Health and Prostate

Outcome variables in treating node-positive prostate cancer have traditionally included local progression (bladder outlet obstruction, ureteral obstruction, impotence), biochemical recurrence or progression, development of distant metastasis, and disease-specific survival. More recently, the issue of quality of life as an outcome measure has surfaced. When reviewing the literature of immediate versus deferred hormonal therapy, that is, observation, for advanced prostate cancer, it is important to be aware of the specific outcome variables being measured and compared. Moul provides an excellent definition of this clinical scenario as well as a review of the hormonal management of advanced prostate cancer, employing data recently published in Britain by the Medical Research Council Prostate Cancer Working Party Investigators Group. The literature examined in Moul’s review clearly and unequivocally confirms that early hormonal therapy delays the time to progression (biochemical and symptomatic), a result that has been confirmed by several authors. The rates of pathologic bone fracture, spinal cord compression, and ureteral obstruction as well as the requirement for transurethral resection of the prostate were all significantly higher in the deferred versus immediate hormonal therapy groups.

The Moul study also revealed that the cause of death from prostate cancer was higher in the deferred versus immediate therapy groups (71% versus 62%). Overall survival improvement with immediate hormonal therapy, however, is not clearly demonstrated. The review contains valuable data confirming the above-noted improvement in outcome variables related to disease progression. However, the study was not blinded, follow-up data regarding compliance in the immediate therapy group were not reported, and a high percentage of men in the deferred treatment group experienced mortality due to prostate cancer without receiving hormonal therapy at all. This suggests that the treatment groups were not uniformly managed. It is, therefore, not accurate to cite an improvement in survival in the patients treated with early endocrine therapy. The key issues in the debate over immediate versus deferred hormonal therapy then become disease-specific survival and quality of life while receiving or not receiving therapy.

Quality-of-life issues have recently become incorporated into research studies addressing prostate cancer and are an important outcome variable in the case of node-positive prostate cancer. Since no clinically significant benefits in quantitative survival can be demonstrated with immediate hormonal therapy over deferred treatment, the quality of the remaining years of life becomes paramount.

TABLE. Complication Rates in Patients given Immediate versus Deferred Hormonal Therapy

Hormonal deprivation can be achieved through several methods, including castration, luteinizing hormone-releasing hormone analogues A, antiandrogens, or combinations of these therapies (maximum/combined androgen blockade, androgen withdrawal, and intermittent androgen blockade). The physiologic basis and mechanism of action of hormonal therapy is reviewed elsewhere. It has been established, however, that combined androgen blockade results in a better survival rate than luteinizing hormone-releasing hormone-A or orchiectomy alone. The morbidity of hormonal therapy is outlined in Table Morbidity of Hormonal Therapy.

The incidence of these side effects varies. Most surgically castrated patients become impotent. The incidence of side effects with luteinizing hormone-releasing hormone analogues are reported as similar to that of surgical castration, with 57% of patients experiencing hot flashes but approximately 5% reporting impotence. Gastrointestinal symptoms are reported in 21 to 46% of patients treated with antiandrogens and gynecomastia in 40%. The incidence and long-term sequelea of osteoporosis remain to be defined in this population but should be considered a potential adverse effect of androgen deprivation.

Screening for Prostate Cancer: the Case for Screening

The American Cancer Society estimates that there will be 179,300 new cases of prostate cancer diagnosed in 1999, making it the most commonly diagnosed malignancy among men in the United States. In addition, a projected 37,000 men will die this year secondary to prostate cancer. As a result, the American Cancer Society and the American Urological Association (AUA) have put forth guidelines recommending that annual serum prostate-specific antigen (prostate-specific antigen) testing and digital rectal examination be offered to men aged 50 and older who have at least a 10-year life expectancy. The prostate-specific antigen and digital rectal examination should also be offered to younger men at high risk for developing prostate cancer, such as African American men or men with a strong family predisposition to the disease (two or more affected first-degree relatives, e.g., father, brother). Information should be provided to patients regarding the risks and benefits of intervention.

In order for prostate cancer screening to be deemed a successful and worthwhile endeavor, three separate and distinct goals must be satisfied. First, we have to demonstrate that screening increases the diagnosis of earlier stage prostate cancer. Second, we have to prove that patient survival is prolonged, and lastly, a decrease in the prostate cancer-specific mortality rate has to be demonstrated.

