INTRODUCTION
Neuroendocrine neoplasms (NENs) are a group of tumors that most commonly arise from the gastrointestinal tract and bronchopulmonary system. The incidence is estimated to be 6.9 cases per 100 000 people [1]. Gastro-entero-pancreatic neuroendocrine neoplasms/tumors (GEP NENs/NETs) derive from diffuse endocrine system (DES) cells located in the gastrointestinal tract and pancreas [2]. Neuroendocrine neoplasms of the small intestine (SI-NENs) originate in the midgut and are the third most common subtype of NENs in the gastroenteropancreatic system [3, 4]. GEP NETs are becoming more common across the world, particularly in North America, Asia, and Europe, with North America seeing the largest rise [5].
GEP NENs may be hormonally productive or not release enough hormones and/or biogenic amines. Non-functional neuroendocrine neoplasms are difficult to diagnose since they do not cause clinical symptoms of the disease.
Carcinoid syndrome (CS) is the most frequent paraneoplastic syndrome with a reported prevalence of approximately 19% in the NET patient population [1]. It is characterized by signs and symptoms linked to the hormonal activity of small intestine NENs. Increased synthesis and secretion to the systemic circulation of 5-hydroxytryptamine (5-HT, serotonin) and/or other biologically active substances such as histamine, kallikrein, prostaglandins, and tachykinin lead to the development of the main clinical manifestations of carcinoid syndrome [4, 6]. Circulating hormones can be inactivated by the liver and lungs. However, in patients with liver metastases, production escapes the metabolism [7].
Carcinoid heart disease (CHD) is the most severe consequence of carcinoid syndrome, characterized by fibrotic valve degeneration, particularly in the right heart chambers. Isolated tricuspid valve regurgitation is found in up to 90% of patients; it causes progressive right heart failure and leads to a worsening of the patient’s oncological prognosis [8–10]. CHD is observed in around 40% of patients with carcinoid syndrome [8].
The development of CHD is related to increased morbidity and mortality [11]. Patients with cardiac involvement have a markedly poorer long-term prognosis, with a 3-year survival rate of 31%, which is half that of patients who do not have cardiac involvement [9, 12–14]. Valvular carcinoid heart disease has a short life expectancy without treatment, with median overall survival (OS) of only 11 months in patients with advanced heart failure [15, 16].
All these facts indicate that, in the present era, focusing on accurate patient diagnosis, treatment, and management under the supervision of a multidisciplinary team, are essential to lengthen OS of patients with CHD. In this review article, we present a detailed description of the pathogenesis, clinical and epidemiological aspects, useful biomarkers and imaging modalities, as well as CHD management methods.
EPIDEMIOLOGY
CHD prevalence estimated in patients with carcinoid syndrome varies from 3% to 66% [8, 17–20], but in recent studies, has tended to be lower [17]. This might be due to an increase in somatostatin analogs usage and their impact on circulating serotonin levels, as well as improvements in diagnostic and surgical techniques [21–23].
Pellikka et al. [24] reported that the majority of CHD cases are associated with SI-NENs (72%), followed by lung, large bowel, pancreatic, and appendiceal neoplasms [24]. According to recent Mayo Clinic research, CHD is rare in individuals with bronchopulmonary NENs (1%) [25].
PATHOPHYSIOLOGY
CHD is characterized by formation of endocardial plaques on the surfaces of valve leaflets, chordae, papillary muscles, heart chambers, and in rare cases, the intima of the pulmonary arteries, and aorta [1, 26]. The plaque is formed as a result of dysregulated inflammatory and remodeling processes, which result in an inappropriate extracellular matrix formation, fibrosis, angiogenesis, and calcification, finally leading to structural valve deformation [1, 27].
