NEW METHODS FOR PROSTATE CANCER TREATMENT: IRREVERSIBLE ELECTROPORATION (IRE) AND PHOTODYNAMIC THERAPY (PDT) - Prof Dr med Michael K Stehling
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Prof. Dr. mult. Michael K. Stehling is a clinician and scientist who has worked in the UK, the USA, Switzerland, and Germany. As a physician and a physicist, he is involved in the development of improved methods of diagnosis and minimally invasive cancer treatment, the development of mesenchymal stem cell-based drugs, and the development of medical devices for the treatment of tumors, to name just a few of his areas of expertise.
Prof. Stehling was one of the pioneers in the field of focal treatment for prostate cancer. He introduced irreversible electroporation (IRE) and photodynamic therapy (PDT) into German clinical practice and is actively developing them. Thanks to his efforts, patients achieve remission from prostate cancer with a lower risk of erectile dysfunction and urinary incontinence.
Prof. Stehling now treats patients at the Vitus Clinic for Innovative Cancer Treatment and is the Head of the Department of Urology. In the interview, Prof. Stehling talks about the success of focal treatment for prostate cancer in Germany and the activation of the patient's immune system to defeat the cancer.
ABOUT STANDARD TREATMENTS FOR PROSTATE CANCER
Surgery remains the standard treatment for prostate cancer, with about 70% of men experiencing erectile dysfunction after surgery. About half of the men develop urinary incontinence, as a result of which urine is released involuntarily, and they have to wear special diapers.
Therefore, I must admit that most of the therapies used today for prostate cancer are ineffective. Although this is difficult for most patients and physicians to realize, this fact is supported by the number needed to treat (NNT). According to this indicator, a prostatectomy would be effective and increase life expectancy in just one patient out of 15 for whom it is indicated.
The life expectancy of the remaining 14 patients does not depend on whether or not surgery to remove the prostate is performed. Therefore, a prostatectomy will not be effective for these patients, but if surgery is performed, they will all be at risk for erectile dysfunction and urinary incontinence.
ABOUT IRREVERSIBLE ELECTROPORATION (IRE)
Clearly, such a situation indicates that the time has come for more sparing treatments for prostate cancer. One such method is irreversible electroporation (IRE). This therapeutic technique was developed by Professor Boris Rubinsky at the University of California, Berkeley. IRE has been around for a little over a decade. When I was a professor at Boston University, my colleague and friend Taksu Kim was the head of the Interventional Radiology Department there, and it was then that I realized that irreversible electroporation was the future of prostate cancer treatment.
ABOUT THE EXPERIENCE WITH IRREVERSIBLE ELECTROPORATION (IRE)
I then became the first physician to purchase two Engine Dynamics IRE units here in Europe. That's how we started treating prostate cancer with irreversible electroporation.
ABOUT THE RESULTS OF IRE FOR PROSTATE CANCER
We have been performing irreversible electroporation for more than 10 years. We have cured more than 1,500 prostate cancer patients from different parts of the world. We have achieved the results we initially expected. In our clinical practice, there are no cases of urinary incontinence after completion of IRE, and the incidence of erectile dysfunction does not exceed 3%.
After the statistics of successful treatment in our clinic were published on the Internet, patients from all over the world began to come to us for treatment with the IRE method. Reputable and well-known urologists, such as Prof. Mark Emberton from London and others, often recommend our services to their patients.
SHOULD IRREVERSIBLE ELECTROPORATION (IRE) BE COMBINED WITH OTHER TREATMENT METHODS?
The advisability of combining IRE with other treatments depends largely on the stage of the prostate cancer. When combining therapies, it is important to understand the indications for their use and the possible effect. For example, antihormone therapy can only suppress tumor growth for a while, but it cannot cure cancer. At the same time, antihormone therapy causes testosterone deficiency in men, which leads to suppression of the immune system. We now know that the immune system is a patient's "best friend" in cancer treatment because it can recognize and destroy tumor cells. Immunotherapy is therefore becoming increasingly popular in this context, and the combination of IRE and immunotherapy is currently the most promising approach to cancer treatment.
In the distant past, cancer was thought to be a tumor that could be surgically removed and cured. But it turns out that this is not the case at all, and a good historical parallel confirms this: in the USA, in the early 1900s, there was a surgeon named Halsted who treated breast cancer in women.
According to this surgeon, extensive breast resection would allow him to achieve the patient's recovery. He began to perform breast amputations on women. This was followed by chest wall, shoulder, and shoulder blade resections. Subsequently, the method that was supposed to cure women of cancer mutilated them. The surgeon's approach and the idea were to blame because he believed that the more extensive the resection he performed, the greater the woman's chances of recovery.
Today, we already know that this approach to treatment does not work. Surgeons perform a lumpectomy and remove the breast tumor, but cancer is a systemic disease, and the cause of death is the spread of tumor cells throughout the body. With prostate cancer, the situation is identical: a tumor in the prostate gland is only part of the oncological process.
It is the cancer cells that have spread throughout the body that cause the growth of metastases that lead to the death of the patient. Therefore, if we want to make prostate cancer treatment more effective, we need to target the systemic aspects of cancer pathology. This can be done with immunotherapy. And in this context, local treatment methods such as irreversible electroporation and photodynamic therapy are of particular interest. Why?
