Prostate gland cancer, prostatic cancer, PCA

A number of possible risk factors was proofed within the last decades in some major studies:

Largely approved are the following risk factors:

Ethnical disposition:
The risk for Asians to suffer from prostate cancer in the USA is considerably increasing but the incidence is still lower as for the Americans living in the USA.

Family disposition:
Men with one ore more family members (father, grandfather, brother) suffering from prostate cancer have a statistically twice as high risk or even a 5 times higher risk of suffering form this cancer from. Therefore it should be started very early with preventive medical examinations, by far earlier than with men having no family disposition.

Overweight:
More and more indications show that overweight leads to a low PSA (= prostate-specific antigen) level in the blood. Because of this phenomenon overweighing patients are tested on prostate cancer delayed. In addition, patients with overweight often have a more aggressive form of tumours.

Nutrition:
The increase of prostate carcinoma with men living in countries with a lower risk of suffering from this cancer forms but, however, with a higher incidence gives indication that the life style of people plays an important role here. Nutrition seems to play an essential role.

Another risk factor is the job-related cadmium exposure that today can merely be prevented from by maintenance of industrial health and safety standards.

Other presumed factors like sexual activity and smoking play no essential role in developing this form of cancer.

Nutrition:
Nutrition and the intake of certain medication is seen as a prevention measure against prostate carcinoma.

It is seen likely that nutrition on the basis of fruits and vegetables (Mediterranean food style, Far Eastern food style) has a favourable effect on developing tumours and its spreading but without having the ingredients described in detail.

Substances that favour the development of a prostate carcinoma to an at least probable certain extend are so-called lycopin (tomatoes have a high level of lycopin). However, recent studies showed some contradictions. Selenium and – at least with smokers – vitamin E are other substances with an assumed preventive character. A final characterization is expected after termination of currently ongoing studies within the year 2008.

Compared with this, especially saturated fatty acids (SFA) and an increased consumption of dairy products can mine the development of prostate carcinoma.

An essential influence of smoke or alcohol does not exist.

Medication
The so-called Prostate Cancer Prevention Trial (PCPT) examined the preventive effect of the 5--Reductase Inhibitor Finasteride (Proscar) in a prospective randomized study with 18.882 healthy men older than 55 years.

Within the study group 24.1% less prostate carcinoma were found. The study results were criticized because the treated patients were diagnosed with considerable more aggressive tumour forms.

The results of the PCPT study were re-evaluated in large-scale studies within the last years. Within these re-evaluations the observed difference could be traced back only to the decreased prostate volume under Finasterid medication.

Other medication that could possibly have a preventive effect on prostate cancer are non-steroid antiphologistic medication (NSAID) like aspirin or so-called cyclooxygenase (COX) (eg. celecoxib) that are, however, complicated because of their side effects.

The stipulation of the prostate specific antigen (PSA) has overhauled the rectal palpation (DRU) in its acceptation. In the Western Industrial Countries the majority of prostate carcinoma is diagnosed due to an increased PSA concentration in the blood. The increasing spreading of the examination has caused a dramatic change in the spreading of the diagnosed tumours. In the year 1986 still more than 70% of all tumours had already spread and were metastatic when diagnosed by the doctors. In this stadium the cancer is incurable; however, today this rate has decreased to less than a third of all patients (picture 5).

However, the PSA stipulation has some disadvantages:

Not every increased PSA level indicates tumour growth (picture….). On the other side informing the patient about an increased PSA level often is a psychical burden for affected persons.

Due to the fact that men have an increased PSA value generally a further clinical diagnostic (tissue sample) is scheduled (however, not with every tumour form) and an immoderate diagnostic is made.

As today we have the possibility to even diagnose a less aggressive tumour (Haustier Cancer = untreated cancer that first becomes dangerous by the medical treatment itself named after Hackethal). However, the share of these benign and non-threatening tumours is very low in Germany.

Despite these indices it is not proofed that healing of prostate cancer is enhancing the expectation of life.

To sum up you can say that only by means of stipulating the PSA level in the blood, a prostate carcinoma can be diagnosed at an early curable stage!

Today it is tried to define the risk of patients more precisely by conducting further studies. The stipulation of the free PSA value in the blood serum or the so-called PCA3-gens out of prostate cells in the urine could give more criterions.