There is a large body of evidence to support the theory that prostate cancer screening increases the diagnosis of earlier stage prostate cancer. The incidence of newly diagnosed, organ-confined prostate cancer has risen significantly since the introduction of prostate-specific antigen testing. Conversely, the diagnosis of previously untreated, metastatic prostate cancer has plummeted.

To fulfill our second goal, we must provide evidence that patient survival is prolonged by screening. Earlier diagnosis leads to prolonged survival by definition. Lead-time bias is the expected increase in survival related to earlier diagnosis. If a patient undergoes screening for pro-static disease and is diagnosed 3 years before he would have presented clinically, the screening test would have increased the patient’s life from time of diagnosis to an endpoint (e.g., death) by 3 years, thereby prolonging survival. Gann and colleagues, in a prospective study of frozen serum samples, estimated that prostate-specific antigen testing provided an average 5.5-year lead time in the diagnosis of clinically significant prostate cancer.

Therefore, the first two prerequisites of any screening program have been satisfied by the use of serum prostate-specific antigen and digital rectal examination. The last objective of screening is to decrease the prostate cancer death rate and this remains to be definitively proven. However, there is a body of evidence amassing that leads us to conclude that this prerequisite will be satisfied.

Given current technology, screening for prostate cancer will always be associated with error. This is because the only way one can exclude a diagnosis of prostate cancer with 100% certainty is to remove the entire prostate and to step section the entire gland with histologic examination. This is clearly both impractical and excessively invasive. However, anything short of total evaluation of the entire prostate will have a reduced sensitivity, that is, some cancers will be missed owing to sampling error.

The issue of whether or not to screen American men for prostate cancer has been a subject of debate. Opponents argue that screening only benefits a select group of patients with clinically aggressive, organ-confined disease, and they believe that treatment of most cases of prostate cancer detected by screening is either ineffective (i.e., tumor not organ-confined) or unnecessary (i.e., tumor not biologically significant). They further maintain that screening results in substantial economic cost, morbidity, and anxiety that are not justified by an increased detection of disease. Finally, and the most valid argument, is the fact that no prostate cancer screening program has been demonstrated to decrease mortality in a prospective, randomized, controlled trial.

Those in favor of screening, including the authors, argue that prostate cancer is a major illness killing about as many men as breast cancer kills women, and that only through screening can this disease be brought under control. Waiting until the benefits of screening have been definitively proven could cost thousands of men their lives. The morbidity of treating early disease is in many instances less than the morbidity of treating advanced disease. Lastly, the economic considerations of screening should not weigh against this endeavor unless screening is proven to be of no benefit. Given the current data, the economic onus is on those who are against, rather than those who are in favor of screening.

Screening by Digital Rectal Examination

Screening by Transrectal Ultrasound

Following the introduction of transrectal ultrasonography of the prostate, there was a great deal of enthusiasm regarding its use in the early detection of prostate cancer. It was felt that transrectal ultrasound would be able to detect many nonpalpable small tumors that were missed by digital rectal examination alone. However, studies have shown that transrectal ultrasound has several limitations with regard to its use as a screening test for prostate cancer.

Most importantly, transrectal ultrasound has low positive and negative predictive values, which were reported to be 36 and 89%, respectively, in one study. Cooner and colleagues reported the positive predictive value of transrectal ultrasound to be only 16% in men with a palpably benign prostate. This number drops to 9.8% when both digital rectal examination and prostate-specific antigen are normal. Additional limitations of transrectal ultrasound as a screening tool include the procedure’s invasiveness, cost, and limited detection rate when the less invasive digital rectal examination and prostate-specific antigen are normal. It is the authors’ belief that the major value of transrectal ultrasound is its ability to allow for anatomic sampling of the prostate when other screening tests are abnormal.

