Prostate Cancer

A lesson in anatomy

            Prostate problems, both benign and malignant, are common. Prostate cancer has been a neglected disease. Recently, however, several “high profile” people such as Michael Mulligan have increased the public’s awareness of this disease. At the same time, new chemotherapeutic agents have been discovered which have efficacy when used to treat this illness.

            The prostate’s location explains most of the symptoms that occur when it enlarges.

            From looking at this picture, you can see that an enlarging prostate will compress the urethra (the tube leading from the bladder thru the penis). This will cause urinary hesitancy, frequency and retention. Also, there may be difficulty starting the stream.

Who gets prostate cancer?

            The older you are, the greater your chances of getting prostate cancer. If you are African American or if you have a close relative diagnosed with prostate cancer, your risk is increased. If you carry a gene called BRCA 2 you also have an increased risk. 1/5 men develop prostate cancer. This means that 230,000 men will develop this illness over the next year. 40,000 men will die this year from prostate cancer.

What are the symptoms of prostate cancer?

            The most common and usually the earliest symptom is difficulty voiding (frequency, slow stream, nocturia (getting up at night to urinate), urgency and straining to empty the bladder.

            Bone pain is a late symptom and usually signifies metastatic disease (tumor “traveled to” bone).

Screening for prostate cancer

            Screening should be considered in otherwise healthy men over the age of 50. Some physicians advise African American men and men with strong family history of prostate cancer to start screening at age 40.

            Elderly men and men with serious medical problems might not benefit from finding an asymptomatic prostate cancer since their co-morbid problems may indicate a short life expectancy.

            Usually screening is done yearly and consists of rectal exam and determination of PSA (prostate specific antigen).

            PSA is a protein normally produced by the prostate in small amounts. When the prostate gland is “well” there is little escape of PSA into the blood. Many things can elevate PSA, an elevated PSA does not diagnose cancer – only a biopsy can do that.

Some conditions that can elevate PSA include:  BPH (benign prostatic hypertrophy), bladder, prostate or testicular infection, instrumentation of the urinary tract such as a cystoscopic exam, prostate surgery and urinary retention.

            Normal PSA values differ with race and age. Some labs are now reporting a “free PSA” value which may be more predictive of cancer than is the total PSA.

            An enlarged prostate is usually NOT cancer. BPH (benign prostatic hypertrophy) is a very common condition.

            Similarly an elevated PSA often does not mean prostate cancer; although levels greater than 70 usually do.

            If your screening exam is not normal, your doctor will probably send you to a urologist for further testing.

            PSA screening has increased the percent of men diagnosed when their cancer is still confined to the prostate and thus potentially curable.

Further testing

            Most likely, the urologist will do a transrectal ultrasound and biopsy.

A transrectal biopsy is usually done in the urologist office. To do this procedure, a probe is inserted into the rectum. The probe “checks out” the prostate using sound waves (ultrasound). The ultrasound tells your urologist if the prostate gland has any

area (s) that “look different” from surrounding glandular tissue. These abnormal areas are then biopsied with a gun that has a small needle attached to it. Usually multiple biopsies are done. Each biopsy takes less than a second. Usually these biopsies cause minimal discomfort and patients resume normal activities the next day.

Cancer

            A pathologist examines the biopsy. A positive result means that cancer has been found. A negative result indicates the absence of a malignancy. Occasionally a biopsy will be a false negative due to sampling error.

When the cancer is examined microscopically, the pathologist notes its differentiation. The more poorly differentiated it is, the more likely it is to metastasize (travel) to areas outside the prostate. The pathologist uses a system called Gleasons grade. The lower the grade the better “behaved” the tumor is likely to be.

Gleason Grade                         Meaning

2-4                                     Well differentiated cancer that looks a lot like normal prostate

5-6                                     This tumor is more aggressive

7                                        Aggressive, moderately to poorly differentiated

8-10                                   Poorly differentiated highly aggressive

Stages

            Whenever a diagnosis of cancer is made, there are two “jobs” to be done. The 1^st is to ask, “Where is the cancer” i.e. what stage is it. 

The second is treatment. Staging for prostate cancer involves determination of the extent of local disease with a CAT scan and PSA.  A bone scan to look for metastatic disease may also be obtained. 

