Therapy with metaiodobenzylguanidine (MIBG)

Therapy of pheochromocytomas/paragangliomas

Background

Pheochromocytoma is one of the most common diseases of the chromaffin cells of the adrenal medulla with an incidence of 1/100,000 persons/year. It is a tumor that produces catecholamines (noradrenaline, adrenaline and metanephrines). It is 85% localized in the adrenal medulla, but also occurs in the nerve cells of the thoracic and abdominal cord (paraganglioma), where it produces almost exclusively noradrenaline. Approximately 15% of pheochromocytomas are malignant, with varying percentages reported in the literature.

Pheochromocytoma occurs in isolation or as part of MEN 2 syndrome (multiple endocrine neoplasia), von Hippel-Lindau syndrome and neurofibromatosis type 1 (Recklinghausen's disease).

Typical symptoms are mainly paroxysmal high blood pressure (paroxysmal hypertension) or permanent increases in blood pressure (persistent hypertension, often in children). During the phases of increased blood pressure, headaches, dizziness, palpitations and sweating may also occur. Other signs include pale skin, increased blood sugar (hyperglycemia), leukocytosis and weight loss.

The diagnosis is based on the clinical symptoms. Particularly suspicious are sporadic attacks of high blood pressure that do not respond to the usual drug therapies. As a pheochromocytoma poses a serious risk to the affected patient, reliable laboratory diagnostics must be carried out. A number of methods are available for this purpose. These are primarily the determination of catecholamines (adrenaline, noradrenaline) or their degradation products (metanephrine and normetanephrine) from the 24-hour urine. The disadvantage of the aforementioned laboratory methods, however, is that neither a positive nor a negative result provides a reliable statement. This is only possible through the quantitative determination of metanephrines in plasma. If these are not elevated, a pheochromocytoma can be ruled out with certainty. The diagnostic sensitivity of this method is almost 100 %. However, if the metanephrines in the plasma are elevated even in repeated cases, there is a strong suspicion of a pheochromocytoma and further localization diagnostics must be carried out. This is done using imaging techniques such as computer tomography and sonography or MRI imaging.

In addition, tumor diagnostics can be carried out using the tumor-specific radiopharmaceutical meta-iodobenzylguanidine (MIBG). MIBG is a substance chemically related to adrenaline and noradrenaline, which is absorbed into the chromaffin granules of sympathoadrenal tissue in a similar way to the aforementioned hormones and is therefore primarily deposited in the affected chromaffin cells of the pheochromocytoma. The nuclear medicine method of MIBG scintigraphy is primarily used to localize pheochromocytomas outside the adrenal gland (pheochromocytomas in the adrenal gland are primarily diagnosed using CT/MRI). A more recent and reliable form of nuclear medicine diagnostics is the so-called [18F]DOPA-PET/CT. This uses the biological property of these tumors to take up more biogenic amines and then accumulate them in specific intracellular stores (vesicles). Compared to the surrounding normal tissue, the tumors show an increased uptake of [18F]DOPA and thus even the smallest metastases or even the primary tumor can be reliably visualized.

Treatment is carried out by surgical resection. In the case of a unilateral pheochromocytoma, the entire adrenal gland on this side is removed; in the case of MEN syndrome, only the adrenal medulla is removed on both sides. In 80 % of patients, catecholamine levels and blood pressure normalize postoperatively.

In the case of inoperable metastasis, systemic forms of therapy such as the administration of somatostatin analogs (Sandostatin) and interferons or, in some cases, chemotherapy can be used. Another option is specific therapy with radioactively labeled meta-iodobenzylguanidine. In this case, the MIBG is labeled with the therapeutically effective radioactive beta emitter iodine-131 ([131I]MIBG). The administration of these substances enables internal radiotherapy, which selectively affects the tumor cells and largely spares the healthy tissue. 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 where surgical or local (radiofrequency ablation/chemoembolization) options have been exhausted. A cure cannot be expected with MIBG therapy, but further progression of the disease can be delayed in up to 50% of cases.

How is [131I]MIBG therapy carried out?

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

Preparation

During MIBG scintigraphy/therapy, reserpine (e.g. as a combination in Briserin or Darebon) and tricyclic antidepressants (amitryptiline, imipramine and corresponding derivatives) have a detrimental effect on storage and should be discontinued beforehand. A less pronounced uptake reduction is caused by the alpha-blocker phenoxybenzamine (dibenzyran), but this medication can still be taken. Furthermore, delayed or reduced MIBG uptake is also described when taking labetalol, calcium channel blockers (diltiazem, nifedipine, verapamil), sympathomimetics (also in nasal drops), cocaine and phenothiazine; in this case, an individual decision should be made as to whether it is necessary to discontinue the medication prior to therapy.

In addition to the usual routine laboratory tests (blood count, liver/kidney parameters), the MIBG storage capacity of the tumor foci is checked with a diagnostic [123I]MIBG scintigraphy before each therapy. Depending on the type of tumor and the symptoms present, further examinations such as tumor marker determination or long-term ECG/blood pressure measurements may be necessary. Optionally, a [18F]fluoride PET scan or alternatively a skeletal scintigraphy with [99mTc]DPD is performed to clarify bone metastasis.

