Diagnosis and treatment of neuroblastoma in Germany

Leading university hospitals today can offer highly effective and affordable treatment of neuroblastoma in Germany for foreign patients.

Neuroblastoma is a cancer of the nervous system that affects mostly infants up to the age of six.

It arises from immature (embryonic) cells of the so-called sympathetic nervous system, SNS.

These cells, being part of the autonomic nervous system, control all the involuntary functions, such as cardiovascular, bowel and bladder function.

In Germany, neuroblastoma is considered the second most common cancer in children after acute lymphoblastic leukemia.

About one in every 100,000 children is affected each year. According to the Children's Cancer Registry, 150 new cases are registered in the country annually.

The likelihood of developing a neuroblastoma decreases rapidly with age. In about half of the cases, the disease occurs within the first 15 months of life. About 90% of children are less than six years old. Boys are slightly more affected than girls.

Choosing the best hospital for diagnosis and treatment of neuroblastoma in Germany, you should give preference to certified centers for pediatric oncology (Kinderonkologische Zentrum). 

Altogether, there are more than 80 specialized clinics and departments that treat children and adolescents with cancer. Of these, 21 currently have the seal of quality of the German Cancer Society (Deutschen Krebsgesellschaft), which is valid for two years. In addition, it is necessary to take into account the clinical experience of a particular specialist, the technical capabilities of the center, as well as the availability of experimental treatment.
 
Among the best centers for the treatment of neuroblastoma in children:
 
• Charité - Universitätsmedizin Berlin
• Hopp Children's Tumor Center at the NCT Heidelberg
• The Comprehensive Cancer Center Freiburg (CCCF)
• University Children`s Hospital of Cologne
• University Children`s Hospital of Frankfurt
• University Children`s Hospital of Essen 

Possible causes and symptoms of neuroblastoma 

Neuroblastoma may also be present in older children and in isolated cases in adults. From the other side, the maldevelopment of the nerve cells may start before birth and may be a consequence of chromosomal changes or gene alterations (mutations). There are families in which neuroblastomas are more common (about 0.2% of patients). However, in the majority of cases, the causes are unknown. There is no conclusive evidence that there is a relationship with any medications or events during pregnancy.

Many patients with neuroblastoma have no symptoms. The tumor is sometimes discovered by chance, for example during a routine examination by the pediatrician or during an ultrasound exam or MRI. As a rule, complaints arise at late stages, including after the formation of metastases.

Other symptoms that may indicate a neuroblastoma in children are:

• Fatigue, weakness, and paleness
• Persistent moderate fever of unknown origin
• Lymphadenopathy (enlarged lymph nodes)
• Abdominal swelling and pain
• Constipation or diarrhea
• Loss of appetite, nausea, and vomiting
• High blood pressure
• Bone pain

The symptoms listed above may be caused by many other diseases. Diagnosis of neuroblastoma should be carried out by professionals with sufficient experience in pediatric oncology.

The symptoms of neuroblastoma vary depending on the location of the tumors. Palpable masses may be the first symptom. Tumors in the abdomen can cause a urinary retention. If the tumor is located in the chest, pressure on the lungs can lead to shortness of breath. Some tumors grow into the spinal canal and lead to paralysis. Horner's syndrome can occur in neuroblastoma of the neck.

In metastatic neuroblastomas, bruising around the eyes (monocular hematoma) may occur.

Diagnosis of neuroblastoma in Germany

If there is a suspicion of a neuroblastoma, your doctor initiates the necessary examinations immediately. Although imaging techniques are very useful, laboratory diagnosis (including tissue microscopy) is crucial in this case. Consultation with an experienced pediatric oncologist in Germany costs at least $400.

Important steps for the detection of a neuroblastoma are:

• Physical examination
• Laboratory tests
• Ultrasound examination (sonography)
• Magnetic Resonance Imaging (MRI) or Computed Tomography (CT)

Blood and urine tests

The so-called tumor markers are determined. Tumor markers are substances that can be elevated in the body in case of a tumor disease. Tumor markers in neuroblastoma include metabolites of certain hormones, catecholamines (homovanillic acid), and neuron-specific enolase (NSE). If these substances are elevated at the time of diagnosis, these laboratory tests can be used during and after cancer treatment to control disease progression and treatment success.

Ultrasound examination

If a neuroblastoma is suspected, an ultrasound examination is usually carried out. Using the power of modern equipment, a doctor can determine the size and location of a tumor. Ultrasound imaging is particularly useful for neuroblastomas in the abdomen or in the neck area. For tumors in the thorax, the ultrasound is not used because air and bones distort the image.

