Assessment of Chemotherapy-Induced Cardiotoxicity

Indication Overview

Some drugs used to treat cancer have been associated with cardiotoxicity (damage to the heart). These agents include anthracyclines (e.g., daunomycin, doxorubicin, epirubicin, idarubicin, and mitoxantrone), trastuzumab (Herceptin) and imatinib (Gleevec).

Anthracycline-related cardiotoxicity is from a cumulative dose of the agent and usually begins as asymptomatic failures in the pumping of the heart that can progress to heart failure.1 It can present as abnormalities on electrocardiograms, irregular heartbeat, pericarditis-myocarditis syndrome (inflammation of the heart muscle or pericardium), or an increase in a brain peptide that is a marker of increased cardiac filling pressures. It is more common in elderly patients.1

Trastuzumab-related cardiotoxicity is not related to cumulative dose and is usually reversible with treatment discontinuation.2 It usually presents as an asymptomatic decrease in left ventricular ejection fraction (LVEF), leading less often to heart failure. Trastuzumab therapy is often used in patients who have already undergone anthracycline therapy regiments and it is therefore sometimes unclear which agent is responsible for cardiotoxicity.

Imatinib-related cardiotoxicity is less common than the previous agents and is likely mediated by the inhibition of the c-ABL protein.3

Nuclear imaging for cardiotoxicity checks cardiac function prior to and during treatment to determine if dose adjustments need to be made or other alternative treatment options explored.1,2,4 A common nuclear medicine heart test is the radionuclide angiogram (RNA). This scan measures the amount of blood ejected from the ventricle with each heart beat (ejection fraction). For example, if the left ventricle ejects 60% of its blood volume with each beat, the LVEF is 0.6 (normal is 0.5 or greater).

Based on a review of tests for monitoring doxorubicin-induced cardiomyopathy,5 congestive heart failure (CHF) is usually dose-related and rarely occurs at cumulative doxorubicin doses below 450 mg/m2. CHF associated with low-dose chemotherapy likely occurs in patients with underlying risk factors. In a review by Appel et al.,6 the incidence of heart failure rises dramatically as cumulated dose rises. For doxorubicin doses of 400 mg/m2, incidence of CHF is reported to be 3% and rises to 18% with doses of 700 mg/m2. For epirubicin, the incidence increased from 4% at 900 mg/m2 to 15% at 1,000 mg/m2.6

Based on pediatric guidelines7 for cardiac monitoring, it is recommended that evaluations should be done at baseline (prior to administration of agents), and then before every other course if the dose of doxorubicin is less than 300 mg/m2, or before every course when the dose is greater than 300 mg/m2. After therapy has been terminated, RNA evaluations should be done at one year post-therapy and then every five years. Echocardiography (Echo) should be done at one year post-therapy and then every two years when values are normal, and every year when values are abnormal.

Population: Adult and pediatric patients undergoing chemotherapy with antineoplastic drugs known to cause cardiotoxicity. 

Intervention: Radionuclide angiography (RNA). Synonyms include gated blood pool scan (GBPS), radionuclide ventriculography (RVG), radionuclide cineangiography (RNCA), and equilibrium radionuclide angiography (ERNA). The term RNA will be used throughout this report.

Red blood cells are labelled with technetium-99m (99mTc). Radioactivity is measured with a gamma camera suitably positioned over the patient's chest as the radioactive blood flows through the large vessels and heart. The number of counts recorded at any time is proportional to the amount of blood radioactivity and these counts are proportional to the left ventricular (LV) volume. RNA accumulates data over a thirty-minute period. LV counts at end diastole and at end systole or throughout the cardiac cycle are measured by constructing LV regions of interest (ROI). The measured LV counts within these LV ROIs are corrected for background scatter (BkCorr). The LVEF = ([BkCorr end-diastolic counts – BkCorr end systolic counts]/BkCorr end-diastolic counts) x 100.8

Comparators: For this report, the following diagnostic tests are considered as alternatives to RNA:

  • Echocardiography (Echo)
  • Cardiovascular magnetic resonance imaging (cardiac MRI or CMRI).

Outcomes: Eleven outcomes (referred to as criteria) are considered in this report:

  • Criterion 1: Size of the affected population
  • Criterion 2 : Timeliness and urgency of test results in planning patient management
  • Criterion 3: Impact of not performing a diagnostic imaging test on mortality related to the underlying condition
  • Criterion 4: Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition
  • Criterion 5: Relative impact on health disparities
  • Criterion 6: Relative acceptability of the test to patients
  • Criterion 7: Relative diagnostic accuracy of the test
  • Criterion 8: Relative risks associated with the test
  • Criterion 9: Relative availability of personnel with expertise and experience required for the test
  • Criterion 10: Accessibility of alternative tests (equipment and wait times)
  • Criterion 11: Relative cost of the test.

Definitions of the criteria are in Appendix 1.

Methods

The literature search was performed by an information specialist using a peer-reviewed search strategy.

Published literature was identified by searching the following bibliographic databases: MEDLINE with In-Process records and daily updates via Ovid; The Cochrane Library via Ovid; and PubMed. The search strategy consisted of both controlled vocabulary, such as the National Library of Medicine's MeSH (Medical Subject Headings), and keywords. The main search concepts were radionuclide imaging, including RNA, and cardiotoxicity from chemotherapy.

Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, and non-randomized studies, including diagnostic accuracy studies. Retrieval was limited to the human population. The search was also limited to English language documents, with no publication date limits. Regular alerts were established to update the search until October 2011. Detailed search strategies are located in Appendix 2.

Grey literature (literature that is not commercially published) was identified by searching relevant sections of the Grey Matters checklist. Google was used to search for additional web-based materials. The searches were supplemented by reviewing the bibliographies of key papers. See Appendix 2 for more information on the grey literature search strategy.

