Therapy of neuroendocrine tumors (NET)

Background

Neuroendocrine tumors are capable to produce hormones according to their source tissue. Most frequent are the so-called GEP tumors (gastro-, entero-, pancreatic tumors; GEP-NET). They occur in stomach, intestine or pancreas. Depending on their respective hormonal activity, the GEP-NET are divided into functionally active tumors (hormone releasing tumors) and functionally inactive tumors (non-hormone releasing tumors). Amongst the hormone releasing tumors are gastrinomas, insulinomas, glucagonomas, VIPomas, somatostatinomas, and carcinoids. The latter are the most frequent GEP-NET, and are predominantly found in small intestine, appendix, stomach and large intestine. Approximately 50% of the carcinoids are inactive and often only cause symptoms like stomach aches, loss of weight or icterus after 5-10 years. These unspecific symptoms are often caused by an increasing tumor volume or displacement of other organs by these slowly growing tumors. This often results in an extended diagnostic work up, until the carcinoid has been finally identified as the reason. The other half of the carcinoids is hormone producing, whereby the hormones can be decomposed in the liver in the early stages. With increasing disease duration, however, the tumor will often metastasize into the liver so that the liver function is reduced whereby the hormones cannot be decomposed sufficiently. This often leads to the typical carcinoid syndrome with flush symptom (red face or upper body), connected to heart trouble and sweats, cramp-like stomach aches, diarrhea and possible respiratory problems. The second frequent GEP-NET is the gastrinoma. It is often found in the pancreas and the duodenum (part of the small intestine), less frequently in other organs. The gastrinoma produces gastrine, which stimulates gastric-acid production. As a result the stomach will acidify, often leading to ulcers in the small intestine and to diarrhea. The insulinoma is almost as frequent as the gastrinoma. It originates from the insulin producing cells of the pancreas and emittes insulin in uncontrollable fashion. Thereby, the blood sugar level will often fall dramatically. This leads to e.g. weakness, shivering, hunger, and sweats. In this case, blood sugar must be controlled regularly.
In addition glucagonomas (pancreas), VIPomes (pancreas) somatostatinomas and, as a special case, the MEN syndrome must be mentioned. The letter means several hormone active tumors, occurring at the same time, such as insulinoma, glucagonoma, and gastrinoma. The common diagnostic procedure is proof of the primary tumor and search for metastases (e.g. by ultrasound, magnetic resonance tomography or computer tomography). In addition, functionally active tumors can be revealed in the laboratory chemistry by a corresponding increase of hormone levels in blood or decomposition products in urine. A peculiarity of the GEP-NET are specific receptors on the tumor cell surface, which serve as docking station for the hormone somatostatin. Whilst these so-called somatostatin receptors (SSTR) also occur in normal tissue, the density at the tumor cell surface is highly elevated.
This property makes these tumors accessible to nuclear medicine procedures for diagnostics and therapy. For that radioactively marked protein elements (somatostatin analogues) similar to somatostatin are intravenously given to the patient. They bind to the somatostatin receptors and, due to the bound radioactive nuclide, can be registered with a dedicated camera (PET/CT scanner) for diagnosis. Since the resolution of the PET/CT examination is clearly better than with a common gamma camera, and since it offers additional morphological information (exact illustration of anatomical structures by computer tomography), sensitivity of tumor detection with these modern procedures can be clearly enhanced.

Somatostatin analogues labelled with therapeutically active nuclides can be used for a specific internal radiation therapy (peptide radio receptor therapy; PRRT). PRRT of neuroendocrine tumors is a new and promising therapy option in addition to the common standard therapies (surgery, local treatments, bio therapy (Sandostatin/Interferon), chemotherapy). Thereby, somatostatin analogues (peptides) are labelled with therapeutically effective radioactive beta emitters (usually Lutetium-177) (e.g. [177Lu]DOTATATE). Administration of these substances makes an internal radiation therapy possible which selectively acts on the tumor cells and only delivers low radiation burden to the healthy tissue (the kidneys are substantially exposed to radiation due to excretion and the bone marrow is substantially less affected). Compared to other radioactively labeled smatostatin analogues the use of [177Lu]DOTATATE, minimizes the risk of permanent damage to the kidneys, if normal or only slightly impared kidney function prior to PRRT is proven. This procedure is in particular suitable for patients with highly differentiated slowly growing tumors/metastases, which are less accessible for chemotherapy as experience shows, and where the surgical or local (radio frequency ablation/chemo-embolization) possibilities are exhausted. Patients with a progress under drugs with somatostatin analogues or patients with marked clinical symptoms may benefit from a PRRT. The treatment results of this therapy from various centers in Europe (Munich, Rotterdam, Basel, Milan, Bad Berka) show a high tumor response rate (response rate up to 40%) and in particular a clearly positive effect on clinical symptoms and survival.