The pathophysiology of fibrosis in NENs is still unknown, and few advances have been made in recent years toward a better understanding of the underlying processes of fibrogenesis. The effects of serotonin, growth factors, and other peptides released by neuroendocrine tumor cells are hypothesized to cause NEN-associated fibrosis although these substances do not act alone, and pathway crosstalk is critical in the pathophysiology of the fibrotic process [28]. Several growth factors, including transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), basic fibroblast growth factor (FGF2), and connective tissue growth factor (CTGF or CCN2), stimulate fibroblasts both directly and indirectly [7].
Serotonin activity appears to be critical in the development of valvular carcinoid heart disease [15, 28]. Several animal studies have shown that 5-HT can promote cardiac fibrosis and valvulopathy, indicating that it may play an important role in the development of CHD [29–34]. In cardiac valve tissues, various subtypes of serotonergic 5-HT1 and 5-HT2 receptors are present, with subtype 5-HT2B receptors being the most common and playing a crucial role in valve pathology [35, 36]. Activation of the 5-HT2B receptor causes the release of inflammatory cytokines, increases the expression of TGF-β, and has mitogenic effects on fibroblasts and smooth muscle cells [1]. TGF is a serotonin downstream mediator and a big contributor to fibrosis [37].
There is also some evidence that serotoninergic pathways can cause oxidative stress, which can induce fibrosis in heart valves [38].
DIAGNOSIS
Clinical presentation
Cardiac symptoms are commonly subtle until CHD progresses [39]. This frequently leads to a delay in the diagnosis of CHD [11]. Early in the disease course, symptoms such as fatigue and exertional dyspnea may appear [40]. Valve disease does not always progress in a predictable manner, and valves can quickly deteriorate over several months [1]. According to a report by Bhattacharyya et al. [41], only around 57 percent of patients with moderate to severe tricuspid regurgitation will have no or mild symptoms [41].
Typical and common symptoms of right-sided heart failure, such as fatigue, peripheral edema, exertional dyspnea, and cardiac cachexia can occur as a result of progressive CHD. Left-sided cardiac failure occurs in approximately 10% of patients because vasoactive hormones are inactivated in the pulmonary vasculature and do not have a chance to reach the left-sided cardiac components [11, 24]. Patients with right-to-left shunts (patent foramen ovale and atrial septal defects), a poorly controlled disease with high levels of circulating hormones, or bronchopulmonary carcinoid disease are more likely to develop left-sided heart disease due to higher levels of vasoactive hormones reaching the left side of the heart [42].
A physical examination may reveal symptoms of right heart failure, such as increased jugular venous pressure, a palpable right ventricular impulse, peripheral edema, hepatomegaly, and ascites. For cardiac auscultation, murmurs of tricuspid and pulmonary valve regurgitation are common although a systolic murmur of pulmonary stenosis or a diastolic murmur of tricuspid stenosis are seldom observed [23, 41].
CHD is also linked to coronary artery vasospasm, which is rare but may occur in patients with non-occlusive coronary artery disease [43, 44]. Serotonin can stimulate either vasodilatory or constrictive responses depending on endothelial conditions. 5-HT can promote vasoconstriction in dysfunctional endothelium, for example, in individuals with atherosclerotic disease, due to the superiority of vasoconstriction-inducing 5-hydroxytryptamine2 (5-HT2) receptors and lack of 5-HT1 receptors that mediate vasodilation [44–46]. Patients experiencing symptoms of acute coronary syndrome and with a history of carcinoid disease should be evaluated for possible coronary vasospasm [9].
Unfortunately, in CS patients, screening or routine assessment for CHD is commonly missed, resulting in late diagnosis when the disease is already advanced [47]. The proposed screening algorithm for carcinoid heart disease in all patients with NEN (especially SI-NEN) is presented in Figure 1.