Targeted searches were done as required for the criteria, using the aforementioned databases and Internet search engines. When no literature was identified that addressed specific criteria, experts were consulted.

Search Results

There were 32 potential clinical articles identified through the MA/SR/HTA filtered search, and 13 were subjected to full text review. There were no meta-analyses of the diagnostic accuracy of RNA.

There were 243 potential articles identified through searching the primary diagnostic accuracy literature, of which 48 were subjected to full-text screening. Three articles comparing the diagnostic accuracy of LVEF measured with RNA and Echo were retained.9-11 An additional seven articles identified through searching primary studies provided information pertaining to the following criteria: affected population;7 mortality;5,12 morbidity and quality of life;5,13,14 and diagnostic accuracy.15,16 The remaining 18 citations were either articles found through searching the grey literature, articles from the targeted searches, or articles from the reference lists of the identified potential articles.

Summary table

Table 1: Summary of Criterion Evidence

Domain 1: Criteria Related to the Underlying Health Condition
Criterion Synthesized Information
1 Size of the affected population Anthracyclines and some monoclonal antibody-based therapies can be cardiotoxic. These drugs are commonly used to treat breast cancer and lymphomas. An estimated 32,220 new cases of breast cancer of lymphoma are expected in Canada in 2011.17

It is recognized that not all patients with these cancer types will receive these treatments. Based on the estimated new cases and assuming they will each undergo cardiac assessment at least once during their treatment, the size of the affected population would be more than 1 in 10,000 (0.01%) and less than 1 in 1,000 (0.1%).
2 Timeliness and urgency of test results in planning patient management Based on the urgency classifications developed by the Saskatchewan Ministry of Health, an RNA scan should be performed within two to seven days of receiving the request for the test for patients requiring cardiotoxic therapy on an urgent basis (Patrick Au, Acute and Emergency Services Branch, Saskatchewan Ministry of Health: unpublished data, 2011). RNA for initial and serial LVEF in patients receiving cardiotoxic chemotherapy should be performed within eight to 30 days of receiving the request for the test (Saskatchewan Ministry of Health: unpublished data, 2011).

Based on findings from the assessment, the dose can be reduced, and concurrent administration of cardioprotective agents can be initiated to reduce the negative effects of the anthracycline drugs.18 No literature describing the urgency of cardiac imaging post-treatment was identified.

Obtaining the test results in the appropriate timely manner has moderate impact on patient management.
3 Impact of not performing a diagnostic imaging test on mortality related to the underlying condition During treatment: Symptomatic CHF is the most serious complication of anthracycline-based chemotherapy.19 The incidence of CHF is between 5% and 48%, depending on the cumulative dose received.19 If early LVEF reduction is unrecognized and untreated, continued treatment with anthracyclines may lead to irreversible severe CHF and may be fatal.5

Post-treatment: Reporting on the epidemiology of cardiotoxicity in children who have received athracycline compounds shows that the risk of mortality from cardiac-related events is eight times higher for long-term cancer survivors than for the normal population.18 The risk of anthracycline-induced clinical heart failure 15 to 20 years after the start of therapy is 4% to 5%.18

Based on the limited information available, diagnostic imaging results are assumed to have a minimal impact on mortality.
4 Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition If early LVEF reduction is unrecognized and untreated, additional therapy may lead to irreversible, severe CHF, impacting patient morbidity and quality of life.5 According to the United States national catalogue of preference-based, health-related quality of life scores,20 the mean ratings of quality of life are lower in patients with CHF compared with age-matched adults without CHF.

Based on the limited information available, diagnostic imaging results are assumed to have a moderate impact on morbidity and quality of life.

 

 

Domain 2: Criteria Comparing 99mTc with an Alternative or Comparing Between Clinical Uses
Criterion Synthesized Information
5 Relative impact on health disparities To be scored locally.
6 Relative acceptability of the test to patients  

No information regarding the patient acceptability of RNA was identified; however, with the assumption that the test is similar to other nuclear medicine tests, RNA is likely to be well- accepted. Patients may have concerns about radiation exposure and the intravenous injection of a radiopharmaceutical agent.

Echo is likely to be well tolerated by patients. Echo may be preferred by some patients, as there is no radiation exposure. 

Because of the closed space of an MRI, patients may experience feelings of claustrophobia, as well as being bothered by the noise. It has been reported that up to 30% of patients experience apprehension and 5% to 10% endure some severe psychological distress, panic, or claustrophobia.21,22 Some patients may have difficulty remaining still during the scan. Patients are not exposed to radiation during an MRI scan, which may be more acceptable to some.

RNA imaging with 99mTc radiolabelled tracers is:

  • minimally less acceptable than Echo
  • minimally less acceptable than MRI.
7 Relative diagnostic accuracy of the test

One study reported that RNA identified a statistically significant larger proportion of patients with decreased LVEF compared with Echo,10 and a second reported a slight underestimation of LVEF by Echo compared with RNA.23

There is modest correlation of 2D TTE with CMRI, and a strong correlation between 3D TTE and RNA compared with CMRI.

Based on the limited information available, the diagnostic accuracy of RNA imaging with 99mTc radiolabelled tracers:

  • is minimally better than Echo
  • has similar accuracy to that of MRI.
8 Relative risks associated with the test

Non–radiation-related Risks

No information was identified regarding the non-radiation-related risks for patients undergoing RNA.

No risks associated with Echo were identified.

MRI is often used in conjunction with the contrast agent Gd. Some patients may experience an allergic reaction to the contrast agent (if required), which may worsen with repeated exposure.24 Side effects of Gd include headaches, nausea, and metallic taste. The frequency of severe, life-threatening reactions with Gd is extremely rare (0.001% to 0.01%), and the frequency of moderate reactions range is also rare (0.004% to 0.7%).25

Radiation-related Risks 

Patients undergoing RNA are exposed to a radiation dose of 6.2 mSv.26 The comparators (Echo and MRI) do not expose the patient to ionizing radiation.