Treatment with local therapies releases tumor antigens. These are markers found on the surface of cancer cells. The immune system is able to recognize these tumor markers. This tells the immune system which cells in the patient's body to attack.
It is impossible to achieve such an effect with surgery to remove a tumor, because surgical removal of a tumor also removes tumor markers. This means that the immune system is deprived of the ability to receive information about cancer cells and recognize them. The use of irreversible electroporation and photodynamic therapy allows it to retain these properties. Many prestigious publications are dedicated to this topic. Thus, immunotherapy makes it possible to increase the immune system's response to cancer, which solves the problem of the systemic aspect of oncological diseases. It is this point that will largely determine the tactics of cancer treatment in the future.
WHICH METHOD IS BETTER: IRREVERSIBLE ELECTROPORATION (IRE) OR PHOTODYNAMIC THERAPY (PDT)?
The choice of the optimal treatment depends largely on the patient's preference, although many patients are concerned about the absence of side effects. We also take into account the location of the tumor in the prostate gland when choosing a treatment method, as each method has its own advantages and disadvantages. Therefore, we discuss everything with the patient, talk about the pros and cons of a particular type of therapy, and the patient makes his own decision.
UP TO WHAT STAGE OF PROSTATE CANCER CAN IRE AND PDT BE PERFORMED?
We can successfully treat stage 4 cancer. Unfortunately, conventional methods of treating T4 prostate cancer are often completely ineffective. For example, there are high risks that the tumor will cause bladder infiltration, and then an additional surgery is required to remove it, with the subsequent creation of an artificial bladder. This is how surgical treatment works. On the other hand, we have the opportunity to treat advanced stages of cancer with local therapeutic procedures without damaging adjacent organs.
Is the presence of metastases an exclusion criterion for prostate cancer treatment with local methods?
No, because even if metastases spread, the treatment is aimed at destroying the primary tumor, since it is the primary tumor that is the source of the cancer cells.
It is also important to reduce the size of the tumor. I mentioned earlier that irreversible electroporation or photodynamic therapy induces a secondary immune response. This is a point that we have noted at the very beginning of the performance of the IRE procedure. We treated patients with lymph node metastases in the pelvis by targeting only the prostate gland locally, and subsequently the lymph nodes shrank in size. This made us wonder why this happened, since the treatment was local and not aimed at reducing the size of the lymph nodes. And the answer was this: it was a secondary immune effect that developed during the treatment of a malignant tumor.
This information soon appeared in publications, and today we know that irreversible electroporation and photodynamic therapy induce immune responses. Today, we also have immunotherapy to further enhance the immune response. Thus, although IRE and PDT are treatments for primary prostate tumors, they also have a therapeutic effect on metastases, significantly reducing their size.
FOR WHAT OTHER DISEASES CAN IRREVERSIBLE ELECTROPORATION (IRE) BE USED?
For the first 10 years of our work with irreversible electroporation, we focused exclusively on prostate cancer. As an exception, we tried to apply IRE for breast cancer, but I was still convinced that we should focus on one thing and optimize the application of the method in a specific area. I believe that we have fully achieved our goal in the treatment of prostate cancer, and today, with the identification of the immune effects that this procedure induces, there are more and more opportunities to use IRE to treat other types of cancer.
Of course, we have to study the patient's medical reports to decide on the possibility of treating them. We are now successfully treating bladder cancer with photodynamic therapy and immunotherapy. We can also offer treatment for cervical cancer and breast cancer, especially triple-negative breast cancer.
Today, our impressive experience is focused on prostate cancer treatment, but we are also working to treat colorectal cancer with proven and effective methods.
ABOUT THE EXPERIENCE WITH IRE AND PDT IN GERMANY
There have been attempts to use IRE and PDT at university hospitals. The IRE procedure was performed at the Charité in Berlin for some time, but I think it is no longer available there. Possibly due to the fact that the specialist responsible for carrying out the IRE procedure no longer works at the hospital. I also once heard from patients that the Martini Clinic in Hamburg offers IRE treatment. There is also a clinic in Heidelberg that deals with IRE. I don't know exactly how many irreversible electroporation procedures were performed there; perhaps 100 or 200 patients received this treatment. Photodynamic therapy is also now available at this clinic. In general, there are doctors in Germany who specialize in performing IRE and PDT. We do not have any information about their experience, but quite often we notice that patients from these hospitals with particularly complex cases subsequently undergo therapy with us.
HOW LONG DOES IT TAKE TO COMPLETE IRE?
Patients are admitted to a private clinic and stay there for a few days. As a rule, the patient is admitted to the clinic the day before the procedure and undergoes preparation. The patient stays in the clinic one night and then another night after the intervention, and then they go home.
So the patient does not necessarily have to stay in our clinic for 10 days and then continue treatment in a rehabilitation center, as is the case with a prostatectomy. For example, if radiation therapy is prescribed, patients sometimes undergo 30-40 radiation sessions. As for our clinic, the patient will spend only 3 days here.