If the doctor actually detects a tumor, the liver and lymph nodes near the tumor are also examined for secondary tumors. Ultrasound exam costs $500 or more, depending on the case. The ultrasound examination is painless and completely safe. The exam can be repeated as often as the clinical situation requires. This method does not cause any harmful effects.

MRI and CT scan

The magnetic resonance imaging (MRI) makes it possible to present the body in multiple layers, using powerful magnetic field and radio waves. No ionizing radiation is involved. The computed tomography (CT) is a special X-ray method. Multiple scans create a cross-sectional image of organs and tissues to visualize the tumor and its relationship to adjacent structures.

In contrast to ultrasound, these methods can also detect very small tumors. If the neuroblastoma is close to the spinal column, magnetic resonance imaging can be used to determine whether the tumor is in contact with the spine and if there is a risk of paraplegia. If the neuroblastoma has already formed secondary tumors, an MRI or cranial CT scan is usually necessary to exclude metastases in the brain. Computed tomography carries certain risks associated with radiation. But there are other medical considerations that outweigh the potential risks.

The choice of imaging method should be entrusted to your doctor. More sophisticated techniques, such as PET / CT, are also used. The cost of PET / CT in Germany is $2000-3500.

MIBG scintigraphy

Scintigraphy is an imaging method that uses radioactive substances to detect metastases. In MIBG scan, small amounts of the radioactively labeled substance meta-iodobenzylguanidine (MIBG) are injected. It accumulates in neuroblastoma cells. Then a special sensor locates areas of suspected metastases, such as the bone marrow, lymph nodes, liver, or brain. This technique can be successfully used in most cases, but a few so-called MIBG-negative neuroblastomas do not accumulate this substance.

Bone marrow examination

Neuroblastoma cells can occupy the bone marrow. Since very little bone marrow involvement cannot be detected by MIBG scan, bone marrow aspiration must be performed to exclude metastases. The doctor uses a thin needle to take a few milliliters of bone marrow into a syringe. In addition, he can use a somewhat thicker hollow needle (bone marrow biopsy punch) to take a 2 cm long tissue cylinder. The pain-sensitive periosteum is anesthetized before the procedure.

Since the neuroblastoma does not always affect the entire bone marrow, punctures are necessary in several places. The tissue is then examined under the microscope.

Even though the above-mentioned methods are very likely to detect or rule out a neuroblastoma, definitive confirmation of the diagnosis is only possible by the histological examination of tumor tissue, which is usually carried out during the surgery.

Additional tests

Today, molecular genetic examinations are usually used for treatment planning. During preparation treatment additional tests may be recommended to test the function of internal organs. These include, for example, liver function tests, hearing test, ECG and echocardiography (to check the function of the heart muscle), kidney ultrasound and a kidney function tests. In some cases, angiography (blood vessel imaging) may also be indicated.

When all the test results are available, your doctors can decide which treatment is better.

Methods of treatment of neuroblastoma in Germany

Once a neuroblastoma has been diagnosed and the tumor stage has been determined, doctors discuss further tactics. Involvement of a multidisciplinary team of specialists ensures the best treatment results and minimizes the risks for a little patient. In pediatric oncology, where patients have to grow and develop over the years after aggressive therapy, a multidisciplinary approach is especially important for making the right decisions.



Standard treatment options for neuroblastoma are:

• Surgical treatment
• Systemic chemotherapy
• Targeted molecular therapy
• Radiation therapy

These options are often used in combination. Sometimes they can be enhanced by 131-I-MIBG therapy, high-dose chemotherapy with autologous stem cell transplantation, and retinoic acid. The treatment choice depends on the type and stage of the tumor and the age of the patient.

Generally, there are three treatment concepts for neuroblastoma:

• Waiting: surgery and further observation without additional treatment
• Standard risk treatment: surgery combined with chemotherapy and radiotherapy
• High-risk treatment: surgery combined with high-dose systemic chemotherapy, possibly also radiation therapy. Additional methods (targeted therapy) are considered.
 
Waiting strategy and standard risk treatment are used in tumors that have not yet spread. Criteria for the classification are the tumor size, molecular genetic changes and the age of the patient. High-risk treatment is used for neuroblastomas that have already formed secondary tumors (metastases) in other organs. In the presence of unfavorable molecular genetic markers, the high-risk strategy is preferred. The therapy can take up to 2 years in this case.
 
If metastatic neuroblastoma occurs in infancy and the metastases limited to bone marrow, skin or liver, low-dose chemotherapy is often sufficient. 

Surgery 

The goal of surgical treatment is to remove the tumor without damage to surrounding structures or organs. A complete removal of the neuroblastoma tissue is not always possible, so that further treatment measures are required, including chemotherapy. Sometimes a surgery cannot be carried out initially because the tumor is too large or unfavorable, so there is a great risk of complications. In such cases, chemo can be used to reduce the size of the tumor (neoadjuvant chemotherapy).