Overall, RNA imaging with 99mTc radiolabelled tracers is:

  • minimally less safe than Echo,
  • minimally less safe than MRI.
9 Relative availability of personnel with expertise and experience required for the test

Expertise: Sensitivity, specificity, and reproducibility of LVEF measures by Echo are strongly influenced by inter-observer variability whereas RNA is not.

Personnel: In Canada, physicians involved in the performance, supervision, and interpretation of diagnostic nuclear imaging, CT scans, MRI, and ultrasound should be diagnostic radiologists or nuclear medical physicians. According to the CMA, there are 1,149 practicing cardiologists in Canada (CMA, 2011). Not all radiologists, nuclear medical physicians, nuclear cardiologists, or cardiologists have the expertise to conduct 99mTc-RNA and all of its alternatives. For example, a 2002 report by the Canadian Cardiovascular Society reported that 43% of cardiologists do echocardiography.

Depending on the centre and assuming the necessary equipment is available, if 99mTc imaging using RNA is not available:

  • more than 95% of the procedures can be performed in a timely manner using Echo
  • 25% to 74% of the procedures can be performed in a timely manner using MRI.
10 Accessibility of alternative tests (equipment and wait times)

Nuclear medicine facilities with gamma cameras are required for RNA. As of January 1, 2007, there was an average of 18.4 nuclear medicine cameras per million people, with none available in the Yukon, Northwest Territories, or Nunavut.27 SPECT/CT scanners were available in only five jurisdictions at that time: New Brunswick, Quebec, Ontario, Saskatchewan, and British Columbia.27

No information was found to identify how many echocardiography machines are available in Canada.

No MRI scanners are available in the Yukon, Northwest Territories, or Nunavut.28  According to CIHI's National Survey of Selected Medical Imaging Equipment database, the average number of hours of operation per week for MRI scanners in 2006–2007 ranged from 40 hours in PEI to 99 hours in Ontario, with a national average of 71 hours.27 In 2010, the average wait time for MRI in Canada was 9.8 weeks.29

Depending upon the centre and assuming that the necessary expertise is available, if 99mTc imaging using RNA is not available:

  • more than 95% of the procedures can be performed in a timely manner using Echo
  • 25% to 74% of the procedures can be performed in a timely manner using MRI.
11 Relative cost of the test

According to our estimates, the cost of RNA with 99mTc-based radioisotopes is $330.40.  Echo is a minimally less costly alternative; while MRI is moderately more costly than RNA with 99mTc-based radioisotopes. 

Relative costs
Test Total costs ($) Cost of test relative to 99mTc-based test ($)
RNA 330.40 Reference
Echo 150.55 -179.85
MRI 759.29 +428.89

 

2D TTE = two-dimensional transthoracic echocardiography; 3D TTE = three-dimensional transthoracic echocardiography; CHF = congestive heart failure; CIHI = Canadian Institute for Health Information; CMRI = cardiac magnetic resonance imaging; Echo = echocardiography; Gd = gadolinium; LVEF = left ventricular ejection fractions; MRI = magnetic resonance imaging; PE = Prince Edward Island; RNA = radionuclide angiography; SPECT/CT = single-photon emission computed tomography/computed tomography; 99mTc = Technetium-99m;.

Criterion 1: Size of affected population (link to definition)

Anthracyclines and some monoclonal antibody-based chemotherapy treatments can be cardiotoxic. These drugs are commonly used to treat breast cancer and lymphomas. An estimated 32,220 new cases of breast cancer of lymphoma are expected in Canada in 2011.17 It is recognized that not all patients with these cancer types will receive chemotherapy. Some patients may undergo more than one cardiac assessment during his or her chemotherapy regimen.

After six years of therapy with anthracyclines, approximately 65% of children treated with a total dose in range between 228 mg/m2 and 550 mg/m2 have abnormalities in cardiac structure and function.18 The risk of anthracycline-induced clinical heart failure 15 to 20 years after the start of therapy is 4% to 5%.18

Return to Summary Table.

Criterion 2: Timeliness and urgency of test results in planning patient management (link to definition)

Based on the urgency classifications developed by the Saskatchewan Ministry of Health, RNA should be performed within two to seven days for patients requiring cardiotoxic chemotherapy on an urgent basis (Patrick Au, Acute and Emergency Services Branch, Saskatchewan Ministry of Health: unpublished data, 2011). The classifications also state that RNA for initial and serial LVEF in patients receiving cardiotoxic chemotherapy should be performed within eight to 30 days (Saskatchewan Ministry of Health: unpublished data, 2011).

The impact on the management of the condition or the effective use of health care resources is assumed to be greatest when the patient is first starting a potentially cardiotoxic treatment. That is when the chemotherapy dose can be reduced and concurrent administration of cardioprotective agents can be initiated to reduce the negative effects of the anthracycline drugs.18

No literature describing the urgency of cardiac imaging post-treatment was found.

Return to Summary Table.

Criterion 3: Impact of not performing a diagnostic imaging test on mortality related to the underlying condition (link to definition)

Symptomatic CHF is the most serious complication of anthracycline-based chemotherapy.19 The incidence is reportedly between 5% and 48%, depending on the cumulative dose received.19 Based on a review of tests for monitoring doxorubicin-induced cardiomyopathy,5 CHF rarely occurs at cumulative doxorubicin doses below 450 mg/m2. CHF attributable to low-dose chemotherapy likely occurs in patients with underlying risk factors.5 If early LVEF reduction is unrecognized and untreated, additional anthracycline therapy may lead to irreversible severe CHF and may be fatal.5

Ruggiero et al.18 reviewed the literature and analyzed the pharmacological features and clinical data on anthracycline compounds. Reporting on the epidemiology of cardiotoxicity in children, the authors found that the risk of mortality from cardiac-related events is eight times higher for long-term cancer survivors than for the normal population.18 The risk of anthracycline-induced clinical heart failure 15 to 20 years after the start of therapy is 4% to 5%.18

The Childhood Cancer Survivor Study is a retrospective cohort study designed to study late effects among long-term survivors of childhood cancers.30 The study followed 20,227 survivors for a total of 208,947 person-years and reported 2,030 deaths.30 Eighty-three deaths (4.5% of study deaths) were attributed to cardiotoxicity.30 Relative to the American population, Mertens et al. found the cancer survivors in the Childhood Cancer Survivor Study to be 8.2 times more likely to die from cardiac events.30 

Return to Summary Table.

