Prostate cancer – Causes, Symptoms, Prognosis, Diagnosis and Latest Treatment

Prostate cancer is the most common form of cancer diagnosed in men in the U.S., with 179,000 new cases diagnosed in 2002 and 31,500 deaths are reported relating to this disease.  The National Cancer Institute estimates that one in six men will develop prostate cancer in their lifetime, typically after the age of 55.   With 29% of all cancers in men being prostate cancer, the incidence of the disease is comparable to that seen with breast cancer. 

In most cases, prostate cancer produces little or no symptoms.  The cancer usually grows very slowly and may remain confined to the gland for many years.  It is not until the tumor has enlarged and pressed on the urethra or has spread to other areas of the body, such as the spine or the pelvic bones, will symptoms begin to appear.  At that time, patients may experience incomplete bladder emptying, decreased urinary stream, urinary hesitancy, nocturia and pelvic pain.  

Unfortunately, when the disease has reached this stage, the prognosis of the patients is usually poor.  As a results, many experts are now recommending routine screening for prostate cancer in men after the age of 40, when the risk of having this disease starts to increase. 

Today, most prostate cancers are diagnosed either by routine digital rectal examination or by prostate-specific antigen (PSA) test.  

In the digital rectal examination, the doctor feels the prostate gland with the index finger to identify any abnormality within the gland.  Thus, a lump or hardness felt on the surface of the gland may suggest abnormal growth.  

In the PSA test, biochemical reagents are used to detect prostate specific antigen in the blood.  A PSA level lower than 4 nanograms per milliliter is considered normal, while a value of 4 to 10 is considered borderline.  However, PSA levels higher than 10 are a strong indication that the patient has abnormal growth in the prostate.  Since such abnormal growth may also be due to another condition known as benign prostate hyperplasia, a biopsy of the gland is needed to confirm the diagnosis.  

After the pathologist has confirmed the diagnosis of prostate cancer, an urologist or an oncologist will then “stage” the cancer.  The prognosis of the patients varies according to the stage of the cancer. In stage I and II, where the tumors have not spread beyond prostate gland, the five-year survival rate could reach 100%.   Once the tumors have spread beyond the prostate gland to distant tissue, however, the survival rate is reduced drastically.  In stage IV, where the tumor has metastases, the five-year survival rate is only 5-10%. (Table 1) 

Fortunately, the majority of prostate cancer patients (70%) are diagnosed at Stage I or Stage II, and only a small fraction of them (20%) are diagnosed at the last stage (Stage IV) — with metastases.  In fact, the greatest trend in prostate cancer epidemiology over recent decades has been the increase in early – stage detection and decrease in patients diagnosed beyond Stage III.  This early diagnosis and treatment has resulted in a 2.5% per year decline in cancer deaths due to prostate cancer between 1992 and 1996. (Figure 1) 

Source: Adapted from American Cancer Society Cancer Medicine 

Another way of grading prostate cancer is by assigning a grade to each of the two largest areas of cancer in a tissue sample.  A score of 2-4 is considered low grade; 5-7, intermediate; 8-10, high grade.  A tumor with a low Gleason score typically grows slowly enough that it may not pose a significant threat to the patient in this lifetime. 

Causes and Treatment

Even thought the exact cause of prostate cancer is unknown, it is well known that the growth of prostate cancer is stimulated by testosterone.  As a result, by suppressing the release or by blocking the action of testosterone, hormonal therapies are able to stop the growth of the some prostate cancers.     

Risk factors, which have been reported to have an association with prostate cancer, include advancing age, family history, hormonal influences and environmental factors such as smoking, toxins, chemicals and industrial products. 

The treatment for patients with prostate cancer depends on the stage and risk level of the disease.  (Table 2) 

Localized prostate cancer (low, intermediate, and high risk)

For organ-confined prostate cancer with low-risk disease (i.e., PSA< 10ng/ml and Gleason score <7), the traditional treatment of choice has been radical prostatectomy.  When cancer is confined to the prostate and the entire gland is removed, prostatectomy is associated with a 90% cure rate nationwide. 