Electrocardiogram
In 50% of patients, the electrocardiogram (ECG) is normal or may indicate nonspecific abnormalities including low-voltage QRS complexes and right bundle branch block [11]. Arrhythmias have been described occasionally in the setting of CHD [9]. In the literature, a single patient without ischemic heart disease, presented with carcinoid-induced ventricular tachycardia [48], which was controlled with the use of metoprolol, and two other identified cases were associated with CHD atrial arrhythmias [49, 50]. Serotonin has been linked to paroxysmal ventricular tachycardias and atrial arrhythmias in canine investigations [51]. The possible mechanism is assumed to be enhanced sympathetic activity caused by a vasoactive substance, resulting in cardiac excitation and tachyarrhythmias [48]. Serotonin-induced coronary vasospasm might result in ST-segment elevation [43].
Biomarkers
Many studies have investigated the usefulness of biochemical markers in monitoring cardiac function, CS activity, and oncologic disease state in CHD patients [17, 52–59].
Natriuretic peptides
N-terminal pro-B-type natriuretic peptide (NT-proBNP) is currently the most effective marker used in echocardiographic screening of CS patients and evaluating CHD severity [8]. NT-proBNP is a neurohormone produced by cardiomyocytes in response to increased ventricular wall stress [54]. NT-proBNP at cutoff values of 235–260 pg/ml revealed sensitivity and specificity of 87%–92% and 80%–89%, respectively, for CHD detection. Levels of NT-proBNP are associated with the severity of CS symptoms, the New York Heart Association functional class, and overall mortality [55, 56].
Although plasma levels of atrial natriuretic peptide (ANP) are significantly elevated in individuals with CHD and indicative of cardiac dysfunction and heart failure, this biomarker is not employed in clinical practice [28, 57].
5-hydroxyindoleacetic acid in the urine
Platelet serotonin and, specifically, levels of the urinary catabolite 5-hydroxyindoleacetic acid (u5-HIAA) have been shown to have a high diagnostic and prognostic value in patients with CS. However, the clinical picture of CS may not correlate with u5-HIAA levels, possibly related to the tumor’s inconsistent hormone release or the synthesis of other biologically active substances [60]. Studies demonstrate that the majority of patients with CHD have greater levels of u5-HIAA than those without [17, 57]. In individuals with worsening CS symptoms, defined as a >50% increase in the frequency of bowel movements or flushing, there was a positive correlation between higher u5-HIAA levels and echocardiographic findings of CHD advancement. In patients with CS, u5-HIAA levels of more than 300 mmol/24 hours indicate a 2- to 3-fold increase in the risk of developing or progressing carcinoid heart disease [52].
Chromogranin-A
Chromogranin A (CgA) is a glycoprotein that NET cells secrete [42]. CgA is a useful biomarker in the diagnosis of NEN since it is affordable and easy to measure using a blood sample for an immunological assay [61]. Modlin et al. [62] reported that CgA did not only reflect tumor burden but appears to be associated with tumor progression or response to treatment [62].
In a report by Tran et al. [63] increased CgA level before SI-NEN-related surgery was associated with lower overall survival (median 87.8 months vs. not reached; P = 0.01) [63]. These data suggest that sequential CgA concentration measurement is effective in both predicting and monitoring progression to CS, as well as progression from CS to CHD [61, 63].
Unfortunately, CgA has only 30% specificity for detecting severe carcinoid heart disease [42] and has therefore a limited value in CHD diagnosis and monitoring [53].
Activin A
Activin A is a TGF family member found to be an independent predictor of CHD although no statistically significant difference in activin A levels is found between patients with early and advanced disease. CHD was detected with 87% sensitivity and 57% specificity when activin A levels were less than 0.34 ng/ml [58].
Chest radiography (X-ray)
Chest radiography is typically inefficient in CHD patients, as 50% of cases appear normal, and abnormalities are commonly non-specific [11]. However, the cardiothoracic ratio could be increased [64].