ARE THERE ANY AGE RESTRICTIONS FOR IRE AND PDT?
There are no age restrictions, but there are certain limitations related to the patient's health. IRE and PDT are performed under general anesthesia, and elderly patients cannot always tolerate it due to health problems. In such situations, therapy is not possible.
In my opinion, the best treatment option for elderly patients is radiation therapy, especially with the CyberKnife system. I believe that radiation therapy makes sense in these cases. And, of course, there are patients for whom treatment is inadvisable because of their age. I do not want to offend anyone, but if the patient is 80 years old and has been diagnosed with cancer with a Gleason score of 6, then treatment is not necessary. In this case, the newly diagnosed prostate tumor does not pose a threat to the patient's life, and this fact is also a relative exclusion criterion. There are patients who say that they cannot live with it and think about their diagnosis all the time, so they want to undergo treatment anyway. In such cases, we explain to patients that in certain situations there is no need for treatment.
HOW OFTEN DO PATIENTS HAVE COMPLICATIONS AFTER PDT?
Photodynamic therapy does not cause any complications. Since we started monitoring patients after PDT, we have never seen the development of erectile dysfunction or urinary incontinence. At the same time, we treat tumors that are located in close proximity to the sphincter or that infiltrate the sphincter.
Most interestingly, our data to date suggest that the ability to ejaculate may be preserved with photodynamic therapy. While we are still observing, we are evaluating this nuance. During IRE, the ability to ejaculate is not preserved. The ejaculatory ducts are tiny ducts that are destroyed during IRE. As far as photodynamic therapy is concerned, we have already had several patients who have had therapeutic interventions in this area and the ability to ejaculate has not been affected.
HOW ARE IRE AND PDT PERFORMED?
Both treatments, although minimally invasive, are performed under general anesthesia because the patient must remain completely still during the procedure. The applicator is positioned with millimeter precision. We are the only medical team to perform this step of the procedure manually. This approach may seem more old-fashioned than inserting the applicator using a special mesh. Most hospitals offer applicator insertion using a brachytherapy mesh, but it has many disadvantages, so I decided against it when I first started doing IRE. Manual insertion of the applicator ensures the highest precision of manipulation, which is very important. It is also necessary to exclude any movement of the patient, including unconscious twitching. Otherwise, the accuracy of the manipulation will be negatively affected.
From a technical point of view, treatment with IRE and PDT is not particularly difficult. The patient lies supine on the operating table. The patient's legs are fixed in an elevated position, which gives the physician free access to the pelvic floor. The pelvic floor is the layer of tissue between the anus and the scrotum, behind which is the prostate gland.
Needle-shaped metal electrodes about one millimeter in diameter are inserted through the pelvic floor. They are placed in the target areas of the prostate. The electrodes are then connected in pairs and generate very short but extremely powerful electrical impulses. Holes are made in the cell membrane between pairs of electrodes. In fact, this method has been around for a very long time and involves inducing the formation of pores in cell membranes, specifically electroporation. In cell biology, the technique is most often used to move a large molecule into or out of the cell, but then these pores close again. In irreversible electroporation, stronger pulses are generated so that the pores do not close and the cell subsequently dies.
WHAT DIAGNOSTIC TESTS DOES A PATIENT NEED TO UNDERGO BEFORE STARTING TREATMENT WITH IRE AND PDT?
Magnetic resonance imaging is currently the only effective and best method for staging prostate cancer and selecting and planning therapy.
ABOUT TREATMENT METHODS FOR BENIGN PROSTATIC HYPERPLASIA
There are several treatment options for benign prostatic hyperplasia. We offer GreenLight laser therapy, which is a standard of care. Excess prostate tissue, mainly around the urethra, is removed with a laser through the urethra. The disadvantage of this method is that a man loses his ability to ejaculate physiologically.
There is another method that we use to treat prostate adenoma, but we are not its authors. The technique is called Rezum and it is based on the use of steam. The principle of this therapeutic procedure is as follows: the prostate is approached through the urethra with an applicator, and then the prostate is treated with water vapor without damaging the urethra. The Rezum procedure allows doctors to relieve pressure on the urethra from the outside, allowing the patient to normalize urination. The procedure also makes it possible to preserve ejaculation. That is why the Rezum technique is very popular and highly effective. We have slightly modified this procedure. As a rule, the Rezum procedure is performed endoscopically, practically blindly, because the doctor can only see the surface of the urethra from the inside. We perform the manipulation under the control of rectal ultrasound, thanks to which we can clearly see where exactly the applicator is located. We also perform an MRI before the procedure. This allows us to better study the anatomical structure of the prostate gland and thus better control the progress of the treatment.
We do not perform surgery for prostate adenoma. We can perform transurethral resection of prostate adenoma using laser techniques or an electrical loop. The second option is the easiest. I have already mentioned that the incidence of complications in the form of problems with ejaculation after the Rezum procedure is much lower than when using other methods that also affect the urethra. It is also necessary to take into account other possible complications, such as bleeding. And it should be noted that when choosing the Rezum technique, other complications are much less common than when using other procedures to reduce the volume of the prostate through the urethra.
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