Criterion 4: Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition (link to definition)

If early LVEF reduction is unrecognized and untreated, additional anthracycline therapy may lead to irreversible, severe CHF, impacting patient morbidity and quality of life.5 According to the United States national catalogue of preference-based, health-related quality of life scores developed by Sullivan and Ghushchyan ,20 the mean EQ-5D score reported by patients with chronic heart failure (n = 284, mean age = 71) is 0.636, compared with a mean score of 0.790 among adults aged 70-79. The EQ-5D is a well-validated measure of five dimensions of health status (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression).

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Criterion 5: Relative impact on health disparities (link to definition)

The risk of cardiotoxicity following breast cancer treatment has been associated with increased age, pre-existing conditions, and black race.19,31 A 2007 retrospective analysis of 43,338 women aged 66 to 80 years found an increased risk of cardiotoxicity among the 71- to 80-year-old patient group versus the 66- to 70-year-old patient group, but did not find an increased risk of heart failure among anthracycline-treated women aged 71 to 80 when compared with non-anthracycline treated women of the same age.19 The same study found that black patients had a 49% higher risk of developing CHF than did white patients; they were also more likely to receive adjuvant anthracycline chemotherapy.19 The unavailability of 99mTc or the replacement with an alternative imaging modality is not likely to worsen any of the disparities mentioned here.

Return to Summary Table.

Criterion 6: Relative acceptability of the test to patients (link to definition)

RNA
No information regarding the patient acceptability of RNA was identified; however, with the assumption that the test is similar to other nuclear medicine tests, RNA is likely to be well- accepted. Patients may have concerns about radiation exposure and the intravenous injection of a radiopharmaceutical agent.

Echo 
This test is likely to be well-tolerated by patients. Echo may preferred by some patients, as there is no radiation exposure.

MRI
Because of the closed space of an MRI, patients may experience feelings of claustrophobia, as well as be bothered by the noise This may be less of a problem with new MRI machines, if available (MIIMAC expert opinion). It has been reported that up to 30% of patients experience apprehension with MRIs and 5% to 10% endure some severe psychological distress, panic, or claustrophobia.21,22 Some patients may have difficulty remaining still during the scan. Patients are not exposed to radiation during an MRI scan, which may be more acceptable to some.

Return to Summary Table.

Criterion 7: Relative diagnostic accuracy of the test (link to definition)

A literature search for systematic reviews and primary studies evaluating the diagnostic accuracy of RNA, relative to its comparators Echo and MRI, found three studies (published in 2001, 2006, and 2010). A 2009 review article by Alterna et al.23 noted that the measurement of LVEF with RNA and Echo can underestimate actual cardiac damage because the reserve of the myocardium facilitates ventricular output, even in the presence of damaged muscle cells. The authors described the evidence supporting the monitoring of cardiovascular effects during and after chemotherapy as being of medium quality, and suggested a need for new methods for detecting and monitoring cardiotoxicity of chemotherapy.23

Walker et al.11 conducted a cohort study (2010) to assess the consistency of RNA scans, two-dimensional transthoracic echocardiography (2D TTE) and three-dimensional transthoracic echocardiography (3D TTE) for determining LVEF, in comparison with cardiac magnetic resonance imaging (CMRI). The study population consisted of 50 breast cancer patients undergoing adjuvant trastuzumab therapy, with a mean age of 52.11 The four imaging examinations were conducted prior to initiation of treatment, after six months, and after 12 months.11 The results, measured in terms of mean differences in LVEF (%) and correlation coefficients, are reported in Table 2.11 There was a modest correlation between 2D TTE and CMRI, while 3D TTE and RNA were more strongly correlated with CMRI.11

Table 2: Mean Difference in LVEF (%) and Correlation Coefficients by Imaging Modality With CMRI as the Reference Standard *

  2D TTE Correlation Coefficient 3D TTE Correlation Coefficient RNA Correlation Coefficient
Baseline 5.24 (4.9) 0.31 –1.1 (2.3) 0.91 –0.52 (2.6) 0.88
6 month follow-up –0.56 (7.7) 0.53 –1.1 (1.9) 0.97 –0.86 (2.0) 0.97
12 month follow-up –3.7 (6.1) 0.42 –1.5 (2.3) 0.90 –0.3 (2.2) 0.87

2D TTE = two-dimensional transthoracic echocardiography; 3D TTE = three-dimensional transthoracic echocardiography; CMRI = cardiac magnetic resonance imaging; LVEF = left ventricular ejection fraction; RNA = radionuclide angiography.
* Values are mean difference (standard deviation)

A 2006 study conducted in Turkey aimed to evaluate the sensitivity of RNA and Echo in a cohort of 21 pediatric cancer patients (median age of 6.9 years, range 1.8 to 14 years).9 Both techniques (RNA and Echo) were performed before the first course of chemotherapy and again in the three months following therapy.9 After the first course of chemotherapy, RNA detected six (29%) patients with a decreased LVEF, compared with three (14%) patients with decreased LVEF with Echo (p = 0.003).9 Both baseline and post-chemotherapy ejection fraction  measurements were higher with Echo (Table 3), but the difference was only statistically significant after treatment.9 According to this study of a relatively small sample size, RNA appears to be more sensitive in detecting cardiac dysfunctions compared with Echo.9

Table 3:  Characteristics of Cardiac Function Measured by Echo and RNA9

  Echo RNA P value
Baseline EF (%) mean ± SD (range) 72 ± 4 (65-80) 64 ± 9 (50-79) 0.649
EF after chemotherapy mean ± SD (range) 68 ± 11 (20-79) 58 ± 10 (32-74) 0.005
No. of patients with decreased EF (%) 3 (14%) 6 (29%) 0.003

Echo = Echocardiography; EF = ejection fraction; RNA = radionuclide angiography; SD = standard deviation.

