Prostate Cancer

Prostate Cancer

Definition of Prostate Cancer :

Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells maymetastasize (spread) from the prostate to other parts of the body, particularly the bones and lymph nodes. Prostate cancer may cause pain, difficulty in urinating, problems during sexual intercourse, or erectile dysfunction. Other symptoms can potentially develop during later stages of the disease.

Prostate cancer tends to develop in men over the age of fifty. Globally it is the sixth leading cause of cancer-related death in men. Prostate cancer is most common in the developed world with increasing rates in the developing world. However, many men with prostate cancer never have symptoms, undergo no therapy, and eventually die of other unrelated causes. Many factors, including genetics and diet, have been implicated in the development of prostate cancer.

The presence of prostate cancer may be indicated by symptoms, physical examination, prostate-specific antigen (PSA), or biopsy. Prostate-specific antigen testing increases cancer detection but does not decrease mortality. 

Management strategies for prostate cancer should be guided by the severity of the disease. Many low-risk tumors can be safely followed with active surveillance. Curative treatment generally involves surgery, various forms of radiation therapy, or, less commonly, cryosurgery; hormonal therapy and chemotherapy are generally reserved for cases of advanced disease (although hormonal therapy may be given with radiation in some cases). Several studies suggest that masturbation reduces the risk of prostate cancer.

The age and underlying health of the man, the extent of metastasis, appearance under the microscope and response of the cancer to initial treatment are important in determining the outcome of the disease. The decision whether or not to treat localized prostate cancer (a tumor that is contained within the prostate) with curative intent is a patient trade-off between the expected beneficial and harmful effects in terms of patient survival and quality of life.

Cause of Prostate Cancer :

• Age – men over 50 years of age.
• Ethnic group –men of African-Caribbean and African descent.
• Family history – having a close male relative – such as a brother, father or uncle - who has had prostate cancer seems to increase the risk. Research also shows that having a close female relative who developed breast cancer may also increase your risk of developing prostate cancer. 
• Obesity 
• Diet – There is evidence a diet high in calcium is linked to an increased risk of developing prostate cancer. In addition, some research has shown prostate cancer rates appear lower in men who eat foods containing certain nutrients including lycopene, found in tomatoes and other red fruit, and selenium, found in brazil nuts.

Signs and Symptoms of Prostate Cancer :

Early prostate cancer usually causes no symptoms. Sometimes, however, prostate cancer does cause symptoms, often similar to those of diseases such as benign prostatic hyperplasia. These include frequent urination, nocturia (increased urination at night), difficulty starting and maintaining a steady stream of urine, hematuria (blood in the urine), and dysuria (painful urination). About a third of patients diagnosed with prostate cancer have one or more such symptoms, while two thirds have no symptoms.

Prostate cancer is associated with urinary dysfunction as the prostate gland surrounds the prostatic urethra. Changes within the gland, therefore, directly affect urinary function. Because the vas deferens deposits seminal fluid into the prostatic urethra, and secretions from the prostate gland itself are included in semen content, prostate cancer may also cause problems with sexual function and performance, such as difficulty achieving erection or painful ejaculation.

Advanced prostate cancer can spread to other parts of the body, possibly causing additional symptoms. The most common symptom is bone pain, often in the vertebrae (bones of the spine), pelvis, or ribs. Spread of cancer into other bones such as the femur is usually to the proximal part of the bone. Prostate cancer in the spine can also compress the spinal cord, causing leg weakness and urinary and fecal incontinence.

Risk factors for Prostate Cancer :

A complete understanding of the causes of prostate cancer remains elusive. The primary risk factors are obesity, age and family history. Prostate cancer is very uncommon in men younger than 45, but becomes more common with advancing age. The average age at the time of diagnosis is 70. However, many men never know they have prostate cancer. Autopsy studies of Chinese, German, Israeli, Jamaican, Swedish, and Ugandan men who died of other causes have found prostate cancer in thirty percent of men in their 50s, and in eighty percent of men in their 70s. Men who have first-degree family members with prostate cancer appear to have double the risk of getting the disease compared to men without prostate cancer in the family. This risk appears to be greater for men with an affected brother than for men with an affected father. Men with high blood pressure are more likely to develop prostate cancer. There is a small increased risk of prostate cancer associated with lack of exercise. A 2010 study found that prostate basal cells were the most common site of origin for prostate cancers.

