Patients undergoing cancer treatment

Case vignette 1: Evaluation of cardiac function

A 33-year-old female presented to her primary care physician with a right breast lump. She was referred for an ultrasound and a mammogram, and both were suspicious for malignancy. Biopsy confirmed estrogen receptor, progesterone receptor, and HER2-positive breast cancer. She underwent bilateral mastectomies. Baseline cardiac function was obtained via ^99m technetium (Tc) red blood cell radionuclide ventriculography (also known as multigated acquisition [MUGA]), and her estimated LV ejection fraction (LVEF) was 65%. She was treated with four cycles of doxorubicin and cyclophosphamide and underwent repeat radionuclide ventriculography, which revealed an LVEF of 60%. She then received 12 weeks of paclitaxel and trastuzumab. Repeat radionuclide ventriculography revealed an LVEF of 61% ( Fig. 25.1 ).

The American Society of Clinical Oncology states that the following patients with cancer are at increased risk for developing cardiac dysfunction:

• those receiving high-dose anthracycline therapy (e.g., doxorubicin ≥250 mg/m ² ),

• those receiving concomitant high-dose radiation therapy (≥30 Gy) where the heart is in the treatment field,

• those receiving lower-dose anthracycline therapy in combination with lower-dose radiation therapy where the heart is in the field,

• those receiving lower-dose anthracycline or trastuzumab therapy alone and who have any of the following risk factors: at least two cardiovascular risk factors, age equal to or greater than 60, or known cardiovascular disease, and

• those receiving treatment with lower-dose anthracycline followed by trasutuzmab.

The guideline recommends assessment of LVEF at baseline in all patients who meet criteria for increased risk with reassessment within 1 year of completing anthracycline therapy. The guideline recommends discontinuation of doxorubicin if there is an absolute decrease in LVEF of at least 10% from baseline to no more than or equal to 50%. The package insert for trastuzumab recommends monitoring cardiac function at baseline and every 3 months during trastuzumab treatment. The European Society for Medical Oncology Clinical Practice Guidelines recommend that if an asymptomatic patient’s LVEF drops 10% below baseline to less than 50%, trastuzumab should be held and LVEF should be reassessed in 3 weeks. Angiotensin-converting enzyme (ACE) inhibitor and beta-blocker therapy should be initiated in asymptomatic individuals with an LVEF of less than 40% and should be considered in individuals, like this patient, with a decline in EF greater than 10% from baseline to an LVEF of less than 50%. If the LVEF is less than 40% on repeat assessment, trastuzumab therapy should be discontinued. If the repeat LVEF is at least 40%, the patient can be rechallenged with trastuzumab with frequent monitoring for a recurrent decline in LV function.

In the following sections, we discuss radionuclide imaging options for evaluation of cardiac function before, during, and after treatment (planar or single-photon emission computed tomography [SPECT] MUGA imaging, echocardiography, and cardiac magnetic resonance [CMR] imaging).

Multigated acquisition imaging

MUGA imaging (also known as radionuclide angiography, equilibrium radionuclide angiography, radionuclide ventriculography, and gated blood pool scan) is used to determine global and regional measures of ventricular function. The technique consists of radiolabeling the patient’s own RBCs, which are then reinjected for imaging. For a full description of the technique, please refer to the American Society of Nuclear Cardiology guidelines. Briefly, there are two methods for labeling the RBCs: (1) using in vivo or modified in vivo/in vitro methods (e.g., using 2 to 3 mg stannous pyrophosphate 15 minutes before injection of ^99m Tc), or (2) using a commercial in vitro kit, which is the more common option. Radiolabeled blood cells are then reinjected and, after 1 to 2 minutes, electrocardiogram (ECG)-gated equilibrium blood pool imaging is obtained with planar or tomographic (SPECT) imaging. End-diastolic and end-systolic volumes are then measured to calculate the LVEF.

