Interventional oncology in prostate cancer.

Prostate cancer is the most common type of cancer in men. In developed countries, one out of every 6 men has prostate cancer. The frequency increases with age; 99% of cases occur above 50 years of age. Although it is a common cancer type, only a small proportion of prostate cancer leads to death; In the autopsy of people over 60 years of age who died due to other reasons, 30-70% were found to have incidental cancer in their prostate. In the first-degree relatives of prostate cancer patients, the risk of disease is twice as high as in normal individuals. This risk is higher in patients whose brother has prostate cancer compared to those whose father has prostate cancer.


What are the symptoms?

Prostate cancer usually does not give any symptoms. However, it can sometimes lead to complaints that mimic benign prostate growth, such as frequent urination, urination at night, pain during urination, and blood in urine. Bone pain, sometimes caused by bone metastases, may be the first sign of prostate cancer. Nowadays, most prostate cancers are detected with prostate biopsy just by chance performed because the PSA (Prostate specific antigen) is high in the blood.


How is it diagnosed?

For the early diagnosis of prostate cancer, it is generally recommended that a PSA (Prostate Specific Antigen) test be performed once a year for men over the age of 50, although it is controversial in some countries. Higher PSA increases the likelihood of cancer and additional tests are performed. However, PSA may also increase in noncancerous diseases such as benign prostate enlargement and prostate inflammation, and may not increase in some cases of prostate cancer. Nonetheless, since PSA is cheap and simple, it is considered the first step in prostate cancer assessment.


In people with high PSA levels, the classical approach is to perform a manual rectal examination followed by a rectal prostate biopsy. A small portion of prostate cancers may be felt in the hand examination and a biopsy can be performed if there is a suspicious finding. The classic prostate biopsy is performed by taking random samples (6-12) from various parts of the prostate, seeing the prostate with an ultrasound probe inserted through the rectum, but without seeing the tumor. These samples are then examined in pathology, and if cancer is seen, the growth rate of the tumor is evaluated by a grading system called Gleason score. For this, the pathologist gives a score ranging from 1 to 5, depending on the extent to which the tumor is different from the normal tissue. Since prostate cancers often have areas with different grades, a grade is assigned to the 2 areas that make up most of the cancer. These 2 grades are added to yield the Gleason score. Therefore, Gleason score is given as binary values like 4 + 3, 3 + 5, 4 + 5 and the sum of these values in practice varies between 5-10. Gleason 5 is the slowest and Gleason 10 shows the fastest growing (aggressive) tumor type.














In prostate cancer, the Gleason score shows the grade of the tumor giving an idea of the tumor's growth rate and the likelihood of metastasis. The prevalence of the tumor in the body is determined by the stage of the tumor and it is demonstrated by imaging methods such as PET-CT, CT and MRI. As with many other cancers, prostate cancer is also divided into 4 stages; In stage 1 and 2 the tumor is limited to prostate, in stage 3 the tumor is spread out of the prostate or into regional lymph nodes. In stage 4, there are distant metastases (usually in bones).


There are some problems in the classical diagnostic methods of prostate cancer:

1. In other organs, such as the liver and lung, a suspicious mass is first detected by methods such as ultrasound, CT and MRI, and then diagnosed is made by doing a biopsy from the suspicious mass under imaging guidance. However, in the prostate, the tumor is usually not seen on ultrasound, so patients with a high suspicion of cancer (high in PSA) are tried to be diagnosed by multiple random biopsies taken from the prostate. The prostate is the only organ in our body where cancer is diagnosed by "blind" biopsy.


2. In blind prostate biopsies, approximately 1/3 of prostate cancers can be overlooked. Furthermore, in about 1/4 of the cases, the Gleason score is lower than it actually is, which means it may appear to be less aggressive than it really is, which may result in delayed or unsuccessful treatment.


3. In some patients, the PSA is high but the biopsy may be normal. In this case, the biopsy is repeated by increasing the number of samples but again in a blind manner. However, many recurrent biopsies can cause problems such as bleeding and infection. In some cases, the biopsy is done from the region called perineum between the anus and the penis, instead of rectum. In this method, which is called saturation biopsy, multiple needle biopsies are performed from equally spaced holes using a mold placed on the perineum. This method is superior to the classical blind biopsy in detecting cancer, but requires more needle passes and therefore, intervention risk is higher.


