Nuclear Oncology, 1 Ed.

CHAPTER 33

RADIONUCLIDE IMAGING FOR THE ASSESSMENT OF TOXICITY DUE TO CHEMOTHERAPY

Marcel P.M. Stokkel • Linda de Wit-van der Veen

INTRODUCTION

Drug toxicities and resistance are among the most important challenges encountered in delivering a curative dose during antineoplastic treatment. Toxicities that affect one or more of the major organ systems, for example, heart, lung, bone marrow, kidneys, and liver, are a rather common side effect of chemotherapeutics (Table 33.1). Over two decades ago, the National Cancer Institute (NCI) introduced the Common Terminology Criteria for Adverse Events (CTCAE version 4.0) to aid in the classification of the side effects associated with antineoplastic therapies. The severity of any event is graded from 1 to 5; one, being asymptomatic or mild symptoms, to five, indicating death related to adverse event. Though this classification system is not discussed in further detail in this chapter, it is an important tool to document toxicities in clinical trials. The CTCAE does not, however, recommend techniques or methods to diagnose and monitor drug-related toxicity.

In general, toxicities can be divided into two forms, those that occur in an acute setting concomitant to the chemotherapy and those that present as long-term side effects, possibly years after treatment. These late effects, in particular, are often either not defined in a preclinical setting or have not been demonstrated during the initial clinical trials with a new drug, and therefore, will only become apparent in the clinical setting in cancer survivors. The NCI estimates that there were over 10 million cancer survivors in the United States in 2002.1,2 This improved patient survival, combined with the aging population and the introduction of new targeted anticancer treatments, has led to interest in long-term toxicity monitoring. This chapter will focus on nephrotoxicity, lung, liver, bone marrow, and cardiovascular toxicity, and the evaluation of these toxicities using nuclear imaging techniques.

CHEMOTHERAPY-INDUCED NEPHROTOXICITY

Mechanisms of Toxicity

Drug-induced nephrotoxicity is a rather common complication of several chemotherapeutic agents.3 In an acute setting, drug-induced toxicity has been implicated in 8% to 60% of all cases and, consequently, it is recognized as a serious source of morbidity and mortality.4,5 The mechanism of action differs among various agents or classes of chemotherapeutic agents. In general, nephrotoxicity is categorized based on the histologic component of the kidney that is affected.68 At this time, six different categories have been described: hemodynamically mediated injury, tubular epithelial cell damage, tubulointerstitial disease, glomerular disease, renal vasculitis and thrombosis, and finally, obstructive nephropathy.

Hemodynamically Induced Renal Toxicity

The kidneys receive approximately 20% to 25% of resting cardiac output.5,6 Blood flow and filtration pressure are regulated by afferent and efferent arterioles to maintain urine production and excretion. A regulatory mechanism based on natriuretic factors, the sympathetic nervous system, and the renin–angiotensin system (RAS) are the cornerstones of blood flow in the kidney. Hemodynamically induced kidney failure results from a decrease in intraglomular pressure caused by vasoconstriction of afferent arterioles or vasodilation of efferent arterioles. Under normal circumstances, the RAS should compensate for this pressure decrease. However, agents such as angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclosporines, and tacrolimus may interfere with this compensating mechanism.4,911 Although the site of interaction may differ per agent, the overall result is a decrease in filtration pressure. Patients at greatest risk for drug-induced renal failure are those with chronic kidney disease, atherosclerotic cardiovascular disease, and elderly patients.

Tubular Epithelial Cell Damage

This is caused by either direct or ischemic effects of nephrotoxic drugs.6,12 This type of damage is usually located in the proximal and distal tubular epithelia. When it is observed as cellular degeneration and sloughing from basement membranes, it is called acute tubular necrosis (ATN). ATN is the most frequently observed renal toxicity in clinical care, for which radiocontrast media, cisplatin, immunoglobulins, and aminoglycosides are well-known causes.5,1316ATN caused by such agents is dose dependent, which means that the higher the dose, the higher the chance and severity.17 Obstruction of the tubular lumen and back-leakage of the glomerular filtrate results in a reduction of GFR. Generally, glomeruli are spared; severe necrosis of tubules and collecting ducts can be found in biopsy specimen. The risk of ATN increases with aging, dehydration, previous irradiation, alcohol abuse, and concurrent use of other nephrotoxic drugs.18

Tubulointerstitial Disease

This condition includes damage to the renal tubules as well as the surrounding interstitial tissue.6,12,19 It is a nondose-dependent toxicity in which a diffuse or focal infiltration of lymphocytes, plasma cells, eosinophils, and neutrophils is observed in the interstitium.12,19 In acute allergic interstitial nephritis, an allergic hypersensitivity response is regarded as explanation for this phenomenon which can be caused by analgesics, diuretics, and NSAIDs. Much of this reaction is reversible. Several drugs, however, may cause progressive and irreversible damage culminating in kidney failure. Lithium and cyclosporine therapy are well-known causes of this phenomenon with an increased risk in dehydrated patients. Nephrocalcinosis, characterized by extensive tubulointerstitial deposition of calcium phosphate, and papillary necrosis caused by analgesics, such as aspirin and NSAIDs resulting in acute kidney injury.5,6,19,20 The interval between exposure and toxicity may range from weeks to months whereas in case of analgesic nephropathy, end-stage renal disease may evolve over years. The exact mechanism of this form of nephropathy remains unclear, and is in many cases underdiagnosed as a cause of end-stage renal disease. The production of free, toxic radicals may be the initiating factor with accumulation of toxic metabolites, decreased blood flow, and impaired cellular energy production as a consequence.

TABLE 33.1

FORMS OF CHEMOTHERAPY-INDUCED ORGAN TOXICITY ACCORDING TO DATA IN THE LITERATURE

Glomerular Disease

Although chemotherapy-induced glomerular disease is rare, a variety of drugs have been implicated. Ampicillin, phenytoin, lithium, and NSAIDs have been known to cause proteinuria, a typical hallmark of glomerular injury.9,21,22Glomerular injury is frequently accompanied by interstitial nephritis, and it is most frequently caused by immune mechanisms rather than direct cellular toxicity. In NSAID-related glomerular injury, a T-lymphocytic interstitial infiltrate is associated but the exact mechanism is not known. Proteinuria usually resolves rapidly after discontinuation of the specific toxic agent whereas a course of corticosteroids may help resolve it more rapidly. Pamidronate, a bisphosphonate used to treat bone metastases-related hypercalcemia, has also been associated with focal segmental glomerulosclerosis. Patients receiving high doses or prolonged therapy with this drug are at high risk.23

Renal Vasculitis and Thrombosis

A large number of drugs have been associated with a vasculitis. Allopurinol, propylthiouracil, hydralazine, and chemotherapeutic agents may induce systemic vasculitis with involvement of small- and/or medium-sized renal arteries.2426 Typical features are hematuria, proteinuria, hypertension, and reduced renal function. To resolve the symptoms, the drugs must be discontinued and a course of prednisone may be necessary. Other drugs, such as interferon, tacrolimus, and mitomycin C may cause a thrombotic microangiopathy. Histologic examination may reveal endothelial proliferation and thrombus formation as typical features of it. A dose-related effect has been described in mitomycin C either with or without the use of other chemotherapeutic drugs and its effect may be irreversible and severe.

Obstructive Nephropathy

This form of nephropathy can be subdivided into intratubular obstruction and nephrolithiasis.6,27 Intratubular obstruction can be caused by intratubular precipitation of tissue degradation products or drugs and/or their metabolites. Acute uremic acid nephropathy because of tumor degradation caused by chemotherapy is the most common cause of this type of nephrotoxicity. Oliguria or anuria usually develops rapidly. Rhabdomyolysis and precipitation of myoglobulin is another frequently observed etiology. Drugs such as simvastatin or lovastatin are also known potentially nephrotoxic agents, especially when used concurrently with cytochrome P450 inhibitors or niacin.28 Other drugs, such as methotrexate, can also cause direct kidney injury by intratubular precipitation.6,21 ­Nephrolithiasis as a cause of an obstructive nephropathy is well known and is usually associated with pain, hematuria, and sometimes with infections. Drug-induced nephrolithiasis is rare and has an estimated incidence less than 1%. An increased excretion of uric acid, a breakdown product of proteins, in combination with dehydration may increase the risk on nephrolithiasis and subsequent kidney injury.6,27

The Role of Nuclear Medicine in the Detection and Follow-up of Nephrotoxicity

Radionuclide renal scintigraphy provides important functional data to diagnose and monitor chemotherapy-induced nephrotoxicity.2931 Data related to this specific application, however, are scarce. The most commonly used tracer for renography is Technetium-99m ­(99mTc) mercapto acetyl triglycine (MAG3). See Table 33.2. After intravenous administration, approximately 45% of this tracer is extracted by the proximal tubules. 99mTc-MAG3 has a higher extraction fraction than diethylene triamine pentaacetic acid (DTPA) and, therefore, it is a better diagnostic agent in patients with impaired function. The clearance of 99mTc-MAG3 is highly correlated with the effective renal plasma flow and, consequently, it can be used as an independent measure of renal function. Iodine-131 (131I) orthoiodohippurate (OIH) is a tracer that is also extracted by the proximal tubules, but because of the suboptimal imaging characteristics of 131I and its β-emission, it is rarely used. DTPA labeled with 99mTc is the second most frequently used radiopharmaceutical for renal scintigraphy. 99mTc-DTPA is filtered by the glomerulus and can, therefore, be used to assess the glomerular filtration rate. Semiquantitative analyses of the scintigrams can be performed, providing measures of time to peak extraction (Tmax), the ratio of the activity at 20 minutes to the maximum activity and the rate of washout (activity at 20 minutes) to the renal function (activity at 2 to 3 minutes). It is important that the patient is adequately hydrated when renal scintigraphy and its semiquantitative analysis is performed. Quite often, hydration is suboptimal in cancer patients. Inadequate hydration results in retention of the radiopharmaceuticals in the tubular cells. Dimercaptosuccinic acid (DMSA) labeled with 99mTc is used for functional imaging of the proximal renal tubular mass and provides high-quality images because of preferential cortical accumulation and limited excretion. This tracer is primarily used to assess residual damage and scar formation.