Screening by Prostate-Specific Antigen

Since the late 1980s there has been an unquestionable increase in the detection of prostate cancer and the diagnosis of curable disease. Since digital rectal examination and transrectal ultrasound have been shown to be ineffective screening tools, most epidemiologists relate this dramatic rise to prostate-specific antigen-based screening. Regarding prostate-specific antigen’s ability to improve detection of curable disease, one may compare stage at time of diagnosis. According to Jacobsen and colleagues, the incidence of clinically organ-confined prostate cancer increased from 61% in the pre-prostate-specific antigen era (i.e., digital rectal examination-detected cancers) to more than 90% in the post-prostate-specific antigen era. The incidence of pathologically organ-confined disease showed a similar upturn from an average of 33% before the widespread use of prostate-specific antigen testing, to as high as 70% following the introduction of prostate-specific antigen into community medical practice.

In large prostate-specific antigen-based prostate screening trials involving thousands of men, cancer detection rates have ranged from 1.5% to 4%. The positive predictive value of prostate-specific antigen testing in these trials has varied between 11 and 34%. The false-negative prostate-specific antigen values were felt to be due to the relatively high incidences of benign prostatic hyperplasia and subclinical prostatic inflammation in the screening population.

Brawer and associates screened 1249 men over the age of 50 with serum prostate-specific antigen levels. Men with a prostate-specific antigen value greater than 4.0 ng per mL were further evaluated by digital rectal examination and transrectal ultrasound-guided biopsy. A total of 187 men (15%) had an elevated prostate-specific antigen. In the 105 men who underwent biopsy, a total of 32 carcinomas were identified (31%). Mettlin and colleagues reported on a series of 2999 men aged 55 to 70 years who were screened for prostate cancer using prostate-specific antigen, digital rectal examination, and transrectal ultrasound. Of the 164 patients that were found to have tumors, 103 underwent radical prostatectomy and 64 (62%) had pathologically organ-confined disease. In 1994, Catalona and colleagues published a multicenter study involving 6630 men aged 50 and above who underwent testing with serum prostate-specific antigen and digital rectal examination. Of the 14.8% of men with a prostate-specific antigen greater than 4 ng/mL, 32% were found to have prostate cancer. Thus, the cancer detection rate for prostate-specific antigen was 4.6%. Again, prostate-specific antigen played a primary role in the diagnosis of pathologically localized disease. Of the 160 patients who underwent radical prostatectomy, 114 (71%) had pathologically organ-confined disease. In fact, the use of prostate-specific antigen and digital rectal examination in combination increased detection of organ-confined disease by 78% over digital rectal examination alone.

In summary, it is the belief of the authors that prostate-specific antigen plays a vital role in the detection of early-stage curable prostate cancer. Serum prostate-specific antigen determinations should be the central modality of prostate cancer detection at this time. However, cancer detection rates, positive predictive value of prostate-specific antigen testing, and the possibility of false-positive results need to be discussed with patients prior to prostate-specific antigen-based screening.

Prostate-specific antigen Derivatives

The Status of Screening

Conclusion

The introduction of routine serum prostate-specific antigen determinations into the annual health physical of older men has dramatically influenced the demographics of prostate cancer diagnosis. In general, prostate cancer is being diagnosed in younger men with a normal digital rectal examination. They are often found to have clinically localized disease of lower grade. Many of these men are seeking the potentially curable therapies of radical prostatectomy and radiation therapy (external beam and brachytherapy). In the past, these patients would have escaped diagnosis owing to a lack of symptoms and a normal digital rectal examination. Accordingly, their tumors would have progressed to the advanced disease so common in the 1980s.

Given these facts, it is impossible for the authors to conclude that prostate-specific antigen screening will not satisfy the three tenets of a successful screening modality. The decreased death rate for prostate cancer now being evidenced in preliminary results and SEER studies will be validated. The naysayers who refuse to accept screening will be left to ponder how many lives could have been saved had the widespread use of prostate-specific antigen been universally accepted sooner.

Before the widespread clinical use of prostate-specific antigen, digital rectal examination was the most common initial test for the diagnosis of prostate cancer. While several earlier reports have concluded that annual screening using digital rectal examination leads to improved early detection of disease and prolonged survival, other studies contradicted these findings. The limitation of digital rectal examination as a screening test appears to be its poor sensitivity in detecting curable (i.e., pathologically organ-confined) disease. In fact, approximately 40 to 60% of men with clinically localized prostate cancer detected by annual digital rectal examination have local or systemic spread of disease when pathologic staging is available.

