Stokkel, Marcel P.M.a; de Wit-van der Veen, Linda J.a; Boekhout, Anneliesb
Depending on tumor characteristics, the treatment of early-stage breast cancer includes adjuvant chemotherapy in certain patients to reduce the risk of tumor recurrence and improve their overall survival. In this respect, anthracyclines have played an important role. Currently, it is also well established that overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer is associated with shorter disease-free and overall survival, compared with HER2-negative breast cancer 1,2. The humanized monoclonal antibody trastuzumab has shown high affinity for the extracellular domain of the HER2 protein. Trastuzumab is used as monotherapy or in combination with chemotherapy in both palliative and adjuvant settings. Incorporation of trastuzumab into (non)antracycline-containing adjuvant chemotherapy regimens has markedly improved treatment outcomes in HER2-positive breast cancer.
Cardiotoxic side effects have been observed in both anthracycline-containing and trastuzumab-containing regimes for breast cancer treatment 2–4. The degree of cardiac dysfunction can vary from a subclinical decrease in cardiac function, which is most often reported, to symptomatic congestive heart failure (CHF). The highest incidence of cardiac dysfunction was reported in patients who were treated concurrently with anthracyclines and trastuzumab 5. Besides cardiac dysfunction, other cardiovascular complications can include myocardial ischemia, hypertension, thromboembolism, QT prolongation, and bradycardia. The mechanisms by which the anthracycline-mediated and trastuzumab-mediated side effects are induced remain unclear.
As cardiotoxicity has a significant impact on overall survival and the quality of life, it is important to diagnose and treat these side effects at an early stage. Accordingly, regular monitoring of the left ventricular ejection fraction (LVEF) by either echocardiography or multigated radionuclide angiography (MUGA) is included in the majority of the treatment schemes. A decrease in LVEF is considered an early sign of cardiotoxicity and may require postponement or adaptation of subsequent chemotherapy cycles. Once cardiac dysfunction is diagnosed, it would be helpful to have an indication of whether the LVEF will improve over time and whether the treatment can be recommenced.
Alterations in cardiac function are generally secondary to structural changes within the myocardium. Indeed, in various cardiovascular diseases, abnormalities in the adrenergic nervous system can precede a temporary or persistent decrease in cardiac function. Myocardial imaging with iodine-123-metaiodobenzylguanidine (I-123-MIBG), a norepinephrine analog, can be used to detect these abnormalities in the cardiac adrenergic nervous system during heart failure 6. Although some reports have been published so far on I-123-MIBG scintigraphy in breast cancer patients treated with anthracyclines 7–10, data on its use in trastuzumab-induced cardiotoxicity are missing. Therefore, the aim of the present pilot study was to assess the value of I-123-MIBG scintigraphy in predicting persistent cardiac dysfunction in trastuzumab-treated breast cancer patients.
Materials and methods
In this pilot study, we included nine consecutive female breast cancer patients who demonstrated a significant decrease in LVEF during adjuvant trastuzumab monotherapy. I-123-MIBG scintigraphy was performed following a decreased LVEF as assessed by MUGA. All patients gave oral informed consent before I-123-scintigraphy. At least 1 month after I-123-MIBG scintigraphy, a follow-up LVEF measurement by MUGA was taken to assess LVEF recovery. The following additional information was gathered: age, general history with emphasis on cardiac history, current symptoms, initial tumor type, grade and stage, and initial and subsequent treatment for breast cancer and/or for tumor recurrence.
Left ventricular ejection fraction measurement
All patients underwent a MUGA scan before treatment (baseline), at the start of the trastuzumab therapy (before administering trastuzumab), and at regular intervals during trastuzumab treatment according to the local clinical protocol. Planar image acquisition was initiated 5 min after injection of 740 MBq Tc-99m-labeled human serum albumin (Vasculosis; IBA Molecular, Louvain, Belgium). Acquisitions were made using a single-head gamma camera (Argus; Philips, Eindhoven, the Netherlands) equipped with a low-energy high-resolution collimator from LAO30° or LAO45°. The MUGA scan was acquired over 1200 cardiac cycles or for a total time of 900 s with 32 frames per R–R interval (20% tolerance window) and stored in a 64×64 matrix. The LVEF percentage was automatically calculated by drawing a region of interest over the left ventricle (LV) both at end systole and at end diastole. A relative decrease in LVEF of more than 10% from baseline or an absolute value less than 50% was regarded as cardiac dysfunction, and on the basis of these criteria patients were selected for I-123-MIBG scintigraphy. A recovery of the LVEF value was defined as a relative increase in LVEF of more than 10% compared with the LVEF measurement before I-123-MIBG imaging.