Functional imaging can also be performed with positron-emitting radiopharmaceuticals. Tracers used for positron emission tomography (PET) perfusion studies of the kidney include Oxygen-15 (15O) labeled water and Rubidium-82 (82Rb). Glomerular filtration can be imaged with either Gallium-68 (68Ga) 2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid (EDTA) or Cobalt-55 EDTA. An advantage of renal PET over scintigraphy is the possibility of true quantification and a better assessment of renal blood flow. A major disadvantage of PET-based renal imaging in oncologic practice is the availability and costs of these tracers. At this time, there is insufficient data to determine the utility of PET tracer assessment of renal viability and function.31

In clinical practice, the role of nuclear medicine is limited in the assessment of chemotherapy-induced renal toxicity. Standard laboratory tests include routine measurement of creatinine, creatinine clearance, and β-2 microglobulins, which can be used to establish a vascular, tubular, or glomerular origin of kidney failure. In contrast to renal scintigraphy, laboratory tests can be performed several times per day and are less expensive. Based on these test results, chemotherapy regimens are modified or discontinued depending upon the severity of the nephrotoxicity. The choice of radiopharmaceutical to be used is based on the type of damage. If tubular damage is suspected, 99mTc-MAG3 is the radionuclide of choice whereas in glomerular toxicity, 99mTc-DTPA might be a better option. In a study by Yetgin et al.,29 the role of MAG3 and DMSA renal scintigraphy in the evaluation of kidney damage was described. They studied 116 children treated with vincristine, daunorubicin, high-dose methylprednisolone or cytarabine, and etoposide for acute lymphoblastic leukemia. 99mTc-MAG3 and DMSA scans were performed in 27 and 84 patients, respectively. Abnormal results were obtained in 40% of the cases. The practical consequences of these findings were not discussed. It was suggested that compared to abnormal serum biochemical tests, renal scintigraphy might be a better predictor of long-term outcome. In a study by Caglar et al.,30 a total of 13 patients treated with ifosfamide were evaluated with 99mTc-DMSA scintigraphy. Serial measurements were performed and a 25% decrease in renal uptake was observed in five patients with nephrotoxicity. The authors concluded that 99mTc-DMSA detects tubular dysfunction prior to clinical deterioration and, therefore, suggested monitoring patients treated with ifosfamide containing chemotherapy.

TABLE 33.2

OVERVIEW OF DIFFERENT RADIOPHARMACEUTICALS FOR IMAGING CHEMOTHERAPY-INDUCED TOXICITY

The role of renal scintigraphy in patients treated with chemoradiation for gastrointestinal malignancies has been reported in several case series. A decline in split renal function with a progressive relative impairment of the involved kidney can be detected as early as 6 months postradiation. In these studies, however, kidney failure was more related to radiotherapy than to chemotherapy.

In summary, the role of renal scintigraphy in oncologic practice is limited. Data in the literature is scarce.

CHEMOTHERAPY-INDUCED LUNG TOXICITY

Many chemotherapeutic agents have been associated with pulmonary toxicities.32 Approximately 10% of all patients treated with chemotherapeutic agents will develop an adverse event related to the lungs. In some cases, the clinical presentation is acute whereas in other cases, it is more insidious. The most commonly observed symptoms are dyspnea, nonproductive cough, and fever. The onset may vary from weeks to years after treatment. In this respect, bleomycin pulmonary toxicity is the most prevalent and well-described chemotherapy-induced pulmonary disease; busulfan is the second most common.32,33 Other agents, such as antimetabolites, nitrosamines, podophyllotoxins, and immune modulatory agents have been associated with pulmonary toxicity. Bleomycin-induced lung disease is associated with a significant decrease in 5-year overall survival in patients with Hodgkin lymphoma. The pathogenesis of lung toxicity seems to be a combination of apoptotic dysfunction and impaired repair. Apoptosis has two fundamental pathways: the mitochondrial pathway and the death receptor. Anticancer agents can activate proapoptic pathways resulting in an increased permeability of the mitochondrial outer membrane and the release of cytochrome C, leading to cell death.34 Regarding the second pathway, epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) signaling and angiogenesis may be the cornerstone in the process of recovery. Inhibition of these factors reduces the ability of pneumocytes to repair.

Types of Lung Toxicity

There are several forms of lung toxicity. The clinical and radiologic manifestations generally reflect the underlying histopathologic process.

Diffuse Alveolar Damage

This is the most common form of lung toxicity related to ­chemotherapy and especially to the use of bleomycin, busulfan, carmustine, and cyclophosphamide. The first phase is the so-called exudative phase, in which alveolar and interstitial edema is seen. The second phase, the reparative phase, is characterized by proliferation of pneumocytes and fibrosis. This latter finding may either improve over time, but also may end in honeycomb lung. Diffusing capacity for carbon dioxide may decrease, whereas radiologic evaluation with high-resolution computed tomography (HRCT) may reveal bilateral ground-glass opacities. Although fibrosis at initial stage may be missed, follow-up CT scans may show progressive distortion of the architecture.35

Nonspecific Interstitial Pneumonia

In nonspecific interstitial pneumonia (NIP), infiltration of the interstitium by mononuclear inflammatory cells is seen, in combination with mild interstitial fibrosis and hyperplastic pneumocytes. It has been associated with amiodarone, methotrexate, and carmustine. Docetaxel may cause an acute form of NIP, especially when coadministered with gemcitabine. Paclitaxel has been described in a number of case reports and clinical studies, but the overall incidence remains low. Targeted therapies with monoclonal antibodies against the VEGF receptor and EGFs tyrosine kinase inhibitors have been correlated with NIP in approximately 1% of the patients. In general, diffusion capacity will decrease whereas HRCT scans show more diffuse areas of ground-glass opacity. Later in the course of this form of lung damage, fibrosis can be observed, especially at the lung bases.

Cryptogenic Organizing Pneumonia

Cryptogenic organizing pneumonia (COP) was formerly known as bronchiolitis obliterans organizing pneumonia. It is characterized by proliferation of Masson bodies which are immature fibroblastic plugs within alveolar ducts and alveolar spaces. Bleomycin, cyclophosphamide, and methotrexate are the drugs most often associated with COP. Dry cough, fever, and dyspnea are typical symptoms. HRCT shows nodular areas of consolidation, centrilobular nodules, and branching linear opacities (tree-in-bud). Generally, it responds well to drug withdrawal but in some cases, corticosteroids are required. Fibrosis is less commonly observed.36,37

Eosinophilic Pneumonia and Pulmonary Hemorrhage

These conditions are less commonly observed than the other forms of drug-induced toxicity. Eosinophilic pneumonia (EP) is characterized by an accumulation of eosinophils and macrophages in the alveoli and thickened septa. The most typical feature on chest radiographs are homogeneous opacities that are typically located peripherally and in the upper lobes. Pulmonary hemorrhage (PH) is a severe complication of cancer treatment. Amphotericin B, cyclophosphamide, and mitomycin are associated with PH with acute respiratory distress as initial symptom. HRCT usually shows bilateral, scattered, or diffuse ground-glass opacity.37

The Role of Nuclear Medicine in the Detection and Follow-up of Lung Toxicity

In clinical practice, the role of nuclear medicine in the detection and follow-up of lung toxicity is limited. The standard diagnostic procedure in patients presenting with symptoms of fever, cough, and dyspnea includes a chest x-ray, arterial blood gas analysis, and HRCT scanning. In most cases, the diagnosis is made, when the symptoms occur shortly after the initiation of cancer treatment. In patients in whom this correlation is less clear because of an extended time interval, bronchoscopy and biopsy may be required to establish a diagnosis. HRCT is of value to demonstrate fibrosis and honey combing.

One of the first tracers that has been studied extensively in this respect is Gallium-67 (67Ga) citrate. Pulmonary uptake of 67Ga citrate has been described in a variety of disorders, such as interstitial pneumonia, sarcoidosis, pneumonia, toxicity to chemotherapeutic agents, and in subradiographic interstitial inflammatory reaction.38,39 See Table 33.2. Gallium scans have been reported as abnormal in pulmonary toxicity caused by amiodarone, busulfan, bleomycin, procarbazine, nitrofurantoin, pentazocine, cephalosporin, cyclophosphamide, and cocaine, even in the absence of radiographic findings. In most of these cases, diffuse pulmonary uptake is observed. This is a nonspecific finding. With the introduction of HRCT, 67Ga citrate scintigraphy no longer used to assess lung toxicity. In clinics where 67Ga may be in use to stage lymphoma, diffuse uptake on the scintigraphic images may be a feature of lung toxicity and should be recognized and reported. However, Fluor-18-fluorodeoxyglucose (18F-FDG) PET scanning has generally replaced 67Ga scintigraphy in many hospitals.

