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Prostate cancer

Reviewed and edited by: Dr. Safaa Mahmoud, M.D. Lecturer of Clinical Oncology.
Cairo University, Egypt.

Saturday 18th October, 2008.

Prostate cancer is the most common type of cancer in men in the United States other than skin cancer. Of all the men who are diagnosed with cancer each year, more than one-fourth have prostate cancer. Research is increasing our understanding of prostate cancer. Scientists are learning more about the possible causes of prostate cancer and are looking for new ways to prevent, detect, diagnose, and treat this disease. Because of this research, men with prostate cancer now have a lower chance of dying from the disease.

The normal prostate

The prostate is a gland in a man's reproductive system. It makes and stores seminal fluid, a milky fluid that nourishes sperm. This fluid is released to form part of semen. The prostate is about the size of a walnut. It is located below the bladder and in front of the rectum. It surrounds the upper part of the urethra, the tube that empties urine from the bladder. If the prostate grows too large, the flow of urine can be slowed or stopped. To work properly, the prostate needs male hormones (androgens). Male hormones are responsible for male sex characteristics. The main male hormone is testosterone, which is made mainly by the testicles. Some male hormones are produced in small amounts by the adrenal glands.

Understanding the cancer process

Cancer is a group of many related diseases. These diseases begin in cells, the body's basic unit of life. Cells have many important functions throughout the body. Normally, cells grow and divide to form new cells in an orderly way. They perform their functions for a while, and then they die. This process helps keep the body healthy. Sometimes, however, cells do not die. Instead, they keep dividing and creating new cells that the body does not need. They form a mass of tissue, called a growth or tumor.

Tumors of the prostate

Tumors can be benign or malignant: Benign tumors are not cancer. They can usually be removed, and in most cases, they do not come back. Cells from benign tumors do not spread to other parts of the body. Most important, benign tumors of the prostate are not a threat to life. Benign prostatic hyperplasia (BPH) is the abnormal growth of benign prostate cells. In BPH, the prostate grows larger and presses against the urethra and bladder, interfering with the normal flow of urine. More than half of the men in the United States between the ages of 60 and 70 and as many as 90 percent between the ages of 70 and 90 have symptoms of BPH. For some men, the symptoms may be severe enough to require treatment.

Malignant tumors are cancer. Cells in these tumors are abnormal. They divide without control or order, and they do not die. They can invade and damage nearby tissues and organs. Also, cancer cells can break away from a malignant tumor and enter the bloodstream and lymphatic system. This is how cancer spreads from the original (primary) cancer site to form new (secondary) tumors in other organs. The spread of cancer is called metastasis.

When prostate cancer spreads (metastasizes) outside the prostate, cancer cells are often found in nearby lymph nodes. If the cancer has reached these nodes, it means that cancer cells may have spread to other parts of the body -- other lymph nodes and other organs, such as the bones, bladder, or rectum. When cancer spreads from its original location to another part of the body, the new tumor has the same kind of abnormal cells and the same name as the primary tumor. For example, if prostate cancer spreads to the bones, the cancer cells in the new tumor are prostate cancer cells. The disease is metastatic prostate cancer; it is not bone cancer.

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Risk factors for prostate cancer

The causes of prostate cancer are not well understood. Doctors cannot explain why one man gets prostate cancer and another does not. Researchers are studying factors that may increase the risk of this disease. Studies have found that the following risk factors are associated with prostate cancer:

• Age. In the United States, prostate cancer is found mainly in men over age 55. The average age of patients at the time of diagnosis is 70.
• Family history of prostate cancer. A man's risk for developing prostate cancer is higher if his father or brother has had the disease.
• Race. This disease is much more common in African American men than in white men. It is less common in Asian and American Indian men.
• Diet and dietary factors. Some evidence suggests that a diet high in animal fat may increase the risk of prostate cancer and a diet high in fruits and vegetables may decrease the risk. Studies are in progress to learn whether men can reduce their risk of prostate cancer by taking certain dietary supplements.
• High testosterone levels. Testosterone hormone stimulates the growth of the prostate gland. Many studies proved that long term testosterone therapy and high testosterone blood level may cause prostate gland enlargement (benign prostatic hyperplasia) and may increase the risk f developing cancer prostate.
• Although a few studies suggested that having a vasectomy might increase a man's risk for prostate cancer, most studies do not support this finding. Scientists have studied whether benign prostatic hyperplasia, obesity, lack of exercise, smoking, radiation exposure, or a sexually transmitted virus might increase the risk for prostate cancer. At this time, there is little evidence that these factors contribute to an increased risk.