Iodine-123-metaiodobenzylguanidine myocardial scintigraphy
None of the patients were on medication known to interfere with MIBG uptake. Thyroid uptake of unbound I-123 was blocked with sodium iodide solution given orally. An average dose of 185 MBq I-123-MIBG (GE Healthcare, Leiderdorp, the Netherlands) was infused slowly over 60 s when the patients were at rest after thyroid blocking. Anterior planar images were acquired 15 min (early) and 4 h (late) after injection using a dual-detector gamma camera (Symbia Truepoint SPECT/CT; Siemens, Erlangen, Germany) equipped with a medium-energy collimator. Images were collected for 10 min with a 20% energy window centered on the 159 keV photopeak and stored in a 256×256 matrix.
Planar I-123-MIBG images were analyzed using regions of interest to calculate the myocardial uptake ratios and washout percentages (WR). A manually drawn region of interest was the LV, and a rectangular region of interest was placed at the mediastinum (nonspecific I-123-MIBG accumulation). The average counts/pixel were calculated in each region for the early and late images. After correcting for the physical decay of I-123, the values were used to calculate the early and delayed heart-to-mediastinum ratio (HMR) and the washout rate (WOR). The WOR was calculated as [100%×(H−M)early−(H−M)late]]/(H−M)early, where H is the mean counts/pixel in the LV and M is the mean counts/pixel in the upper mediastinum. The results were interpreted according to the proposal of the European Association of Nuclear Medicine (EANM) for standardization of I-123-MIBG scintigraphy.
Nine female patients (mean age 52 years; range 36–69 years) diagnosed with HER2-positive invasive ductal carcinoma, treated with trastuzumab, were included in the present study. For all patients, treatment with trastuzumab was discontinued until recovery of the LVEF was recorded. During this period no protective treatment was initiated.
All patients had a T1 tumor stage without distant metastases at first presentation. Four of nine patients had lymph node metastases, for which, in addition to primary tumor resection, an axillary lymph node dissection was performed. In six patients, additional treatment comprised four courses of doxorubicin (60 mg/m2 per course) with cyclophosphamide (600 mg/m2 per course). Acute cardiotoxicity was not observed in any of these patients during this initial course of chemotherapy. Two patients were treated with fluorouracil, epirubicin, and cyclophosphamide. Demographics, tumor characteristics, and details of treatment are presented in Table 1. These eight patients were subsequently treated with 12 courses of paclitaxel (80 mg/m2 per course) in combination with trastuzumab, which was followed by trastuzumab monotherapy. One patient did not receive chemotherapy and was started on trastuzumab as monotherapy directly. Although she had an indication for adjuvant chemotherapy, she refused treatment because of her age, possible side effects, and the duration of the therapy. Finally, none of the patients had a history of cardiac events, diabetes mellitus, or hypertension.
The pretrastuzumab LVEF function was normal (>50%) in eight patients, indicating that there were no signs of chemotherapy-induced cardiotoxicity. In one patient, a pretrastuzumab LVEF function was not available. The first MUGA in this case was performed after 3 months of trastuzumab monotherapy. The interval between the last chemotherapy and the initial LVEF measurement is mentioned in Table 2. Eight patients demonstrated a decreased cardiac function (LVEF<50%) during trastuzumab treatment. In one patient the LVEF decreased by at least 10%; however, the absolute LVEF remained within its normal limits. The interval between the pretrastuzumab LVEF and the LVEF indicating cardiotoxicity also has been mentioned in Table 2.
The mean interval between the indicative LVEF and I-123-MIBG scintigraphy was 4 weeks. In three patients (patients 1–3) I-123-MIBG scintigraphy showed abnormal 4 h HMR and increased WR. LVEF recovery was not observed in any of these patients during 3, 6, and 13 months of follow-up. In two of five patients both 4 h HMR and WORs were normal (patients 5 and 6), whereas in three patients slightly increased WORs were found (patients 4, 7, and 8). All five patients demonstrated a recovery of LVEF function during follow-up. One patient (patient 9) with a normal 4 h HMR and WR initially showed a decrease in LVEF, which reduced further during follow-up and eventually stabilized at 53% (Table 2). None of the patients had cardiac symptoms during the course of the evaluation period.
Patient 5 initially demonstrated a rapid decrease in LVEF during treatment with trastuzumab, as a result of which this therapy was discontinued. After recovery of the LVEF (Table 2), trastuzumab was recommenced. Three months later, a significant reduction in LVEF was observed again (37%). Measurement of the LVEF 2 months thereafter revealed a value of 44%, again indicating significant recovery. In this patient normalization was not been observed after the fifth month of follow-up.