The clinical evidence on 18F-FDG PET imaging in lung toxicity is limited to retrospective studies or observational case series. In a study by Kazama et al.,40 a total of 677 18F-FDG PET scans on 460 patients with lymphoma, non-Hodgkin lymphoma (351), Hodgkin disease (92), and 17 patients with both Hodgkin and non-Hodgkin lymphoma were performed. In 51 patients, abnormal accumulation on both sides of the chest was reported. In 10 patients (six men and four women, average age 47.3) representing 2.2% of cases, probable drug toxicity was identified. In all 10 cases, diffuse and ­subpleural-dominant FDG accumulation was seen on 18F-FDG PET scans, and scattered or diffuse ground-glass opacities were observed on chest CT. Four of the patients reported symptoms, 18F-FDG PET imaging may be able to detect pulmonary drug toxicity in asymptomatic patients but diffuse uptake appears to be a nonspecific finding. In a case report by Yamane et al.,41 a 51-year-old man presented who developed drug-induced pneumonitis during chemotherapy for non-Hodgkin lymphoma. Pneumonitis was detected earlier by 18F-FDG PET than by HRCT. Accordingly, the authors concluded that 18F-FDG PET imaging can be used to detect drug-induced pneumonitis at an earlier stage than HRCT. Buchler et al.42 described a case in which 18F-FDG PET was used in a patient with Hodgkin disease who developed bleomycin lung toxicity following the fourth cycle of chemotherapy. The 18F-FDG PET scan performed 2 months after the acute presentation, showed diffuse uptake of FDG in the lungs. Following treatment with corticosteroids, the FDG avidity in the lungs disappeared, whereas conventional CT scanning was not able to distinguish between residual changes and active inflammation. The authors also concluded that 18F-FDG PET represents a useful diagnostic tool and demonstrates the resolution of disease activity even in the presence of residual pulmonary scarring. A comparable case was reported by Rohr et al.43 stressing the fact that in patients with diffuse lung uptake on the 18F-FDG PET scan should be evaluated for drug-induced toxicity. Kalkanis et al.44 retrospectively evaluated 18F-FDG PET scans of patients who have been treated with rituximab, a chimeric anti-CD20 monoclonal antibody widely used in the treatment of B-cell non-Hodgkin lymphomas (NHLs). In their case series, none of the patients had pulmonary lymphoma or other pulmonary disease before therapy and all remained asymptomatic during ­follow-up. New pulmonary interstitial FDG uptake was detected on follow-up 18F-FDG PET/CT between 1 and 3 months posttreatment. The 18F-FDG PET findings preceded CT. FDG uptake was subpleural with maximum standardized uptake value (SUV) from 2 to 5.84. Although rarely observed, diffuse FDG uptake should increase awareness of toxicity and should not be confused with lymphoma activity. This data does not support the use of 18F-FDG PET imaging in all patients suspected for having drug-induced lung toxicity when lung toxicity is diagnosed and a HRCT fails to demonstrate recovery, 18F-FDG PET has a role in assessing disease activity.

99mTc-DTPA aerosol scintigraphy has been used to detect lung toxicity. DTPA and other small molecules move across the alveolar epithelium through paracellular pathways by passive diffusion after deposition on the alveolar surface. Increased surfactant over the alveolar epithelium lengthens the distance of diffusion pathway of DTPA. In 1993, the first report on the use of 99mTc-DTPA aerosol scintigraphy in bleomycin-induced lung toxicity in patients with germ cell tumor was presented by Ugur et al.45 Based on scintigraphy, the percentage decrease in activity per minute (Kep) was evaluated. Pretreatment Kep values (0.891 ± 0.286) were significantly lower than those obtained following 180 and 360 mg bleomycin treatment (1.176 ± 0.336 and 1.389 ± 0.477, respectively; P < 0.0005). The Kep values obtained with 180 and 360 mg bleomycin treatments were also significantly different (P < 0.005). Suga et al.46 reported on this effect in irradiated canine lung, in which 14 irradiated animals were studied. The histologic and bronchoalveolar lavage studies revealed an increase in alveolar surfactant material without histologic changes in the alveolar structure. The radioaerosol is delivered via a ventilation circuit until a minimum count rate over the lung fields was obtained and the clearance study was started immediately after disconnection of the ventilation unit. In all animals, the half-life of DTPA in the lung increased significantly compared to the baseline study. In a subsequent study by Durmus-Altun et al.,47 99mTc-DTPA was evaluated in a rabbit model for the detection of amiodarone-induced pulmonary toxicity. In this study, the radioearosol technique was compared to scintigraphic imaging of Iodine-123-metaiodobenzylguanidine (123I-MIBG), a norepinephrine analog. 123I-MIBG has been used to study pulmonary endothelial function as the uptake patterns may reflect pulmonary endothelial cell injury. It was shown that the 123I-MIBG retention index, as well as the 99mTc-DTPA clearance time, was significantly higher in the amiodarone-induced pulmonary toxicity group compared to the control group. Twelve nonsmoking chemotherapy naive patients without evidence of pulmonary disease who were treated with bleomycin underwent 99mTc-DTPA scintigraphy. Scintigraphy was performed before the first cycle and every 3 weeks until the third month after the end of chemotherapy.48 Comparing the pre- and posttreatment scans, the clearance was significantly lower. The authors concluded that cumulative bleomycin doses are related to pulmonary epithelial permeability at a dose of 256.5 mg. Since nonradioactive techniques have become available, this method has not entered clinical practice.

CHEMOTHERAPY-INDUCED LIVER TOXICITY

The liver is the most important organ in drug metabolism. Many chemotherapeutic agents will be metabolized and excreted into the biliary tract and subsequently into the bowel. Consequently, dysfunction of the liver may result in increased levels of many agents causing greater toxicity to other organs such as bone marrow and kidneys. On the other hand, some chemotherapeutic agents are inactive after administration but become activated in tumor or other tissues following localization. If liver function is required for activation of the prodrug, liver impairment may reduce the chance of a meaningful response. Risk factors for drug-induced liver disease include age, gender, and familial predisposition. Pre-existing liver impairment, however, due to alcohol abuse, for example, or liver dysfunction due to metastatic disease and the use of concurrent medications may increase the risk of toxic effects and side effects of chemotherapy.4952 The most hepatotoxic agents described in the literature are methotrexate, asparaginase, carmustine, and mercaptopurin. Less-toxic agents are capecitabine, dacarbazine, etoposide, gemcitabine, and cyclophosphamide. Most agents are lipophilic compounds that are taken up rapidly by the liver and cannot be excreted without break down into smaller fragments. It may disturb lipid metabolism resulting in steatosis in the liver. Because of this the liver becomes more vulnerable and repeated chemotherapy may finally induce irreversible hepatocellular damage through recruitment of inflammatory cells and especially by monocytes.

Based on the biochemical alterations, liver toxicity can be subdivided into hepatocellular and cholestatic dysfunction. In hepatocellular dysfunction, aspartate aminotransferase and alanine aminotransferase levels are elevated greater than two times the upper limit of normal. In cholestatic dysfunction, alkaline phosphatase and γ-glutamyltransferase are elevated greater than two times the upper limit of normal.

In the acute phase hepatocellular and cholestatic liver disease, functional imaging may show minimal or no changes at all. Both forms of liver disease may resolve after stopping treatment but occasionally acute (fatal) necrosis has been reported. Other drugs besides the chemotherapeutics, such as allopurinol and ketoconazole, may induce fulminant liver necrosis. In general, the severity of liver disease is based on a combination of biochemical and clinical parameters. The Child-Turcotte-Pugh score is a combined measure of ascites, encephalopathy, and biochemical indices that was originally developed to assess alcohol-related cirrhosis in the liver.53 This score is not used in current oncologic practice as the correlation with the Child-Turcotte-Pugh and clearance of chemotoxic agents is weak. The model for end-stage liver disease (MELD) was developed in 2000 and had been introduced for the selection of patients for liver transplantation.54 In the oncologic setting, it has only been used to identify patients with hepatocellular carcinoma for transplantation; not to assess prognosis in case of ­chemotherapy-induced liver toxicity. In patients with persistent biochemical alterations, as well as in patients in whom recovery is observed after cessation of treatment, radiologic techniques can be used to assess morphologic alterations. The combination of biochemical information and radiologic findings can be used to assess prognosis in ­general.

Hepatocellular and Cholestatic Dysfunction

Fatty Liver Disease

Also known as steatosis hepatis, this is defined as accumulation of fat globules in the hepatocytes. It may be observed during extensive administration of irinotecan for liver metastasis of colorectal cancer. It may progress to a severe form, steatohepatitis, a severe form with limited hepatic reserve. Although the final diagnosis is made by biopsy and histologic examination of the specimen, CT may show fatty changes.

Pseudocirrhosis

Retraction of the capsule is observed in patients with metastases or primary tumors in the liver treated with chemotherapy. These findings may occur within 1 to 3 months after treatment and can be focal or more diffuse. It is probably due to nodular regenerative hyperplasia. There is no association with treatment response, as it can be seen in tumors that are decreasing and increasing in size and, therefore, it has no prognostic value.