Genetic

Genetic background may contribute to prostate cancer risk, as suggested by associations with race, family, and specific gene variants. Men who have a first-degree relative (father or brother) with prostate cancer have twice the risk of developing prostate cancer, and those with two first-degree relatives affected have a fivefold greater risk compared with men with no family history.

No single gene is responsible for prostate cancer; many different genes have been implicated. Mutations in BRCA1 and BRCA2, important risk factors for ovarian cancer and breast cancer in women, have also been implicated in prostate cancer. Other linked genes include the Hereditary Prostate cancer gene 1 (HPC1), the androgen receptor, and the vitamin D receptor. TMPRSS2-ETS gene family fusion, specifically TMPRSS2-ERG or TMPRSS2-ETV1/4 promotes cancer cell growth.

Loss of cancer suppressor genes, early in the prostatic carcinogenesis, have been localized to chromosomes 8p, 10q, 13q,and 16q. P53 mutations in the primary prostate cancer are relatively low and are more frequently seen in metastatic settings, hence, p53 mutations are late event in pathology of prostate cancer. Other tumor suppressor genes that are thought to play a role in prostate cancer include PTEN (gene) and KAI1. “Up to 70 percent of men with prostate cancer have lost one copy of the PTEN gene at the time of diagnosis”^[27] Relative frequency of loss of E-cadherin and CD44 has also been observed.

Two large genome-wide association studies linking single nucleotide polymorphisms (SNPs) to prostate cancer were published in 2008. These studies identified several SNPs which substantially affect the risk of prostate cancer. For example, individuals with TT allele pair at SNP rs10993994 were reported to be at 1.6 times higher risk of prostate cancer than those with the CC allele pair. This SNP explains part of the increased prostate cancer risk of African American men as compared to American men of European descent, since the C allele is much more prevalent in the latter; this SNP is located in the promoter region of the MSMB gene, thus affects the amount of MSMB protein synthesized and secreted by epithelial cells of the prostate.

Dietary

While some dietary factors have been associated with prostate cancer the evidence is still tentative. Evidence supports little role for dietary fruits and vegetables in prostate cancer occurrence. Red meat and processed meat also appear to have little effect in human studies. Higher meat consumption has been associated with a higher risk in some studies.

Lower blood levels of vitamin D may increase the risk of developing prostate cancer.

Taking multivitamins more than seven times a week may increase the risk of developing the disease.

A 2009 study on folic acid supplements showed an association with an increased risk of developing prostate cancer.

Medication exposure

There are also some links between prostate cancer and medications, medical procedures, and medical conditions. Use of the cholesterol-lowering drugs known as the statins may also decrease prostate cancer risk.

Infection or inflammation of the prostate (prostatitis) may increase the chance for prostate cancer while another study shows infection may help prevent prostate cancer by increasing blood to the area. In particular, infection with the sexually transmitted infections chlamydia, gonorrhea, orsyphilis seems to increase risk. Finally, obesity and elevated blood levels of testosterone may increase the risk for prostate cancer. There is an association between vasectomy and prostate cancer however more research is needed to determine if this is a causative relationship.

Research released in May 2007, found that US war veterans who had been exposed to Agent Orange had a 48% increased risk of prostate cancer recurrence following surgery.

Viral

In 2006, a previously unknown retrovirus, Xenotropic MuLV-related virus or XMRV, was associated with human prostate tumors, but subsequent reports on the virus were contradictory, and the original 2006 finding was instead due to a previously undetected contamination. The journals Science and PlosONE both retracted XMRV related articles.

