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Wednesday, December 12, 2007

Prostate Cancer

Prostate cancer is a disease in which cancer develops in the prostate, a gland in the male reproductive system. It occurs when cells of the prostate mutate and begin to multiply out of control. These cells may spread (metastasize) from the prostate to other parts of the body, especially the bones and lymph nodes. Prostate cancer may cause pain, difficulty in urinating, erectile dysfunction and other symptoms.

Rates of prostate cancer vary widely across the world. Although the rates vary widely between countries, it is least common in South and East Asia, more common in Europe, and most common in the United States. According to the American Cancer Society, prostate cancer is least common among Asian men and most common among black men, with figures for white men in-between. However, these high rates may be affected by increasing rates of detection.

Prostate cancer develops most frequently in men over fifty. This cancer can occur only in men, as the prostate is exclusively of the male reproductive tract. It is the most common type of cancer in men in the United States, where it is responsible for more male deaths than any other cancer, except lung cancer. However, many men who develop prostate cancer never have symptoms, undergo no therapy, and eventually die of other causes. Many factors, including genetics and diet, have been implicated in the development of prostate cancer.

Prostate cancer is most often discovered by physical examination or by screening blood tests, such as the PSA (prostate specific antigen) test. There is some current concern about the accuracy of the PSA test and its usefulness. Suspected prostate cancer is typically confirmed by removing a piece of the prostate (biopsy) and examining it under a microscope. Further tests, such as X-rays and bone scans, may be performed to determine whether prostate cancer has spread.

Signs and Symptoms

Early prostate cancer usually causes no symptoms. Often it is diagnosed during the workup for an elevated PSA noticed during a routine checkup. Sometimes, however, prostate cancer does cause symptoms, often similar to those of diseases such as benign prostatic hypertrophy. These include frequent urination, increased urination at night, difficulty starting and maintaining a steady stream of urine, blood in the urine, and painful urination. Prostate cancer may also cause problems with sexual function, such as difficulty achieving erection or painful ejaculation.

Advanced prostate cancer may cause additional symptoms as the disease spreads to other parts of the body. The most common symptom is bone pain, often in the vertebrae (bones of the spine), pelvis or ribs, from cancer which has spread to these bones. Prostate cancer in the spine can also compress the spinal cord, causing leg weakness and urinary and fecal incontinence.


The cause of prostate cancer isn't fully understood at present. But there are certain factors that make prostate cancer more likely, which are listed below.

* The risk of prostate cancer increases steadily with age and it is rare in men under 50.
* Your risk is higher if you have close relatives (a father, uncle or brother) who have had prostate cancer.
* If several women in your family have had breast cancer (especially if they were diagnosed at under 40 years of age) an inherited faulty gene may be present. The gene may also increase the risk of the men in that family getting prostate cancer.
* If you are African-Caribbean or African-American you are at highest risk whereas if you are Asian, you are at lower risk.
* A high fat diet may increase your risk.


When a man has symptoms of prostate cancer, or a screening test indicates an increased risk for cancer, more invasive evaluation is offered.

The only test which can fully confirm the diagnosis of prostate cancer is a biopsy, the removal of small pieces of the prostate for microscopic examination. However, prior to a biopsy, several other tools may be used to gather more information about the prostate and the urinary tract. Cystoscopy shows the urinary tract from inside the bladder, using a thin, flexible camera tube inserted down the urethra. Transrectal ultrasonography creates a picture of the prostate using sound waves from a probe in the rectum.


If cancer is suspected, a biopsy is offered. During a biopsy a urologist obtains tissue samples from the prostate via the rectum. A biopsy gun inserts and removes special hollow-core needles (usually three to six on each side of the prostate) in less than a second. Prostate biopsies are routinely done on an outpatient basis and rarely require hospitalization. Fifty-five percent of men report discomfort during prostate biopsy.

Gleason score

The tissue samples are then examined under a microscope to determine whether cancer cells are present, and to evaluate the microscopic features (or Gleason score) of any cancer found.

Tumor markers

Tissue samples can be stained for the presence of PSA and other tumor markers in order to determine the origin of malignant cells that have metastasized.

