New treatment of bone metastases

New treatment of bone metastases in prostate cancer

Illustration 1: Con focal microscopic immunofluorescence image of metastatic cancer cells. 

Bone metastases are the most common form of metastases in prostate cancer. The high-grade (Gleason score >/= 8) prostate tumors, in particular, metastasize in bones in more than 50% of all cases. Even in case of early detection, surgery and/or radiation therapy of the prostate will not protect against a renewed growth of the cancer (called recurrence), lymph node or bone metastases.

With ECT (Electrochemotherapy) and IRE (Irreversible Electroporation), two new, more gentle methods are available for the local treatment of bone cancer. Both methods destroy the cancer by means of strong electric fields, without the necessity of irradiation, while preserving surrounding organs and the bone structure. The precise control of these therapies is ensured by a virtual space, generated by infrared sensors, MRI (Magnetic Resonance Imaging) and 3D CT (Computer Tomography), in which the surgeons can look into the patient. 

Diagnosis: bone metastases because of prostate cancer

Bone metastases, also known as osseous metastases, are malignant secondary tumors in the bones, which are developed by the colonization (metastasizing or “spreading”) of cancer cells of the primary tumor in the prostate. Bone cancer is most commonly a result of a primary tumor which formed metastases in the bones. In men the most common of these primary tumors is prostate cancer. Even if the prostate is removed by surgeon and/or treated with irradiation, metastases may have already formed.

Once the prostate cancer reaches the stage of metastases, the statistical life expectancy declines rapidly: a guideline is a 5-year survival rate of around 30%. Of course for the individual patient this mean value does not say much: the actual survival time depends on many individual factors, like the strategy of the treatment and the ability of the immune system to keep the cancer at bay. Latest studies have shown a correlation of the rigorous reduction of the tumor mass (meaning the selective destruction of as many metastases as possible) with the longest survival time. The concept of treating metastasizing cancers with just systemic treatment (treatment which includes the whole body) with hormones and/or chemotherapy is obsolete.

In an early stage prostate cancer as well as in prostate cancer which has already scattered, a precise diagnostic for the exact assessment of all cancer foci and the targeted use of the latest technologies and best therapies are the keys to success.

Diagnosis of bone metastases: PSA, MRI and the PSMA-PET

Symptoms of bone metastases (bone cancer) are:

  • pain in the bones
  • weak bones, high risk of bone fractures
  • spinal compressions and accompanying back pain, and possibly weakness or numbness in extremities
  • high calcium levels in the blood values
  • stiffness or pain in the hip or back
  • before treatment of the prostate itself: usually very high PSA values (higher than 20 ng/ml)
  • after treatment of the prostate (ectomy and/or antihormonal therapy): re-increase of the PSA value to over 0

Despite prostate cancer screenings, these forms of cancer occasionally are still discovered as late as when the bone metastases are already formed. The reason is simple: prostate cancer itself does not cause any pain in the first place and problems with urinating or blood in the urine are rare too. So a prostate cancer can grow undetected for decades, until it is discovered incidentally and after it has already scattered. Now the osseous metastases cause problems and pain.

In case of noticing any of these symptoms, an immediate and precise diagnostic procedure is essential. Although ultrasound and bone grafting are still used today for the so called re-staging, these diagnostic methods are obsolete. Multiparametric MRI of the prostate, full-body MRI and PSMA-PET (Prostate-Specific Membrane Antigen Positron Emission Tomography) are much more precise, can detect cancer foci earlier and can distinguish them from benign growths much more reliably. So MRI and PET are the basis of modern, cancer-focused therapies such as IRE and ECT.

IRE and electrochemotherapy (ECT): a new treatment of bone metastases without irradiation and surgery

The most commonly used method to treat bone metastases is irradiation (radiation therapy). Due to the high doses of radiation (up to 60 Gy, 30,000 times the natural annual radiation doses), a certain amount of damage to healthy tissue is unavoidable. The ionizing radiation causes damage to the genome of the affected cells, which can lead to chronic inflammation and scarring. The natural healing capacity is reduced rapidly as well, so the bones are more likely to fracture and heal worse. Also, operations in the radiated area are severely restricted. Irradiation is usually not repeatable, since doses higher than 60 Gy lead to tissue necrosis.

If, nevertheless, radiation therapy has to be performed, for example because the patient is not able to be anesthetized due to a poor health situation, use of a more modern and more targeted radiation-surgical method, such as NanoKnife or proton therapy should be considered.

With NanoKnife and ECT it is now possible to treat bone cancer more gently and with minimal side effects. Fine electrodes are placed in a minimally-invasive manner into the bone, while under control of MRI and CT. Than latest generators apply ultrashort very high electric fields (voltage), which cause a Reversible Electroporation (RE) or Irreversible Electroporation (IRE) of the cell membranes. Find more details here. 