A bone scan is a nuclear medicine study during which a radioactive tracer is injected IV (in the vein) and the bones checked to see if they “darken” (hot spots). Bone scans are very sensitive, but also very non-specific – i.e. a positive bone scan will occur with tumor, infection, trauma, Paget's disease, etc. Normally hot spots are x-rayed or examined by MRI or CAT scan.

Prostate cancer is staged as follows:

Stage A:                 Tumor is not suspected by exam or PSA but is found when resection of the prostate done for other reasons such as BPH.

Stage B:                 Tumor can be felt on rectal exam.

Stage C:                 Tumor has spread outside the capsule of the prostate gland but has not metastasized to distant sites.

Stage D:                 Metastatic disease.

(Note-each stage can be further subdivided)

            Many urologists use a TNM system of staging. T refers to the size of the tumor,

N refers to involvement of lymph nodes and M means metastatic disease. This system is more detailed and its use is increasing.

Treatment of Early Disease

Treatments for prostate confined cancer include surgery, radiation (external beam radiation or brachytherapy (“seeds”) or cryotherapy.  Some men without symptoms who have low-grade tumors and multiple other medial problems are observed (watchful waiting). 

It is probably not prudent to watch high grade or large tumors; but low grade, small tumors in elderly or frail patients can often be safely watched. 

A study from Sweden randomized 695 men with small tumors (T₁ or T₂) to prostatectomy or observation.  After 6 years 9% of the men who were observed versus 4.6% of men treated with surgery had died of prostate cancer.  13% of men treated with surgery were alive but had metastatic disease versus 27% of the men in the observation group who were alive but had metastatic tumor.

Surgery involves the removal of the prostate gland and surrounding lymph nodes. This is a technically difficult procedure. Side effects include impotence and urinary incontinence.

There are no randomized controlled trials published that compare radiation to surgery.  One such trial is in progress, but no results are yet available.

External beam radiation therapy involves lying on table and having radiation delivered to the prostate. The use of IMRT radiation limits the exposure of normal tissue to radiation. However, both the bladder and the rectum will receive some radiation. Side effects include cystitis (inflammation of the bladder) and proctitis (inflammation of the rectum). Radiation takes 4 to 7 weeks to complete. The incidence of impotence is less than with surgery.  Cure with surgery or radiation is similar and patient preference and co-morbidities play a major role in the treatment decision. 

Brachytherapy (“seeds”) involves the placement of tiny radioactive seeds into the prostate. The seeds are inserted under general anesthesia by going thru the perineal skin (area between the anus and scrotum). Seed treatment should be limited to men with small or moderate sized prostates. Side effects are usually few; they include irritation of the bladder and/or rectum. Seeds have a very good short-term outcome; but, because the technique is so new, long-term data are limited.

Cryotherapy (freezing) involves placing multiple probes into the prostate and freezing it.  This procedure is only used for small (T₁, T₂, T₃) tumors without involved nodes.  In this procedure, under spinal anesthesia, multiple cold probes are placed in the prostate and the tissue is frozen.  Complications may include impotence and incontinence postoperative.  Pain is minimal.  Patients usually have a Foley catheter for 3 weeks after the procedure. 

A repeat biopsy should be considered at about 3 months.  If positive for residual tumor, another cryosurgery treatment should be given. 

            At this time, the role of cryosurgery in the treatment of prostate cancer is unclear.  Preliminary data suggest a higher recurrence rate when retrospectively compared with radical prostatectomy. 

            In men with early prostate cancer, reducing testosterone (androgen ablation) may be used as the only treatment or as an adjunct to surgery or radiation.  Androgen ablation may be accomplished by castration (surgical removal of the testicles) or by drugs (Lupron, Zoladex).            

Follow-up of Prostate Cancer After Definitive Local Treatment

            Men who receive radical prostatectomy or radiation therapy are unfortunately not always cured.  Treatment failure (i.e. recurrence of disease) is usually herald by an increasing PSA. 

Men at high risk of failure (disease recurrence) include those with positive surgical margins, seminal vesicle involvement, high Gleason’s grade (greater than 6) and high initial PSA (greater than 7). 

