Therapy of neuroendocrine tumors

Background

Neuroendocrine tumors are able to produce hormones according to the degenerated tissue. The most common are the so-called GEP tumors (gastro-, entero-, pancreatic tumors). These occur in the stomach, intestine or pancreas. Depending on the respective hormone production, GEP tumors are divided into functionally active tumors (hormone-releasing tumors) and functionally inactive tumors (non-hormone-releasing tumors). Hormone-releasing tumors include gastrinomas, insulinomas, glucaconomas, VIPomas, somatostatinomas and carcinoids. The latter are the most common GEP tumor and are mainly found in the small intestine, appendix, stomach and colon. Around 50 % of carcinoids are inactive and often only cause symptoms such as abdominal pain, weight loss or jaundice after around 5 - 10 years of disease progression. These unspecific symptoms, which are often caused by an increasing mass or displacement of other organs by these slow-growing tumors, often lead to a lengthy diagnosis until the carcinoid is identified as the cause. The other half of carcinoids are hormone-producing, whereby the hormones can be broken down in the liver in the early stages of the disease. However, as the disease progresses, metastasis of the liver often occurs, which reduces liver function and the hormones can no longer be broken down sufficiently. This leads to the typical carcinoid syndrome with flushing symptoms (reddening of the face and upper body) combined with heart problems and sweating, cramp-like abdominal pain, diarrhea and possible breathing difficulties.

The second most common tumor of the so-called GEP tumors is gastrinoma. This is often found in the pancreas and the duodenum (section of the small intestine), less frequently in other organs. Gastrinomas produce gastrin, which stimulates the production of stomach acid. This leads to hyperacidity of the stomach with frequent development of ulcers in the small intestine and diarrhea.

Almost as common as gastrinoma is insulinoma, which develops in the insulin-producing cells of the pancreas and releases insulin in an uncontrolled manner. This leads to a drop in blood sugar levels. The consequences are, for example, weakness, trembling, feeling hungry and sweating. In this case, regular blood sugar checks are necessary.

Glucagonomas (pancreas), VIPomas (pancreas), somatostatinomas and, as a special case, MEN syndrome should also be mentioned. The latter involves several hormone-active tumors occurring simultaneously, such as insulinoma, glucagonoma and gastrinoma.

The usual diagnostic procedure consists of detecting the primary tumor and searching for metastases (e.g. by ultrasound, magnetic resonance imaging or computed tomography). In addition, functionally active tumors can be detected in the laboratory by means of elevated hormone levels in the blood or the degradation products in the urine. A special feature of GEP tumors are special receptors on the tumor cell surface that serve as a docking site for the hormone somatostatin. While these so-called somatostatin receptors (SSTR) are also found in normal tissue, the density on the tumor cell surface is greatly increased.

This characteristic makes these tumors accessible to nuclear medicine diagnostic and therapeutic procedures:

For this purpose, radioactively labeled protein building blocks similar to somatostatin (somatostatin analogs) are administered intravenously to the patient. These bind to the somatostatin receptors and, due to the bound radioactive nuclide, can be registered for diagnostic purposes with a nuclear medicine camera (PET/CT scanner) or used for specific internal radiotherapy using therapeutically effective nuclides. Due to the significantly better resolution of the PET/CT examination compared to the conventional gamma camera and the additional morphological information (exact representation of the anatomical structures by computer tomography), the sensitivity of tumor detection can be significantly increased with these newer methods.