Screening for prostate cancer

• Blood test for prostate-specific antigen (PSA): A lab measures the levels of PSA in a blood sample. The level of PSA may rise in men who have prostate cancer, BPH, or infection in the prostate. The traditional PSA level at which biopsy is recommended was 4.0 ng/mL, now many physicians consider recommending a biopsy at a PSA level in the range of 2.5 to 4.0 ng/mL.
• PSA derivatives: Percent-free PSA: PSA exists in the body in different forms either free or bound to other proteins. The percentage of the free PSA level to the total PSA is what we call Percent-free PSA. This is an alternative test used when the total PSA levels between 4-10 ng/mL and a biopsy can not be done. A value of ≤25% means a biopsy is recommended and the probability of having cancer is high.
• PSA Velocity: The rate of change in PSA over time is called the PSA velocity (PSAV). A cutoff of 0.75 ng/mL/year raises the suspicion of cancer when PSA levels were between 4-10 ng/ml.

It is also important to know that there are opponents for routine early detection programs since no available data from randomized trials proved the advantage of early disease detection in terms of decreasing death rates from the disease. For this reason, the US Preventive Services Task Force and the American College of Physicians do not recommend performing routine PSA evaluation for prostate cancer screening.

However, all agree that screening programs have allowed the early detection of localized cancer and markedly decreased the frequency of metastatic disease at diagnosis.

Symptoms of Prostate cancer

Early prostate cancer often does not cause symptoms. But prostate cancer can cause any of these problems:

• A need to urinate frequently, especially at night;
• Difficulty starting urination or holding back urine;
• Inability to urinate;
• Weak or interrupted flow of urine;
• Painful or burning urination;
• Difficulty in having an erection;
• Painful ejaculation;
• Blood in urine or semen; or
• Frequent pain or stiffness in the lower back, hips, or upper thighs.

Any of these symptoms may be caused by cancer or by other, less serious health problems, such as BPH or an infection. A man who has symptoms like these should see his doctor or a urologist (a doctor who specializes in treating diseases of the genitourinary system).

Diagnosis of prostate cancer

If a man has symptoms or test results that suggest prostate cancer, his doctor asks about his personal and family medical history, performs a physical exam, and may order laboratory tests. The exams and tests may include a digital rectal exam, a urine test to check for blood or infection, and a blood test to measure PSA. In some cases, the doctor also may check the level of prostatic acid phosphatase (PAP) in the blood and PSA derivatives, especially if the results of the PSA indicate there might be a problem. The doctor may order exams to learn more about the cause of the symptoms. These may include:

• Transrectal ultrasonography -- sound waves that cannot be heard by humans (ultrasound) are sent out by a probe inserted into the rectum. The waves bounce off the prostate, and a computer uses the echoes to create a picture called a sonogram.
• Intravenous pyelogram -- a series of x-rays of the organs of the urinary tract.
• Cystoscopy

Biopsy

If test results suggest that cancer may be present, the man will need to have a biopsy. During a biopsy, the doctor removes tissue samples from the prostate, usually with a needle. A pathologist looks at the tissue under a microscope to check for cancer cells. If cancer is present, the pathologist usually 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. One way of grading prostate cancer, called the Gleason system, uses scores of 2 to 10. Another system uses G1 through G4. Tumors with higher scores or grades are more likely to grow and spread than tumors with lower scores.

If the physical exam and test results do not suggest cancer, the doctor may recommend medicine to reduce the symptoms caused by an enlarged prostate. Surgery is another way to relieve these symptoms. The surgery most often used in such cases is called transurethral resection of the prostate (TURP or TUR). In TURP, an instrument is inserted through the urethra to remove prostate tissue that is pressing against the upper part of the urethra and restricting the flow of urine. (Patients may want to ask whether other procedures might be appropriate).

Stages of prostate cancer

• Staging system for prostate cancer

If cancer is found in the prostate, the doctor needs to know the stage, or extent, of the disease. Staging is a careful attempt to find out whether the cancer has spread and, if so, what parts of the body are affected. The doctor may use various blood and imaging tests to learn the stage of the disease. Treatment decisions depend on these findings.

Prostate cancer staging is a complex process. The doctor may describe the stage using a Roman number (I-IV) or a capital letter (A-D).

Treatment for prostate cancer

Treatment for prostate cancer may involve watchful waiting, surgery, radiation therapy, or hormonal therapy. Some patients receive a combination of therapies. In addition, doctors are studying other methods of treatment to find out whether they are effective against this disease.