Post surgery, PSA values should be below 0.2 and should remain there.  Post radiation therapy the lowest PSA may take 1-2 years to achieve and should be below 1.0. 

Patients who have been treated by surgery and who have a rising PSA may be cured by salvage radiation.  Radiation should be given before the PSA reaches 1.  PSA doubling time is an important predictor of prognosis.  Patients with a very short PSA doubling time (less than 3 months) have a very poor outlook and should receive aggressive treatment.  Those with doubling times of 3-10 months have a high likelihood of prostate specific mortality and should consider additional treatment.  Men should receive a PSA and rectal exam every 3 months for 1 year and then every 6 months after completion of their initial treatment. 

Treatment of Advanced Prostate Cancer

Treatment of Locally Advanced Disease

            Locally advanced disease is a common problem.  Depriving the tumor of androgen (testosterone) will cause cancer cell death and thus tumor shrinkage.  The tumor will then be easier to encompass in a radiation field.  This approach is called neoadjuvant treatment.  Studies have shown that androgen ablation followed by radiation therapy is superior to radiation therapy alone when survival is used as the end point. 

Treatment of Metastatic Prostate Cancer

Metastatic prostate cancer is not currently curable. However, a long life is often possible. Many treatments improve the quality of life as well as its duration.  Patients with advanced prostate cancer (i.e. node positive) should receive androgen ablation as part of their initial treatment. 

Prostate cancer usually metastasizes (travels) to bone. This occurrence may result in bone pain and fractures. When the tumor involves a vertebral body, compression of the spinal cord may occur.  This complication is a medical emergency because once the cord has been damaged recovery is not likely. 

Advanced (metastatic) disease can be treated with several different modalities. These include: hormones (deletion of male hormones or addition of “antihormones” or use of female hormones) chemotherapy and radiation therapy.

The decision of which modality to use depends on the patient’s past treatment and the urgency of treatment.

Usually hormonal treatment is given first.

Hormones

            Decreasing the level of testosterone by castration was the 1^st treatment for advanced prostate cancer that proved to be beneficial. The female hormone, estrogen, is also very effective as first line treatment.

            Estrogen is rarely used anymore due to the increased incidence of MIs, strokes and blood clots seen with its use. 

There are several newer approaches to depriving the cancer of testosterone. These include Zoladex and Lupron. These medications work on the brain and prevent “messengers” from reaching the testes and “telling” them to make testosterone.  These agents are very effective as 1^st line treatment for advanced disease.  They are called LHRH antagonists. 

These agents are the most common 1^st line medical treatment.  With their use, there is an initial testosterone surge, and the disease may “flare” for up to 7 days.  Thus, patients with painful bone mets, cord compression or severe urethral obstruction should receive short-term (7 days before and 7 days after the start of) anti-androgen therapy when one of these agents is used.

Abarelix does not cause a testosterone surge and achieves castrate levels more quickly.  Unfortunately, immediate allergic reactions and the occurrence of hypotension and syncope limit its use. 

Unfortunately, androgen ablation (testosterone removal) has side effects, which include impotence, hot flashes, osteoporosis and muscle wasting.  Many men also develop a mild anemia.  Gynecomastia (enlargement of the breasts) may be prevented by low dose radiation to breast tissue.  Hot flashes are often troublesome and are similar to those experienced by women during menopause.  Both progesterone and Effexor (an antidepression drug) may be helpful. 

Bone loss and loss of muscle are common.  Bone loss should be treated with a Bisphosphonate, Calcium, Vitamin D and walking (or other weight bearing exercise).  Muscle mass loss can be lessened with an exercise program that emphasizes resistance training. 

There are several antiandrogen pills available which are very effective. These include Casodex and Eulexin.

Anti-androgens compete with the patient’s own androgen for binding sites on the cancer cell.  These drugs are usually used in combination with another agent.  Breast tenderness and enlargement, nausea and diarrhea are common side effects. 

Ketoconazole is an antifungal agent that interferes with the synthesis of androgens.  Ketoconazole is often difficult for patients to tolerate, and compliance may be poor.  One major benefit of this drug is its rapid onset of action – androgen levels fall dramatically within 24 hours. 