Modern diagnostic methods in prostate cancer
While prostate cancer cannot be seen by most radiological imaging methods, it has been possible for the first time to detect it at an early stage thanks to the recent developments in MR imaging. Especially in new MR devices, approximately 80% of prostate cancers can be detected early with a technique called "multiparametric imaging". It is thought that cancers that MRI cannot show are more slowly progressing and thus, have less clinical importance. The tumors detected by MRI, can then be subjected to "imaging-guided" biopsy rather than "blind", and the patient can be diagnosed more accurately by targeted biopsy using much less needle passes . Imaging-guided prostate biopsy can be performed directly on the MRI device, as well as on ultrasound devices by fusion imaging (fusion imaging) combining MRI with ultrasound images.

MRI's ability to show prostate cancer at an early stage dramatically changed both the diagnosis and treatment of prostate cancer. Today, classical approaches are still applied in many centers around the world. However, in many developed centers, classical transrectal biopsy performed in prostate cancer was abandoned. In these centers, a multiparametric MRI is made in patients with high PSA levels and biopsy is performed only if a suspicious mass is detected. If the MRI is normal, the patient is continued to be followed up periodically.






How is prostate cancer treated?
Classical treatment methods in a newly diagnosed prostate cancer are surgery (radical prostatectomy), radiotherapy and active surveillance. In radical prostatectomy, the entire prostate is removed and the surrounding suspicious lymph nodes are taken out. If the cancer is aggressive (Gleason 7 and above) and limited to the prostate gland, the ideal treatment is radical prostatectomy. However, some patients may not be eligible for surgery (due to advanced age, heart-lung problems, etc.). The second most common treatment in such patients is the irradiation of the entire prostate (radiotherapy). In some cases, freezing (cryoablation) or heating (HIFU) treatments can be applied to the entire prostate.

If prostate cancer is not aggressive (Gleason 6 and below), if it is small, does not produce symptoms and the patient's average life expectancy is less (<10 years), "active surveillance" may be a suitable approach. This is because in this group of patients the cancer does not grow rapidly or metastasize and usually does not lead to loss of life. However, for this approach, non-aggressive prostate cancers should be reliably separated from aggressive prostate cancers. For this distinction, blind prostate biopsy alone is not enough. Therefore, multiparametric MRI and, if required, MRI or fusion guided biopsies are increasingly used in active surveillance. PSA testing, MRI and biopsy should be carried out at regular intervals in the active surveillance and the course of the tumor should be closely monitored. If necessary, treatment should be considered at any time. 

If prostate cancer has metastasized, hormonal therapy or chemotherapy is administered. In a significant proportion of prostate cancers, male hormones have an enlarging effect on the tumor. Therefore, the growth of the tumor can be slowed with some treatments that reduce these hormones. In some cases, classical chemotherapy drugs can be used to increase survival and reduce complaints.

Side effects of classical therapies in prostate cancer
Removing prostate cancer completely with the prostate gland (radical prostatectomy) can cure prostate limited cancer, but may cause significant side effects in many patients. The most important of these side effects are urinary incontinence, impotence and urethral stricture. In many studies, it has been reported that approximately 50% of patients developed urinary incontinence, 70-80% impotence and  10-20% urinary canal narrowing after radical prostatectomy. Robotic surgery developed in recent years is very popular among patients, but in many studies conducted in recent years, it has been shown that the rates of side effects of classical surgery and robotic surgery are the same. Since these side effects can reduce the quality of life considerably, many patients are reluctant to undergo surgery and search nonsurgical minimally invasive treatment methods.

Radiotherapy is the most commonly used one among these methods. The long-term survival rates of radiotherapy and surgery are similar in many studies. However, there are many serious side effects after prostate radiotherapy. As the bladder and large intestine receive high doses of radiation along with the prostate, urinary and stool problems, urinary tract and rectal hemorrhage are frequently seen after treatment. In about 1/3 of these patients, these complaints may persist for years. Just as in the surgery, approximately 60% of the patients develop impotence and 10-20% urinary canal narrowing following radiotherapy. In addition, radiotherapy itself is an important cause of cancer, and in about 1 to 2% of patients undergoing prostate radiotherapy, urinary bladder or small bowel cancer develops later.