Transthoracic echocardiography
Echocardiography should be conducted in all patients with carcinoid syndrome and high suspicion of CHD, according to an expert statement released by the American College of Cardiology on the diagnosis and management of CHD. Transthoracic echocardiography (TTE) should be performed in patients with known CHD every 3–6 months or if there is a change in clinical status [8]. In contrast, the European Neuroendocrine Tumor Society (ENETS) recommends TTE screening for patients with CS – once or twice a year for patients with or without cardiac involvement, respectively [9, 65]. Patients with CS should also be screened with TTE if their 5-hydroxyindoleacetic acid levels are markedly increased according to the ENETS recommendations. The severity of CHD can be determined by the constellation of abnormalities observed on TTE [66]. There have been several scoring systems based on echocardiographic findings, including the first (and possibly the most well-known) scoring system based on tricuspid valve morphology, tricuspid regurgitation severity, pulmonary stenosis severity, and pulmonary regurgitation severity [20].
Two-dimensional TTE is the most common imaging modality used in CHD evaluation because it can examine both, morphological and functional, components of the heart (Figure 2).
Valvular involvement can range from mild thickening of a single valve leaflet with no major functional impairment to severe thickening, retraction, and immobility of several valves in advanced conditions. Tricuspid regurgitation is the most common right-sided valve abnormality, followed by pulmonary regurgitation and/or pulmonary stenosis. On 2D TTE, initial fibrous deposition of the tricuspid and/or pulmonary valve leaflets typically shows up as a thickening [67]. Fibrous deposition may also damage the chordae and papillae, causing further abnormal function of the valve. The leaflets become retracted and locked in a semi-open position as the condition progresses, resulting in stenosis and regurgitation [66]. When tricuspid regurgitation is present in CHD patients, the Doppler profile usually shows a typical “dagger-shaped” spectrum (early peak pressure rise with a subsequent rapid decline).
To determine the existence of a patent foramen ovale (PFO), a TTE with a “microbubble” contrast can be conducted [66].
CHD may have an impact on ventricular strain due to valvular anomalies. In one study, right ventricular (RV) strain was found to be lower in CHD patients than in controls (a mean of 20.6 versus 26.9). Patients with carcinoid syndrome showed identical RV strain regardless of whether they had evident valvular involvement, suggesting that abnormal RV strain might be a sensitive and early predictor of CHD before apparent valvular abnormalities occur. In addition to RV strain, patients with CHD have slightly decreased global left ventricular (LV) strain as compared to healthy individuals [68].
When compared to 2D TTE, three-dimensional TTE (3D TTE) has several notable advantages. In the case of the tricuspid and pulmonary valves, 3D TTE allows for simultaneous visualization of all valve leaflets. 3D TTE also provides a comprehensive image of subvalvular structures including chordae and papillary muscles, which might be affected by carcinoid “plaque”. In advanced stages of CHD, 3D TTE can in addition detect abnormalities of neighboring structures, for example, poststenotic dilatation of the pulmonary artery. In comparison to 2D TTE, 3D TTE enables the detection of myocardial metastasis with a better ability to differentiate their borders from surrounding structures, allowing for a more precise estimation of the real dimensions and mass effects. 3D TTE may have value in operation planning in patients who are prepared for surgical valve repair [69].
Transesophageal echocardiography (TEE) offers better imaging of the pulmonary valve than TTE and may reveal minor tricuspid valve anomalies when TTE is ambiguous.
2D TTE is a useful tool for screening asymptomatic CS patients and monitoring established disease development with excellent sensitivity and specificity [70].
Cardiac magnetic resonance
Cardiac magnetic resonance (CMR) is becoming a useful technique for detecting CHD, particularly when echocardiographic findings are ambiguous [71], and is beneficial when echocardiography cannot offer good images of the pulmonary valve [69]. Late gadolinium enhancement of the tricuspid and/or pulmonary valves may show evidence of CHD when valvular anomalies are not visible on TEE. This is not specific and can occur in a variety of cardiovascular conditions [66]. When compared to echocardiography, CMR gives a better estimation of RV size and function with reduced interobserver variability [72].