When patients having an increased PSA level or a conspicuous palpation finding, a tissue sample is withdrawn (punch biopsy). By means of this examination at least 6 tissue samples are taken from the patient under ultrasound control (picture 6). A number of urologists refer to the so-called “Vienna Nomogram” when it comes to the number of tissue samples. The Vienna Nomogram indicates the number of tissue samples to be taken under consideration of the patient’s age and the gland’s volume (chart 2 is missing). By means of the Vienna Nomogram an immoderate diagnostic as well as an insufficient diagnostic shall be avoided.

Special diagnostic challenges are patients where despite an unobtrusive tissue sample (negative results) a further increase of the PSA level can be observed.

In Germany, different than in most other Western Countries, the stipulation of the PSA level the costs for the test are not beard by the public health insurance. The argumentation of the health insurances tends to the fact that an extension of the patient’s life due to the PSA testing is not yet approved. However, It is critically annotated that several other medical services are beard by the public health insurances to a full extent. These medical services are by far not as good for the collection of further medical data as the PSA test is.

Advisory and stipulation are therefore not deducted on basis of the scale of fees for doctors (called GOÄ) and are largely calculated between EUR 20 – 25.

Screening:
Screening means a systematic examination of patients having no symptoms; these patients were chosen on the basis of certain rules and regulations.

The prostate carcinoma is due to its characteristics generally suitable for a screening. However, up to now it is not definitely clarified if a screening for example with men aged between 50 and 75 years has in actual fact extended their expectation of life. Nevetheless, there are numerous indications for a life-prolonging effect of the screening. Eagerly awaited are the results of the European ERSPC (=European Randomized Study of Screening for Prostate Cancer) and American PLCO (=Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial) screening trial.

Compared with this there is a wide reconciliation that the stipulation of the PSA level is currently the only screening instrument that really makes sense.

The so-called “opportunistic screening” is currently the most effective preventive examination. Men who wish to have a preventive examination for different various reasons (eg. alteration in urination, studying respective literature, internet search, cancer disease within the family or diseased friends) are undergoing a prostate palpation and a stipulation of the PSA level. If necessary, they also undergo a transrectal ultrasound of the prostate.

Dissemination and diagnostic measures
An important meaning for planning the medical treatment is the question how far the tumour has already spread. That is why the diagnostic measures to characterize dissemination play an important role. By means of all information that is on hand it shall be estimated if the tumour is confined to the prostate or if the cancer is already metastatic. Only as long as the cancer is limited to the prostate it can be healed.

The so-called staging of the cancer is made internationally after the so-called TNM system, whereby T stands for the primary tumour in the prostate, N stands for the revulsive lymph nodes and M stands for distant metastases.

The estimation of the T stadium is still made by rectal palpation. After it has come out that the spreading is often underestimated, today the so-called nomograms are used. The so-called Kattan nomogram calculates out of the palpation findings, the PSA level and the Gleason Score of the punch biopsy the plausibility that the tumour has only affected the prostate. A reliable tumour marker by means of imaging techniques (transrectal CT, Cholin PET) is not possible up to now. The application of these procedures is therefore limited to individual cases.

The Gleason Score provides information about the aggressiveness of a tumour and is ascertained in the course of a microscopic examination of tissue by a pathologist. The scale reaches from 2 to 10. The higher the score is, the more aggressive is the tumour.

If there is a bare possibility of the tumour spreading already sometimes a clarification is resigned at an N and M stage.

Despite all success in the field of modern imaging techniques (ultrasound, CT, nuclear spin tomography) it is not absolutely proven that there are no lymph node metastases. The removal of lymph nodes – either in the course of a radical prostatectomy or in a separate operation before having a radiation therapy – today is still the Golden Standard. In some centres a variation of the lymph node removal is conducted by marking the lymph nodes belonging to the prostate radioactively. By this means the so-called “Schildwächter” or sentinel lymph nodes can be identified.

Distant metastases of the prostate cancer preferably occur in the bones. Therefore the conducting of a bone scintigram is at least obligatory in case the PSA level is over 10ng/ml or a very aggressive tumour with a high Gleason-Score is diagnosed. X-rays of the lungs and a CT or ultrasound of the liver complete the M-staging.

Therapy: locally limited PCA

The treatment of a tumour that is only affecting the prostate leans on four aspects:

Radical prostatectomy
Radiation therapy
a) from external (external radiation therapy)
b) from internal (interstitial radiation therapy)
Brachytherapy (LDR) or “after-loading” (HDR)
HIFU/ cryotherapy
Watchful waiting/active surveillance

Aim of the medical treatment of the prostate carcinoma is not necessarily the healing of the patient but moreover the avoidance of the tumour-related death or the tumour-related side effects (eg. pain, fractures, ischuria).