How is the PRRT done?

All patients will be discussed prior to therapy in an interdisciplinary tumor board, with specialists for internal medicine, surgery, radiation therapy and nuclear medicine participation, to distinguish the best therapy strategy.

Preparation

To prevent occupation of SSTR with the depot sandostatine which is often administered in therapy (thereby, less binding sites for the radioactive peptide would exist), this treatment needs to be stopped at least 6 weeks prior to therapy. Due to the possible induction of kidney damage by the PRRT, detailed tests of the kidney function prior to the start of the therapy and as follow-up controls prior to further therapy cycles are performed. These include measurement of the glomerular filtration rate and tubular extraction rate of the kidneys with two nuclear-medical processes (99mTc-DTPA-scintigraphy and 99mTc-MAG3-scintigraphy) in addition to the common laboratory tests (creatinine and urea). Furthermore the SSTR expression of the tumor will be tested prior to further therapy cycles with the above mentioned nuclear medical diagnosic prcedures (PET/CT). Depending on the kind of tumor and the prevailing symptoms, further tests such as tumor marker (chromogranin A, NSE etc.), long-term ECG/blood pressure measurement or blood sugar day profile may be needed.

Therapy

For the actual therapy, a venous cannula is set and connected to an infusion system. Approximately 30 minutes prior to the actual application of the therapeutic substance, an amino acid solution for protection of the kidneys is administered, preventing an extensive uptake of radioactive peptide in the kidneys. This is continued for 4 hours. The radioactively marked peptide is then also applied via the same venous cannula by an perfusor for 15 minutes. During the therapy, pulse and blood pressure will be controlled regularly. According to the radiation protection guideline, staying in the therapy unit for 48 hours is mandatory after therapy. During this period, whole-body scintigraphies are done directly after infusion of the radio-peptide, as well as after 24, 48 and 72 hours for dosimetric purposes in order to estimate the doses in the tumor and the kidney. In addition, blood will be controlled regularly. During the therapy, sufficient liquid must be taken.

Which side-effects may the PRRT have?

Amongst the side-effects known to date are unspecific symptoms such as headache and fatigue. An increased flush symptomatology may occur for several days. After therapy, nausea and vomiting may occur. Rarely an accelerated tumor cell destruction can cause a high emission of hormones, that may result in circulatory and respiratory problems, headaches and neurological symptoms. Moreover, changes to the blood count with a reduction of the number of red blood corpuscles (erythrocytes), blood platelets (thrombocytes) and white blood corpuscles (leucocytes) are possible; therefore, monthly control after therapy is recommended. Due to the radiation burden on the healthy liver tissue, the liver function may be impaired. Therefore, the liver parameters should be controlled, too. Loss of hair is temporarily possible. Rarely allergic reactions to the therapy substance might occur. A repeated therapy may result in a reduction of the kidney function. Precaution is taken in our team, that a competent specialist is available if side-effects occur. The therapy is usually performed in several cycles, depending on the SSTR expression of the tumor, kidney function and organ dose achieved (limiting organ is the kidney). This is controlled prior to each cycle. After therapy, regular controls with sonography, PET/CT and kidney scintigraphy are planned.

Which drugs will be given additionally?

To ensure sufficient hydration, 1.5 liters saline solution per day will be infused via the vein starting with therapy. Optionally, painkillers and drugs against nausea/vomiting will be given if needed.

Inclusion and exlusion criteria