Transcatheter valve implantation to inferior vena cava to control carcinoid symptoms

Abstract

Severe carcinoid syndrome and carcinoid heart disease in neuroendocrine tumours can have a significant impact on a patient’s quality of life and are a major cause of morbidity and mortality. We present a novel approach to managing a patient with medically uncontrollable carcinoid syndrome. Inferior and superior vena cava placement of transcatheter heart valves has been used to treat patients with right heart failure due to severe tricuspid and pulmonary regurgitation. However, this procedure has not been attempted to specifically reduce hormone secretion, primarily from the liver, in order to control carcinoid syndrome symptoms. We attempted this procedure in a patient with severe carcinoid disease and tricuspid regurgitation as a bridge to later definitive therapy. The procedure was technically successful, but did not improve carcinoid symptoms. The possible reasons for the failure are discussed here.

Background

We have documented a reduction in urinary 5-hydroxyindoleacetic acid (5-HIAA) levels following heart valve surgery for carcinoid heart disease. We therefore postulated that this beneficial effect was due to a reduction of regurgitation into the inferior vena cava (IVC) leading to a reduction of IVC/hepatic venous pressures. We thereforepostulated that a transcatheter heart valve (THV) placed in the IVC would similarly reduce carcinoid hormone levels and improve symptoms in a patient with severe carcinoid syndrome symptoms that had persisted despite maximum medical treatment in this patient.

Systemic therapy with peptide receptor radionuclide therapy (PRRT) was considered but not used as it is slow acting, taking up to a year for adequate response. Transarterial embolisation was felt to be unsafe in the presence of uncontrolled severe tricuspid regurgitation (TR) and features of right heart failure.

Although the treatment did not succeed in this patient, a number of useful lessons have been learnt that give hope to achieving better outcomes in treating this challenging group of patients, where coexisting severe carcinoid heart disease and medically uncontrolled carcinoid syndrome make treatment of either entity safely very difficult.

Case presentation

A 69-year-old female neuroendocrine tumour (NET) patient initially presented to the local hospital with symptoms of syncope, severe diarrhoea and facial flushing. She had markedly raised tumour markers including chromogranin A 844 pmol/L (normal <60) and urinary 5-HIAA 586 μmol/24 hours (normal <45). A CT scan showed a mesenteric mass and the presence of liver lesions replacing approximately 30% of the liver by volume. An octreotide scan demonstrated focal uptake in multiple bone and liver lesions. The patient was treated with Lanreotide 60 mg with an improvement of carcinoid symptoms. She was referred to the local cardiology department and a transthoracic echocardiogram (TTE) confirmed carcinoid heart disease involving the tricuspid and pulmonary valves with severe TR. A liver biopsy was also performed, and histology confirmed a well-differentiated grade 1 NET with a Ki-67 index of 2%.

The Lanreotide dose needed to be increased to 120 mg every 4 weeks. The facial flushing greatly improved, but she continued to experience diarrhoea. Due to the progressive symptoms and deterioration in her health, she was referred to this specialist NET centre.

When seen in the NET and cardiology clinics, the patient felt very weak and required a scooter for long travel distances. She had to give up activities due to ill health impacting on her quality of life. Examination revealed significant hepatomegaly, facial features of chronic flushing and the precipitation of a severe flush on minimal palpation of the abdomen. JVP was elevated with CV waves and a grade 4/6 pansystolic murmur consistent with severe TR was heard, in addition to a grade 3/6 pulmonary diastolic murmur. Bilateral ankle oedema was also present.

A transoesophageal echocardiogram (TOE) was performed to ensure that there was no evidence of left-sided heart valve disease. This confirmed the presence of severe TR secondary to carcinoid heart disease and a dilated right ventricle (RV) with good RV systolic function. There was also evidence of pulmonary regurgitation seen on the TOE but this was not quantifiable (figure 1 and figure 2).

Figure 1.

Transoesophageal echocardiogram. A, right atrium; B, tricuspid valve; C, dilated right ventricle; D, interatrial septum; E, mitral valve and F, interventricular septum.

Figure 2.

Transoesophageal echocardiogram demonstrating severe tricuspid regurgitation.