Sexual factors

Several case-control studies have shown that having many lifetime sexual partners or starting sexual activity early in life substantially increases the risk of prostate cancer. This correlation suggests a sexually transmissible infection (STI) may cause some prostate cancer cases; however, many studies have unsuccessfully attempted to find such a link, especially when testing for STIs shortly before or after prostate cancer diagnosis. Studies testing for STIs a decade or more prior to prostate cancer diagnosis find a significant link between prostate cancer and various STIs (HPV-16, HPV-18 and HSV-2). This evidence could be explained by a yet-to-be-identified sexually transmissible infection and a long latency period between onset of infection and clinical prostate cancer.

Diagnosis of Prostate Cancer :

The American Cancer Society’s position regarding early detection is “Research has not yet proven that the potential benefits of testing outweigh the harms of testing and treatment. The American Cancer Society believes that men should not be tested without learning about what we know and don’t know about the risks and possible benefits of testing and treatment. Starting at age 50, (45 if African American or brother or father suffered from condition before age 65) talk to your doctor about the pros and cons of testing so you can decide if testing is the right choice for you.”

The only test that 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, less invasive testing can be conducted.

According to Professor Hardev Pandha, The Prostate Project Chair of Urological Oncology at the University of Surrey’s Postgraduate Medical School, a non-invasive test looking for the presence of the protein Engrailed-2 (EN2) in the urine to be more reliable and accurate than existing tests.

“In this study, we showed that the new test was twice as good at finding prostate cancer as the standard PSA test. Only rarely did we find EN2 in the urine of men who were cancer free, so if we find EN2 we can be reasonably sure that a man has prostate cancer. EN2 was not detected in men with non-cancer disorders of the prostate such as prostatitis or benign enlargement. These conditions often cause a high PSA result, causing considerable stress for the patient and sometimes also unnecessary further tests such as prostate biopsies.” 

There are also several other tests that can be used to gather more information about the prostate and the urinary tract. Digital rectal examination (DRE) may allow a doctor to detect prostate abnormalities. 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.

Prostate imaging

Ultrasound (US) and Magnetic Resonance Imaging (MRI) are the two main imaging methods used for prostate cancer detection. Urologists use transrectal ultrasound during prostate biopsy and can sometimes see a hypoechoic area (tissues or structures that reflect relatively less of the ultrasound waves directed at them). But US has poor tissue resolution and thus, is generally not clinically used. In contrast, prostate MRI has superior soft tissue resolution. MRI is a type of imaging that uses magnetic fields to locate and characterize prostate cancer. Multi-parametric prostate MRI consists of four types of MRI sequences called T2 weighted imaging, T1 weighted imaging, Diffusion Weighted Imaging, MR Spectrocopic Imaging and Dynamic-Contrast Enhanced Imaging. Genitourinary radiologists use multi-parametric MRI to locate and identify prostate cancer. Currently, MRI is used to identify targets for prostate biopsy using fusion MRI with ultrasound (US) or MRI-guidance alone. In men who are candidates for active surveillance, fusion MR/US guided prostate biopsy detected 33% of cancers compared to 7% with standard ultrasound guided biopsy. Prostate MRI is also used for surgical planning for men undergoing robotic prostatectomy. It has also shown to help surgeons decide whether to resect or spare the neurovascular bundle, determine return to urinary continence and help assess surgical difficulty. Some prostate advocacy groups believe prostate MRI should be used to screen for prostate cancer–”manogram”—like mammogram is for breast cancer. NIH-funded clinical trials are underway to delineate the value of MRI for some of these applications.

Biopsy

If cancer is suspected, a biopsy is offered expediently. During a biopsy a urologist or radiologist 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. Prostate specific membrane antigen is a transmembranecarboxypeptidase and exhibits folate hydrolase activity. This protein is overexpressed in prostate cancer tissues and is associated with a higher Gleason score.

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.