Biliary Sclerosis

Chemotherapy related biliary sclerosis results either from toxic effects on the biliary system or ischemic changes secondary to fibrosis of the pericholangitic venous plexus, both of which can result in stricture of the duct. CT scanning demonstrates narrowing of the bile ducts with the extrahepatic ducts most commonly involved whereas the intrahepatic bile ducts are less involved. Clinically, it should be differentiated from jaundice observed in chemical hepatitis due to chemotherapy in which case, only cessation of treatment is required whereas in biliary sclerosis stent placement may also be necessary.

Hepatoveno-occlusive disease is a serious complication characterized by obliteration of small hepatic venules with surrounding fibrosis and clogging of the sinusoids with debris form cell necrosis. The basic mechanism is thought to be damage of the endothelial cells of central and sublobular veins in the liver.55,56 It is a common finding in myeloablative chemotherapy with jaundice, ascites, and hepatomegaly as typical features. Although CT scanning may reveal nonspecific findings, Doppler ultrasonography will show decreased blood flow in the portal vein that can be observed within 3 weeks after initiation of treatment.

The Role of Nuclear Medicine in the Detection and Follow-up of Liver Toxicity

Functional imaging of the liver with radiopharmaceuticals aims to provide a method to assess drug uptake and excretion by the liver. Radiopharmaceuticals for this purpose include 99mTc-methoxyisobutylisonitrile (MIBI), 99mTc-DTPA-galactosyl human serum albumin (GSA), and 99mTc-iminodiacetic acid (IDA) for hepatobiliary scintigraphy. See Table 33.2.

In the liver, biliary transporter-mediated excretion has a role in drug clearance involving many enzymes including adenosine triphosphate-binding cassette transporters such as the ABCB1, ABCC1, ABCC2, and ABCG2. 99mTc-MIBI is a substrate for ABCB1 enzyme in the liver, and consequently, it can be used as an indicator of drug clearance before therapy is initiated. This radionuclide has been studied in patients treated with vinorelbine. It was shown that 99mTc-MIBI clearance was an independent predictor of this chemotherapeutic agent clearance.57 Imatinib, a tyrosine kinase inhibitor, is an agent that is excreted in bile presumably via ABCB1. In a study by Gurney et al.,5899mTc MIBI liver clearance was studied in 22 patients treated with imatinib but the authors did not find a correlation between the clearance of both. Finally, in a study by Michael et al.,59 99mTc-MIBI was studied in patients treated with irinotecan. 99mTc-MIBI excretion was prolonged in patients with the ABCB1 exon 26 TT variant allele relative to the wild type (P = 0.015). From these data, it was suggested that functional imaging of hepatic uptake and excretory pathways may have potential to predict irinotecan pharmacokinetics but further studying is required. Although 99mTc-MIBI seems to have potential to study the ABCB1 transporter, it has never been used in oncology to assess liver toxicity. It remains, however, of interest whether MIBI liver clearance can be regarded as indicator for liver toxicity or as indicator for clearance of chemotherapeutic agents and, consequently, a predictor of other toxic effects, such as neutropenia.

99mTc–labeled IDA derivates were initially reported by Loberg et al.60 These lidocaine analogs are predominantly bound to albumin and transported to the liver. Thereafter, it is dissociated in the hepatic space of Disse after which the radiopharmaceutical is taken up by hepatocytes and follows the path of intracellular transit similar to bilirubin, toxins, or drugs. Without any transformation, IDA derivates are excreted into the biliary tract and are ideal tracers for biliary tract imaging. In general, the uptake of IDA derivates is affected by high bilirubin plasma levels but 99mTc-mebrofenin is efficiently excreted and, therefore, is considered as the most suitable. Hypoalbuminemia may hinder the uptake and increases the urinary excretion of mebrofenin. Decreased liver uptake and increased urinary excretion reflects impaired liver function. Uptake rates, time-to-peak, T1/2 peak values, and functional liver volumes can be derived from dynamic image analysis.6163 The clinical use of this tracer is mostly described in liver transplanted patients. In addition, case series have been published on its value in patients with primary sclerosing cholangitis.64,65These studies conclude that this technique is capable of assessing different aspects of liver function for the total liver, as well as for individual segments. Dynamic imaging and serial scanning provides quantitative physiologic data that may be useful in the longitudinal follow-up of patients with sclerosing cholangitis. Nevertheless, although a role in the assessment of biliary sclerosis because of chemotherapy could be suggested, data is not available because of the fact that ultrasonography is usually the procedure of choice.

99mTc–labeled GSA was developed to visualize and quantify the binding to asialoglycoprotein receptors expressed on hepatocytes, but not on other cells in the human body. This receptor consists of two subunits (type 1 and 2 hepatic lectins) and is expressed on the sinusoidal surface, close to the extracellular space of Disse.66 After binding to the receptors, asialoglycoproteins are taken up via endocytosis and thereafter delivered to lysosomes where they are degraded. In patients with chronic liver disease, the expression of the receptors is diminished and, consequently, it was expected that 99mTc-GSA could be a noninvasive technique to assess liver function. Initial studies demonstrated a good correlation with the Child-Pugh classification or other laboratory tests, such as bilirubin, antithrombin III, or prothrombin time.67,68 Several parameters from dynamic scintigraphy have been described: Modified receptor index, hepatic uptake ratio, blood clearance ratio, blood clearance constant, and maximal removal rate seem to be good estimates of the total liver function.69,70 The advantage of this tracer is that the uptake is not directly affected by elevated bilirubin levels. Its use has been extensively studied in the preoperative assessment of liver function and postoperative liver regeneration patients.7173 Extrapolating from these data, 99mTc-GSA may have a role in differentiating reversible from irreversible liver damage. This was demonstrated in a study by Urganci et al.74 in which 99mTc-GSA uptake and subsequent ­endocytosis of labeled asialoglycoproteins distinguished between ­functional regions of hepatocytes and nonfunctional zones. In ­chemotherapy-induced liver toxicity, however, it has not been applied.

CHEMOTHERAPY-INDUCED BONE MARROW TOXICITY

Bone marrow is a compartment of bone in which hematopoietic cells are produced. Hematopoietic stem cells (HSCs) reside in ­specific areas of this bone marrow. HSCs are able to proliferate and differentiate into different cell lineages, such as the myeloid, erythroid, and megakaryocytic lineages.75 HSCs, however, are also capable of self-renewal to keep the number of HSC constant over time. This complete process and ultimate balance between these two aspects depend on many factors and can, therefore, be easily distorted by chemotherapeutic agents. Consequently, hematologic toxicity is usually the limiting factor in chemotherapy. Indeed, depressed bone marrow reserve before initiating anticancer therapy hampers the use of cytotoxic agents, thus influencing overall morbidity and mortality. The induction of bone marrow disorders by chemotherapy can be amplified by the additional use of radiotherapy. These disorders may occur as acute effect during treatment, but also months to years after completing treatment. In general, acute side effects will show recovery after cessation of anticancer treatment but it may also go on to other bone marrow disorders.

Types of Bone Marrow Toxicity

Myeloproliferative Diseases

Myeloproliferative disease is a bone marrow disorder that resembles a proliferation process of one or more cell lines resulting in an increased production of granulocytes, erythrocytes, or cells of the megakaryocytic cell line. Usually a combination of increased proliferative cell lines is observed. For example, polycythemia vera is commonly associated with a mild increase in white blood cell (WBC) counts and myelofibrosis is frequently associated with an increase in immature WBC. Despite the increased proliferation, the cells show a relatively normal maturation at the initial stage of the disease. However, myeloproliferative diseases usually show a stepwise progression that leads to bone marrow failure due to myelofibrosis. The clinical outcome depends on the cell lineage involved in this myeloproliferative disease. The correlation between cancer treatment and induction of myeloproliferative disorders has been reported in the literature.76,77 Therapy-related myeloid neoplasms are preferentially observed following the treatment with cytostatic drugs such as alkylating agents, topoisomerase II inhibitors, and antimetabolites but have also been described in patients receiving intensive immunosuppressive treatment, radiotherapy, or treatment with radioiodine.7881

Myelodysplastic Syndromes

Myelodysplastic syndromes are bone marrow disorders in which dysplasia and ineffective hematopoiesis in one or several cell lineages can be observed. Differentiation into subgroups is based on cytology and cytogenetic findings and typical groups are refractory anemia and myelodysplastic syndrome. The primary form of this syndrome predominantly occurs in older adults. The secondary form of myelodysplastic syndrome is often a result of chemotherapy and/or radiotherapy. This form is not related to aging and tends to be more severe than the primary form. The clinical presentation depends on the cell line involved in the syndrome but is usually predominated by anemia. The end stage of this syndrome, however, results in pancytopenia.82

Aplastic Anemia

This is characterized by an immune-mediated destruction of the stem cells resulting in an extremely low red blood cell count. It is a life-threatening disorder with a high mortality rate.83,84 In approximately 50% of the patients the etiology is unknown. Exposure to certain drugs such as chloramphenicol, carbamazepine, and quinine, however, are associated with aplastic anemia. The clinical presentation is related to anemia, thrombocytopenia, and/or granulocytopenia.8588

Hemolytic Anemia

This hematologic disorder is not located in bone marrow but is a result of an abnormal breakdown of red blood cells in either blood vessels or an overactive spleen. It can be either immune or nonimmune mediated or inherited. With the use of immune-modulatory agents in cancer treatment, an increased risk of this phenomenon is observed. Clinical symptoms are related to anemia, such as fatigue and palpitations, whereas jaundice can be the first sign as a result of increased hemoglobin degradation.8992

The Role of Nuclear Medicine in the Detection and Follow-up of Bone Marrow Toxicity

Regular peripheral blood counts and, occasionally, bone marrow biopsies are standard techniques to evaluate the status and recovery of chemotherapy-induced bone marrow toxicity. Despite the fact that these procedures are easily performed in clinical practice, they are regarded as indirect methods of systemic marrow status, limited by sampling errors and influenced by inflammatory changes. A complete overview of status of the marrow is achieved with nuclear medicine techniques. Because of the costs, most of these techniques are not routinely applied in the acute phase of chemotherapy-induced bone marrow toxicity. PET tracers, however, can provide quantification and give better estimates of the bone marrow status.