Watchful waiting

Watchful waiting also known as deferred treatment or active surveillance is decided based on estimation of the patient life expectancy, complete staging, comorbidities and the reliability of close follow up and monitoring. A lot of work is being done to better define the criteria for selecting patients who would benefit the most from this approach without negatively affecting their survival.

Watchful waiting may be suggested for some men who have prostate cancer that is found at an early stage and appears to be slow growing. Also, watchful waiting may be advised for older men or men with other serious medical problems. For these men, the risks and possible side effects of surgery, radiation therapy, or hormonal therapy may outweigh the possible benefits. Men with early stage prostate cancer are taking part in a study to determine when or whether treatment may be necessary and effective.

Although men who choose watchful waiting avoid the side effects of surgery and radiation, there can be some negative aspects to this choice. Watchful waiting may reduce the chance of controlling the disease before it spreads. Also, older men should keep in mind that it may be harder to manage surgery and radiation therapy as they age. Some men may decide against watchful waiting because they feel they would be uncomfortable living with an untreated cancer, even one that appears to be growing slowly or not at all. A man who chooses watchful waiting but later becomes concerned or anxious should discuss his feelings with his doctor. A different treatment approach is nearly always available.

Surgery

Surgery is a common treatment for early stage prostate cancer. The doctor may remove the entire prostate (a type of surgery called radical prostatectomy) or only part of it. In some cases, the doctor can use a new technique known as nerve-sparing surgery. This type of surgery may save the nerves that control erection. However, men with large tumors or tumors that are very close to the nerves may not be able to have this surgery.

The doctor can describe the types of surgery and can discuss and compare their benefits and risks. In radical retropubic prostatectomy, the doctor removes the entire prostate and nearby lymph nodes through an incision in the abdomen.

In radical perineal prostatectomy, the doctor removes the entire prostate through an incision between the scrotum and the anus. Nearby lymph nodes are sometimes removed through a separate incision in the abdomen.

In transurethral resection of the prostate (TURP), the doctor removes part of the prostate with an instrument that is inserted through the urethra. The cancer is cut from the prostate by electricity passing through a small wire loop on the end of the instrument. This method is used mainly to remove tissue that blocks urine flow.

Laparoscopic and Robot-assisted radical prostatectomy are commonly used now. They give comparable results to traditional surgery in experienced centers and with less blood loss.

Whether to remove lymph nodes during radical prostatectomy or not is now evaluated using especial tables or special computer programs (nomograms) that tell the possible risk of having lymph node metastases that warrants their removal.

If the pathologist finds cancer cells in the lymph nodes, it is likely that the disease has spread to other parts of the body. Sometimes, the doctor removes the lymph nodes before doing a prostatectomy. If the prostate cancer has not spread to the lymph nodes, the doctor then removes the prostate. But if cancer has spread to the nodes, the doctor usually does not remove the prostate, but may suggest other treatment.

Patients are often uncomfortable for the first few days after surgery. Their pain usually can be controlled with medicine, and patients should discuss pain relief with the doctor or nurse. The patient will wear a catheter (a tube inserted into the urethra) to drain urine for 10 days to 3 weeks. The nurse or doctor will show the man how to care for the catheter.

It is also common for patients to feel extremely tired or weak for a while. The length of time it takes to recover from an operation varies. Surgery to remove the prostate may cause long-term problems, including rectal injury or urinary incontinence. Some men may have permanent impotence. Nerve-sparing surgery is an attempt to avoid the problem of impotence. When the doctor can use nerve-sparing surgery and the operation is fully successful, impotence may be only temporary. Still, some men who have this procedure may be permanently impotent.

Men who have a prostatectomy no longer produce semen, so they have dry orgasms. Men who wish to father children may consider sperm banking or a sperm retrieval procedure.

Radiotherapy

Radiation therapy (also called radiotherapy) uses high-energy x-rays to kill cancer cells. Like surgery, radiation therapy is local therapy; it can affect cancer cells only in the treated area. In early stage prostate cancer, radiation can be used instead of surgery, or it may be used after surgery to destroy any cancer cells that may remain in the area. In advanced stages, it may be given to relieve pain or other problems.

Radiation may be directed at the body by a linear accelerator, or it may come from tiny radioactive seeds placed inside or near the tumor (internal or implant radiation, or brachytherapy). Men who receive radioactive seeds alone usually have very small tumors confined to the prostate. Some men with prostate cancer receive both kinds of radiation therapy.