In recent years, however, barchytherapy (the placement of radioactive I-125 or palladium Pd-103 pellets through needles into the prostate gland) has become an attractive alternative.  This “radioactive seeding” technique offers similar clinical effects as surgery, but lower incidence of major complications associated with radical prostatectomy (i.e. lower incidence of impotence, urinary incontinence).  Overall, both radical prostatectomy and brachytherapy produce 10-year progression-free survival rates of close to 65%  Due to similar efficacy and reduced morbidity, more patients are expected to select brachytherapy in the future. 

For patients with intermediate (organ-confined prostate cancer with PSA 10-20ng/ml and Gleason score = 7) or high-risk disease (organ-confined prostate cancer with PSA >20ng/ml and Gleason score >8), clinicians are increasingly utilizing adjunctive hormonal therapy with surgery or radiation to produce a more sustained disease-free response.  The anti-androgens most commonly used in this setting are Lupron^® (leuprolide) and Zoladex^® (goserelin).  These two products produce similar clinical responses.   Several clinical trials have demonstrated extension of progression-free survival with these agents beyond that typically seen with surgery or radiation. 

Locally advanced stage III prostate cancer

When patients have locally advanced prostate cancer, it typically involves the seminal vesicles or other tissues around the prostate and has a much poorer prognosis than localized disease.  For these patients, standard therapy involves a combination of LHRH agonists with either surgery or radiation or both. With this regimen, progression-free survival can approaches 55% at five years. 

Metastatic stage IV prostate cancer

The first-line therapy for patients with metastatic prostate cancer is testicular androgen suppression with an LHRH (Luteinizing hormone releasing hormone) agonist, either Lupron (leuprolide) or Zoladex (goserelin).  

By inhibiting the release of LHRH and effectively reducing testicular testosterone, these agents halt the growth of prostate cancer in 2 to 3 weeks.   Testicular androgen suppression with Lupron^® and Zoladex^® typically produces responses rates of up to 85% and results in median survival of 24-30 months. These therapeutic modes are the functional equivalent to chemical orchiectormy, or castration.   

Another type of agent that is sometime used in this setting is anti-androgens (Casodex^® and Nilandron^®).  These agents block the effect of testosterone produced by the adrenal gland on prostate cancer.  Even though the concept of testosterone blockade is attractive, these agents failed to show definitive advantage over single-agent therapy with Lupron^® or Zoladex^®.  As a result, these agents are used only in a small subset of patients, especially in those who do not respond to Lupron^® or Zoladex^®.     

Chemotherapy is generally reserved for patients with hormone-refractory prostate cancer who have stopped responding to LHRH agonists such as  Lupron^® or Zoladex^®. 

Category Analysis 

LHRH agonists such as leuprolide (Lupron^®) and goserelin (Zoladex^®) are the most commonly prescribed drugs.  There are no differences in efficacy between these compounds and the only way to improve these drugs is to introduce products with long duration of actions and less frequent administrations.  Lupron 4-month^® injection is one of the long-acting LHRH agonist introduced in 2002.

 Antiandrogens agents (Casodex^®, Nilandron^® and Eulexin^®) are considered as second line agents in the treatment of advanced prostate cancer.  Among antiandrogens agents, Casodex is the most commonly prescribed agent. 

+++ – Strong

++ – Moderate

+ – Low 

Hormonal Treatment 

Hormonal treatment, also referred to as androgenic deprivation (depriving the prostate of testosterone), can be accomplished either surgically or medically. 

Surgical hormonal treatment involves the removal of the testes in an operation called an orchiectomy, while medical hormonal treatment requires the intake of either LHRH agonist or antiandrogen agents.  LHRH agonists work by inhibiting the release of testosterone, while antiandrogens block the effect of testosterone on the prostate.  