A right heart cardiac catheterisation was performed which revealed normal right heart function and an unremarkable mean right atrial pressure (9 mm Hg), right ventricular pressure (20/0 mm Hg) and an elevated V wave pressure (18 mm Hg). These pressures indicate an absence of increased pulmonary resistance and therefore normal pulmonary artery pressures. The low right ventricular end-diastolic pressure (RVEDP) is likely to reflect preserved systolic function but may have also been partly due to changes in volume status and due to venodilator and inotropic medication.¹

The patient was discussed at the NET and cardiology multidisciplinary team (MDT) meetings. She was considered too high risk for open heart surgery in view of the severe uncontrolled carcinoid symptoms and overall poor fitness. The patient was not for PRRT either as she was too unstable to be left alone in an isolated room to receive the treatment. Additionally, given the slow-acting nature of this treatment, it was not ideal as the cardiac complications needed to be dealt with imminently. The plan was for a procedure to control the effects of TR on the liver, with implant of a THV into the IVC, in order to allow transarterial embolisation of the liver metastases to be safely performed as treatment for carcinoid syndrome.

An octreotide infusion was commenced pre-procedure (5000 μg in 50 mL 0.9% normal saline running from 1 to 5 mL/hour) and continued post-procedure. Two stents were implanted into the IVC, and a 29 mm S3 THV was then deployed within the IVC stent. Immediately prior to valve deployment, the phasic pressure in the IVC was 32/20 mm Hg with a mean of 22 mm Hg. Following valve deployment, the IVC pressure fell to 15/8 mm Hg with a mean of 10 mm Hg, and venography confirmed only minor paravalvular regurgitation. The valve was deployed as far into the right atrium (RA) as could be achieved while still ensuring that the sealing skirt of the THV would be effective. The THV requires a continuous rim of tissue surrounding it otherwise there will not be an effective seal. The procedure was well tolerated throughout.

Unfortunately in the days following the procedure, the patient failed to improve clinically despite very high doses of somatostatin analogues. She passed away 10 days later as a result of severe carcinoid crisis (figure 3 and figure 4).

Figure 3.

A venogram illustrating the right side of the heart. IVC, inferior vena cava; LHV, left hepatic vein; RA, right atrium; RHV, right hepatic vein.

Figure 4.

A is the Edwards Sapien valve deployed within the inferior vena cava stents. Bis the overlapping self-expandable stents to anchor the valve.

Investigations

• Tumour markers including chromogranin A and 24-hour urinary 5-HIAA.

• CT scan

• Octreotide scan.

• TTE.

• Liver biopsy.

• TOE.

• Coronary angiography.

Treatment

An octreotide infusion was commenced pre-procedure (5000 μg in 50 mL 0.9% normal saline running from 1 to 5 mL/hour) and continued post-procedure.

Outcome and follow-up

Unfortunately the patient passed away 10 days following the procedure. Follow-up not applicable.

Discussion

Carcinoids are slow growing, rare NETs originating from enterochromaffin cells. They commonly start in the gastrointestinal tract. The term ‘carcinoid’ generally describes a well-differentiated serotonin secreting tumour in the midgut.^{2 3} Other substances secreted include prostaglandins and tachykinins. The liver is the major site of inactivation for these products. However, once metastases occur to the liver itself, the vasoactive substances can reach the systemic circulation via the hepatic veins. This can result in the onset of symptoms of carcinoid syndrome including diarrhoea, flushing and bronchospasm.³ Carcinoid heart disease can affect up to 60% of patients with carcinoid syndrome.⁴ Carcinoid heart disease is associated with high levels of serotonin. It is likely related to serotonin and other vasoactive substances secreted by the metastases in the liver, reaching the right side of the heart. These substances cause deposition of carcinoid plaques, resulting in fibrosis and thickening of the endocardial surface of the heart. This results in valve incompetence. The tricuspid and pulmonary valves are commonly involved resulting in valve dysfunction and right-sided heart failure.^{4 5} The left side of the heart is usually not affected in carcinoid heart disease due to the breakdown of serotonin in the lungs.⁵ Left-sided lesions can occur in up to 15% of patients with carcinoid syndrome. Foramen ovale patency is commonly involved in those with a left-sided lesion.⁶

There are case reports of the use of THV procedures to treat TR. Severe TR leads to a reduction in cardiac output and an increase in the central venous pressure, resulting in secondary organ dysfunction.⁷ Surgery for severe TR is a high-risk procedure that needs to be performed after carcinoid symptoms have been brought under reasonable control, such that it would be hoped to minimise the risk of carcinoid crisis and severe haemodynamic instability perioperatively.

Our patient’s case was discussed in the NET and cardiac MDT meetings and a plan was made for THV implantation into the IVC. This method has been shown to be effective in treating complications and symptoms associated with right heart failure for those in whom cardiac valve replacement operation is deemed too high a risk.^{7 8} However, it has not been used for controlling carcinoid syndrome as a bridge to definitive surgery.