Small cell carcinoma is a very rare (1%) type of prostate cancer that cannot be diagnosed using the PSA. As of 2009 researchers are trying to determine the best way to screen for this type of prostate cancer because it is a relatively unknown and rare type of prostate cancer but very serious and quick to spread to other parts of the body. Possible methods include chromatographic separation methods by mass spectrometry, or protein capturing by immunoassays or immunized antibodies. The test method will involve quantifying the amount of the biomarker PCI, with reference to the Gleason Score. Not only is this test quick, it is also sensitive. It can detect patients in the diagnostic grey zone, particularly those with a serum free to total Prostate Specific Antigen ratio of 10-20%.

The oncoprotein BCL-2, has been associated with the development of androgen-independent prostate cancer due to its high levels of expression in androgen-independent tumours in advanced stages of the pathology. The upregulation of BCL-2 after androgen ablation in prostate carcinoma cell lines and in a castrated-male rat model further established a connection between BCL-2 expression and prostate cancer progression.

The expression of Ki-67 by immunohistochemistry may be a significant predictor of patient outcome for men with prostate cancer.

ERK5 is a protein that may be used as a marker. ERK5 is present in abnormally high levels of prostate cancer, including invasive cancer which has spread to other parts of the body. It is also present in relapsed cancer following previous hormone therapy. Research shows that reducing the amount of ERK5 found in cancerous cells reduces their invasiveness.

Classification

An important part of evaluating prostate cancer is determining the stage, or how far the cancer has spread. Knowing the stage helps define prognosis and is useful when selecting therapies. The most common system is the four-stage TNM system (abbreviated from Tumor/Nodes/Metastases). Its components include the size of the tumor, the number of involved lymph nodes, and the presence of any other metastases.

The most important distinction made by any staging system is whether or not the cancer is still confined to the prostate. In the TNM system, clinical T1 and T2 cancers are found only in the prostate, while T3 and T4 cancers have spread elsewhere. Several tests can be used to look for evidence of spread. Medical specialty professional organizations recommend against the use of PET scans, CT scans, or bone scans when a physician stages early prostate cancer with low risk for metastasis. Those tests would be appropriate in such cases as when a CT scan evaluates spread within the pelvis, a bone scan look for spread to the bones, and endorectal coil magnetic resonance imaging to closely evaluate the prostatic capsule and the seminal vesicles. Bone scans should reveal osteoblastic appearance due to increased bone density in the areas ofbone metastasis—opposite to what is found in many other cancers that metastasize.

After a prostate biopsy, a pathologist looks at the samples under a microscope. If cancer is present, the pathologist reports the grade of the tumor. The grade tells how much the tumor tissue differs from normal prostate tissue and suggests how fast the tumor is likely to grow. The Gleason system is used to grade prostate tumors from 2 to 10, where a Gleason score of 10 indicates the most abnormalities. The pathologist assigns a number from 1 to 5 for the most common pattern observed under the microscope, then does the same for the second-most-common pattern. The sum of these two numbers is the Gleason score. The Whitmore-Jewett stage is another method sometimes used.

Prevention from Prostate Cancer :

Diet and lifestyle

The data on the relationship between diet and prostate cancer is poor. In light of this the incidence of prostate cancer is correlated with the consumption of the Western diet. Trans fats, saturated fats, and carbohydrates may be associated with an increased risk, and while Omega-3 fatty acids may result in some benefit, the evidence is inconclusive. Vitamin supplements appear to have no effect and some may increase the risk. High calcium intake has been linked to advanced prostate cancer. Consuming fish may lower prostate cancer deaths but does not appear to affect its occurrence. Some evidence supports lower rates of prostate cancer with a vegetarian diet. There is some tentative evidence for foods containing lycopene and selenium. Diets rich in cruciferous vegetables, soy, beans and other legumes may be associated with a lower risk of prostate cancer, especially more advanced cancers.

