Interventional oncology in neuroendocrine tumors.

Neuroendocrine tumors (NET)

Neuroendocrine tumors (NET) originate from the cells that secrete some hormones by nerve stimulation. Since these cells are all over the body, NETs can originate from any organ. However, they are most commonly derived from the digestive system, pancreas and lung. The frequency of NETs has increased by about 5 times in the last 30 years. Part of this increase is thought to be due to better detection of tumors by CT, MRI and PET-CT, while some of them are due to actual increase in tumor prevalance. However, NETs are less common compared to other types of cancer. However, as the patients live longer, the number of patients with NET (community) is increasing.

A significant portion of NET is benign and not metastatic. Some of them may metastasize but are very slow, especially NETs from the small intestine which are called "carcinoid" tumors. However, some NETs exhibit an aggressive course like classic cancers. The pathologic examination of the biopsy material can give important information about the course of NETs; in pathological examination, according to the grade of the tumor (the degree of differentiation of the cancer cell from normal cells), the division of cells (mitosis) rate, dead tissue (necrosis), and the amount of Ki-67 protein indicating the rate of division of the cells, NETs are divided into 3 groups. The well-differentiated NETs are the slowest and the poorly differentiated are the most aggressive.

What are the symptoms?

The majority of NETs do not secrete hormones and do not give any symptoms. Such tumors are detected incidentally in investigations such as ultrasound, CT, and MRI performed for other reasons. In these patients, diagnosis of NET is made with a needle biopsy. In some patients, NETs can secrete hormones and may cause various complaints according to the type of hormone secreted. For instance, an insulin-secreting NET (insulinoma) in the pancreas can cause sudden falls in blood glucose level and fainting. A gastrin-secreting NET (Zollinger-Ellison Syndrome) may increase the acid secretion in the stomach and intestine can form a large number of ulcers and can cause abdominal pain and stomach bleeding. A serotonin secreting NET may cause fever, diarrhea, increased blood pressure, palpitations and arrhythmia. In patients with these type of complaints, ultrasound, CT and MRI are performed and diagnosis of NET can be made by performing a needle biopsy. In NET, the biopsy not only diagnoses the NET, but also provides insight into the rate of spread of the tumor based on criteria such as grade, mitosis, necrosis and Ki-67, which can modify the treatment plan.

Sometimes NETs may contain both slow and aggressive tumor areas in the same patient or even within the same mass (tumor heterogeneity). As a result, it can sometimes be seen that while the tumors in the patient are generally shrinking, some tumors grow, or a portion of the same tumor shrinks with the treatment being applied and the remainder grows. In such cases, it may be necessary to examine the tumor by doing a needle biopsy from the growing parts.

Staging:

The most useful methods for staging NETs are needle biopsy and imaging findings. Biopsy is used to differentiate the good, middle and poorly differentiated forms of NETs, while CT, MRI and PET-CT imaging techniques are used to evaluate the extend of the disease. In NETs, sometimes a single organ (thyroid, stomach, bowel, pancreas, etc.) is involved. However, most NETs, particularly the poorly differentiated ones have metastases to distant organs, especially the liver, at the time of diagnosis. The classical methods used to show metastases are ultrasound, CT and MRI. Conventional PET-CT (FDG PET) does not show good and moderate differentiated NETs, but it is highly successful in showing poorly differentiated or aggressive NETs and their metastases. The most successful method of demonstrating good-to-medium differentiated NETs is the gallium 68 PET-CT. In this method, somatostatin receptors on the surfaces of NET cells are used for diagnosis. A protein called Ga-68 DOTATATE binds to these receptors, making these tumors visible on PET-CT. With this method, NET metastases which cannot be seen on CT, MRI and conventional PET-CT can also be detected. This approach is also used for the treatment of well differentiated NETs; the protein DOTATATE is combined with a radioisotope called lutetium 177, and this substance can destroy the NET cells by sticking to receptors and exposing them a high dose of radiation (Lutetium DOTATATE treatment).