An anthracycline-associated reduction in LV systolic function was first observed in the 1970s via MUGA imaging. In a study published from Yale University School of Medicine in 1979, MUGA imaging was used to estimate LVEF in 55 patients receiving doxorubicin therapy. The investigators found that all five patients who had clinical HF had an ejection fraction of less than 30% by quantitative MUGA imaging at the time of symptom development. Additionally, six patients who had moderate toxicity, which involves a decline in ejection fraction by at least 15% to a final value of less than 45%, in whom doxorubicin was discontinued, did not have clinical HF or a further decline in ejection fraction during the follow-up period. Therefore the authors concluded that “assessment of radionuclide LVEF during doxorubicin therapy may make it possible to avoid congestive heart failure.” A follow-up study that monitored 1487 patients with cancer over a 7-year period with serial resting MUGA imaging developed criteria for monitoring LVEF in patients receiving doxorubicin and for deciding when to discontinue doxorubicin therapy. The occurrence of symptomatic HF was compared in patients followed according to these criteria and in patients who were not. They found that the former group had a significantly lower incidence of symptomatic HF (2.9% vs. 20.8%), and there were no deaths from HF in that group.

Echocardiography

Over time, echocardiography has become the modality of choice for baseline and serial LVEF assessment in patients with a history of malignancy. Unlike radionuclide MUGA (average effective radiation dose: ∼10 mSv), echocardiography uses ultrasound and does not involve radiation. This is an advantage in imaging patients with cancer who may have a history of radiation therapy or who may be candidates for future treatment with radiation and for whom reducing cumulative radiation exposure is important. Echocardiography can also provide valuable information regarding the presence or absence of valvular heart disease, as well as hemodynamic measures such as estimated RV systolic and left atrial filling pressures.

Although the modality is commonly used in cardio-oncology, there are important limitations to echocardiography that should be considered on a case-by-case basis. Most importantly, poor overall image quality can severely limit its ability to accurately estimate LVEF and can lead to reduced reproducibility. This can occur because of a lack of suitable windows for the ultrasound probe on the patient’s body; surgical changes on the patient’s body that prohibit the placement of the ultrasound probe (e.g., chest bandages after a mastectomy); prosthetics, such as breast implants; morbid obesity; or severe obstructive lung disease (as can be associated with lung cancer in some patients). Poor endocardial border delineation can also be problematic, especially if contrast agents are not available to opacify the LV blood pool. Planar or SPECT MUGA or CMR should be considered in these cases. Finally, planar and SPECT MUGA have high accuracy, high reproducibility, and have a lower interobserver variability (<5%) than has been reported for two-dimensional echocardiography in adults (e.g., 14% ).

Cardiac magnetic resonance imaging

CMR imaging is also used to assess LV function before, during, and after cancer therapy and, like echocardiography, does not use ionizing radiation. LVEF is quantified via CMR, most frequently using a series of contiguous short-axis slices from the cardiac apex to the base using a steady-state cine imaging technique. End-diastolic and end-systolic LV cavity areas are obtained from each slice, and volumes are obtained by multiplying them by the slice thickness. The volumes are added up and then LVEF is calculated by subtracting the end-systolic volume from the end-diastolic volume. Advantages of CMR imaging for evaluation of cardiac function include high spatial and temporal resolution, reproducibility, and accuracy for LVEF quantification to detect subclinical declines in LVEF. A study that included 22 patients before and after anthracycline chemotherapy found that CMR was able to detect a reduction in LVEF after just 28 days of therapy.

Although CMR has many advantages due to its high image quality, precision, and reproducibility, there are important disadvantages worthy of consideration. CMR imaging is costlier than planar MUGA imaging and echocardiography, is not as widely available as echocardiography, and has important patient-related contraindications, including claustrophobia and the presence of metallic implants that are not magnetic resonance imaging (MRI)–compatible.

Table 25.1 summarizes and compares the modalities for cardiac function assessment previously discussed, and Fig. 25.2 outlines suggestions for monitoring patients receiving anthracyclines. ^,