New tests being investigated

Currently, an active area of research involves non-invasive methods of prostate tumor detection. Adenoviruses modified to transfect tumor cells with harmless yet distinct genes (such as luciferase) have proven capable of early detection. So far, though, this area of research has only been tested in animal and LNCaP models.


Another potential non-invasive methods of early prostate tumor detection is through a molecular test that detects the presence of cell-associated PCA3 mRNA in urine. PCA3 mRNA is expressed almost exclusively by prostate cells and has been shown to be highly over-expressed in prostate cancer cells. PCA3 is not a replacement for PSA but an additional tool to help decide if, in men suspected of having prostate cancer, a biopsy is really needed. The higher the expression of PCA3 in urine, the greater the likelihood of a positive biopsy, i.e. the presence of cancer cells in the prostate. Company Diagnocure has an exclusive worldwide license for all diagnostic and therapeutic applications related to PCA3

Early prostate cancer

It was reported in April 2007 that a new blood test for early prostate cancer antigen-2 (EPCA-2) is being researched that may alert men if they have prostate cancer and how aggressive it will be.


Genetics play some role in risk of prostate cancer. Specifically, around 9% of prostate cancers appear to be familial.

The male hormone, testosterone, and its analogues are definitely involved in the pathogenesis of prostate cancer. The National Cancer Institute lists the following as support for the role of male sex hormones in prostate cancer.

· Neither benign prostatic hypertrophy (BPH) nor prostate cancer have been reported in men castrated prior to puberty.

· Many studies have shown that populations with higher levels of testosterone and most importantly dihydrotestosterone have higher incidences of prostate cancer. For example the highest levels are found in blacks males, intermediate levels in white males, and lowest levels in native Japanese. The incidence of prostate cancer parallels the levels.

· Deprivation of androgens (males sex hormones) leads to decreased levels of PSA, and death of prostate cancer cells.

Dietary fat appears to play a role in prostate cancer but studies are conflicting. If dietary fat is a risk factor, it appears that saturated fat from animal origins is a greater risk factor than unsaturated fat from vegetable origin. The mechanism by which fat may be involved in prostate cancer has been hypothesized. First, dietary fat increases serum levels of male sex hormones (androgens). Some studies indicate that omega 3 oils (fish oil, flaxseed oil) may actually prevent prostate cancer. Finally, many studies have found that there is a relationship between the amount of fat eaten by the mother during pregnancy and the later development of prostate cancer in her male offspring.

Previous articles have outlined the benefits of eating a Mediterranean style diet, consisting of plenty of fresh fruits and vegetables, fish, and olive oil. This type of diet has benefits for cardiovascular health, and appears to be advisable for prevention of cancers of all types.

Finally, there is some evidence that exposure to pesticides and heavy metals may be a risk factor for prostate cancer. Specifically there may be a relationship between dioxin (a contaminant of herbicides) and prostate cancer. Likewise, the metal cadmium found in NiCad batteries is suspect. Workers in plants that manufacture or recycle these batteries should take extreme precautions to prevent exposure.

Prostate cancer develops when the rates of cell division and cell death are no longer equal, leading to uncontrolled tumor growth. Following the initial transformation event, further mutations of a multitude of genes, including the genes for p53 and retinoblastoma, can lead to tumor progression and metastasis. Most prostate cancers are adenocarcinomas (95%).

Approximately 4% of cases of prostate cancer have transitional cell morphology and are thought to arise from the urothelial lining of the prostatic urethra. Few cases have neuroendocrine morphology. When present, they are believed to arise from the neuroendocrine stem cells normally present in the prostate or from aberrant differentiation programs during cell transformation.

Of cases of prostate cancer, 70% arise in the peripheral zone, 15-20% arise in the central zone, and 10-15% arise in the transitional zone. Most prostate cancers are multifocal, with synchronous involvement of multiple zones of the prostate, which may be due to clonal and nonclonal tumors.

Natural history

The natural history is still relatively unknown, and many aspects of progression are poorly understood. Symptoms or abnormal DRE findings in the pre-PSA era only brought 40-50% of patients with prostate cancer to medical attention, and these patients usually had locally advanced disease. The advent of PSA testing has helped identify patients with less-advanced, organ-confined disease.