CMR can be used for more accurate assessment of RV volumes, LV volumes, and cardiac index following a tricuspid valve replacement, in addition to predicting regurgitant volumes after surgical intervention [73]. CMR has various disadvantages, including a higher cost as compared to echocardiography, and the probable requirement for contrast [66].
Cardiac computed tomography scanning
Cardiac computed tomography (CT) can also be used to assess the degree of valve damage, particularly in cases of severe calcification, as well as to quantify RV diameters, evaluate coronary arteries [66], and assess pulmonary post-surgical prosthetic valve thrombosis (Figures 3 and 4).
Positron emission tomography
Functional imaging with radiolabeled somatostatin analogs (typically Gallium-68-DOTATOC/DOTATATE positron emission tomography [PET]/CT) may help to detect carcinoid cardiac metastases (myocardial and/or pericardial) [66]. For the detection of metastatic neuroendocrine neoplasms, this approach has been shown to be >97% sensitive and 92% specific [74].
TREATMENT
The treatment of patients with CHD is multifaceted because of the need to treat both systemic cancer disease and cardiac pathology at the same time [75]. The aim of CHD management is symptom alleviation and increased survival rather than definitive treatment and cure, requiring a multidisciplinary approach involving both medical and surgical therapies for optimal care [76]. This multidisciplinary approach should be used to design a treatment strategy based on symptoms, histological grade, overall performance status, as well as nutritional status, NEN stage (stable disease, progressive, or metastatic disease), the function of major organs (mainly kidney and liver), and the impact of CHD on the proceedings of the underlying NEN [75, 76].
Pharmacotherapy for heart failure
To date, the standard of treatment for asymptomatic patients is to wait for symptoms to appear. On the contrary, loop or thiazide diuretics and aldosterone antagonists are recommended for treatment in individuals who develop signs of right-sided heart failure, particularly peripheral edema. However, because these drugs might cause intravascular volume depletion and decreased cardiac output, they should be used with caution. Other drugs, such as digoxin or angiotensin-converting enzyme inhibitors, have been used, but their benefit in CHD patients has yet to be established [77]. Improvement in heart failure symptoms with medication should not be seen as reassurance that management is adequate and sufficient, but rather as a window to optimize and assess the patient for consideration of valve surgery if required [39].
Cardiac surgery
In patients with well-controlled systemic disease, cardiac valve replacement remains the most effective treatment in severe stages of CHD [77]. Patients with symptomatic right heart failure or ventricular dysfunction, as well as at least 12 months of predicted survival due to their oncologic disease status, are usually candidates for a cardiac procedure [78]. Valve surgery has been shown to enhance long-term prognosis in CHD patients by reducing right heart failure, increasing functional capacity, allowing for more aggressive oncological treatment, and decreasing right heart failure. A multidisciplinary assessment of total operability in relation to oncological status and cardiac function should be used to decide whether to replace a valve [79]. Advances in surgical techniques, better patient selection, anticancer and hormonal control treatments have resulted in tolerable early mortality rates and survival benefits [78].
The Mayo Clinic’s 30-year study by Nguyen et al. [80] involving 240 CHD-operated patients, represents the largest study investigating the relationship between several clinical and echocardiographic factors and early mortality and late survival. Between 1985 and 1994, the early mortality rate was 29% but fell to 7% from 1995 to 2004, and 5% from 2005 onwards. Overall survival rates were 69%, 48%, and 34% after one, three, and five years, respectively [80]. According to the mortality rates reported, valve surgery for carcinoid heart disease is a high risk procedure, but may be beneficial to some patients due to symptomatic relief [81].