The reticuloendothelial system (RES) is the compartment most readily imaged. This compartment consists of phagocytic cells that can be found in the reticular connective tissue and is imaged with radiolabeled colloids. 99mTc-sulfacolloids and 99mTc-nanocolloids are most commonly used. After intravenous administration, both tracers are rapidly cleared from the plasma and taken up by the RES. Nanocolloids are smaller in size than other colloids and, consequently, the uptake is high in bone marrow. See Table 33.2. The normal pattern of bone marrow scintigraphy varies with age. In adults, there is homogeneous uptake in the axial skeleton and the proximal long bones. In younger patients, activity is seen in the juxta-articular areas.93 Colloid scintigraphy is not used in the follow-up of chemotherapy-induced toxicity because the distribution pattern alone is not useful and quantitation is not readily performed. In patients treated with radiotherapy, however, well-demarcated defects in bone marrow can be observed.

Several tracers are available to image either the erythroid or myeloid bone marrow. Indium-111 (111In) chloride is a tracer that binds to transferrin; marrow uptake probably reflects the distribution of erythropoietic marrow. In patients with myelofibrosis or chemotherapy-induced toxicity, an extension of 111In-chloride uptake can be observed beyond the central skeleton.9496 Increased uptake is seen especially in juxta-articular areas, such as the hips, shoulders, and knees. Severely diminished uptake correlates with a poor prognosis indicating the absence of bone marrow reserve.97,98 Because there is low uptake in erythrocytes and the radiation-absorbed dose is relatively high for a diagnostic study, 111In-chloride is not generally used to assess bone marrow. Iron-52 (Fe-52), a cyclotron-produced PET tracer, identifies erythroid bone marrow by incorporation into hemoglobin. There are no data on its use in chemotherapy-induced abnormalities.

Radiolabeled WBCs are also useful as bone marrow tracers. Labeling can be performed with 99mTc, 111In, or 99mTc–labeled ­monoclonal antigranulocyte antibodies. Radiolabeled WBCs and antibodies have been used to identify granulocytic marrow elements in the bone marrow but it is difficult to distinguish between specific WBC localization and trapping by the RES. Consequently, imaging the bone marrow by these techniques is comparable to radiocolloids. Antibodies identify an antigen on both circulating WBCs and mature myeloid cells in the marrow.99 With this tracer, bone marrow can be evaluated by identifying the distribution pattern, identification of focal lesions, and calculating uptake ratios. In patients with myelodysplastic syndrome, focal defects in uptake can be visualized whereas in myelofibrosis, diffusely decreased uptake is seen.93 Because of the cumbersome labeling techniques of WBCs and the costs of radiolabeled antibodies, its use in the assessment of bone marrow toxicity and prognosis has been limited.

18F-FDG PET is routinely used in the evaluation of many oncologic and infectious diseases. Uptake of FDG in hematopoietic marrow and the uptake pattern show great variation with age and the level of marrow function at the time of PET. Diffuse uptake may resemble bone marrow activation by either the presence of malignancy or hematopoietic disease but may also result from recent chemotherapy or the use of granulocyte-(macrophage) colony-stimulation factors (G-CSF or GM-CSF).100102 Consequently, 18F-FDG PET appears to be a sensitive tool to visualize bone marrow stimulation and to assess the reserve capacity. In case of myelodysplastic syndromes, diffusely increased activity is usually observed in the skeleton. In contrast, decreased uptake throughout the skeleton in combination with an increased uptake in the liver and spleen may be indicative for myelofibrosis.103 Although 18F-FDG PET is not used on a routine basis to assess chemotherapy-induced bone marrow disorders, it has to be recognized that the marrow pattern and activity is observed on follow-up PET scans performed to monitor treatment outcome or to assess tumor recurrence.

The use of 3-deoxy-3-fluor-18 fluorothymidine (18F-FLT) in clinical practice is increasing. Thymidine, a pyrimidine analog, is incorporated into DNA and after phosphorylation by TK1 remains trapped in the cell and can, therefore, be regarded as proliferation marker.104 Because of high proliferation activity in bone marrow, high uptake of 18F-FLT is observed. In patients with leukemia, diffuse increased uptake is seen, whereas in case of myelodysplastic syndrome and myeloproliferative disorders, expansion of the bone marrow compartment is seen. Following G-CSF or GM-CSF administration increased proliferation is expected and generalized increased uptake is observed. In contrast, in myelofibrosis, bone marrow expansion is observed but usually in combination with decreased uptake.105,106 Finally, radiotherapy either with or without chemotherapy affects bone marrow 18F-FLT uptake. Agool et al.107 found diminished uptake at irradiated sites consistent with 18F-FDG; 18F-FLT can be used to assess bone marrow reserve as well as to assess long-term side effects of chemotherapy and/or radiotherapy. Quantification of local or regional uptake provides noninvasive follow-up of bone marrow disorders induced by chemotherapy. Other tracers that can also be used to visualize proliferation, such as Carbon-11 (11C) methionine (i.e., amino acid activity) and 11C- or 18F-choline (i.e., phospholipid metabolism in cells), may have the potential to noninvasively assess bone marrow function.108111 Their role is, however, still hypothetical without confirmation in clinical practice.

CHEMOTHERAPY-INDUCED CARDIOTOXICITY

Several chemotherapeutics have been associated with an increased risk of cardiovascular complications.2,112 Cardiotoxicity is roughly defined as damage to cardiomyocytes or the conductive system of the heart resulting in (sub-)acute or chronic events depending on the development of the actual injury. In the acute setting, complications may include hypertension, repolarization abnormalities, arrhythmias, pericarditis, and ischemia whereas chronic events are generally characterized by a decline in ventricular function that may develop into dilated cardiomyopathy (CMP). In general, two major groups can be defined based on the histopathologic processes: (1) irreversible cardiovascular damage (type I) related to an actual loss of cells and (2) reversible damage (type II) as a consequence of transient cellular dysfunction. Unlike type I effects, which are dose dependent, type II effects are not dose related, do not affect all patients and when they occur, there is a broad range of clinical severity but is rarely lethal. Assignment of these diagnoses is not always straight forward as type II injuries can, when left untreated, also result in a cellular loss and ventricular ­dysfunction.112,113

The fact that cardiac complications are exceptionally diverse is in part explained by the so-called “multiple hit” theory.114 Prior to chemotherapy, all individuals have a risk for developing cardiovascular events that depends on genetic factors (e.g., predisposition), cardiovascular risk factors (i.e., diabetes, hypertension, hyperlipidemia, elevated body mass index, etc.), and certain lifestyle choices (i.e., smoking, reduced physical activity, diet, etc.). The likelihood of developing cardiotoxicity during or following anticancer therapy increases depending on the type of therapy and the treatment regime. Furthermore, the limited ability of myocyte regeneration affects the capacity of these cells to cope with subsequent stressors such as hypertension, coronary artery disease, radiation therapy, or other cardiotoxic drugs. Accordingly, combined regimens wherein chemotherapeutics, targeted therapies, and thoracic radiation are given concurrent or subsequent, commonly show the highest incidence of cardiotoxicity. In the following section, the main cardiotoxic entities, left ventricular dysfunction, cardiovascular ischemia, thromboembolic events, hypertension, and arrhythmias are described.

Mechanisms of Toxicity

Left ventricular dysfunction is one of the most profound manifestations of cardiotoxicity. It is defined as a (sub-)clinical reduction of ejection fraction that is often, but not necessarily, accompanied by symptoms of congestive heart failure (CHF), such as tachypnea, a gallop rhythm, tachycardia, and pulmonary edema. However, a consensus on an explicit definition and classification system of cardiac dysfunction had not been established. In an oncologic setting, two types of dysfunction can be discriminated, a transient decline in function (type II cardiotoxicity) and a persistent decline (type I cardiotoxicity). This latter type is recognized as a serious source of morbidity and mortality on long-term follow-up.