In addition, a study by Gerber and colleagues that evaluated disease-specific survival following routine screening by digital rectal examination in over 4000 men suggests that this approach will not decrease the mortality rate from prostate cancer. The investigators compared cancers diagnosed during the initial screen (prevalence group) with those identified during subsequent screens (the incidence group). It was hypothesized that the cancer-specific mortality would be lower in the incidence group. In fact, the cancer-specific mortality was significantly higher in this group. These findings led to the conclusion that routine screening by annual digital rectal examination may be insufficiently frequent and/or sensitive to prevent significant mortality from prostate cancer.

The limitations of digital rectal examination as a sole screening modality have been further clarified by Flanigan and colleagues. In a multicenter study, more than 6000 men underwent screening by digital rectal examination and prostate-specific antigen. An abnormal result in either screening test led to a recommendation of transrectal ultrasonography (transrectal ultrasound) with four-quadrant prostate biopsy. Of the 624 men who underwent biopsy, 1002 quadrants were suspicious by digital rectal examination, and 110 (11%) contained cancer. The positive biopsy rate for nonsuspicious quadrants was 9% (p = .97) and was statistically no different from that of a suspicious quadrant. In fact, 74% of cancers were diagnosed in prostate quadrants normal to palpation.

In summary, it is clear that more clinically localized cancers can be detected through the use of annual screening by digital rectal examination. Unfortunately, a significant percentage of these tumors have already spread beyond the prostatic capsule at the time of diagnosis, rendering a cure unlikely. Therefore, although we are strongly in favor of prostate cancer screening and recognize that digital rectal examination is an extremely inexpensive screening tool, we do not believe that digital rectal examination alone will satisfy the three necessary prerequisites of successful screening.

The sensitivity of prostate-specific antigen has never been questioned. It is the test’s lack of specificity (i.e., the number of false-positives that result in invasive evaluations) that has caused most concern. In an attempt to improve specificity, several investigators have tried to modify the interpretation of prostate-specific antigen values. These modifications have been termed prostate-specific antigen derivatives. Numerous prostate-specific antigen derivatives have been developed and tested clinically with the purpose of optimizing the use of prostate-specific antigen as a screening tool. This can only be achieved by increasing the test’s specificity while preserving its sensitivity.

Prostate-specific antigen Density

Prostate-specific antigen density is one such variation and is defined mathematically as total prostate-specific antigen (ng/mL) divided by the volume of the prostate gland (cc). The concept of Prostate-specific antigen density is based on the assumption that the Prostate-specific antigen density calculation would standardize the amount of prostate-specific antigen produced per cubic centimeter of prostate tissue. A volume occupied by cancer will result in a higher serum prostate-specific antigen than a volume occupied by benign tissue. It was postulated that Prostate-specific antigen density would be able to identify which patients had an elevated prostate-specific antigen secondary to benign enlargement, benign prostatic hyperplasia, versus those with elevations secondary to prostate carcinoma.

The concept of Prostate-specific antigen density was introduced at Columbia-Presbyterian Medical Center by the authors in collaboration with Dr. William Cooner of Mobile, Alabama. The objective was to derive a means of decreasing the number of false-positive prostate-specific antigen results and thus the number of unnecessary biopsies.

TABLE. Age- and Race-Specific Reference Ranges for Prostate-Specific Antigen

An analysis of 773 patients with a normal digital rectal examination and a prostate-specific antigen between 4 to 10 ng per mL who subsequently underwent transrectal ultrasound led to the proposal of a Prostate-specific antigen density cut off value of 0.15 mg per mL. In this preliminary study, only patients with an abnormal transrectal ultrasound (hypoechoity or asymmetry) underwent an initial biopsy. The positive prostate biopsy rate in this group was 6% for patients with a Prostate-specific antigen density less than 0.15 versus 18% for patients with a Prostate-specific antigen density greater than 0.15. Another investigation by Bazinet and colleagues confirmed these findings. In their study, 142 patients with a negative digital rectal examination and a prostate-specific antigen between 4 to 10 ng per mL underwent prostate biopsy. They noted that only 2 patients who had a Prostate-specific antigen density less than 0.15 biopsied positive, while 20 patients had positive biopsies with a Prostate-specific antigen density greater than 0.15.