While the available evidence is weak, tentative results suggest that frequent ejaculation may decrease the risk of prostate cancer. Men who get regular exercise may have a slightly lower risk, especially vigorous activity and the risk of advanced prostate cancer.

Medications

In those who are being regularly screened 5-alpha-reductase inhibitor (finasteride and dutasteride) reduce the overall risk of being diagnosed with prostate cancer however there is insufficient data to determine if they have an effect on the risk of death and may increase the chance of more serious cases.

Treatment of Prostate Cancer :

The first decision to be made in managing prostate cancer is whether treatment is needed. Prostate cancer, especially low-grade forms found in the elderly, often grows slowly that no treatment is required. Treatment may also be inappropriate if a person has other serious health problems or is not expected to live long enough for symptoms to appear.

Which option is best depends on the stage of the disease, the Gleason score, and the PSA level. Other important factors are age, general health, and a person’s views 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. A combination of the treatment options is often recommended for managing prostate cancer.

Guidelines for treatment for specific clinical situations requires a good estimation of a person’s long-term life expectancy. People can also use an 18-item questionnaire to learn whether they have good knowledge and understanding about their treatment options before they choose. Most of those who are newly diagnosed and made a treatment choice can not correctly answer over half of the questions.

If radiation therapy is done first, and fails, then radical prostatectomy is very technically challenging surgery and may not be feasible. On the other hand, radiation therapy done after surgical failure may have many complications.

In localized disease it is unknown if radical prostatectomy is better or worse than watchful waiting.

Surveillance

Many men diagnosed with low-risk prostate cancer are eligible for active surveillance. This term implies careful observation of the tumor over time, with the intention of treatment for cure if there are signs of cancer progression. Active surveillance is not synonymous with watchful waiting, an older term which implies no treatment or specific program of monitoring, with the assumption that palliative, not curative, treatment would be used if advanced, symptomatic disease develops.

Active surveillance involves monitoring the tumor for signs of growth or the appearance of symptoms. The monitoring process may involve serial PSA, physical examination of the prostate, and/or repeated biopsies. The goal of surveillance is to avoid overtreatment and the sometimes serious, permanent side effects of treatment for a slow-growing or self-limited tumor that would never cause any problems for the patient. This approach is not used for aggressive cancers, but it may cause anxiety for patients who wrongly believe that all cancer is deadly or themselves to have a life-threatening cancer.

For 50% to 75% of people with prostate cancer it will cause no harm before a person dies.

Aggressive cancer

Treatment of aggressive prostate cancers may involve surgery (i.e. radical prostatectomy), radiation therapy including brachytherapy (prostate brachytherapy) and external beam radiation therapy, High-intensity focused ultrasound (HIFU), chemotherapy, oral chemotherapeutic drugs (Temozolomide/TMZ), cryosurgery, hormonal therapy, or some combination.

Although the widespread use of prostate specific antigen (PSA) screening in the USA has resulted in diagnosis at earlier age and cancer stage, the vast majority of cases are still diagnosed in men older than 65 years, and approximately 25% of cases are diagnosed in men older than 75 years. Though US National Comprehensive Cancer Network guidelines recommend using life expectancy greater than or less than 10 years to help make treatment decisions, in practice, many elderly patients are not offered curative treatment options such as radical prostatectomy or radiation therapy and are instead treated with hormonal therapy or watchful waiting. This pattern can be attributed to factors such as medical co-morbidity and patient preferences is regard to quality of life in addition to prostate cancer specific risk factors such as pretreatment PSA, Gleason score and clinical stage. As the average life expectancy increases due to advances in treatment of cardiovascular, pulmonary and other chronic disease, it is likely that more elderly patients will be living long enough to suffer the consequences of their prostate cancer. Therefore, there is currently much interest in the role of aggressive prostate cancer treatment modalities such as with surgery or radiation in the elderly population who have localized disease. The results of one randomized controlled trial published by the Scandinavian Prostate Cancer Group 4 evaluated cancer-specific mortality in patients treated with RP compared with watchful waiting. The patients receiving radical prostatectomy had a relative risk reduction of 30.7% , but an absolute risk reduction of 6% [95% confidence interval 0.5%-11.5%]. The number needed to treat was calculated to be 16. This means that, over the median follow up period of approximately 10 years, 16 patients with localized prostate cancer would need to receive radical prostatectomy rather than watchful waiting in order to prevent one death due to prostate cancer. Further subset analysis revealed that this benefit did not apply to all ages equally. In men younger than 65 years, patients randomized to receive radical prostatectomy actually had a 10-18% absolute risk reduction in cancer-specific mortality compared to those randomized to watchful waiting. However, in men older than 65, there was no statistically significant risk reduction even when adjusted for PSA level, Gleason score and tumor stage. Randomized, controlled trials comparing radical prostatectomy, radiation therapy, hormonal therapy and watchful waiting would provide the best evidence for how to best treat elderly patients.