            Most doctors start androgen blockade at the time of local therapy in high-risk patients. This approach has been shown to prolong survival compared to starting treatment when metastatic disease has become evident.

            About 80% of patients have tumor regression or stabilization with the use of endocrine (adding or ablating hormones) therapy.  Many patients do well for several years, but most have progressed by 24 months.  When one mode of endocrine therapy fails, the patient may be observed off therapy to see if a tumor regression will occur (androgen withdrawal regression). 

            Combined androgen blockade is the use of 2 agents to reduce androgen level to a very low level.  Usually an anti-androgen such as Casodex is combined with an LHRH antagonist such as Zoladex or Lupron.  It remains controversial if combined therapy is better than monotherapy; combined analysis of several trials suggests a 2 to 3% benefit at 5 years. 

            Many times, several types of hormones are tried in sequence. Once a tumor no longer responds to endocrine treatment, it is called androgen independent. The median time for progression in men with metastatic disease is 18 to 24 months.  Becoming androgen independent appears to be part of the natural history of this cancer

Radiation

            Radiation therapy may be used in an emergency, such as cord compression (tumor presses on the spinal cord and “kills” it).  If started early, it may be very effective in preventing permanent paralysis. However, cord compression must be treated immediately or irreversible damage will occur.

            Radiation is also helpful in “touching up” painful bony lesions.  If there are multiple lesions and if other treatment has not been helpful, Metastron, an injectable form of radiation can be considered. This treatment often decreases pain. However, it also “hurts” the bone marrow and usually no treatment, other than hormones, can be given for 3-4 months after its use.

            Bone weakened by tumor growth may fracture spontaneously or with minor trauma (pathological fracture). Often radiation therapy is used to try to prevent these fractures.  Zometa, an antiosteoporosis drug can be given IV once a month to help prevent bone fractures. 

When patients become refractory to hormones, median survival without additional treatment is about 9 months.

Chemotherapy

            Chemotherapy is starting to play an increasing role in the treatment of prostate cancer.

            Previously, men with prostate cancer where not though be good candidates for chemotherapy. Now, however, we have much better supportive care and more active agents. Also, prostate cancer patients are seeing a medical oncologist earlier in the course of their illness; thus they have less extensive disease and often respond more favorably to treatment.

            Chemotherapy refers to cytotoxic drugs (drugs that kill cells). These drugs are usually given IV (in the vein); several are available p.o. (by mouth).

            Chemotherapy does have side effects; however, these are usually easily managed. They may include alopecia (hair loss), leukopenia (low white count), anemia, nausea and fatigue. Each drug has a different toxicity profile. Toxicities are usually quickly reversible once treatment has stopped.

            The response of prostate cancer to treatment is measured by PSA level – a fall of 50% or more is considered a good response. Patients often notice a reduction in pain after only 1 or 2 treatments.  

            Recently, treatment with a drug named Taxotere has been shown to prolong survival.  The previous standard chemotherapy drug was Novantrone and Prednisone.  In this randomized trial, there was a survival advantage for men who received Taxotere and Prednisone.

            Prednisone was given orally; Taxotere was given by a 1-hour infusion every 3 weeks. 

            Side effects were generally transient and easily managed.  They included fatigue, low white count and some minor degree of hair loss. 

            Other drugs that have some benefit include Emcyt and Novantrone. 

Reports of side effects from treatment make many patients and families anxious. However, with newer antiemetics (anti nausea drugs) only occasionally is nausea a problem. If you are unsure of “quality of life” with treatment, one dose can be tried and, if you feel the drug is “not right for you”, no further doses need be given.

            Please remember that if you or a loved one is not doing well with hormonal treatments, see a medical oncologist at that time. Don’t wait until you are “down in the bed”.

Prostate cancer patients have many new options and can expect exciting new treatments. Several major cancer centers have trials under way with investigational agents, some of which show great promise.

Supportive Care

            Complications of advanced disease include pathologic fracture, severe anemia requiring frequent blood transfusion, difficult to manage pain, spinal cord compression and generalized weakness. Each of these problems can be lessened by seeing an oncologist. While cure may not be possible, improvement in the quality of your remaining life is an important part of your treatment.