Ever since the introduction of anthracyclines (doxorubicine, epirubicine, idarubicine) in the 1960’s, they have been associated with dose-dependent, progressive, nonreversible cardiac dysfunction.115,116 Multiple pathways, ultimately leading to DNA damage and free radical formation, are believed to be responsible for the antineoplastic effects of anthracyclines. Free radical formation is thought to induce irreversible, structural damage to the myocytes. Myocardial biopsies after anthracycline therapy show (1) a loss and disorganization of myofibrils, (2) enlargement of the endoplasmatic reticulum and mitochondria, and (3) increased numbers of vacuoles and lysosomes.116 Certain metabolites of anthracyclines have a poor clearance rate from cardiomyocytes, thus inducing long-lasting changes in cellular architecture. These structural changes are directly associated with cellular calcium-ion transport, energy homeostasis, and proapoptic pathways in myocytes, consequently, increasing myocardial stiffness and reducing conductance. In term, this will initiate a vicious circle of distorted contractility–relaxation cycle, endothelial dysfunction, ventricular hypertrophy, myocardial ischemia, and persistent ventricular dysfunction.

Even low cumulative (i.e., lifetime) dosages, doxorubicin and epirubicin, have been shown to induce dilated CMP and CHF at long-term follow-up.117,118 Acute events occur infrequently (less than 1% of the patients) and manifest as a reversible decline in contractility. The incidence of anthracycline-induced cardiotoxicity is dose dependent, in which complication rates increase disproportionally for high dosages with an applied cumulative dose limit of 400 to 500 mg/m2 for doxorubicin and 720 mg/m2 for epirubicin.119 The 5-year incidence of CHF in adjuvant anthracycline regimes has been implicated in 2% to 20% of the patients. Despite the development of new generations of anthracyclines which have resulted in a lowered incidence of cardiotoxicity incidence, ventricular dysfunction is still a serious side effect.

Nonanthracycline-based therapies like alkylators (e.g., cyclophosphamide, ifosfamide, cisplatin), microtubuli inhibitors (e.g., paclitaxel, docetaxel, vincristine), and antimetabolites (e.g., clofarabine, fluorouracil, capecitabine) have a lower incidence of ventricular dysfunction compared to anthracyclines. A study of Goldberg et al.120 showed a dose-dependent incidence of 7% to 28% for cardiac events after cyclophosphamide therapy including pericardial effusion, pericarditis, ventricular dysfunction, and heart failure. Paclitaxel and docetaxel have also been associated with an increased risk of developing heart failure (incidence 2% to 8%). Ventricular dysfunction following nonanthracyclines is primarily triggered by endothelial injury or coronary spasm. Persistent coronary injury may over time lead to diastolic dysfunction, increasing the risk of myocardial infarction.121 In combined treatment regimen, an increase in the incidence of cardiac complications after nonanthracyclines has been shown which is consistent with the “multiple hit theory.”116,122 Although these combined regimes are associated with progressive cardiac dysfunction, the precise pathogenesis of cardiotoxicity has not been elucidated.

Ventricular dysfunction has also been regularly related to therapeutics that target the human epidermal growth factor receptor type 2 (ErbB2, or also known as HER2).123 Stimulation of this ­receptor pathway promotes cell proliferation and opposes cellular ­apoptosis. In 20% to 30% of breast cancer patients, overexpression of this pathway is associated with aggressive tumor phenotypes. In the cardiovascular system, the ErbB-Neuregulin-1 signaling pathway is related to fetal cardiac development, repair after cardiovascular stress, angiogenesis, and myofibril organization.123,124 Deletion of certain ErbB genes in mice has consistently resulted in the development of CMP.125Trastuzumab (an anti-ERbB2 monoclonal antibody)-related cardiotoxicity presents as an asymptomatic decline in cardiac function.

The incidence seems to be higher in longer therapeutic regimes.126128 The exact molecular pathways that induce cardiotoxicity after ErbB2 inhibition are highly complex, however, and remain largely unclear. Combinations of anthracyclines and trastuzumab adversely affect the risk of developing cardiac dysfunction, from approximately 10% for anthracycline monotreatment to approximately 30% in the combined regimes. Lapatinib (a kinase inhibitor that inhibits both ERbB1 and ERbB2), like trastuzumab, has also been used in patients with metastatic breast cancer overexpressing ERbB2. It appears that incidence of cardiac symptomatic or asymptomatic dysfunction related to lapatinib is lower (around 1%) than those described in trastuzumab regimes. In this instance also, the main symptom was a decline in systolic left ventricular function.129 It has been indicated that interruption of either trastuzumab or lapatinib after a significant decline in ventricular function may result in normalization of function in many patients.128,130 Although this observation suggests that the cardiotoxicity of ErbB2 inhibitors is reversible, long-term follow-up studies are needed.

In a recent study by Russo et al.,131 it has been hypothesized that renal dysfunction may increase the myocardial sensitivity to potentially cardiotoxic chemotherapeutics such as trastuzumab and anthracyclines. The renal-cardiac systems are connected by the RAS which controls fluid volume, blood pressure, and cardiac function. Overactivity of this hormonal system has been associated with both cardiac and renal diseases, and generally leads to an imbalance in reactive oxygen species and nitric oxide, overactivation of the sympathetic nervous system, and activation of the immune system. In turn, oxidative stress and activation of the immune system are known to affect left ventricular function adversely and may hasten the induction of renal dysfunction.

Cardiovascular ischemia and thromboembolic events are regularly the result of endothelial cell injury. These specialized cells coordinate important activities such as coagulation, permeability, immune response, inflammation, and angiogenesis. Consequently, relatively small abnormalities in the endothelial lining can develop into coronary atherosclerosis, myocardial ischemia, and fibrosis. Though angina-like complaints are an important indicator of early coronary damage, in many patients coronary damage initially manifests as a subclinical disease.

Fluorouracil, a pyrimidine base antimetabolite associated with thymidine syntheses, has been associated with angina pectoris, vasospasm, arrhythmias, pericarditis, myocardial ischemia, and even cardiogenic shock.132 Angina-like symptoms and myocardial ischemia have also been reported in capecitabine use (also a pyrimidine antimetabolite) in various case studies.133,134 Pathophysiologic mechanisms such as coronary vasospasm, thrombosis, endothelial dysfunction, and autoimmune activation have all been proposed as possible causes. Still, the underlying mechanisms of chemotherapy-induced ischemia and incidence of these complications have yet to be confirmed. However, generally these events are thought to appear hours or days after infusion and are considered to be reversible, thus suggesting a type II cardiotoxicity. Ischemic ECG changes and elevations in serum cardiac markers (i.e., arterial natriuretic peptide and troponin I) are frequently observed.135 In later stages, myocardial ischemia and infarction may lead to a permanent decline in cardiac function. These complications can also be observed with other nonanthracycline chemotherapeutics such as cisplatin, paclitaxel, and docetaxel.136 Consequently, it has been advised to discontinue chemotherapy if patients develop angina-like symptoms.

New therapies that inhibit tumor angiogenesis by affecting the VEGF signaling pathway are also associated with ischemic events.137 Within the cardiovascular system, the VEGF pathway is not only essential for vessel growth but also affects the formation, maturation, and migration of hematologic cells, and regulates permeability of microvessels. In the myocardium, upregulation of VEGF is associated with conditions of cardiac stress and will initiate repair.138,139 Sorafeni and sunitinib are both multikinase inhibitors that not only target VEGF but also platelet-derived growth factor (PDGF), stem cell factor Kit (tyrosine kinase) receptor, and hypoxia-­inducible factor (HIF) pathway.140 Hence, multikinase inhibitors are actually not single-targeted drugs but rather affect an array of physiologic and pathologic cellular pathways that are not limited to tumor genesis alone. The HIF pathway plays an important physiologic role in regulating myocardial remodeling and vascular permeability after acute or chronic myocardial ischemia. Consequently, inhibition of these cascades is related to a reduction in capillary density, ventricular dysfunction, fibrosis, and eventually heart failure. Although the incidence of cardiovascular ischemia associated with the anti-VEGF monoclonal antibody bevacizumab is still reasonably low, arterial thrombosis has been described.137 As with the other targeted drugs, long-term follow-up studies are needed.

Hypertension is often present in cancer patients and may well be one of the most frequently observed comorbidities in therapeutics that interfere with angiogenesis.141 Although epidemiologic data concerning hypertension is conflicting, roughly one in four patients is believed to develop hypertension. A study by Maitland et al.142 suggested that if the systolic blood pressure is over 200 mm Hg, or diastolic pressure is over 100 mm Hg, discontinuation of targeted therapies like VEGF inhibitors should be considered. Elevated blood pressure due to inhibition of the VEGF pathway is probably related to increased vascular stiffness, disturbed endothelial function, and decreased production of vasodilators like nitric oxide.137,143 The incidence and severity of a rise in blood pressure depends on the type of antiangiogenic agent, treatment regime, and underlying comorbidities. Incidences of 8% to 45% for high-grade hypertension associated with VEGF inhibitors have been reported. In combined treatment regimens, the incidence can rise to even 90%.144,145 Interpretation of these data, however, can be difficult as definitions, classification criteria, and hypertension control vary among trails. Other, less frequently observed side effects of VEGF inhibitors include thromboembolism, ischemia, proteinuria, CHF, and supraventricular tachycardia.137 Although some of these complications can be directly related to poorly controlled hypertension, other signaling pathways may also be involved.