After shrinking the tumor, surgical removal is often possible.

The cost of surgical treatment of neuroblastoma in Germany varies, as the tumor can be located anywhere in the body. In general, this figure is 2-3 times lower compared to the same procedure in the United States.

Chemotherapy of neuroblastoma

Chemotherapy is based on the use of cytostatics, which suppress the cancerous cells division. Cytostatics work well against rapidly growing cells. In neuroblastoma, chemotherapy is used when the tumor cannot be completely removed or when metastases are present. But even after complete removal, chemotherapy may be necessary to prevent cancer recurrence.

In order to achieve the greatest possible effectiveness against the tumor and to reduce the risk of side effects, combinations of different-acting cytostatics are used. They are usually administered IV. Therapy is given in several cycles with recovery periods.

Side Effects of Chemotherapy

Chemotherapy for neuroblastoma not only damages cancer cells, but also healthy cells that divide quickly. This can cause side effects that vary depending on the type and dosage of the medication. Although cytostratics are a serious problem for a growing children's body, German oncologists use advanced protocols to minimize toxic effects and to protect young patients during therapy. Side effects usually disappear with the end of chemotherapy. Common side effects include hair loss, nausea, vomiting, ulcers, constipation or diarrhea.

The effects of chemo on the bone marrow are particularly serious. The cytostatics affect the formation of healthy blood cells and platelets. As a result, there is a high risk of infections and anemia during the treatment. Bleeding may also occur, including bruising and nosebleeds.

If parents notice such signs, they should consult a doctor immediately!

Some cytostatics can also cause long-term damage to the heart, ears, kidneys or liver. Regular tests are therefore necessary in order to reduce the dose of chemo and initiate treatment if necessary.

High-dose chemotherapy

High-dose chemotherapy is designed to kill the neuroblastoma cells left in the body after standard chemo. It is usually used when the tumor has already spread to other organs. Unfortunately, the intensive treatment not only destroys the cancerous cells, but also the blood-forming bone marrow. For this reason, stem cells from the blood or bone marrow are taken from the patient before starting the high-dose therapy and reintroduced after the treatment (autologous blood stem cell or bone marrow transplantation).



The blood stem cells (the "mothers" of all blood cells) migrate back into the bones, settle there and begin to form new functional blood cells – erythrocytes, leukocytes, and platelets. Vital blood functions are gradually restored, and the child should feel a significant improvement.

During and after the phase of bone marrow transplantation, the patient is at high risk of infection. Therefore, strict measures must be taken to prevent complications. The technical complexity causes a very high cost of such treatment, which can exceed 150 thousand dollars.

Radiotherapy and Cyber Knife

Irradiation with high-energy beams inhibits the growth of neuroblastoma. Radiotherapy is not necessary for everyone. Typically, this method is used to destroy tumor tissue left after surgery. High hopes are pinned on modern computer-enhanced technologies, such as the Gamma Knife and Cyber Knife. The problem is that they are used only in the best hospitals of Germany and are much more expensive compared to the traditional radiotherapy.

Other methods of treatment

Occasionally, in addition to the standard procedures used to treat a neuroblastoma, additional methods are recommended. For example, innovative treatment with radioactively labeled methyl iodobenzylguanidine (131-I-MIBG therapy). Because MIBG binds mainly to neuroblastoma cells, this substance can be used not only to search but also to kill this tumor. MIBG molecules deliver a deadly radioactive load directly to the center of the tumor, keeping healthy cells safe.

MIBG therapy can be used after chemotherapy, if tumor is still found in the body. In recent years, German researchers have published many scientific papers on the use of MIBG therapy in high-risk neuroblastomas. Some centers, such as the University Hospital of Cologne, have accumulated vast clinical experience in this area. Other methods are also being tested to improve the treatment of neuroblastoma in Germany.

New methods are used to influence the body's own defense system in such a way that it can fight the cancerous cells (immunotherapy). Targeted therapy of neuroblastoma is actively developing, including the so-called ALK inhibitors. Furthermore, after successful standard therapy, retinoic acid is often used over a prolonged period in order to destroy any remaining neuroblastoma cells in the body.

These methods are also being tested to provide better treatment for patients with cancer recurrence and in the absence of a response to initial treatments.

Prognosis

Five-year survival in neuroblastoma in Germany today exceeds 80% (for children under 15, regardless of other factors). But the stage of the disease, the aggressiveness of the tumor and the age of the patient play a role.

The prognosis is better at stage 4S and also in younger patients with limited tumors. In older children with metastatic neuroblastoma, the chances of recovery are still unfavorable.

© Analytical reviews and oncology news by K. Mokanov: clinical pharmacist and professional medical translator