A 2001 prospective study of 28 adult patients with lymphoma compared Echo and RNA in the monitoring of left ventricular systolic function.10 Nousiainen et al.10 measured patient LVEF at baseline, and at cumulative doses of 200, 400, and 500 mg/m2 doxorubicin, using RNA and Echo. A decrease in LVEF of more than 10% units and below 50% was observed in 10 patients (36%) by RNA, in three patients (11%) with M-mode Echo, and five patients (19%) using 2D TTE.10 The authors also reported that the M-Mode Echo gave a mean of 12% LVEF units higher than RNA.10 The conclusion noted that the agreement between results with Echo and RNA is suboptimal, and therefore guidelines based on the use of RNA cannot be applied to Echo.10

Return to Summary Table.

Criterion 8: Relative risks associated with the test (link to definition)

Non–radiation-related Risks

RNA
No information was identified regarding non–radiation-related risks for patients.

Echo
Three relatively large studies — with sample sizes of 42,408 patients (2009),32 26,774 patients (2009),33 and 5069 patients (2008)34 — compared cardiac outcomes (non-fatal myocardial infarction or death) between patients who underwent contrast-enhanced Echo with patients who had an Echo without contrast. All three studies concluded that the risk of an adverse event is low and is no different than that of patients who received no contrast. No additional risks associated with Echo were identified.

MRI
MRI is contraindicated in patients with metallic implants including pacemakers.35 MRI is often used in conjunction with the contrast agent gadolinium (Gd). Some patients may experience an allergic reaction to the contrast agent (if required) which may worsen with repeated exposure.24 Side effects of Gd include headaches, nausea, and metallic taste. Gd is contraindicated in patients with renal failure or end stage renal disease, as they are at risk of nephrogenic systemic fibrosis.  According to the American College of Radiology Manual on Contrast Media25 the frequency of severe, life-threatening reactions with Gd is extremely rare (0.001% to 0.01%). Moderate reactions resembling an allergic response (i.e., rash, hives, urticaria) are also very unusual and range in frequency from 0.004% to 0.7%.25

Radiation-related Risks

Among the modalities to assess chemotherapy-induced cardiotoxicity, RNA is the only one to expose the patient to ionizing radiation. The average effective dose of radiation delivered with each of these procedures can be found in Table 4.

Table 4: Effective Radiation Doses for Various Imaging Tests

Test Effective Radiation Dose (mSv)
RNA 6.226
Average background dose of radiation per year 1-3.036-38

Echo = Echocardiography; MRI = magnetic resonance imaging; mSv = millisievert; RNA = radionuclide angiography

Return to Summary Table.

Criterion 9: Relative availability of personnel with expertise and experience required for the test (link to definition)

The personnel required for the performance of the imaging tests to assess chemotherapy-induced cardiotoxicity are presented by imaging modality. A summary of the availability of personnel required for the conduct of methods to assess patients undergoing or having undergone chemotherapy, by RNA or any of the alternative imaging modalities, is provided in Table 5.

RNA
In Canada, physicians involved in the performance, supervision, and interpretation of cardiac nuclear imaging (specifically RNA using 99mTc-labelled radiotracers) should be nuclear medicine physicians with particular expertise in nuclear cardiology (nuclear cardiologists). For cardiac imaging, cardiologists provide much of the nuclear cardiology, cardiac MRI, and echocardiography services. According to the Canadian Medical Association (CMA), there are 1,149 practicing cardiologists in Canada (CMA, 2011).

Nuclear medicine technologists are required to conduct RNA scans. Technologists must be certified by the Canadian Association of Medical Radiation Technologists (CAMRT) or an equivalent licensing body.

All alternative imaging modalities
In Canada, physicians involved in the performance, supervision, and interpretation of diagnostic CT scans, MRI, and ultrasound should be diagnostic radiologists27 and must have a Fellowship or Certification in Diagnostic Radiology with the Royal College of Physicians and Surgeons of Canada and/or the Collège des médecins du Québec. Foreign-trained radiologists are also qualified if they are certified by a recognized certifying body and hold a valid provincial license.39 According to the CMA, there are 1,149 practicing cardiologists in Canada (CMA, 2011).

Medical radiation technologists must be certified by CAMRT or an equivalent licensing body.

Service engineers are needed for system installation, calibration, and preventive maintenance of the imaging equipment at regularly scheduled intervals. The service engineer's qualification is ensured by the corporation responsible for service and by the manufacturer of the equipment used at the site.

Qualified medical physicists (on site or contracted part time) should be available for the installation, testing, and ongoing quality control of CT scanners, magnetic resonance scanners, and nuclear medicine equipment.39

Echo 
Echocardiography is an ultrasound-based test. Cardiologists provide much of the Echo service. A 2002 report by the Canadian Cardiovascular Society reported that 43% of cardiologists do Echocardiography. According to the CMA, there are 1,149 practicing cardiologists in Canada (CMA, 2011). It is assumed that less than 500 of them do Echocardiography. 

