: ). The anterior chest wall and the internal mammary nodes were given 10- to 14-MeV electrons in daily fractions of 2 Gy, 5 days/week. The lateral chest wall was treated with photons (not affecting the heart). The supraclavicular lymph nodes were treated with 4- to 6-MV photons from an anterior field, while the axillary nodes were treated from an anterior plus a posterior field. The average dose was 46 Gy in the whole target.
    Technique B: Breast without nodes was target. Radiotherapy was given through oblique opposed 4- to 6-MV photon fields, to a total dose of 50 Gy in 25 fractions 5 days/week
  • ECHOCARDIOGRAMS:
    The LV diameters and the systolic function of the patients were all normal. The average ejection fraction was similar before (66.9%, range 53%-78%) and after radiotherapy (67.1%, range 56%-76%). No new wall motion abnormalities were found.
    Six patients had left ventricular hypertrophy. The wall thickness was unchanged during the follow-up.
    EXERCISE STRESS TEST RESULTS:
    Patient‘s average exercise level was 95% both before and after radiotherapy, compared with the age-adjusted predicted maximal values.
    In f/u: no pts had symptoms of IHD and none had EKG changes during stress test (>1.5 mm ST depression).
    SCINTOGRAPHY:
    All patients had normal results before radiotherapy. Six of the 12 patients who underwent the follow-up study had new perfusion defects at scintigraphy. All defects were fixed and located in the anterior, anteroseptal, anterolateral or apical region of the left ventricle.
    -- Avg size of defect on bull’s eye view: 63.3 pixels (range 36-80)
    -- Avg size of defect on depth: 247.8 pixels (range 143-333) … 3.9x the standard deviation
    Of the three patients who also received chemotherapy,only the one who was treated with the smallest total
    dose of anthracycline showed a defect on scintigraphy.
  • No data are available on the frequency of risk factors predicting the probability of coronary artery disease (CAD) for the group of women diagnosed with early-stage breast cancer before starting radiotherapy. Specifically, when compared with healthy women, no data are available on the number of CAC (i.e., coronary artery calcium, or CAC) deposits. Therefore, in our study, these baseline CAC scores were compared with the CAC scores of a healthy female population. In doing so, the CAC scores in 80 consecutive female breast cancer patients were compared with the CAC scores of a healthy, asymptomatic female cohort, the MESA cohort.
    The reasons for the use of CAC scores in our study design were as follows: a number of studies concluded that the amount of calcium deposits in the coronary arteries predicts the risk of subsequent cardiovascular events in cases without symptomatic CAD. Furthermore, Pletcher et al. stated in their systematic review and meta-analyses that CAC is an independent predictor of CAD (7). Finally, it was suggested that CAC deposits can be useful in deciding whether further diagnostic testing is necessary in asymptomatic patients or patients with nonanginal chest pain and was shown that low-dose CT has proved to be a sensitive, noninvasive method for quantifying CAC deposits (8).
    With this study we attempted to identify differences in CAC scores for several cohorts to assess the risk on CAD before starting the radiation treatment.
    the determined CAC values are categorized as follows:
    low-risk calcium scores: CAC values 0-100
    medium-risk calcium scores: 100 < CAC values <400
    high-risk calcium scores: CAC values >400
  • As a first step, the CAC scores of the Caucasian RCWEST cohort were compared with those of the (female) Caucasian MESA cohort. We then excluded patients suffering from diabetes mellitus and those diagnosed beforehand with cardiovascular diseases. By doing so, we created a cohort that was better comparable (specifically with respect to cardiac risk factors) to that of the MESA cohort. Finally, the CAC scores of this latter selected RCWEST cohort were compared with the (female) Caucasian MESA data. The calcium scores were classified into percentiles, e.g., the 25th percentile implies that 25% of all cases have a CAC value lower than the given value.
    the determined CAC values are:
    categorized as follows: low-risk calcium scoresdCAC values
    0e100; medium-risk calcium scoresd100 < CAC values <400;
    high-risk calcium scoresdCAC values >400
  • the fact that the women in the RCWEST cohort experience a higher BMI compared with the Dutch female population corresponds to the finding that overweight is a risk factor for breast cancer. Remarkably, a BMI higher than 30 kg/m2.seems to correlate with a worse disease-free survival in breast cancer patients
  • In some radiotherapy centres, advanced radiotherapy techniques to spare the heart, such as respiratory gating or breathing-adapted radiotherapy, are available. However, such techniques can be costly and time-consuming to implement, and may be unnecessary for the majority of patients but perhaps critical in others.
    Field is still working to further research and better characterise the consequences of radiation exposure of specific regions and structures of the heart in terms of increased risk of heart disease many years later. Only when such information is available will it be possible to formulate appropriate, evidence-based, limits on cardiac dose.
  • Transcript

    • 1. Breast Cancer RadiationBreast Cancer Radiation Treatment & CoronaryTreatment & Coronary DiseaseDisease 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)
    • 6. • 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)).·
    • 7. • 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
    • 8. • 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
    • 9. • 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)
    • 10. • 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
    • 11. • 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)
    • 12. • 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.
    • 13. • 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)
    • 14. • 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
    • 15. 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)
    • 16. • 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
    • 17. • 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
    • 18. Coronary “Hot Spots”
    • 19. Breast Tissue Thoracic Wall Lymph Nodes AxillaIMCSCV 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)
    • 20. “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
    • 21. • 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]
    • 22. • 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.
    • 23. • 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
    • 24. • 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?
    • 25. RT Techniques to Reduce Dose to the Heart
    • 26. Active Breathing Control (ABC)
    • 27. Breath Hold at Normal Exhale Pressure Volume Flow Valve closed, Breath held Valve open
    • 28. End-Inspiration Gating
    • 29. • 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
    • 30. Technique A – Shallow 6mV tangents – Matched oblique e- fields for IMNs – Gantry and Collimator rotation to minimize RT to heart and lung
    • 31. Technique A – With wedges: superior corners of tangents blocked with MLCs to compensate for collimator rotation and for SCV inferior match border
    • 32. Technique B – IMNs covered with deep tangent fields
    • 33. Deep Tangents & IMRT (Free Breath) Deep Tangents/IMRT (Inspiration Hold) (Heart) (Heart) IMNsIMNs SCV SCV
    • 34. Shallow Tangents (Free Breath) Deep Tangents (Free Breath)Deep Tangents (Inspiration Hold)
    • 35. • 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%
    • 36. • 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)
    • 37. • 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)
    • 38. • 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
    • 39. • 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
    • 40. • 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)
    • 41. • Patterns for breathing modes:  Free Breathing & Gaiting  DIBH
    • 42. • 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)
    • 43. • 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.
    • 44. Free Breathing Inspiratory Gaiting DIBH
    • 45. • 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.
    • 46. • 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
    • 47. Modalities for Assessing Cardiac Toxicity in Breast CA Pts
    • 48. 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)
    • 49. • 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]
    • 50. • 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)
    • 51. • SS trends towards higher incidence of perfusion defects seen at 6,12,18, and 24 months with increasing volumes of LV having been irradiated.
    • 52. • 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.
    • 53. • 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.
    • 54. • 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
    • 55. • 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
    • 56. • 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)
    • 57. • 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).
    • 58. • 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
    • 59. 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