Evidence suggests that most prostate cancers are multifocal and heterogeneous. Cancers can start in the transitional zone or, more commonly, the peripheral zone. When these cancers are locally invasive, the transitional zone tumors spread to the bladder neck, while the peripheral zone tumors extend into the ejaculatory ducts and seminal vesicles. Penetration through the prostatic capsule and along the perineural or vascular spaces is a relatively late event.

The mechanism for distant metastasis is poorly understood. The cancer spreads to bone early, occasionally without significant lymphadenopathy. Currently, 2 predominant theories have been proposed for spread, the mechanical theory and the seed-and-soil theory.

* The mechanical theory involves direct spread through the lymphatics and venous spaces into the lower lumbar spine.

* Advocates of the seed-and-soil theory believe tissue factors must be present that allow for preferential growth in certain tissues, such as the bone. Lung, liver, and adrenal metastases have also been documented. Specific tissue growth factors and extracellular matrices are possible examples.

The doubling time in early-stage disease is as slow as 2-4 years, but this changes as the tumor grows and becomes more aggressive. Larger tumors usually have a higher Gleason grade and a faster doubling time.

Natural history by stage

* T1a - Progression over 10 years (uncommon)

* T1b - Tumor-related death rate of 10% in 10 years

* T2 - Ten-year metastasis-free survival rate of 81% with grade 1, 58% with grade 2, and 26% with grade 3

* T3 - Lymph node metastasis at presentation in 50% and approximately 25% rate of 10-year disease-free survival

The natural history of clinically localized disease is variable, with lower-grade tumors having a more indolent course, while some high-grade lesions progress to metastatic disease with relative rapidity. Several studies have examined the cancer-specific and quality-of-life outcomes associated with a watchful waiting approach to localized disease.

* Albertsen et al followed patients who received no initial treatment for prostate cancer. As disease progression occurred, many received antiandrogens. Men with poorly differentiated tumors lost 6-8 years of life, while those with moderately differentiated tumors lost 4-5 years. Of all men followed for 10 years, 40% died of causes other than prostate cancer. This study was performed prior to PSA screening.

* Graversen et al compared watchful waiting with radical prostatectomy. They found no overall difference in survival, but they did find that a high Gleason score was associated with poor survival in both groups.

* Chodak et al confirmed this finding by analyzing 6 studies and finding a 34% survival rate with grade 3 tumors versus an 87% disease-specific survival rate for grade 1 and 2 tumors. The metastasis-free survival rate also significantly dropped as the grade progressed from 1 to 3.

* Johansson reported their recent update on a population-based cohort study with a mean observation period of 21 years. In this study, 223 patients with early-stage, initially untreated prostatic cancer were observed. Patients with tumor progression received hormonal treatment (orchiectomy or estrogens) if they had symptoms. Thirty-nine (17%) experienced metastatic disease, with most cancers having an indolent course during the first 10-15 years. However, further follow-up at 15-20 years revealed a substantial decrease in cumulative progression-free survival (from 45% to 36%), survival without metastases (from 76.9% to 51.2%), and prostate cancer–specific survival (from 78.7% to 54.4%). Prostate cancer mortality increased from 15 deaths per 1000 person-years during the first 15 years to 44 deaths per 1000 person-years beyond 15 years of follow-up.

Taken together, these data suggest that although most prostate cancers diagnosed at an early stage have an indolent course, local tumor progression and aggressive metastatic disease may develop in the long term. In addition, these findings would support early radical treatment, notably among patients with an estimated life expectancy exceeding 15 years.