Arrhythmias in cancer patients can be caused by pre-existing cardiac conditions or radiotherapy which induces fibrosis within the cardiac muscle resulting in disturbances in the conduction system. These are common risk factors in the development of arrhythmias during chemotherapy. The arrhythmias attributed to certain chemotherapeutic agents often manifest in an acute or subacute setting as prolongation of the QT interval, (supra-)ventricular arrhythmias, or ventricular repolarization abnormalities on electrocardiography (ECG). Paclitaxel is well known to induce reversible asymptomatic bradycardias even in patients without pre-existing cardiac conditions supposedly related to either a direct effect on the cardiac conductive system, on the autonomic control or because of release of histamines in a hypersensitivity reaction. The reported incidence of paclitaxel-related bradyarrythmias varies greatly in the literature from around 0.1% to 30%.136,146

Arsenic trioxide has been effectively used in patients with acute promyelocytic leukemia. It is known, however, to induce life-­threatening arrhythmias. ECG abnormalities such as QRS widening, ST depression, QT prolongation, torsade de points, atrioventricular block, and tachycardia have all been described in the literature. Barbey et al.147 described the effects of arsenic trioxide on the conductive system in 99 patients. In 68% of the patients, a gradual prolongation of the QT interval was observed. Two patients developed clinically significant arrhythmias during the study. In general, QT prolongation is associated with an increased risk of developing fatal cardiac arrhythmias including torsade de pointes, and sudden death. Therefore, appropriate monitoring of ECG abnormalities and electrolyte disturbances has been advised during arsenic trioxide therapy.

Targeted kinase inhibitors such as angiogenesis inhibitors and the ERbB2 inhibitor lapatinib can also cause prolongation of the QT interval. For the multikinase inhibitors, sunitinib and sorafenib, a dose-dependent prolongation of the action potential has been demonstrated in a preclinical setting in canines and monkeys. Although in a preclinical setting, QT prolongation has not been demonstrated for lapatinib, it has been described in a clinical setting.129 The incidence of these side effects in a clinical setting needs to be established.

Thoracic Radiotherapy

Although this chapter primarily focuses on the effects of chemotherapeutics, radiotherapy is a major factor in the “multiple hit” theory of cardiotoxicity development in an oncologic setting. The adverse effects of thoracic radiotherapy on the cardiovascular system have been demonstrated in long-term survivors of breast cancer, esophagus carcinomas, lymphomas, and childhood cancers in which thoracic irradiation has been performed.148151 In breast cancer, and especially left-sided breast cancer, irradiation has shown to increase the prevalence of (acute) myocardial infarction, pericardial diseases, and valvular heart disease. CHF, valvular heart disease, and pericardial diseases were frequently observed in the population with total fractionated doses >15 Gy. The aggregated incidence of radiation-related cardiac disease is estimated to be 10% to 30% 5- to 10-year posttreatment.2

At therapeutic dosages, cardiotoxicity is mainly related to inflammatory and thrombotic alterations in endothelial cells, leading to structural abnormalities within the microcirculation. High cardiac dosages (single dose >15 Gy, fractionated dose >40 Gy) may even result in acute pericarditis.152 The incidence of these events is primarily influenced by concurrent systemic therapies, irradiation technique, fractionation, and presence of pre-existing cardiovascular risk factors (i.e., smoking, reduced physical activity, elevated body mass index, diabetes, hypertension, hyperlipidemia, etc.). Modern irradiation techniques such as intensity-modulated radiotherapy (IMRT) and computer-based dose optimization models are thought to result in a lower risk of complications, as they can reduce the absorbed dose in critical organs while still assuring an optimal tumor dose. These principles are described in detail by the “International Commission on Radiation Units and Measurements” (ICRU).153

The Role of Nuclear Medicine in the Detection and Follow-up of Cardiotoxicity

Over the last decade, several clinical guidelines emphasized the need for monitoring cardiotoxicity.2,119,154,155 Timely detection of cardiotoxicity allows initiation of cardioprotective medication such as renin–angiotensin inhibitors, calcium channel blockers, diuretics, nitrates, and β-blockers at an early stage. Several clinical parameters have been identified that can be used for periodic evaluation of various aspects of cardiac performance prior to, during, and after therapy. These include physical assessment (i.e., ECG, blood pressure, exercise testing), cardiac output measures (i.e., systolic and diastolic volume, stroke volume, ejection fraction), biomarkers, and cellular metabolism imaging. In the last decade, these latter two methods have been used more frequently to monitor cardiotoxicity in clinical trials. Cardiac troponin measurements to identify (sub-)acute damage to cardiomyocytes are recommended because they are highly specific and highly sensitive for this purpose.156 Nuclear imaging methods still have a prime role in both the detection and follow-up of cardiotoxicity (Table 33.2).

Radionuclide Ventriculography

Serial assessment of left ventricular function is at present the main parameter to diagnose cardiotoxicity during and after anticancer treatment especially in anthracycline-based regimes. Several ­imaging-based techniques can be used to determine ventricular function, of which gated equilibrium radionuclide ventriculography (e.g., multiple-gated acquisitions also known as MUGA) is the prime scintigraphic method. The key principle of ventriculography is to image the blood pool over time with either 99mTc-labeled erythrocytes or human serum albumin (HAS). Though erythrocytes can be labeled in vitro and in vivo, each procedure requires the so-called “pretinning.” In this process, stannous pyrophosphate is used to increase cell-labeling efficiency. Five to ten minutes after tracer injection, planar images are acquired in a left anterior oblique (LAO) projection.157 Concordant registration of an ECG signal allows for the allocation of counts into specific intervals within the cardiac cycle. See Figure 33.1.

Quantitative analysis of cardiac function entails detection of the boundaries of the left and the right ventricular blood pool, which correspond with the endocardial borders. Based on these measures, a time versus count density curve can be derived that incorporates information on cardiac function (Fig. 33.2). Determinants of ventricular function include systolic volume, diastolic volume, filling rates, emptying rates, stroke volume (diastolic volume minus systolic volume), cardiac output (stroke volume times heart rate), and ejection fraction (stroke volume divided by diastolic volume). Commercial software systems are available for semiautomated evaluation.

Normal values for the left ventricular ejection fraction (LVEF) based on ventriculography range from 55% to 75%, with an LVEF less than 50% indicating a lowered cardiac function. A decline below 50%, or a drop is LVEF of more than 10% compared to baseline, can be considered cardiac dysfunction.119 Seidman et al.126 proposed a criteria to diagnose cardiac dysfunction in trastuzumab studies including (1) CMP characterized by a decline in LVEF (global or septal), (2) signs or symptoms of CHF, (3) a decline in LVEF of at least 5% to less than 55% accompanied with signs or symptoms of CHF, or a decline in LVEF of at least 10% to less than 55% without symptoms. In general, this scintigraphic measure of LVEF is considered a robust and observer-independent measure although its value partly depends on the software system used.157 The duration of follow-up, especially in patients that are nonsymptomatic, is unclear. Whether the LVEF is the most appropriate measure for the early detection of left ventricular dysfunction is controversial. A decline in systolic function, and hence LVEF, is considered a late sign of cardiotoxicity, because of the physiologic capacity of the heart to compensate for regional myocardial damage. In the case of type II cardiotoxicity, detection of a reduction in cardiac function requires that actual irreversible damage to the myocardium has already occurred. Markers that focus on specific aspects of cardiac function such as regional contraction patterns and filling or emptying rates might provide more specific information.135,158,159

FIGURE 33.1. Principle of electrocardiography gating using 10 intervals or gating frames. Based on the time interval between subsequent R-peaks the duration in milliseconds of a single frame is determined. The detection of an R-peak, which roughly matches with end-diastole, triggers the system to detect counts allocating them to frame one. Subsequently, counts are allocated to frames two, three, four, and so on until a new R-peak is detected. Eventually, all counts in frame one over many heart cycles are summed resulting in a single image for frame one. This process is repeated for all frames, creating a set of images at different moments within the cardiac cycle.

Myocardial Perfusion Imaging

Radionuclide myocardial perfusion imaging may also have a role in the evaluation of drug-induced cardiovascular ischemia and dysfunction.160162 Cardiac perfusion can be evaluated by both SPECT- and PET-based tracers. Since PET, however, involves more complex imaging procedures, relative higher costs and a limited number of large multicenter studies prepared to perform perfusion PET, SPECT imaging is still the predominant technique to assess cardiac perfusion and function in the clinical setting. SPECT has proven to be highly sensitive to detect abnormal myocardial perfusion patterns while also providing information on left ventricular function.165

Currently, the tracers used for myocardial perfusion SPECT (MPS) are either Thallium-201 (201Tl) or 99mTc based. 201Tl chloride exchanges between inter- and intracellular space by the Na/K-pumps of the myocytes. Therefore, accurate timing of especially the stress images is very important. The compounds 99mTc-tris(1,2 bis(dimethylphosphino)ethane), [99mTc-tetrofosmin], and 99mTc-hexakis-2-methoxy-2-methylpropyl isonitrile, [99mTc-sestamibi], are both lipophilic cations that passively diffuse across myocyte cell membrane. Because of their relatively positive charge, they remain trapped in mitochondria of viable myocytes. Because of their widespread availability, shorter half-life, and more favorable energy peak of 99mTc, at present, these 99mTc compounds are generally being used as an alternative to 201Tl.166

To provoke an ischemic response in areas with abnormal coronary vasculature, stress is applied to the cardiac system, thus increasing the overall oxygen demand. In the presence of diseased coronary vasculature, the augmentation of blood flow is inadequate, resulting in regional ischemia. In the resting state, coronary blood flow will return to baseline and the supply–demand ratio is restored. As the distribution and accumulation of perfusion tracers is highly related to the regional coronary blood flow, a difference in uptake patterns after stress and in resting state reveals areas of ischemia (i.e., reversible defects). Areas that show reduced tracer uptake in both poststress and rest images (i.e., fixed defects) represent infarcted or scarred regions. This difference in stress-rest blood flow in the presence of coronary artery disease is the principal value of MPS. See Figure 33.3. All regional abnormalities in perfusion are defined with respect to the maximal tracer uptake in the entire myocardium and not as an absolute measure. Accordingly, each area of diminished uptake should be reported with respect to severity, location, and extent.166

FIGURE 33.2. Radionuclide ventriculography images of a patient at baseline and after trastuzumab treatment in end-systole (left) and end-diastole (right). The quantitative evaluation of all frames of the cardiac cycle indicates a decline in left ventricular ejection fraction from 60% at baseline to 47% after the first cycle of trastuzumab. This decline is primarily explained by an inadequate systolic function, as can be seen in the curve on the graph. EDV, end-diastolic volume; ESV, end-systolic volume.