Surgical hormonal therapy

Since testicular testosterone accounts for approximately 95% of circulating androgens, orchiectomy remains a possible intervention.  Orchitectomy is the removal of the testes, resulting in a rapid reduction in circulating testosterone.  It is important to note that orchiectomy has no effect on the production or suppression of FSH, which may be responsible for the prostate cancer cell growth.  

Due to the irreversible side effect (impotence) associated with this therapeutic mode, and the availability of medical treatments to block testosterone, this procedure is performed less often today.  It is now reserved for patients with extensive bony metastases who are at imminent risk of spinal cord compression, bladder neck obstruction and retroperitoneal adenopathy.  

LHRH agonists

Since the launch of LHRH agonists (Zoladex^® and Lupron^®) in 1980s, these compounds dominate the category of hormone treatment for prostate cancer.  Together, Zoladex^® (goserelin) and Lupron^® (leuprolide) represented 70% of the hormone treatment category for prostate cancer in 2002.  These products are available in depot preparations, which allowed periodic administration every three to four months.  Multiple clinical trials, however, did not demonstrate any difference in efficacy between these products.  

Initially, the effect of LHRH agonists is to stimulate the release of luteinizing hormone (LH) and subsequently the release of testosterone from the testes.  After this initial stimulatory effect, however, LHRH agonists act to down-regulate LHRH release and effectively reduce testicular testosterone to castrate levels within two to three weeks.  As stated above, treatment with Lupron^® and Zoladex^® typically produces response rates of up to 85% and results in median survival of 24-39 months with a 12 to 18 month progression-free interval. 

One of the major drawbacks with Lupron^® and Zoladex^® is the fact that they cause an initial surge of testosterone production before actually blocking its production.  This transient testosterone surge which occurs during the first few weeks on LHRH agonist therapy may cause symptomatic worsening of prostate cancer, particularly in those patients with metastatic disease, resulting in bone pain, cognitive decline, acute obstruction, and generalized malaise.  To reduce the surge, some clinicians will prescribe LHRH agonists with antiandrogens.  Other side effects commonly seen with LHRH agonists include loss of libido and osteoporosis due to long-term androgen deprivation.  

Recently, LHRH agonists have also been studied in conjunction with external radiation.   Initial results indicated that combination therapy of LHRH agonists and radiation resulted in lower treatment failure rate and higher survival rate. 

Zoladex^®, Eligard^®, Lupron^®, Viadur^®

Goserelin (Zoladex^®) and leuprolide (Eligard^®, Lupron^®, Viadur^®) are parenteral synthetic agonist analogs of gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH).   All LHRH agonists are indicated as palliative treatments of advanced prostate cancer and have similar efficacy.  The only difference between them is their subcutaneous formulation.  Some products, such as Lupron^® injection requires daily administration while others, such as Lupron^® 4mo Depot, needs only 1 injection every 4 months.  (Table 4) 

(Source: PDR 2002) 

Lupron^® (leuprolide) is the first LHRH agonist approved by the FDA.  Lupron^® has several different formulations, but only the Lupron^® depot and Lupron^® injection are indicated for the treatment of advanced prostate cancer.  From 1989 to 1997, the FDA approved three formulations of Lupron^® for the palliative treatment of advanced prostate cancer:

Lupron^® 7.5 mg, approved in March 1989, delivers leuprolide acetate over 1 month

• Lupron 3-months^® 22.5 mg, approved in January 1996, delivers leuprolide acetate over three months
• Lupron 4-months^® 30 mg, approved in July 1997, delivers leuprolide acetate over four months 

Zoladex^® (goserelin), is the second LHRH agonist, introduced to this category.  Zoladex^® has two different implantable dosage forms. The once-monthly implant form of Zoladex^® was originally approved by the FDA in 1993 and came off patent in 1997.  Another implant that releases drug for 3 months was approved in January 1996 for treating prostate cancer.  Unlike Lupron^®, Zoladex^® does not have an implant that release drug for 4 months. 