Improvement of the local control using radiation therapy was an area of active research. Passing from the standard two dimensional 2D radiation therapy technique through the three dimensional 3D conformal radiation therapy (3DCRT) that uses computer systems to the most recent techniques, the intensity modulated system. These advances allowed the delivery of higher radiation doses to cancer cells with less exposure of the normal surrounding tissues and organs to radiation therapy.

Radiation doses differ according to the patient risk group (his stage, PSA, and Gleason score). As for surgery, whether to treat pelvic lymph nodes or not depends on patient risk categorization, only low risk patients do not receive pelvic radiation therapy.

For external radiation therapy, patients go to the hospital or clinic, usually 5 days a week for several weeks. Patients may stay in the hospital for a short time for implant radiation.

Radiation therapy may cause patients to become extremely tired, especially in the later weeks of treatment. Resting is important, but doctors usually encourage men to try to stay as active as they can. Some men may have diarrhea or frequent and uncomfortable urination.

When men with prostate cancer receive external radiation therapy, it is uncommon for the skin in the treated area to become red, dry, or tender, however there may be hair loss in the treated area. The loss is usually temporary.

Both types of radiation therapy may cause impotence in some men. While internal radiation therapy may cause temporary urinary incontinence, external radiation therapy causes temporary bowel inflammation. Long-term side effects from internal radiation therapy are uncommon.

Hormonal therapy

Hormonal therapy keeps cancer cells from getting the male hormones they need to grow. It is called systemic therapy because it can affect cancer cells throughout the body. Systemic therapy is used to treat cancer that has spread. Sometimes this type of therapy is used to try to prevent the cancer from coming back after surgery or radiation treatment in patients considered at high risk for recurrence. .

There are several forms of hormonal therapy:

• Orchiectomy is surgery to remove the testicles, which are the main source of male hormones.
• Drugs known as luteinizing hormone-releasing hormone (LH-RH) agonists can prevent the testicles from producing testosterone. Examples are leuprolide, goserelin, and buserelin.
• Drugs known as antiandrogens can block the action of androgens. Two examples are flutamide and bicalutamide.
• Drugs that can prevent the adrenal glands from making androgens include ketoconazole and aminoglutethimide.

After orchiectomy or treatment with an LH-RH agonist, the body no longer gets testosterone from the testicles. However, the adrenal glands still produce small amounts of male hormones. Sometimes, the patient is also given an antiandrogen, which blocks the effect of any remaining male hormones. This combination of treatments is known as total androgen blockade (TAB), combined hormonal therapy (CHT), combined androgen blockade (CAB), or maximal androgen deprivation (MAD). Studies have not shown a superior efficacy for combined hormonal blockade over castration alone. Doctors may use combined hormonal blockade only during the initial 7 days of radiation therapy to bone aiming to avoid flare of symptoms, a known side effect during the initiation of an LH-RH agonist treatment (as explained later).

Prostate cancer that has spread to other parts of the body usually can be controlled with hormonal therapy for a period of time, often several years. Eventually, however, most prostate cancers are able to grow with very little or no male hormones (hormone refractory). When this happens, hormonal therapy is no longer effective, and the doctor may suggest other forms of treatment that are under study.

The side effects of hormonal therapy depend largely on the type of treatment. Orchiectomy and LH-RH agonists often cause side effects such as impotence, hot flashes, and loss of sexual desire. When first taken, an LH-RH agonist may make a patient's symptoms worse for a short time. This temporary problem is called "flare." Gradually, however, the treatment causes a man's testosterone level to fall. Without testosterone, tumor growth slows down and the patient's condition improves. (To prevent flare, the doctor may give the man an antiandrogen for a while along with the LH-RH agonist.)

Antiandrogens can cause nausea, vomiting, diarrhea, or breast growth or tenderness. If used a long time, ketoconazole may cause liver problems, and aminoglutethimide can cause skin rashes. Men who receive total androgen blockade may experience more side effects than men who receive a single method of hormonal therapy. Any method of hormonal therapy that lowers androgen levels can contribute to weakening of the bones in older men.

Treatment for those who have disseminated disease and are hormone refractory is chemotherapy. The currently approved drugs are Docetaxel, Novantrone, and Estramustine and more recently satraplatin.

Follow up care

During and after treatment, the doctor will continue to follow the patient. The doctor will examine the man regularly to be sure that the disease has not returned or progressed, and will decide what other medical care may be needed. Follow up exams may include x-rays, scans, and lab tests, such as the PSA blood test.

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