If the cancer has spread beyond the prostate, treatment options significantly change, so most doctors that treat prostate cancer use a variety of nomograms to predict the probability of spread. Treatment by watchful waiting/active surveillance, external beam radiation therapy, brachytherapy, cryosurgery, HIFU, and surgery are, in general, offered to men whose cancer remains within the prostate. Hormonal therapy and chemotherapy are often reserved for disease that 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 (the process of freezing the tumor), hormonal therapy, and chemotherapy may also be offered if initial treatment fails and the cancer progresses.

Sipuleucel-T has been found result in a benefit ( a four month increase in survival ) for men with metastatic prostate cancer.

Castration-resistant

Most hormone dependent cancers become refractory after one to three years and resume growth despite hormone therapy. Previously considered “hormone-refractory prostate cancer” or “androgen-independent prostate cancer”, the term castration-resistant has replaced “hormone refractory” because while they are no longer responsive to castration treatment (reduction of available androgen/testosterone/DHT by chemical or surgical means), these cancers still show reliance upon hormones for androgen receptor activation. Before 2004, all treatments for castration-resistant prostate cancer (CRPC) were considered palliative and not shown to prolong survival. However, there are now several treatments available to treat CRPC that improve survival.

The cancer chemotherapic docetaxel has been used as treatment for CRPC with a median survival benefit of 2 to 3 months. A second-line chemotherapy treatment is cabazitaxel.

Off-label use of the oral drug ketoconazole is sometimes used as a way to further manipulate hormones with a therapeutic effect in CRPC. However, many side effects are possible with this drug and abiraterone is likely to supplant usage since it has a similar mechanism of action with less toxic side effects.

A combination of bevacizumab (Avastin), docetaxel, thalidomide and prednisone appears effective in the treatment of CRPC.

The immunotherapy treatment with sipuleucel-T is also effective in the treatment of CRPC with a median survival benefit of 4.1 months.

The second line hormonal therapy abiraterone (Zytiga) increased overall survival increased by 4.6 months when compared to placebo. Abiraterone acetate in combination with prednisone to treat people with late-stage (metastatic) castration-resistant prostate cancer who have received priordocetaxel (chemotherapy). Enzalutamide is another second line hormonal agent which has demonstrated a 5 month survival advantage over placebo. Both abiraterone and enzalutamide are currently being tested in clinical trials with CRPC patients who have not previously received chemotherapy. Enzalutamide was approved by the US FDA in 2012 as for the treatment of castration-resistant prostate cancer.

Only a subset of a patient respond to androgen signaling blocking drugs and certain cells with characteristics resembling stem cells remain unaffected. Therefore, the desire to improve outcome of CRPC patients has resulted into the claims of increasing doses further or combination therapy with synergistic androgen signaling blocking agents. But even these combination will not affect stem -like cells that do not exhibit androgen signaling. It is possible that for further advances, a combination of androgen signaling blocking agent with stem-like cell directed differentiation therapy drug would prove ideal.