Therapy

For the actual therapy, an indwelling venous cannula is inserted and connected to an infusion system. The radioactively labeled MIBG is administered via an intravenous access as an infusion over 2 hours under constant blood pressure and ECG monitoring, as high blood pressure crises may occur, which must be treated with medication. Due to the radioactive radiation emitted, isolation on the therapy ward is necessary until a discharge value is reached. The length of stay on the therapy ward is usually between 3 and 6 days from the start of therapy. After therapy, a whole-body scintigraphy is carried out on the day of discharge to document the whereabouts of the radioactive substance. In addition, regular blood tests are carried out. Sufficient fluid intake must be ensured during therapy.

What side effects can [131I]MIBG therapy have?

Side effects do not usually occur; in rare cases in which the tumor tissue produces hormone-active substances, side effects may occur during therapy due to increased release of these substances from the tumor tissue into the bloodstream. The side effects known to date include non-specific symptoms such as headaches and fatigue. Acute high blood pressure crises in particular are possible. 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. In patients with extensive liver metastasis, radioactive irradiation of the liver tissue may cause swelling of the liver with temporary stretching of the liver capsule, which may cause pain. Prophylaxis with cortisone is therefore recommended for patients with pronounced liver metastasis. Precautions are 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 MIBG storage and laboratory parameters checked before each cycle. After therapy, regular check-ups are planned with sonography, CT and MIBG scintigraphy or [18F]DOPA PET/CT if necessary.

What additional medication is given?

A thyroid blockade with medication is administered before the start of therapy (Irenate administration: from 5 days before therapy until 10 days after therapy: 3 x 30 drops). In order to avoid possible side effects, concomitant medication is administered parallel to the MIBG therapy. One beta-blocker (propanolol (Dociton) 10 mg (1-0-1)) and one alpha-blocker (phenoxybenzamine (Dibenzyran) 10 mg (1-0-1)) are administered to prevent blood pressure crises in hormone-active tumors. Fortecortin is administered (intravenously on the day of therapy, then orally) to prevent any swelling of the liver in the case of extensive liver metastasis. As this medication can in turn lead to stomach problems, gastric protection (Pantozol) is also given during Fortecortin administration. If necessary, painkillers and anti-nausea/anti-vomiting medication are administered as an option.

Inclusion and exclusion criteria

Therapy for children with neuroblastoma

Neuroblastoma accounts for 7-8% of all childhood malignancies. In Germany, around 130 children are diagnosed each year. This corresponds to an incidence of 1 child/100,000/year.

It is a tumor disease of the nervous system that mostly affects small children up to the age of six. The average age at which a neuroblastoma is diagnosed is 2 years. Neuroblastoma arises from degenerated, immature (embryonic) cells of the sympathetic nervous system, which - as part of the autonomic nervous system - controls involuntary functions such as cardiovascular, bowel and bladder activity. Neuroblastomas can occur anywhere where sympathetic nerve tissue is located. They occur most frequently in the adrenal medulla (approx. 50% of cases) and in the area of the nerve plexuses on both sides of the spinal column, the so-called borderline cord. Accordingly, neuroblastomas can arise at any level along the spine: in the abdominal, pelvic, thoracic and cervical regions. In the majority of these cases, the tumor is located in the abdominal area, while around a fifth of tumors are located in the chest and neck area.

The first symptom is usually the visible or palpable tumor, which is often noticed during routine examinations and can secondarily lead to feeding disorders, vomiting or enteritis-like symptoms. The intrathoracic or mediastinal tumors, which occur mainly in infants, manifest themselves in coughing, the occurrence of stridor and dyspnoea and even the development of a paraplegic syndrome. In addition, there are general symptoms such as bone pain (very common), which can lead to a misdiagnosis of rheumatic disease or osteomyelitis. Fatigue and fever are also common. Signs of metastasis include pallor, fatigue and bleeding (bone marrow metastases), nodules on the skin (skin metastases) or changes in the eye (orbital infiltration).

Neuroblastoma is diagnosed in a similar way to pheochromocytoma/paraganglioma in adults by determining elevated concentrations of catecholamines or their metabolites in the urine. metabolites in the urine, the imaging detection of tumor tissue (sonography, MRI/CT), the histological detection of tumor cells from tumor tissue samples, the detection of tumor cells in the bone marrow aspirate and by the specific accumulation of [123I]MIBG in the primary tumor and, if applicable, the metastases in the scintigraphy (see Diagnostics for pheochromocytoma/paraganglioma).

In the early stages, surgical removal of the tumor alone is the treatment of choice; in more advanced stages, surgery is preceded by chemotherapy. Radiotherapy is also used if necessary. For children suffering from metastatic neuroblastoma, specific therapy with radioactive [131I]MIBG is also possible in principle. This is also carried out in our department under inpatient conditions, butthe indication and preparation for therapy are carried out exclusively by the Hauner Children's Hospital (Tel. Onkol. Day Clinic: 089/5160-4498 or 4499; contact: Dr. U. Graubner/Dr. I. Schmid).