Despite these encouraging initial data, other studies have failed to confirm improved cancer detection rates using Prostate-specific antigen density compared with total serum prostate-specific antigen. Factors responsible for the conflicting results and conclusions may involve anatomic and technical difficulties in determining prostate volume, lack of uniformity regarding the statistical analysis applied to the different studies, and the fact that the epithelial-stromal ratio differs considerably from patient to patient. Differences in the amount of epithelium versus stroma in an individual’s prostate allow for a wide range of prostate-specific antigen production in prostates of similar volume. Because of these observations, Prostate-specific antigen density as a means of increasing the specificity of serum prostate-specific antigen testing is not universally accepted.

Age-Specific prostate-specific antigen

An age-specific reference range for serum prostate-specific antigen is a variation of total prostate-specific antigen which was designed to increase sensitivity in younger men and to increase specificity in older men. The concept of age-specific prostate-specific antigen follows that as most men get older they develop benign prostatic hyperplasia, with a resultant increase in their prostate size and an increase in their serum prostate-specific antigen. In a community-based study, Oesterling and colleagues enrolled 537 men aged 40 to 79 into a screening protocol that included serum prostate-specific antigen, digital rectal examination, and transrectal ultrasound. Of the 537 men, 471 had all three tests performed without any evidence of prostate cancer. Utilizing this subset of patients, they correlated serum prostate-specific antigen with age and prostate volume. The results indicated that prostate-specific antigen increased by 0.04 ng per mL (3.2%) per year. From these data, using 95th percentile confidence limits, age-specific reference ranges for serum prostate-specific antigen were developed.

Several investigators have tested this hypothesis and examined its clinical usefulness in lowering the normal prostate-specific antigen value in younger men and raising the normal value in older men. It appears that lowering the normal range in younger men is valid and appropriate. In a multi-institutional study, Catalona and colleagues utilized a patient population base consisting of 6630 men undergoing prostate-specific antigen and digital rectal examination screening followed by transrectal ultrasound, with prostate biopsy for those with abnormal results. They reported that a cutoff of 3.5 ng per mL in men 50 to 59 years old resulted in a 15% increase in cancer detection versus a cutoff of 4.0 ng per mL. Partin and colleagues studied a population of clinical stage Tic prostate cancer who had undergone radical prostatectomy. The authors concluded that in men younger than 60 years, a significant number of additional tumors would be detected by using age-specific ranges. Thus, it appears that the prostate-specific antigen cutoff of 4.0 ng per mL may be too high for younger men. However, it must be taken into consideration that the added sensitivity of a lower prostate-specific antigen cutoff would be at the cost of decreased specificity and the resultant added morbidity (more false-positive results leading to more negative biopsies).

The validity of increasing the normal prostate-specific antigen range in older men is less established. Had age-adjusted reference ranges been used in the Catalona study, men aged 60 to 69 would have undergone 15% fewer biopsies. However, 8% of organ-confined tumors would have been missed in this age group. In men older than 70, 44% fewer biopsies would have been performed with 47% of organ-confined cancers missed. Partin and colleagues also made the observation that raising the prostate-specific antigen range for older men would result in decreased sensitivity, but they also raised the question of clinical significance and clinical consequence of the missed tumors.

In summary, investigators support the theory that the use of age-specific reference ranges would improve the sensitivity of prostate-specific antigen in younger men, allowing for the diagnosis of more organ-confined prostate cancer. For now, most experts are unwilling to raise the upper limit of normal in older men.

Race and Age-Specific prostate-specific antigen

The database that led to the development of age-specific ranges for prostate-specific antigen was composed almost entirely of Caucasian men. It has been known for a long time that Asian men generally have smaller prostates and a lower incidence of prostate cancer than Caucasian or African American men. African American men have the highest incidence of prostate cancer in the world. These facts led investigators to evaluate the effect of race on age-specific ranges. Oesterling and colleagues performed a study similar to the one outlined above in an attempt to clarify age-specific reference ranges in Japanese men.