How is it treated?

After the evaluation of the differentiation and extent of NET with biopsy and imaging methods, treatment is started. Rarely, the tumor can be in a single organ and the tumor can be removed by surgical operation or percutaneous ablation. Percutaneous ablation can be preferred especially in some patients because of it is minimally invasive, repeatable and has a low risk.

In the majority of patients with NET, there are metastases to distant organs, especially liver. In these patients, medications are given firstly; somatostatin receptor analogues such as ocreotide and lanreotide can be given in the mid-poorly differentiated NETs. In those with well-to-medium differentiated NETs, the amount of somatostatin receptors in tumor cells is investigated first by Ga-68 PET-CT. If there is intense involvement in the Ga-68 PET (the receptor level is high), Lutetium DOTATATE is given as a targeted treatment. In this treatment, the lutetium 177 isotope with high dose radiation adheres to somatostatin receptors in NET cells and destroys the tumor cell with radiation. It is possible to increase the effectiveness of this treatment by applying it directly into the tumor (intraarterial lutetium) via the feeding artery.

New treatments in liver metastases of NET

More than 90% of patients with NETs develop liver metastases at any stage of the disease. Metastases may be in the liver only as well as in other organs besides the liver. In any case, however, liver metastases need to be treated more aggressively because one of the most important factors affecting survival is the status of liver metastases.

In patients with metastatic liver disease only or metastases predominantly in the liver, firstly chemotherapy or lutetium treatment is applied. The administration of lutetium treatment through the liver artery may further improve treatment efficacy. In addition, if metastases are few in number, percutaneous ablation methods such as radiofrequency, microwave and cryoablation can be preferred. Percutaneous ablation can also be applied to primary tumors in some cases with metastases.

Transarterial therapies such as (bland) embolization, radioembolization and chemoembolization may be applied in patients who are not suitable for or have not benefited from these therapies. Transarterial therapies are highly effective in NET metastases because:

1. The normal tissue of the liver and the tumor tissue are fed by separate vessels; the hepatic artery, which is the artery of the liver, feeds the normal tissues by 30% while it feeds the NETs by 99%. Therefore, these transarterial treatments performed via the hepatic artery directly kill NET cells without causing too much damage to normal tissue.

2. NET masses are vessel-rich (hypervascular), just like hepatocellular cancer, and in transarterial treatments, they attract the injected particles like a siphon. Thus, the particles will go into the vessels of NET cells much more than those of normal liver tissue, affecting tumors more and harming normal tissue less.

One of the most widely used intervention in liver metastasis of NETs is chemoembolization. In chemoembolization, a chemotherapy drug called doxorubusin is either loaded into drug eluting beads or mixed with a substance called lipiodol which is held by tumor cells. Then, it is delivered into the feeding arteries of the tumors. In this way, both the feeding vessels are clogged and the doxorubicin drug is released into the tumors from the particles for days or weeks. Both chemoembolization methods have been successfully used in NETs. Besides chemoembolization, bland (no drug loaded) embolization was performed in this patient group and very successful results were obtained. It has been reported in some studies that bland embolization is as effective as chemoembolization and its side effects were minimal, especially when particles smaller than 100 microns are used.

Another method effective in liver metastases of NET is radioembolization (TARE or SIRT). In this method, the radioactive isotope named Yttrium 90 is loaded into special particles of 50 microns in diameter and injected into the vessels feeding the tumor through the hepatic artery. Thus, a much higher radiation dose may be given to the tumors than the conventional radiotherapy by preserving the normal liver and surrounding organs. Several studies have shown that radioembolization is very effective and safe in NET liver metastases.

As with many cancer types, minimally invasive therapies in NET also provide complete cure in some cases, and in some cases increase the duration and quality of life of the patient. At what stage and which order these treatments should be applied varies from patient to patient and it should be determined by a team experienced in such treatments.