Preoperative preparation should mainly focus on optimizing patient status and symptoms with appropriate medical therapy. The severity of tricuspid valve disease, right ventricular dysfunction, right atrial dilatation, pulmonary hypertension, and high central venous pressures are significant risk factors [78]. Preoperative nutritional optimization and somatostatin analog treatment for carcinoid hormonal activity are critical parts of surgical planning [79]. Intravascular volume depletion and electrolyte disturbances are typical in CHD patients and must be treated. Patients with CS are at risk of developing a possibly life-threatening carcinoid crisis, which can be triggered by surgery or any invasive intervention, so therapies aimed at lowering high u5-HIAA levels, such as dose escalation with somatostatin analogs and add-on therapy with telotristat ethyl, should be used. Carcinoid crisis is characterized by hemodynamic instability, with predominant hypotension, tachycardia, arrhythmias, bronchoconstriction, and flushing caused by the release of biologically active substances. The administration of octreotide infusion at a dosage of 50 μg/h administered 12 hours before the procedure and continued throughout the operation and until the patient is hemodynamically stable and off inotropes is the primary preventative therapy aimed at reducing the occurrence of carcinoid crisis. The dosage can be increased to 100–200 μg/h if necessary [82]. Depending on the patient’s recovery, the octreotide infusion should be progressively reduced postoperatively [78].
The type of valve selected for use (biological or mechanical valve prosthesis) is a complex matter that should be based on a particular patient’s risk of bleeding, tumor-related life expectancy, and possible future therapeutic interventions [81, 83]. According to research by Albåge et al. [79], surgery of the left-sided valves is not linked to poorer outcomes and ought to be conducted concomitantly with right-sided valve surgery if needed [79].
Bioprosthetic valves are mostly favored when CHD patients have an enhanced bleeding risk due to significant liver disease and hepatic dysfunction, but still, thrombus formation on the tricuspid bioprosthesis is the most prevalent cause of valve dysfunction in right-sided valve replacements [98]. Postoperative right ventricular failure, an overall reduced flow condition on the right side of the heart, and a hypercoagulable state with high serotonin levels acting as a stimulus for platelet activation all seem to be risk factors for valve thrombosis [78]. Patients with bioprosthetic valves in sinus rhythm should begin and continue warfarin anticoagulation for 6 months, but patients with mechanical valve prosthesis or with atrial fibrillation and bioprosthetic valves should continue anticoagulation permanently [82].
TTE should be conducted as soon as possible after surgery [84]. In uncomplicated conditions during follow-up, TTE should be performed every 3 to 12 months, depending on comorbidities [8].
It should be highlighted that, despite medical and surgical developments, valve surgery in subjects with CHD is always challenging and associated with significant risk. In high-risk patients with severe CHD for whom open-heart surgery is hazardous, transcutaneous catheter-based interventions represent a minimally invasive option [84, 85].
In addition, the recent introduction of percutaneous valve-in-valve technology in subjects with a failing bioprosthetic valve has broadened treatment selections for less invasive procedures, and a transcatheter heart valve placed in the inferior vena cava may decrease carcinoid hormone levels and relieve symptoms in patients with severe carcinoid syndrome symptoms [86, 87].
Primary tumor resection
Primary tumor resection with metastatic disease (resectable and unresectable) has been shown to improve survival in all patients with SI-NENs (with and without CHD) [14]. This may relate to decreased synthesis of vasoactive substances [12], as well as a reduction in potentially fatal complications such as intestinal obstruction caused by tumor growth and blockage [14]. Uema et al. [88] found that removing the primary tumor reduced mortality in 139 patients with advanced disease, carcinoid symptoms, and/or elevated u5-HIAA [88].
Polcz et al. [89] recently published significant findings from a retrospective cohort analysis of 4076 patients with metastatic SI-NETs, with 2025 (61%) receiving primary tumor resection (PTR). Patients who were more likely to have PTR were younger, had been diagnosed sooner, and had lower-grade small intestine primary tumors. Patients who had PTR had longer median overall survival than those who did not (71 months vs. 29 months, P = 0.001). According to the findings of Polcz et al. [89], patients treated in an academic or research facility were, likewise, less likely to have PTR, and primary resection has become less common over time. One possible explanation is the increasing use of somatostatin analogs as first-line treatment for metastatic disease, which gives both excellent symptom alleviation and inhibition of tumor progression. Although these findings were also associated with improved survival, it should be noted that they apply to the entire group of SI-NET patients — both with and without CHD — and that, despite proven benefits in progression-free survival, no OS benefit with somatostatin analogs has been demonstrated to date [89], which indicates that primary tumors should be removed when possible.