Between 2010 and 2013, six of eight patients who underwent cardiac surgery in this centre exhibited a reduction in urinary 5-HIAA values postoperatively. Assessing the cohort in its entirety, we observe a mean 33% reduction from presurgery to postsurgery urinary 5-HIAA (p=0.039; Wilcoxon signed rank test) (figure 5). The aim in placing a THV in the IVC was to replicate this effect and stabilise the patient sufficiently to then enable more aggressive intervention to take place. Once the hormone load had been reduced and the patient’s functional status had improved, the plan was always to proceed with definitive surgery.

Figure 5.

Urinary 5-HIAA values are presented pre valvular heart surgery and post valvular heart surgery. Statistical comparisons performed using the Wilcoxon signed-rank test. 5-HIAA, 5-hydroxyindoleacetic acid.

THVs, such as the Edwards Sapien valve, are normally used to treat severe symptomatic aortic stenosis. The prosthesis is anchored by frictional resistance imparted by the calcified aortic valve leaflets. To anchor the THV in the case described, two overlapping self-expanding stents were deployed in the IVC at the entry into the right atrium (RA) as previously described by Laule et al.⁹ Within this, a 29 mm Edwards Sapien S3 THV was deployed.

A case series by Laule et al showed the beneficial effects of percutaneous single or dual caval valve implantation for severe TR. No valve regurgitation or leakage was seen at 30 days and antegrade flow into the IVC from the hepatic veins was seen. An improvement in right ventricular function occurred, and a reduction in the volumes of the RA and the RV in addition to the hepatic veins diameter were also demonstrated. A decrease in the hepatic, peripheral and abdominal venous congestion was noted, due to resolving right heart failure.⁹ Lauten et al demonstrated the success of a percutaneous bicaval valve implantation to treat TR in a patient 12 months following the procedure, with haemodynamic improvement and significant clinical improvement in heart failure symptoms that has sustained over this time period, in addition to continual excellent valve function.⁹

In summary, valve implantation into the vena cava to treat severe TR in patients considered unsuitable for open heart surgery has shown promising results. There has been one case report recently that has demonstrated an overall beneficial outcome to the patient where two Edwards Sapien valves were implanted percutaneously into the pulmonary valve and into the IVC valve to treat the effects secondary to TR.¹⁰ These promising findings are being further evaluated through two clinical trials, TRICAVAL and HOVER, looking at the use of IVC valves in severe TR. The TRICAVAL trial is assessing the efficacy and safety of implanting an Edwards Sapien valve into the IVC in patients with severe TR and signs of right heart failure.¹¹ The HOVER trial is assessing the short-term safety (<30 days) and efficacy (6 months) of the heterotopic implantation of an Edwards Sapien valve into the IVC in patients with severe TR who are unable to undergo tricuspid valve replacement.¹²

IVC valve implantation as a temporising treatment for severe TR, in order to then safely treat the liver lesions through arterial embolisation and then perform heart valve replacement surgery, did not result in a favourable outcome in this case. The procedure, in fact, precipitated uncontrollable, prolonged carcinoid crisis that led to the patient’s death. The premise for treating patient’s TR had been to reduce hormone release from liver metastases by reducing hepatic congestion.

Sadly this novel approach to managing patients with a difficult combination of problems did not result in an overall positive outcome. Technically, the procedure appeared to be successful; haemodynamically, the pressure in the IVC was reduced and the regurgitation to the liver was also eliminated.

A possible reason for the poor outcome is interference to the flow of hepatic venous blood drainage. As can be seen in figure 4, the left hepatic ostium is partially covered by the lower part of the valve. Since the drainage of a major tumour lesion was mainly in the territory of the left hepatic vein, it is possible that this prevented a drop in vasoactive hormones. However, the liver has a rich collateral venous drainage that should have abrogated any obstructive effects to the left hepatic vein (figure 6).

Figure 6.

CT scan showing large metastasis in segment 4 which is mainly drained by the left hepatic vein.

Learning points.

The reasons for the negative outcome are likely multifactorial:

• Unpredictable consequence of intervention with a paradoxical rise in circulating hormones.

• Possible sepsis, as evidenced by rising white cell count and C-reactive proteins levels, leading to carcinoid crisis.

• Care needs to be taken when implanting covered valves in the inferior vena cava, especially if patients have carcinoid symptoms, to prevent the onset of potential carcinoid crisis following the procedure.

• In these patients, it may be prudent to implant the valve only if it can be placed above the first hepatic vein in order to ensure there is no obstruction to blood flow drainage. Given natural variation in anatomy, it may mean transcatheter valve implantation is not suitable for some patients however.

At present, there appears to be no safe treatment choices in these rapidly deteriorating patients with severe carcinoid syndrome and coexistent severe carcinoid heart disease. We feel it would be worth repeating this treatment in similar patients.