In the present pilot study we assessed the value of I-123-MIBG scintigraphy in breast cancer patients who had a significant decrease in LVEF during trastuzumab monotherapy. In three patients with decreased 4 h HMR, a persistent decrease in LVEF was observed, without signs of recovery after discontinuation of trastuzumab. In five of six patients with normal 4 h HMR, a recovery of the LVEF was observed after discontinuation of trastuzumab. Three patients with abnormal WR had a normal 4 h HMR, suggesting that this latter value is more indicative of LVEF recovery compared with the WR. Accordingly, these initial results suggest that an abnormal I-123-MIBG scan might be an indicator for persistent trastuzumab-induced cardiac dysfunction.
As MIBG is a norepinephrine analog, it resembles norepinephrine with respect to its uptake, storage, and release in the efferent sympathetic neurons. MIBG is stored in the vesicles of sympathetic nerve endings after intravenous infusion and is coreleased with norepinephrine during nerve excitement. I-123-MIBG uptake can be quantified by placing regions of interest over the heart (specific uptake) and mediastinum (nonspecific uptake) in both early and delayed images. The washout of I-123-MIBG over time represents the actual turnover of norepinephrine, whereas the delayed HMR is more indicative of the extent of cardiac denervation 11.
Currently, the clinical application of I-123-MIBG scintigraphy for the assessment of myocardial innervation is established only in patients with CHF 12. Besides its role as a diagnostic tool, it provides prognostic information for this specific population. HMR in particular is generally associated with future cardiac events. It has been described previously that the risk for major cardiac events in patients with CHF due to ischemia or diabetes is significantly lower in patients with a 4 h HMR of at least 1.6 when compared with patients with a 4 h HMR lower than 1.6 13. Abnormalities in I-123-MIBG uptake have been demonstrated in patients with common cardiac pathologies such as coronary artery disease, diabetes mellitus, ventricular arrhythmias, heart failure, and nonischemic cardiomyopathy.
In clinical practice, I-123-MIBG scintigraphy is an uncommon measure for monitoring cardiac function during anticancer treatment 14. This is mainly because of the cost of I-123-MIBG in relation to the limited number of patients who finally develop acute chemotherapy-induced CHF. In the majority of patients, cardiotoxicity is reversible, and therefore the less expensive LVEF measures are still regarded as the method of choice for the identification of cardiotoxicity. However, LVEF measured by either MUGA or echocardiography may underestimate the actual cardiac damage due to chemotherapy. Structural damage to the myocardium, including denervation, usually precedes functional impairment. This is because of the compensatory reserve of the myocardium for impaired pump function, which enables adequate cardiac output even in the presence of dysfunctional or nonvital myocytes. An increased I-123-MIBG WR in combination with normal HMR will identify actual cardiac damage in such cases 11,15.
Trastuzumab-induced cardiac dysfunction
Previous studies have shown that trastuzumab induces myocardial dysfunction in 3–18% of patients. A type II cardiotoxicity has been ascribed, which means that it is not dose dependent, is largely reversible, and does not produce clear structural changes on histological examination. Several mechanisms have been proposed to explain this cardiotoxicity, such as immune-mediated destruction of myocytes, impaired HER2 signaling required for the maintenance of cardiac contractility, and interference with cardiomyocyte survival signals 4. The reported incidence of trastuzumab-induced symptomatic CHF ranges from 0 to 3.9%, and the overall prognosis in such cases is poor 16. To differentiate between acute (reversible) and chronic (nonreversible) cardiotoxicity, appropriate schedules of LVEF monitoring have been recommended, but the optimal intervals between such measurements remain controversial 17,18. The method of choice for LVEF monitoring is arbitrary as long as the same imaging modality is used during follow-up. Consequently, it may be a while before this differentiation can be made with intervals of several weeks to months between the LVEF measurements. Therefore, it would be helpful to have a tool that can be used at an earlier stage to differentiate between reversible and nonreversible trastuzumab-related toxicity.
This pilot study is the first to be conducted on the possible value of I-123-MIBG scintigraphy in monitoring and predicting trastuzumab-related cardiotoxicity. The initial results suggest a diagnostic role of I-123-MIBG scintigraphy, and especially of 4 h HMR, in trastuzumab-induced persistent cardiac damage. Previous data on this application are currently not available.