Because of the electroporation, small pores (nanometer-sized holes) are formed in the cell membranes for a short time, which makes them permeable to molecules which normally cannot pass through the cell membrane (Illustration 2). If during this phase of the pore formation a chemotherapeutic (which under normal circumstances is not able to pass through the membrane) is applied (like Bleomycin) it will be absorbed in a greatly increased manner. As a result the chemotherapeutic has to be applied only once and in a smaller doses. Bleomycin is not causing any damage in healthy cells under these conditions. But in cancer cells Bleomycin has a particularly strong effect, because it will attack the DNA, which is accessible only during cell division. Cancer cells have a significantly higher cell division rate than healthy cells. That is why the chemotherapeutic, which is 1,000 to 10,000 times more effective under electroporation, primarily kills cancer cells (cancer cell selectivity).

Illustration 2: The left picture shows the placement of the electrodes through the skin into the affected bone. Under general anesthesia usually 2-10 needles are placed computer controlled, depending on the size and the location of the metastasis. The diagram on the right shows the procedure of the ECT: after the intravenous injection of the chemotherapeutic it will not be absorbed by the cell until the electric pulses cause pores in the cell membrane. Now Bleomycin can enter the cell. After the electroporation ends the pores will close again, the chemotherapeutic remains trapped in the cell and kill it at the next division (mitosis).1

The use of IRE and ECT is not accompanied by an increase of temperature in the tissue nor with denaturation of proteins. Since the effects are based on formatting of the cell membrane and not on the extracellular matrix, a complete recovery of the surrounding tissue is possible. The structural integrity of the bone is maintained during the whole process, which makes this treatment a very gentle procedure for the bone.

Within a month, the osteogenic activity of the bone in the treatment zone will increase, so the normal bone structure will be restored.

Illustration 3: Microtomographic images of treated bone metastases: Control = no metastases; MET= untreated bone metastases; MET + Bleo = bone metastases treated several times with Bleomycin I.v. MET + EP = Bone metastases treated with electroporation ECT= bone metastases treated by electrochemotherapy While the treatment of the osteolytic lesions with Bleomycin and EP will cause a damage on the bones (or is completely ineffective), no damage is seen in a treatment with ECT, while the metastasis is removed completely. 2


The treatment is performed only once, is completed within 24 hours and requires only one overnight stay in the clinic. Due to the minimal invasiveness, patients can return to their daily routine the next day.

Precise surgery instead of large area radiation: the combination of CT, virtual systems and MRI allows reliable diagnostic and precise treatment of bone metastases

Medicine is moving towards more and more selective, more biologic and more gentle methods. The new methods based on PEFs (Pulsed Electric Fields) such as IRE (Irreversible Electroporation) and ECT (Electrochemotherapy) present a new peak of precision, effectiveness and selectivity. Completely computer-assisted, designed and performed with modern imaging techniques like MRI and CT, they allow maximum precision for a wide range of cancer—without radiation, burning or surgery.

Illustration 4: Cascination CAS ONE Infratorot VR-Computer Guidance System. 

Illustration 5: CT controlled treatment of a bone metastasis in our Center


Using immune effects: new possibility for CRPC (Castration-resistant Prostate Cancers) by combining therapies

ECT and IRE both cause strong secondary immunological side effects. These can be used synergistically with immunotherapies, like monoclonal antibodies. 

Local therapies, antihormonal therapies and immunotherapies—we’ll give you get the best advice

Rarely, a metastatic prostate carcinoma can be cured by a single intervention or radiation. In order to achieve maximum tumor control with minimum loss of life-quality, a guided therapy is necessary which optimally takes into account all available methods: local tumor removal, antihormonal therapy, as well as irradiation, chemotherapy and immunotherapy. To control and combine all of these methods in the most useful way, various medical specialists as well as modern diagnostic methods by means of tumor marker and optimal imaging techniques are required. Only in our Center in Offenbach can you can find a cross-disciplinary team with all these requirements together in one specialized Center.

No matter which path of therapy you choose, we will inform you about all the possibilities that are at your disposal.

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References:

1. Haberl, S., Frey, W., & Rubinsky, B. (2013). Cell Membrane Electroporation — Part 2: The Applications. IEEE Transactions on Biomedical Engineering, 29(1), 29–37.

2. Fini, M., Salamanna, F., Parrilli, A., Martini, L., Cadossi, M., Maglio, M., & Borsari, V. (2013). Electrochemotherapy is effective in the treatment of rat bone metastases. Clinical & Experimental Metastasis, 30, 1033–45. Also: Fini, M., Tschon, M., Ronchetti, M., Cavani, F., Bianchi, G., Mercuri, M., … Cadossi, R. (2010). Ablation of bone cells by electroporation. Journal of Bone & Joint Surgery, 92, 1614–1620. https://doi.org/10.1302/0301-620X.92B11.24664