In March 2000, the FDA approved Viadur^® DUROS titanium alloy implant for the palliative treatment of advanced prostate cancer.  Viadur^® is a subcutaneous device which provides continual leuprolide therapy for one-year.  However, since its launch, this product has not enjoyed wide acceptance.

Antiandrogens

The nonsteroidal antiandrogens (Casodex^® (bicalutamide), Eulexin^® (flutamide), and Nilandron^® (nilutamide)) are considered second line agents for the treatment of advanced prostate cancer.  These products inhibit the progression of prostate cancer by interfering with the binding of testosterone and dihydrotestosterone to the androgen receptor.  

These agents are less effective than castration with either orchiectomy or LHRH agonists.  In clinical trials, a smaller percentage of patients treated with antiandrogens had PSA normalization (an indication of disease progression) and higher percentage of them were treatment failures when compared with patients treated with LHRH.  As a result, antiandrogens are currently not recommended as monotherapy, but as adjunctive therapy with LHRH agonists. 

Eulexin^®, Casodex^®, Nilandron^®

Basically, there are no differences among the existing antiandrogens.  The only difference is the longer half-life of Casodex^® which allowed once-daily dosing compared with the three times daily dosing requirement for Eulexin^®. 

Combined Androgen Blockade (CAB)

Although monotherapy with LHRH agonists results in a decline of 90 percent of circulating testosterone, 10 percent of circulating testosterone is still present in castrated men due to peripheral conversion of circulating adrenal steroids to testosterone.  In order to block this 10% of circulating testosterone, some physicians suggest to combine LHRH agonists with antiandrogens in the treatment protocol.    

Although initial results with this idea were very promising, more recent data does not support the use of combined androgen blockade in all patients.  In a recent meta-analysis, investigators found that CAB did not improve survival when compared with androgen suppression alone.  The five-year survival was 25.4% with CAB versus 23.6% with androgen suppression alone, a non-significant gain of 1.8%.  The only improvement is the reduction in surge among patients treated with the combination therapy.  The lack of improvement when combining LHRH agonists and antiandrogens might be related to the fact that neither antiandrogens nor LHRH blocks the effect of FSH, a sex hormone that might be related to tumor growth. 

Couple with additional cost and the inconvenient dosing schedule, CAB is used only in patients with metastases who could not tolerate the surge associated with LHRH mono-therapy. 

GnRH Antagonists

The GnRH antagonist is the latest and the most appealing class of agents developed for the hormonal therapy of prostate cancer.  Represented by abarelix depot, this new class offers a number of therapeutic advantages, which are not available in its competitors. 

First, abarelix suppresses not only testosterone, but also FSH, which may prove to be a significant factor in the treatment of prostate cancer.  Second, these agents are able to suppress testosterone levels as quickly and effectively as orchietomy, or DES (Diethylstilbestrol), but without the irreversible side effects of impotence or cardiovascular complications.  Third, unlike LHRH agonists, abarelix antagonists do not cause the androgen surge or hormone flare, thus obviating the need for antiandrogen agents.  Lastly, abarelix acts faster than combination therapy to suppress testosterone.  

In a phase III clinical trial, higher percentage of patients treated with abarelix (75%) had serum testosterone levels lowered to castration levels by day 15 than patients treated with leuprolide (10%).  Also, the percentage decrease in PSA was significantly greater in the abarelix group on day 15 after treatment.  At day 29 and beyond, PSA levels were similar for both leuprolide and abarelix.  In another study with 290 patients, abarelix depot was able to cause a rapid reduction in testosterone level within 24 hours after administration without a hormonal surge. 

Even though the results from early clinical trials on this product look very appealing, the full potential of it remains to be seen as this product undergoes Phase III clinical trials. 

Chemotherapy

For patients who are resistant to hormone treatment, chemotherapy is the last resort.  Due to the limitation of this paper, use of chemotherapy in prostate cancer will be reviewed in another paper. 

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