Sonographers (or ultrasonographers) should be graduates of an accredited school of sonography or have obtained certification by the Canadian Association of Registered Diagnostic Ultrasound Professionals. They should be members of their national or provincial professional organization. Sonography specialties include general sonography, vascular sonography, and cardiac sonography.27 In Quebec, sonographers and medical radiation technologists are grouped together; in the rest of Canada, sonographers are considered a distinct professional group.27

MRI
Medical technologists must have CAMRT certification in magnetic resonance or be certified by an equivalent licensing body recognized by CAMRT.

Table 5: Medical Imaging Professionals in Canada, 200627

Jurisdiction Diagnostic Radiology Physicians Nuclear Medicine Physicians MRTs Nuclear Medicine Technologists Sonographers Medical Physicists
NL 46 3 263 15 NR NR
NS 71 5 403 71 NR NR
NB 47 3 387 55 NR NR
PE 7 0 57 3 NR 0
QC 522 90 3,342 460 NR NR
ON 754 69 4,336 693 NR NR
MB 58 8 501 42 NR NR
SK 61 4 359 36 NR NR
AB 227 18 1,229 193 NR NR
BC 241 21 1,352 212 NR NR
YT 0 0 0 0 NR 0
NT 0 0 26 1 NR 0
NU 0 0 0 0 NR 0
Total 2,034 221 12,255 1,781 2,900* 322*

AB = Alberta; BC = British Columbia; MB = Manitoba; MRT = medical radiation technologist; NB = New Brunswick; NL = Newfoundland and Labrador; NR = not reported; NS = Nova Scotia; NT= Northwest Territories; NU = Nunavut; PE= Prince Edward Island; ON = Ontario; QC = Quebec; YT = Yukon.
* this represents a total for all of the jurisdictions

Return to Summary Table.

Criterion 10: Accessibility of alternative tests (equipment and wait times) (link to definition)

There are notable variations in the availability of medical imaging technologies across Canada. Table 6 provides an overview of the availability of equipment required to assess chemotherapy-induced cardiotoxicity. Data were not available for Echo.

Table 6: Diagnostic Imaging Equipment in Canada27,28

  Nuclear Medicine Cameras MRI Scanners SPECT/CT Scanners
Number of devices 60327 21828 9628
Average number of hours of operation per week (2006-2007)27 40 71 n/a
Provinces and Territories with no devices available YT, NT, NU YT, NT, NU PE, YT, NT, NU

NT = Northwest Territories; NU = Nunavut; PE = Prince Edward Island; YT = Yukon

RNA
Nuclear medicine facilities with gamma cameras are required for RNA imaging. Three jurisdictions, the Yukon, the Northwest Territories, and Nunavut, do not have any nuclear medicine equipment.27

Echo
No information was found to identify how many Echocardiography machines are available in Canada.

MRI
No MRI scanners available in the Yukon, Northwest Territories, or Nunavut.28 According to CIHI's National Survey of Selected Medical Imaging Equipment database, the average number of hours of operation per week for MRI scanners in 2006–2007 ranged from 40 hours in PEI to 99 hours in Ontario with a national average of 71 hours.27 In 2010, the average wait time for MR imaging in Canada was 9.8 weeks.29

Return to Summary Table.

Criterion 11: Relative cost of the test (link to definition)

Fee codes from the Ontario Schedule of Benefits were used to estimate the relative costs of RNA and its alternatives. Technical fees are intended to cover costs incurred by the hospital (i.e. radiopharmaceutical costs, medical/surgical supplies, and non-physician salaries). Maintenance fees are not billed to OHIP — estimates here were provided by St. Michael's Hospital in Toronto. Certain procedures (i.e., PET scan, CT scan, MRI scan) are paid for, in part, out of the hospital's global budget; these estimates were provided by The Ottawa Hospital. It is understood that the relative costs of imaging will vary from one institution to the next.

According to our estimates (Table 7), the cost of RNA with 99mTc-based radioisotopes is $330.40. Echo is a minimally less costly alternative; while MRI is moderately more costly than RNA with 99mTc-based radioisotopes.

Table 7: Cost Estimates Based on the Ontario Schedule of Benefits for Physician Services Under the Health Insurance Act (September 2011)40

Fee Code Description Tech. Fees ($) Prof. Fees ($) Total Costs ($)
RNA
J813 Myocardial wall motion — studies with ejection fraction 138.60 82.25 220.85
J866 Application of SPECT (maximum 1 per examination) 44.60 31.10 75.70
Maintenance fees — from global budget 33.85   33.85
TOTAL 217.05 113.35 330.40 
Echo
G570/G571 Complete study — 1 and 2 dimensions 76.45 74.10 150.55
TOTAL 76.45 74.10 150.55 
MRI
X441C MRI — thorax — multislice sequence   77.20 115.85
X445C (×3) Repeat (another plane, different pulse sequence — to a maximum of 3 repeats)   38.65 (×3) =  115.95 115.95
X499 3-D MRI acquisition sequence, including post-processing (minimum of 60 slices; maximum 1 per patient per day)   65.40 65.40
X487 When gadolinium is used   38.60 38.60
X486 When cardiac gating is performed (must include application of chest electrodes and ECG interpretation), add 30%   89.14 89.14
Technical cost — from global budget 300.00   300.00
Maintenance fees — from global budget 73.00   73.00
TOTAL 373.00 386.29 759.29

3-D = three-dimensional; ECG = electrocardiogram; MRI = magnetic resonance imaging; prof. = professional; RNA = radionuclide angiogram; SPECT = single-photon emission computed tomography; tech. = technical.

Return to Summary Table.