Management of carcinoid syndrome
Considering the significance of 5-HT in the sequence of events that leads to the development of CHD, controlling serotonin synthesis from the tumor is critical. This can be accomplished by either medical or surgical intervention methods. Long-acting somatostatin analogs, peptide receptor radionuclide therapy (PRRT), and the new drug telotristat ethyl are among the available medical treatments. Transcatheter arterial embolization (TAE) or chemoembolization (TACE), as well as surgical debulking of hepatic metastases, are interventional alternatives [8].
Long-acting somatostatin analogs
Long-acting somatostatin analogs (SSAs), synthetic octo-amino acid peptides, which primarily act on the somatostatin receptor subtype 2, are recommended for first-line antiproliferative therapy in advanced NETs due to their proven effectiveness in controlling symptoms of carcinoid syndrome [28, 75–77, 90]. The somatostatin analogs octreotide and lanreotide improved symptoms in 65%–72% of patients and had a biochemical response in 45%–46%. In 72%–84% of patients, increasing the dose or frequency or switching classes resulted in a decrease in flushes and/or diarrhea [90].
Long-acting somatostatin analogs extended time-to-tumor progression (TTP) in patients with metastatic well-differentiated, predominantly G1, midgut neuroendocrine tumors compared to placebo (NET; octreotide LAR: PROMID study) [91]. Progression-free survival (PFS) was as well enhanced in individuals with advanced, nonfunctioning enteropancreatic NETs of grade 1 or 2 with confirmed progression of the disease (lanreotide autogel: CLARINET study) [92].
Although the optimal levels of u5-HIAA used to reduce the development of CHD are yet to be determined, long-acting SSAs are unquestionably important in CHD patient management [78].
In CS patients, infusion of short-acting octreotides should begin in the perioperative setting to avoid the onset of carcinoid crisis. Furthermore, in patients with recurrent CS symptoms, short-acting octreotide (half-life 1.5 to 2 hours) may be administered as a rescue drug in addition to the long-acting formulations [78].
Telotristat ethyl
Telotristat, an oral inhibitor of peripheral 5-HT synthesis, was recently approved by the Food and Drug Administration for the treatment of symptomatic CS-related diarrhea that has not responded to SSAs therapy. Telotristat ethyl is converted to its active metabolite, telotristat, which inhibits tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin production. Two double-blind, randomized phase 3 clinical trials (TELESTAR and TELECAST) found that telotristat ethyl reduced bowel movement in 40%–44% of patients treated, compared to 0–20% of patients who received a placebo [78, 93]. After three months, there was a substantial decrease in urinary 5-HIAA. The findings of this study supported the safety and effectiveness of telotristat when combined with somatostatin analog treatment in individuals with CS. The impact on the development of carcinoid heart disease and mesenteric fibrosis residues is unidentified because this endpoint has not been adequately powered in clinical studies [94].
Everolimus
Everolimus is a small molecule oral inhibitor of the serine/threonine protein kinase mammalian target of rapamycin (mTOR), which promotes cancer cell growth and survival in a variety of malignancies, including NETs [78]. Pavel et al. [95] reported that everolimus plus octreotide LAR increased progression-free survival in patients with advanced neuroendocrine tumors associated with carcinoid syndrome when compared to placebo plus octreotide LAR [95]. Due to everolimus-related adverse effects including infections, edema, and diarrhea, patients with CHD should be treated with caution [8, 78].