Especially elderly men suffering from a relatively benign tumour (low Gleason Score) are under certain circumstances not need to be treated medically. The course of the disease is only watched closely (watchful waiting). As the diagnostic measures are more and more improving the respective tumours are diagnosed to a larger extent.

Also young men suffering from a strongly benign tumour do not have to be treated medically at all events. Aim of the “active surveillance” is to retard the side effects and the complications of a medical treatment.

“Active surveillance” and “watchful waiting” happen under regular PSA level controls and rebiopsy in order to induce a medical treatment in time (PSA level up to 5 no therapy necessary).

The most effective therapy is the complete removal of the prostate (radical prostatectomy). Disadvantage of this procedure is the psychic stress and the possible medical complications like wound infection or similar complications; 5 to 10% suffer from a postoperative consistent urinary incontinence. Also the potency is affected negatively. However, the radical prostatectomy has become technically improved during the past years (eg. by conceiving the vascular bundle of nerves that is responsible for the erection of the penis) and the complications could be diminished. This has become possible due to the fact that today the tumours are diagnosed earlier than in the past.

Further technical innovations are the laparoscopic prostatectomy and the robotic-supported prostatectomy that is also conducted minimal-invasive and without abdominal laparotomy (Pict. 10, only picture of the abdomen). Advantage of this operation technique is less post-operative bleeding. The functional results (continence and potency) come closer to the outcomes of a normal operation after a long learning curve. However, it needs to be taken into consideration that the alternative operation techniques are still in a development stage.

The radiation from external, the external radiation, is an alternative treatment option for the locally restricted prostate carcinoma (prostate pict. 6, radiation). On the basis of a CT the calculation of the dosage and the radiation field is made computer-assisted. The actual standard is the so-called 3-D-conformal technique that is available in all major cancer centres in Germany. The radiation dosage for a tumour should amount to 72 Gy. The radiotherapy is made hyperfractionated which means that the overall dosage is allocated in small dosages in order to make the side effects tolerable. Therefore the outpatient radiotherapy is made within at least a period of 7 weeks with 5 treatment days each.

Urine incontinency is exceptional when it comes to radiation therapy, a deterioration of voiding and stool are typical side effects of the radiotherapy. As the vascular nerve bundle is also treated with radiotherapy, after a certain amount of time it comes to a impairment of the potency.
After a period of 3 to 5 years around 40% of all patients suffer from erection disturbances.

Other procedures like the neutron therapy or the intensity-modulating radiation therapy (IMRT) are still in a pilot stage. It cannot be taken a stand to advantages and disadvantages of the 3-D conformal technique currently.

In the last 15 years the brachytherapy or the interstitial radiation therapy has experienced a renaissance. In the course of this therapy the source of radiation is inserted into the prostate. Due to a radiation dosage that is falling away sharply the radiation therapy is more indulgent for the surrounding tissue. It must not be reckoned with skin irritations which is a classical side effect of the external radiation therapy. Other side effects could affect the urinary bladder, urethra and hindgut and are similar to side effects of the radiation.

When it comes to brachytherapy it is differentiated between 2 forms: the more often conducted low-dose rate (LDR) brachytherapy where approximately 0,5 cm long radioactively laded titanium particles are inserted into the prostate on the basis of a treatment plan that was calculated in advance. Today mainly 125 iodine laded particles (seeds) are inserted. They remain in the prostate and radiate from there. The dosage for 125 iodine seeds is mostly around 145 Gy. The treatment is only made once and is made under general anaesthesia. The LDR brachytherapy is rather applied and indicated when it comes to benign and not very advanced tumours. The results so far show after a period of ten years very goods results as far as the indication was adjusted respectively.

In comparison to the LDR-brachytherapy there is the high-dose rate (HDR) brachytherapy. With the HDR brachytherapy the source of radiation is inserted into the prostate over a capsula (so-called afterloading technique). The treatment is conducted twice with a time lag of some few days. This therapy is not very common in Germany. Due to so far missing long-term results a final appraisal is not possible so far.