References

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Appendix 1: Multi-Criteria Decision Analysis Definitions

Domain 1: Criteria Related to the Underlying Health Condition
Criterion Definition
1. Size of the affected population The estimated size of the patient population that is affected by the underlying health condition and which may potentially undergo the test. The ideal measure is point prevalence, or information on how rare or common the health condition is.
2. Timeliness and urgency of test results in planning patient management The timeliness and urgency of obtaining the test results in terms of their impact on the management of the condition and the effective use of health care resources.
3. Impact of not performing a diagnostic imaging test on mortality related to the underlying condition Impact of not performing the test, in whatever way, on the expected mortality of the underlying condition. Measures could include survival curves showing survival over time, and/or survival at specific time intervals with and without the test.
4. Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition Impact of not performing the test, in whatever way, on the expected morbidity or on the quality of life reduction of the underlying condition. Measures of impact may include natural morbidity outcome measures such as events or disease severity, or might be expressed using generic or disease-specific quality of life rating scales with and without the test.
Domain 2: Criteria Comparing 99mTc with an Alternative, or Comparing between Clinical Uses
Criterion Definition
5. Relative impact on health disparities Health disparities are defined as situations where there is a disproportionate burden (e.g., incidence, prevalence, morbidity, or mortality) amongst particular population groups (e.g., gender, age, ethnicity, geography, disability, sexual orientation, socioeconomic status, and special health care needs).

Impact on health disparities is assessed by estimating the proportion of current clients of the 99mTc-based test that are in population groups with disproportionate burdens.

(Explanatory note: The implication of this definition is that, everything else being the same, it is preferable to prioritize those clinical uses that have the greatest proportion of clients in groups with disproportionate burdens.)
6. Relative acceptability of the test to patients Acceptability of the 99mTc-based test from the patient's perspective compared with alternatives. Patient acceptability considerations include discomfort associated with the administration of the test, out-of-pocket expenses or travel costs, factors that may cause great inconvenience to patients, as well as other burdens. This criterion does not include risks of adverse events but is about everything related to the experience of undergoing the test.
7. Relative diagnostic accuracy of the test Ability of the test to correctly diagnose the patients who have the condition (sensitivity) and patients who do not have the condition (specificity) compared with alternatives.
8. Relative risks associated with the test Risks associated with the test (e.g., radiation exposure, side effects, adverse events) compared with alternatives. Risks could include immediate safety concerns from a specific test or long-term cumulative safety concerns from repeat testing or exposure.
9. Relative availability of personnel with expertise and experience required for the test Availability of personnel with the appropriate expertise and experience required to proficiently conduct the test and/or interpret the test findings compared with alternatives.
10. Accessibility of alternatives (equipment and wait times) Availability (supply) of equipment and wait times for alternative tests within the geographic area. Includes consideration of the capacity of the system to accommodate increased demand for the alternatives. Excludes any limitation on accessibility related to human resources considerations.
11. Relative cost of the test Operating cost of test (e.g., consumables, heath care professional reimbursement) compared with alternatives.

99mTc = technetium-99m.

 

Appendix 2: Literature Search Strategy

OVERVIEW
Interface: Ovid
Databases: Ovid Medline

Ovid Medline In-Process & Other Non-Indexed Citations

Ovid Medline Daily

EBM Reviews - Cochrane Central Register of Controlled Trials

EBM Reviews - Database of Systematic Reviews

EBM Reviews - Database of Abstracts of Reviews of Effects

EBM Reviews - NHS Economic Evaluation Database (NHSEED)

EBM Reviews - Health Technology Assessments

Note: Duplicates between databases were removed in Ovid.
Date of Search: February 2, 2011
Alerts: Monthly search updates began February 2011 and ran until October 2011
Study Types: Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies, and diagnostic accuracy studies
Limits: English language

Human population
SYNTAX GUIDE
/ At the end of a phrase, searches the phrase as a subject heading
.fs Floating subheading
exp Explode a subject heading
* Before a word, indicates that the marked subject heading is a primary topic; or, after a word, a truncation symbol (wildcard) to retrieve plurals or varying endings
? Truncation symbol for one or no characters only
ADJ Requires words are adjacent to each other (in any order)
ADJ# Adjacency within # number of words (in any order)
.ti Title
.ab Abstract
.hw Heading word: usually includes subject headings and controlled vocabulary 
.tw Text word: searches title, abstract, captions, and full text
.mp Keyword search: includes title, abstract, name of substance word, subject heading word and other text fields
.pt Publication type
.nm Name of substance word: used to search portions of chemical names and includes words from the CAS Registry/EC Number/Name (RN) fields
.jw Journal words: searches words from journal names
/du Diagnostic use
/ri Radionuclide imaging

 