In patients with prostate cancer who are not suitable for surgery or radiotherapy or who have recurrent cancer after these treatments, freezing (cryoablation) and heating (HIFU) treatments can be applied. In cryoablation, a special needle is inserted into the prostate under ultrasound guidance and the prostate gland is frozen. In HIFU, a special ultrasound probe placed in rectum sends sound waves focused in a single point within the prostate. In this focus, a temperature of about 80-100 degrees occurs while the temperature decreases as it moves away from the focus. This focus is also moved in the prostate and thus the entire prostate gland is destroyed by applying 80-100 degrees of heat.

Both cryoablation and HIFU are very successful methods for the treatment of prostate cancer. They are generally used in patients who are not suitable for surgery or radiotherapy, or have relapsed after radiotherapy, and are applied to the entire prostate gland. However, when applied in this way, cryoablation and HIFU may also cause complications such as incontinence, impotence, urethral stricture and fistula. For this reason, in recent years, these methods are preferably used a part of the prostate where tumor(s) are located (focal therapy). In this manner, not only cancer is killed but also serious side effects may be prevented.

New concept in prostate cancer: focal treatment

Focal therapy is the treatment of the region of the tumor, not the entire prostate gland. For this treatment to be appropriate, the tumor must be small, limited to the prostate and non-aggressive (Gleason score <7). For the following reasons, focal therapy is increasingly used nowadays:

1. Today, just like breast cancer and thyroid cancer, most prostate cancers can also be detected at the early stage, ie when the tumor is still small and has not metastasized. This is due to the widespread use of PSA testing, MR imaging and biopsy.

2. Most of these detected cancers have a slow course therefore, do not lead to death.  Active surveillance may be recommended for these patients. However, many patients prefer being treated by a method with little side effects rather than waiting.

3. In about 1/4 of patients, prostate cancer is more aggressive, and classical therapies are surgery or radiotherapy in these patients. However, some patients may still prefer focal therapy because of the high rate of side effects after these treatments.

How is focal therapy done?
Today, there are options such as Cryoablation, HIFU, Laser and Nanoknife for focal therapy. The most commonly used ones are cryoablation and HIFU. In cryoablation, several cryo needles are placed at the edges of the tumor and the cancerous tissue is frozen by freezing. A reliable ablation can be performed by preserving the surrounding tissues as the ablation area can be easily seen on ultrasound, MRI and CT. Since the side effect is much lower, it is generally preferred to freeze half of the prostate where the tumor is located, instead of freezing the gland completely. 


HIFU kills the tumor with sound waves sent into the prostate from a probe located in the rectum. These sound waves are focused at one point through a lens and 80 to 100 degrees of heat is generated. This focus is moved around in the tumor and the entire tumor is destroyed. It is a noninvasive treatment method (no needles are put into the patient). However, the ablation area cannot be clearly monitored during the procedure. There is also the possibility of damage to tissues and organs close to the focus where the heat is formed. However, it is still one of the most common treatment options for focal therapy.





In recent years, Nanoknife (IRE) method has also been used in prostate cancer. The most important advantage of this method is the less damage to nerves and urine channels. Therefore, it may be preferred in tumors close to the urethra and important nerves in the prostate. For nanoknife ablation, 3-4 special electrodes are placed around the tumor with ultrasound guidance and these electrodes are given very high dose (3000 volts-50 ampere) but very short duration electric current. Due to permanently increased cell wall permeability, tumor cells lose their vitality. This method, which is applied in some liver and pancreatic tumors, is one of the most promising methods in the focal treatment of prostate cancer.

Prostate cancer

Image guided biopsy in the diagnosis of prostate cancer.
Nanoknife ablation (Irreversible electroporation) in prostate cancer.
HIFU in prostat cancer.
Cryoablation is a viable treatment option in prostate cancer.
Value of multiparametric MRI in the detection of prostate cancer.

Interventional oncology in cancer management

Prof Saim Yilmaz, MD

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