Interferon-alpha
For refractory CS and negative somatostatin receptor NETs, interferon-alpha (IFN-α) is a supplementary treatment to SSAs. However, usage of this drug is limited due to its adverse effects (e.g., flu-like symptoms, chronic fatigue, liver and bone marrow toxicity) [78]. The reported response rates of IFN monotherapy in CS patients ranged from 0% to 90% for clinical control and 50%–80% for biochemical control [90].
Peptide receptor radionuclide therapy
Peptide receptor radionuclide therapy (PRRT) is primarily used to inhibit growth in progressive NETs with high somatostatin receptor expression [96]. It has been shown to improve quality of life and symptoms such as diarrhea in patients with midgut NETs [97]. Due to the requirement for simultaneous amino acid and fluid infusions in patients with CHD and heart failure, caution is advised [8, 78].
Transcatheter arterial embolization, chemoembolization, selective internal radiotherapy, radiofrequency ablation
Transcatheter arterial embolization (TAE), local administration of high doses of chemotherapy (TACE), and selective internal radiotherapy (SIRT) employing Yttrium-90 microspheres are examples of vascularly accessed interventional methods that provide diverse treatment modalities [78].
TAE and TACE are implemented to minimize tumor burden and have been shown to be effective in the treatment of NET, particularly in individuals with liver involvement. Circulating hormone levels drop as tumor burden decreases, resulting in symptom control in 50%–100% of patients with NET and liver metastasis [98]. Patients with severe CHD and/or a significant hepatic tumor burden may have serious treatment complications such as hemorrhage or even liver failure, and as such, loco-regional therapies must be used with extreme caution. TAE and TACE are relatively contraindicated in patients with total portal vein occlusion, poor performance status, or underlying hepatic impairment [77]. TAE, TACE, and SIRT radiological response rates were estimated to be 25%–92%, 22%–100%, and 22%–63%, respectively [78].
Radiofrequency ablation and microwave ablation, done either percutaneously or in association with surgical resection, have also been shown to improve symptom management [78].
Surgical debulking of hepatic metastases
Surgical debulking (cytoreductive surgery) of liver tumor burden has been shown to be a significant advancement in the management of NETs in recent years [77]. Bernheim et al. [99] reported that patients with CHD who undergo hepatic resection had delayed progression of the disease and a better prognosis [99]. This method may be risky in individuals with severe CHD since it is associated with significant morbidity and mortality. There is also a greater risk of preoperative hemorrhage due to elevated right atrial pressure and a pulsatile liver. In selected individuals, liver surgery may be an option following heart valve replacement and cardiac function restoration to lower circulating serotonin, relieve carcinoid symptoms, and avoid recurrence of CHD [8, 77].
Kinney et al. [100] presented peri-operative findings of 169 patients who had partial hepatic resection due to metastatic NETs at Mayo Clinic Rochester. The most prevalent adverse events were persistent tachycardia (8.9%), followed by hypotension (5.3%), flushing, cardiac conduction abnormalities, and acidosis with pH 7.2, with an occurrence of less than 1%. There were no incidents of carcinoid crises [100].
CONCLUSIONS
All patients with SI-NENs, particularly those without primary tumor resection and high concentration of u5-HIAA require a cyclic assessment of clinical status and TTE performance every 3-6 months to detect the onset of CHD. The therapeutic methods include pharmacotherapy for symptomatic management, as well as medications and interventional approaches, for successful control of serotonin excess, most notably somatostatin analogs.
Despite medical and surgical improvements, carcinoid heart disease remains a significant challenge. Valve surgery for carcinoid heart disease is a high-risk intervention, given the mortality rates, although it may be beneficial for patients with symptomatic severe right heart valve disease who have a 12-month survival prognosis owing to symptomatic improvement. It should be emphasized that early risk linked to valve surgery has decreased in the present era. A multidisciplinary team should be involved in patient selection for valve surgery, adequate preoperative planning, and perioperative treatment procedures.
Article information
Conflict of interest: None declared.
Funding: None.
Open access: This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially. For commercial use, please contact the journal office at kardiologiapolska@ptkardio.pl.