The most suitable therapy for the respective person is found out in several consultations with the patients and, if requested, together with the patient’s life partner. In the course of these talks the tumour characterization (spreading, aggressiveness), the patient’s constitution (age, concomitant diseases), the necessary effectiveness of the medical therapy as well as the wishes and fears of the patient shall influence the treatment decision. Taking a second opinion regarding the patient’s diagnose should not be the exception but, however, the regular case.

Strongly advertised within the last years were other innovative treatment concepts like the treatment with a high-energetic ultrasound (HIFU) and also the kryotherapy. Both are medical procedures that have not yet been sufficiently tested and where no clinical studies have yet been available. These studies should urgently be made before used in cancer therapy.

Therapy: local progressed PCA
In case the tumour has already exceeded organ borders (stage T3 or T4) or lymph node metastases have already been diagnosed maybe other therapy measures so-called adjuvant treatments become necessary.

The necessity of an adjuvant therapy becomes already apparent in the course of radiation. So maybe the palpation of the prostate or the PSA level give indication for a tumour growth that is exceeding the prostate or lymph nodes metastases could already be diagnosed in the course of an advanced lymph node removal. In such situations a hormone therapy is induced before radiation (neoadjuvant) and/or after the radiation. It turned out that such a combination has increased the survival rate of patients considerably.

When it comes to radical prostatectomy there is a necessity of an adjuvant therapy often due to the histopathological findings. The so-called risk tumours (prostate pict. 7 risk factors) a adjuvant therapy makes sense under certain circumstances. The therapy can consist of after-radiation or hormone therapy. Also with these therapy forms we have indications that the patient’s life expectation can be affected positively.

Therapy: metastatic PCA
The prostate carcinoma is spreading metastatic preferably in bone material. The conducting of a bone scintigram is therefore the most important examination for exclusion or diagnosing bone metastasis. Other organs that can be affected from metastasis could be the liver, lungs and sometimes the brain.

The treatment of the metastatic PCA is based on withdrawal of the gonads hormones also called testosterone. Testosterone is converted by the enzyme 5--reductase into the more effective form, the dehydro-testosterone (DHT).

By the operative removal of the testicles (orchiectomy) the production of testosterone is deactivated. Today this is managed by medications with so-called LHRH-analoga. This medication is normally administered by means of a 3-months-injection and deactivates the production of LH managed by the hypophysis. The production of testosterone in the testicles is stopped by this (prostate pict. 8, metastatic). LHRH analoga does not influent the production of testosterone in the adrenal gland. This testosterone makes out 10% of the overall testosterone production.

An alternative concept is the elimination of the testosterone appeal to the prostate. In the course of this treatment the anti-androgens occupy the testosterone receptors situated on the prostate cells. Therefore the testosterone cannot take effect on the prostate.

By means of a concomitant intake of LHRH analoga and anti-androgens the effect of testosterone is completely stopped. This therapy is also called maximum androgen-blockage (MAB).

The hormone therapy is distinguished by a number of side effects that especially when it comes to long-term treatments burden the patient (chart 11). Especially the osteoporosis was diagnosed as an important side effect of the hormone therapy. So the risk of fractures is already considerably increasing after having a 1.5 year LH-RH treatment (prostate pict. 9 testosterone withdrawal). After 8 to 10 years every second patient has already suffered from fractures. These side effects can be prevented by the intake of anti-androgens, but only where it is possible. Alternatively also biphosphonates can be prescribed. In a large study it was proofed that the patients can be prevented from fractures by the dosage of 4mg zoledronic acid (zometa) every day in a three month period.

Hormone impervious PCA
The disadvantage of a hormone therapy is that the tumour cells learn after a differentiating time period to grow also without the presence of testosterone. This situation is called hormone refractory.

Until some years ago the prostate carcinoma seemed to be insensitive to chemotherapy. Only until 2003 two independent randomized studies showed that an active substance called docetaxel that is made out of a yew tree can decrease the progress of the prostate carcinoma significantly and can also positively influent the survival rate of cancer patients (prostate pict. 10 diagram docetaxel).

Aftercare treatment:
The aftercare of a prostate carcinoma has two major objectives:

Especially in an early stage of the prostate cancer a progression of the disease or a reoccurrence shall be recognized in time to start as early as possible with the medical treatment. This can be managed by regular blood tests checking the PSA level.

At an advanced stage the attention is turned on the avoidance of tumour-related complications. Besides the control of the PSA level also a bone scintigram is conducted (if necessary, also x-rays), ultrasound examination of the kidney and the remaining urine as well as further diagnostics adapted to the current situation.