Radiopeptide therapy of neuroendocrine tumors opens up a promising new therapeutic option in addition to conventional standard therapy (surgery, local treatment procedures, biotherapy (Sandostatin/Interferon) chemotherapy). Somatostatin analogs (peptides) are labeled with therapeutically effective radioactive beta emitters (usually lutetium-177) (e.g. [177Lu]DOTATATE). The administration of these substances enables internal radiotherapy that selectively affects the tumor cells and largely spares the healthy tissue (the kidneys (excretion) and to a much lesser extent the bone marrow are mainly exposed to radiation). However, the use of [177Lu]DOTATATE can minimize the risk of permanent kidney damage, assuming normal kidney function prior to radiopeptide therapy. Depending on the tumor type and metastasis pattern, radiopeptide therapy can alternatively be carried out with yttrium-90 labeled DOTATATE (90Y-DOTATATE). This procedure is particularly suitable for patients with highly differentiated, slow-growing tumours/metastases, which experience has shown to be less amenable to chemotherapy and for whom surgical or local (radiofrequency ablation/chemoembolization) options have been exhausted. Patients who show progression under drug therapy with somatostatin analogs or patients with pronounced clinical symptoms can also benefit from radiopeptide therapy. The treatment results of this form of therapy from various European centers (Munich, Rotterdam, Basel, Milan, Bad Berka) show a high tumor response rate (response rates of up to 40 %) and, in particular, a clearly positive effect on clinical symptoms and survival.

How is radiopeptide therapy carried out?

All patients are discussed prior to therapy in an interdisciplinary tumor board involving internists, surgeons, radiotherapists and nuclear medicine specialists in order to determine the best possible therapy strategy.

Preparation

In order to avoid occupying the SSTR with the often therapeutically administered depot sandostatin (this would result in fewer binding sites for the radioactive peptide), this should be discontinued at least 6 weeks before therapy. Due to the possible kidney-damaging effect of the radiopeptide, a thorough examination of kidney function is planned before starting therapy and as a follow-up before possible further therapies. In addition to the usual laboratory tests (creatinine and urea), the glomerular filtration rate and the tubular extraction rate of the kidneys are determined using two nuclear medicine procedures (99mTc-DTPA scintigraphy and 99mTc-MAG3 scintigraphy). Furthermore, the SSTR expression of the tumor is examined prior to each therapy using the above-mentioned nuclear medicine diagnostic procedures (PET/CT). Depending on the type of tumor and the symptoms present, further examinations such as tumor marker determination (chromogranin A, NSE, etc.), long-term ECG/blood pressure measurements or daily blood sugar profile determinations may be necessary.

Therapy

For the actual therapy, an indwelling venous cannula is inserted and connected to an infusion system. Approximately 30 minutes before the start of therapy, an amino acid solution is administered to protect the kidneys and prevent excessive absorption of the radioactive peptide in the kidneys. This is continued over a period of 4 hours. The radiolabeled peptide is then also administered via the indwelling cannula using the perfusor over a period of 15 minutes. Regular pulse and blood pressure checks are carried out during the therapy. According to the radiation protection guidelines, a 48-hour stay on the therapy ward is prescribed after therapy. During this period, three whole-body scintigraphies are carried out immediately after infusion of the radiopeptide and after 24, 48 and 72 hours to document the fate of the radioactive substance and, in particular, to estimate the focal doses reached (tumor and kidney doses). In addition, regular blood checks are carried out. Sufficient fluid intake must be ensured during therapy.

What side effects can radiopeptide therapy have?

The side effects known to date include non-specific symptoms such as headaches and tiredness. Increased flushing symptoms are possible, which can last for several days. Nausea and vomiting may also occur after therapy. In rare cases, tumor cell destruction leads to a very high release of hormones, which can be accompanied by circulatory and respiratory problems, headaches and neurological symptoms. In addition, blood count changes with a reduction in the number of red blood cells (erythrocytes), platelets (thrombocytes) and white blood cells (leukocytes) are possible in the medium term; monthly blood count checks after therapy are therefore recommended. Due to the radiation exposure of healthy liver tissue, liver function may be impaired. For this reason, monitoring of liver parameters is also recommended. Temporary hair loss may occur. Allergic reactions rarely occur when the therapeutic substance is administered. Repeated therapy may result in impaired renal function. Precautions have been taken to ensure that competent medical care is available for all side effects.

The therapy can be carried out in several cycles depending on the SSTR storage, kidney function and the organ doses achieved up to that point (the kidney is the limiting organ), which are checked before each cycle. After therapy, regular check-ups are planned with sonography, PET/CT and kidney scintigraphy.

What additional medication is given?

In order to ensure adequate hydration, 1.5 liters of saline solution are infused into the vein every day from the start of therapy. If necessary, painkillers and anti-nausea/anti-vomiting medication are administered as an option

Inclusion and exclusion criteria