Several medications and vitamins may also help prevent prostate cancer. Two dietary supplements, vitamin E and selenium, may help prevent prostate cancer when taken daily. Estrogens from fermented soybeans and other plant sources (called phytoestrogens) may also help prevent prostate cancer. The selective estrogen receptor modulator drug toremifene has shown promise in early trials. Two medications which block the conversion of testosterone to dihydrotestosterone, finasteride, and dutasteride, have also shown some promise. The use of these medications for primary prevention is still in the testing phase, and they are not widely used for this purpose. The problem with these medications is that they may preferentially block the development of lower-grade prostate tumors, leading to a relatively greater chance of higher grade cancers, and negating any overall survival improvement. Green tea may be protective (due to its polyphenol content), though the data is mixed. A 2006 study of green tea derivatives demonstrated promising prostate cancer prevention in patients at high risk for the disease. In 2003, an Australian research team led by Graham Giles of The Cancer Council Australia concluded that frequent masturbation by males appears to help prevent the development of prostate cancer. Recent research published in the Journal of the National Cancer Institute suggests that taking multivitamins more than seven times a week can increase the risks of contracting the disease. This research was unable to highlight the exact vitamins responsible for this increase (almost double), although they suggest that vitamin A, vitamin E and beta-carotene may lie at its heart. It is advised that those taking multivitamins never exceed the stated daily dose on the label. Scientists recommend a healthy, well balanced diet rich in fiber, and to reduce intake of meat. A 2007 study published in the Journal of the National Cancer Institute found that men eating cauliflower, broccoli, or one of the other cruciferous vegetables, more than once a week were 40% less likely to develop prostate cancer than men who rarely ate those vegetables. Scientists believe the reason for this phenomenon has to do with a phytochemical called Diindolylmethane in these vegetables that has anti-androgenic and immune modulating properties. This compound is currently under investigation by the National Cancer Institute as a natural therapeutic for prostate cancer.


Capsaicin, the chemical found in peppers, has been shown to cause 80% of cancerous prostate cells to undergo apoptosis in mice. For prostate cancer cells whose growth is dependent upon testosterone, Capsaicin curbed the proliferation of such cells by freezing the cells in a non-proliferate state, and cancerous prostate cells that are androgen independent "suicided" as well.

"Capsaicin had a profound anti-proliferative effect on human prostate cancer cells in culture," said Sören Lehmann, M.D., Ph.D., visiting scientist at the Cedars-Sinai Medical Center and the UCLA School of Medicine. "It also dramatically slowed the development of prostate tumors formed by those human cell lines grown in mouse models."

Peppers which rank higher on the Scoville scale and thus have a higher piquancy contain a higher amount of Capsaicin. Habaneros, for example, have a Scoville rating of over 300,000, while red chili peppers have a rating of 5,000. While the UCLA and Samuel Oschin Comprehensive Cancer Institute studies show promising implications, the same effects have not yet been duplicated in men.


Treatment for prostate cancer may involve watchful waiting, surgery, radiation therapy, High Intensity Focused Ultrasound (HIFU), chemotherapy, cryosurgery, hormonal therapy, or some combination. Which option is best depends on the stage of the disease, the Gleason score, and the PSA level. Other important factors are the man's age, his general health, and his feelings about potential treatments and their possible side effects. Because all treatments can have significant side effects, such as erectile dysfunction and urinary incontinence, treatment discussions often focus on balancing the goals of therapy with the risks of lifestyle alterations.

The selection of treatment options may be a complex decision involving many factors. For example, radical prostatectomy after primary radiation failure is a very technically challenging surgery and may not be an option. This may enter into the treatment decision.

If the cancer has spread beyond the prostate, treatment options significantly change, so most doctors who treat prostate cancer use a variety of nomograms to predict the probability of spread. Treatment by watchful waiting, HIFU, radiation therapy, cryosurgery, and surgery are generally offered to men whose cancer remains within the prostate. Hormonal therapy and chemotherapy are often reserved for disease which has spread beyond the prostate. However, there are exceptions: radiation therapy may be used for some advanced tumors, and hormonal therapy is used for some early stage tumors. Cryotherapy, hormonal therapy, and chemotherapy may also be offered if initial treatment fails and the cancer progresses.


The list of complications that have been mentioned in various sources for Prostate Cancer includes:

* Metastatic cancer
* Bone pain

Complications and sequelae of Prostate Cancer include:

* Red cell production reduced
* Osteosclerosis
* Prostate specific antigen levels raised (plasma or serum)
* Back pain
* Bone pain
* Hematospermia
* Bone metastases
* Incontinence, urine
* Urethral stricture
* Hematuria
* Pathological fracture
* Acid phosphatase levels raised (plasma or serum)


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