Ovid MEDLINE Strategy
Line # Search Strategy
  Filter: health technology assessments, systematic reviews, meta-analyses
1 meta-analysis.pt.
2 meta-analysis/ or systematic review/ or meta-analysis as topic/ or exp technology assessment, biomedical/
3 ((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or overview*))).ti,ab.
4 ((quantitative adj3 (review* or overview* or synthes*)) or (research adj3 (integrati* or overview*))).ti,ab.
5 ((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool* adj3 analy*)).ti,ab.
6 (data synthes* or data extraction* or data abstraction*).ti,ab.
7 (handsearch* or hand search*).ti,ab.
8 (mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*).ti,ab.
9 (met analy* or metanaly* or health technology assessment* or HTA or HTAs).ti,ab.
10 (meta regression* or metaregression* or mega regression*).ti,ab.
11 (meta-analy* or metaanaly* or systematic review* or biomedical technology assessment* or bio-medical technology assessment*).mp,hw.
12 (medline or Cochrane or pubmed or medlars).ti,ab,hw.
13 (cochrane or health technology assessment or evidence report).jw.
14 (meta-analysis or systematic review).md.
15 or/1-14
  Filter: randomized controlled trials, and non-randomized studies
16 exp "Sensitivity and Specificity"/
17 False Positive Reactions/
18 False Negative Reactions/
19 du.fs.
20 sensitivit*.tw.
21 (predictive adj4 value*).tw.
22 Comparative Study.pt.
23 (Validation Studies or Evaluation Studies).pt.
24 Randomized Controlled Trial.pt.
25 Controlled Clinical Trial.pt.
26 (Clinical Trial or Clinical Trial, Phase II or Clinical Trial, Phase III or Clinical Trial, Phase IV).pt.
27 Multicenter Study.pt.
28 (random* or sham or placebo*).ti.
29 ((singl* or doubl*) adj (blind* or dumm* or mask*)).ti.
30 ((tripl* or trebl*) adj (blind* or dumm* or mask*)).ti.
31 (control* adj3 (study or studies or trial*)).ti.
32 (non-random* or nonrandom* or quasi-random* or quasirandom*).ti.
33 (allocated adj "to").ti.
34 Cohort Studies/
35 Longitudinal Studies/
36 Prospective Studies/
37 Follow-Up Studies/
38 Retrospective Studies/
39 Case-Control Studies/
40 Cross-Sectional Study/
41 (observational adj3 (study or studies or design or analysis or analyses)).ti.
42 cohort.ti.
43 (prospective adj7 (study or studies or design or analysis or analyses or cohort)).ti.
44 ((follow up or followup) adj7 (study or studies or design or analysis or analyses)).ti.
45 ((longitudinal or longterm or (long adj term)) adj7 (study or studies or design or analysis or analyses or data or cohort)).ti.
46 (retrospective adj7 (study or studies or design or analysis or analyses or cohort or data or review)).ti.
47 ((case adj control) or (case adj comparison) or (case adj controlled)).ti.
48 (case-referent adj3 (study or studies or design or analysis or analyses)).ti.
49 (population adj3 (study or studies or analysis or analyses)).ti.
50 (cross adj sectional adj7 (study or studies or design or research or analysis or analyses or survey or findings)).ti.
51 (distinguish* or differentiat* or enhancement or identif* or detect* or diagnos* or accura* or comparison*).ti,ab.
52 or/16-51
53 case reports.pt.
54 52 not 53
  Cardiotoxicity concept
55 cardiotoxic*.mp.
56 ((cardio* or cardiac) adj toxic*).mp.
57 exp Heart Failure/
58 exp Ventricular Dysfunction/
59 exp Heart Diseases/ci [Chemically Induced]
60 exp Arrhythmias, Cardiac/ci [Chemically Induced]
61 exp Cardiomyopathies/ci [Chemically Induced]
62 (cardiomyopathy or heart failure or cardiac failure or myocardial failure).ti,ab,hw.
63 (cardiac function* adj2 (monitor* or assess*)).ti,ab,hw.
64 or/55-63
  Chemotherapy concept
65 (chemotherap* or chemo therap*).mp.
66 (anthracyclin* or non-anthracyclin* or nonanthracyclin* or antineoplastic*).mp.
67 (trastuzumab or Herceptin or imatinib or Gleevec or doxorubicin or Adriamycin or Myocet or Caelyx or Doxil or daunorubicin or DaunoXome or Cerubidine or idarubic* or Idamycin or epirubicin or Pharmorubicin or Ellence or mitoxantrone or Novantrone).mp.
68 (fluorouracil or 5-FU or 5-fluorouracil or Adrucil or Efudex or Carac or Fluoroplex).mp.
69 (valrubicin or Valtaxin or Valstar).mp.
70 or/65-69
  Radionuclide imaging concept
72 Technetium/
73 exp Technetium Compounds/
74 exp Organotechnetium Compounds/
75 exp Radiopharmaceuticals/
76 radioisotope*.mp.
77 (Technetium* or Tc-99 or Tc99 or Tc-99m or Tc99m or 99mTc or 99m-Tc).tw,nm.
78 ((radionucl* or nuclear or radiotracer*) adj2 (imag* or scan* or test* or diagnos*)).ti,ab.
79 radionuclide imaging.fs.
80 exp Radionuclide Imaging/
81 Tomography, Emission-Computed, Single-Photon/
82 (single-photon adj2 emission*).ti,ab.
83 (SPECT or scintigraph* or scintigram* or scintiphotograph*).ti,ab.
84 exp Radionuclide Angiography/
85 exp Radionuclide Ventriculography/
86 (radionuclide adj2 (ventriculograph* or angiograph* or angiocardiograph*)).ti,ab.
87 MUGA.ti,ab.
88 (MUGA or RNCA or ERNA).ti,ab.
89 (gated adj2 (blood pool or acquisition)).ti,ab.
90 ((LVEF or left ventricular or ejection fraction) and radionucl*).ti,ab.
91 ((radionucl* or nuclear or radiotracer*) adj2 (imag* or scan* or test* or diagnos*)).ti,ab.
92 or/72-91
  Filter: Human (non-animals)
93 exp animals/
94 exp animal experimentation/
95 exp models animal/
96 exp animal experiment/
97 nonhuman/
98 exp vertebrate/
99 animal.po.
100 or/93-99
101 exp humans/
102 exp human experiment/
103 human.po.
104 or/101-103
105 100 not 104
  Results
106 64 and 70 and 92
107 106 not 105
108 Remove duplicates
109 Limit to English language [Limit not valid in CDSR,DARE,CCTR,CLCMR; records were retained]
110 15 and 109
111 54 and 109

 

OTHER DATABASES
PubMed Same MeSH, keywords, limits, and study types used as per MEDLINE search, with appropriate syntax used.

 

GREY LITERATURE SEARCHING
Dates for Search: February 2011
Keywords: Included terms for cardiotoxicity from chemotherapy and diagnostic imaging including gated blood pool scans (MUGA) and comparators
Limits: Publication dates last 10 years, human population

The following sections of the grey literature checklist, "Grey matters: a practical search tool for evidence-based medicine" (http://www.cadth.ca/en/resources/grey-matters) were searched:

  • Health Technology Assessment Agencies (selected)
  • Clinical Practice Guidelines
  • Databases (free)
  • Internet Search