FIGURE 33.3. Two-dimensional representations of slices perpendicular through the central axis of the left ventricle (e.g., oblique views). Arrows indicate perfusion defects in the poststress acquisition (upper), whereas these defects are normal in the rest acquisition (bottom). This typical distribution is indicative of ischemic heart disease. MPS, myocardial perfusion SPECT.

Relevant variations within MPS protocols have been described in the recent guidelines.166 The basic elements of the protocols include stress induction, tracer administration, and acquisition. Stress is preferably induced by bicycle or treadmill exercise. When a patient is not able to exercise or hemodynamic response is not sufficient, the so-called pharmacologic stress can be utilized. At peak stress the tracer is injected intravenously. Images are acquired 30 minutes to 2 hours after tracer injection. The majority of the MPS studies are acquired using ECG gating to obtain functional evaluation of the heart.167 The principles of gating are similar to those described for radionuclide ventriculography.

Using specific software systems to delineate the endo- and epicardial borders, functional indices can be derived from these images. Frequently, an increased specificity of gated MPS is reported which can be assigned to the more effective characterization of abnormal perfusion patterns. Areas with moderate-to-severe ischemia or areas with infarction will display some degree of regional dysfunction. Consequently, combining visual interpretation of perfusion patterns with functional indices increases the prognostic value of MPS.168,169

Evaluation of Myocardial Adrenergic Innervation

An increase in adrenergic drive is one of the cardiac compensatory mechanisms to preserve adequate cardiac output by increasing heart rate, contractility, and conduction. In several cardiovascular diseases, the circulating levels of norepinephrine, and hence, myocardial adrenergic neuron activity is upregulated. Recently, it has been postulated that adrenergic denervation precedes significant perfusion defects and cardiac dysfunction.170,171 Given that neurons are more sensitive to ischemia than myocytes, microvascular dysfunction may lead to denervation and eventual ventricular dysfunction. Accordingly, adrenergic denervation may also be present in the early stages of chemotherapy- or radiotherapy-induced cardiotoxicity.

A growing number of tracers have come up to assess various pre- and postsynaptic processes. However, the majority of the PET tracers are being used in a research setting. Some (i.e., 11C noradrenaline and 11C catecholamine analogs) even require an on-site cyclotron. At present, 123I-MIBG is the only clinically approved SPECT radiotracer available to assess adrenergic nerve function. 123I-MIBG resembles the neurotransmitter norepinephrine with respect to its molecular structure, synaptic uptake, and intracellular storage. Figure 33.4 provides a schematic overview of the kinetics of 123I-MIBG in comparison with norepinephrine. An 123I-MIBG acquisition protocol consists of images obtained within minutes (early) and several hours after tracer injection (delayed).172 Anterior planar images are acquired to assess global 123I-MIBG uptake and washout (i.e., the difference between early and delayed accumulation) from the cardiac region in relation to the nonspecific 123I-MIBG uptake. To quantify the differences in 123I-MIBG uptake, regions of interest are placed around the heart and in mediastinum. Early heart-to-mediastinum (HM) ratio reflects the blood flow and initial uptake of 123I-MIBG by the uptake-1 mechanism (Fig. 33.5), whereas the washout rate (WOR) is considered a measure for the integrity and activity of the neurons. Although the regional assessment of myocardial innervation using SPECT is less established than planar imaging, it might be beneficial when innervation is heterogeneously affected.

FIGURE 33.4. The pathways shared by both norepinephrine (NE) and iodine-123 metaiodobenzylguanidine (123I-MIBG) are shown in black. NE is synthesized within postganglionic neurons by a series of enzymatic steps and eventually stored in vesicles. Once released, NE will interact with adrenergic receptors, enter the neuron (uptake 1), enter the myocytes (uptake 2), or diffuse into the bloodstream. Intravenous-administered 123I-MIBG disperses through the bloodstream and will enter the neuron by uptake-1 pathway, whereafter it is stored in the vesicles and coreleased with NE after nerve excitement. These processes will result in a physiologic washout of 123I-MIBG from the neurons over time. COMT, catecholamine O-methyl transferase; MOA, monoamine oxidase.

FIGURE 33.5. Normal early and delayed iodine-123 metaiodobenzylguanidine (123I-MIBG) uptake in a patient with diabetes but without any other cardiovascular risk factors. In this instance early heart-to-mediastinum (HM) ratio was 1.91 and the delayed HM ratio was 2.18. Moreover, physiologic uptake of 123I-MIBG can be seen in the liver, thyroid gland, and lungs. In severely abnormal 123I-MIBG distributions, the heart will have an intensity that is visually roughly similar to the mediastinum, with delayed HM ratios ranging from 1.2 to 1.6.

Visual heterogeneity in regional 123I-MIBG uptake patterns and lowered HM ratios are associated with several cardiovascular diseases.173,174 Anthracycline-induced heart failure has also been shown to induce abnormalities in adrenergic innervation in various small-scale studies.175177 A decrease in 123I-MIBG uptake is hypothesized to precede a decline in LVEF, thus providing a method for early detection of cardiotoxicity.

Future Cardiovascular Tracers

111In-antimyosin imaging has been used to study the actual degree of irreversible myocardial damage, whether this is caused by apoptosis or necrosis, in an early stage. Antimyosin, a myosin antibody, only binds to the intracellular myosin in myocytes if the cell membrane is disrupted. Studies on doxorubicin-induced toxicity shows that antimyosin accumulation relates to the degree of damage. It precedes deterioration in cardiac function measured by ventriculography.176,178 After discontinuation of anthracycline therapy, antimyosin uptake remained abnormal for a number of years, supporting the hypothesis that type 1 cardiotoxicity develops as a progressive disease over time.

123I-BMIPP (β-methyl-iodophenylpentadecanoic acid) is a fatty acid analog that is used to image the degree of myocardial fatty acid metabolism. In general, an impaired uptake is highly suggestive of regional myocardial dysfunction, even when wall function and perfusion seem normal. Saito et al. found that 50% of the patients on a taxane–carboplatin combination treatment exhibited reduced fatty acid metabolism. Other studies in patients undergoing thoracic radiation and doxorubicin therapies also suggested a relation between a reduction in fatty acid metabolism and cardiotoxicity.179,180

111In-trastuzumab, (111In-DTPA anhydride—trastuzumab), targets the HER2 receptor. Several other radiolabeled antibodies directed against the ErbB pathway have been described in the past. Trastuzumab was the first clinically available in vivo imaging tracer.181 It has been primarily used to evaluate receptor expression in tumors and assess the possibilities of radionuclide therapy in HER2 expressing tumors. Nonetheless, prediction of trastuzumab-related cardiotoxicity is an ongoing challenge mostly because of the relative low incidence of severe toxicity and the long follow-up periods that are required.182,183 Labeling of these monoclonal antibodies with long-lived PET-based isotopes like Zirconium-89 (89Zr), Iodine-124 (124I), and Yttrium-86 (86Y) may provide a tool for quantification of tracer uptake in various therapies. 89Zr-trastuzumab PET imaging has been applied to quantify tracer uptake in various organs, and hence, establish toxicity profiles.184,185

CONCLUSIONS

The role of nuclear medicine in the assessment of toxicity caused by chemotherapy is limited. In lung, liver, renal, and bone marrow, biochemical tests are usually used for the identification and follow-up of toxicity and metabolic dysfunction of organs. In addition, radiologic techniques, such as ultrasonography and HRCT, are mainly used to differentiate between chemotherapy-induced abnormalities and other explanations, such as in lung and liver disorders. In chemotherapy-induced cardiotoxicity, the role of nuclear medicine is established. In this respect, regular measurements of the LVEF are used to monitor cardiotoxic chemotherapy guiding the clinician in the proper direction. Although myocardial MIBG scintigraphy can be used for prognostic stratification in patients with a persistent decreased LVEF, it is still not a common clinical practice.

FUTURE DIRECTIONS

The future role of nuclear medicine in the assessment of toxicity is unclear. As biochemical tests are inexpensive and readily available alternatives, the role of nuclear medicine will remain limited in monitoring chemotherapy. However, as survival rates increase in oncology, chemotherapy-induced long-term side effects and organ failure will become more and more important issues to be assessed at an early stage. MIBG is an important tracer for prognostic stratification in cardiology; other tracers may become available to evaluate lung, liver, and renal toxicity. The focus of research, however, is not in this direction. With the development of new tracers, it may become a useful component of nuclear oncology practice.

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