Diagnosing chemotherapy-induced cardiotoxicity using I-123-MIBG scintigraphy
In contrast to trastuzumab-related cardiotoxicity, the value of I-123-MIBG scintigraphy was described previously in anthracycline-related cardiac side effects in the early 1990s. One of the first reports on this subject was published in 1992 by Valdes Olmos et al. 7. They demonstrated increased WORs (ranging from 43 to 56%) in six patients, suggesting a global myocardial adrenergic derangement. Anthracyclines can in some patients cause acute side effects such as arrhythmias, tachycardia, and pericarditis–myocarditis syndrome. However, these side effects are commonly reversible and do not have to be regarded as a preclusion for further treatment. Chronic cardiotoxicity, in contrast, is regarded as type I toxicity, which means that is it irreversible, dose dependent, and associated with structural changes in the myocardium. This toxicity may occur even after 10–20 years, and the prognosis related to CHF is poor with a 50% 2-year survival rate 19. Anthracyclines seem to cause cardiomyocyte death, which is initially balanced by compensatory mechanisms; however, after a dose of at least 400 mg/m2 this mechanism starts to fail. In a study by Carrio et al. 8 a significant decrease (P<0.05) in MIBG uptake was observed at doxorubicin doses ranging from 420 to 600 mg/m2. In these 36 patients, the LVEF also decreased significantly (P<0.05) from 61% at baseline to 52% during follow-up. In four of nine patients with a decrease in LVEF of at least 10%, symptoms of CHF were observed with 4 h HMR ranging from 1.50 to 1.63. These initial findings were confirmed in a study by Lekakis et al. 9, who also used planar imaging for quantification. They found a cutoff value of 1.73 as indicative for doxorubicin-induced cardiotoxicity. In a study by Takano et al. 10, I-123-MIBG single-photon computed tomography (SPECT) was used for evaluation of cardiac innervation. Although this three-dimensional imaging method provides the option for segmental evaluation of the myocardium instead of the global analysis used in two-dimensional planar imaging, standard HMR and WR were calculated, revealing the same conclusions as earlier studies.
Despite its novelty, there are some limitations to this study that we have to consider. The first limitation is related to the selection of the included patients. We studied patients with a decreased or decreasing LVEF function during trastuzumab treatment and, as stated before, the LVEF will only decrease after a certain amount of damage to the myocardium. Second, eight patients had already been treated with cardiotoxic agents such as anthracyclines, cyclophosphamide, and taxanes before the start of trastuzumab therapy 20. Eight patients received paclitaxel in combination with trastuzumab, and, when combined, the risk on cardiac side effects increased substantially. Accordingly, it is difficult to distinguish between true trastuzumab-induced cardiotoxicity and toxicity related to prior treatments. In this respect, a baseline I-123-MIBG scintigraphy before the start of trastuzumab would have provided important information on the presence of myocardial damage at the time of inclusion. In addition, LVEF measurements were not taken on a regular basis at set time intervals, making it difficult to assess the time point at which recovery of LVEF occurred during follow-up. Despite these two important limitations, these initial results still suggest a prognostic role for I-123-MIBG in the prediction of persistent dysfunction. Moreover, it cannot be ruled out that chemotherapy itself may have influenced the MIBG uptake profiles. Although the minimum interval between the last chemotherapy course and I-123-MIBG scintigraphy was 4 months, making a direct effect less plausible, it has to be taken into account in further studies. Consequently, it will be interesting to study this prognostic stratification in larger case series including more patients in whom both LVEF measurements and I-123-MIBG scintigraphy have been performed at regular intervals.
In the present study we used planar imaging to assess and quantify global I-123-MIBG uptake in the myocardium. In clinical practice, SPECT is being used increasingly more to evaluate myocardial innervation, as it probably provides more detailed regional information 21. In patients with ischemic cardiomyopathy and diabetes, this segmental information is of prognostic and therapeutic importance. However, it is uncertain whether this detailed information is required for diagnosis and prognosis after cancer treatment, as chemotherapy-related cardiotoxicity generally affects the whole myocardium. In a recent study by Chen et al. 22, planar scintigraphy revealed equivalent results to SPECT. The receiver-operating characteristic curves from both acquisition techniques were not significantly different. Nevertheless, additional research is required to establish the role of both planar and SPECT I-123-MIBG imaging in oncologic clinical practice.
In summary, we assessed the value of I-123-MIBG scintigraphy in nine breast cancer patients with asymptomatic cardiotoxicity, measured by a decreased or decreasing LVEF during trastuzumab therapy. Patients with a 4 h HMR less than 1.6 showed no recovery of the LVEF during follow-up, whereas patients with a 4 h HMR of at least 1.6 showed significant improvement in LVEF values over time. Despite its limitations, this pilot study suggests a possible role for I-123-MIBG scintigraphy in risk stratification of patients with trastuzumab-related cardiotoxicity. I-123-MIBG scintigraphy might be indicative of whether LVEF recovery will occur, and, consequently, it could alter the trastuzumab treatment schemes for individual patients. However, prospective studies are needed to evaluate the true role of I-123-MIBG scintigraphy in breast cancer patients during trastuzumab treatment.
Conflicts of interest
There are no conflicts of interest.
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