Morgan and colleagues completed a study examining age-specific reference ranges in African American men. This study confirmed that the prostate-specific antigen concentration correlates with age, and that the upper limit of normal serum prostate-specific antigen should also be age dependent in African Americans. Morgan determined that if traditional age-specific reference ranges were used as outlined by Oesterling for Caucasian men, 41% of cancers in their African American cohort would have been missed. The differences appear minor, but they have tremendous clinical significance because it is in African Americans that prostate cancer is more prevalent; it occurs at an earlier age, and it has the highest mortality rate.

Prostate-specific antigen Velocity

Another derivative used to improve prostate-specific antigen screening is known as prostate-specific antigen velocity. Utilizing data and frozen serum from the Baltimore Longitudinal Study of Aging, Carter and colleagues were able to plot the prostate-specific antigen values of 73 men, aged 60 or older, over a 7-year period. They observed that men without prostate symptoms or prostate cancer had little change in their prostate-specific antigen value over time. Patients with benign prostatic hyperplasia had a linear slope of prostate-specific antigen velocity, while patients with prostate cancer had an initial linear component that became exponential. Investigators calculated prostate-specific antigen velocity with an equation utilizing at least three separate points and suggested that a prostate-specific antigen velocity greater than 0.75 ng per mL per year was suspicious for prostate cancer.

The “normal” prostate-specific antigen velocity was examined by several studies including one by Smith and Catalona, which prospectively enrolled 982 men to examine the efficacy and utility of prostate-specific antigen velocity This study calculated that for patients with a prostate-specific antigen less than 4.0 ng per mL, the cutoff prostate-specific antigen velocity predictive of cancer was 0.75 ng per mL per year. However, for patients with prostate-specific antigen greater than 4.0 ng per mL, the cutoff point which predicts cancer was 0.4 ng per mL per year.

The major question surrounding prostate-specific antigen velocity is how many serum measurements are required and how far apart they should be spaced. Carter and colleagues addressed these issues by retrospectively examining serial prostate-specific antigen measurements in 806 men. They focused on the number of prostate-specific antigen determinations, the time interval between prostate-specific antigen measurements, and the effect on the calculated prostate-specific antigen velocity. The authors concluded that three or more values with time intervals greater than 6 months between readings are necessary to determine velocity.

This severely limits the clinical utility of prostate-specific antigen velocity, in that it is of greatest value retrospectively, and of least value when the prostate-specific antigen determinations occur within 1 year of each other. Therefore, at a minimum, 2 years of prostate-specific antigen determinations are required to accurately stratify patients by prostate-specific antigen velocity. With this lengthy time frame, patient anxiety and the possibility of disease progression become issues which push toward an early biopsy. As a result, prostate-specific antigen velocity would appear to be of greatest utility in men who have already undergone a biopsy which proved negative for cancer.

Free to Total prostate-specific antigen Ratio

One of the more recent prostate-specific antigen derivatives is the comparison of unbound (free) prostate-specific antigen to the total amount of prostate-specific antigen in the serum. The prostate-specific antigen can exist as free prostate-specific antigen and as prostate-specific antigen bound to a2-antichymotrypsin (ACT) or a2-macroglobulin (A2M).’ The prostate-specific antigen bound to A2M (prostate-specific antigen-A2M) is anti-genically shielded and not measurable by any prostate-specific antigen assay. The prostate-specific antigen-ACT complex, however, is immunoreactively unique and can be measured in the serum as a separate moiety. As a result, it is possible to compare the amount of free prostate-specific antigen to the total amount of prostate-specific antigen (free + prostate-specific antigen-ACT). Lilja and colleagues documented that the majority of prostate-specific antigen in the serum is complexed to ACT, accounting for approximately 85% of the total serum prostate-specific antigen. They later compared the ratio of free:total prostate-specific antigen in men with benign prostatic hyperplasia to the free:total prostate-specific antigen of men with prostate cancer. They found that the free:total ratio was significantly lower in men with prostate cancer than men with benign prostatic hyperplasia (18 versus 28%, respectively, p < .0001). Importantly, this difference was present for prostate-specific antigen values above and below 10 ng per mL. They concluded that the use of free:total prostate-specific antigen ratio would allow for a differentiation of elevated prostate-specific antigen levels secondary to benign prostatic hyperplasia and prostate cancer without decreasing the sensitivity of prostate-specific antigen.

The explanation of why prostate-specific antigen secreted from benign prostatic hyperplasia is less likely to be bound to ACT (higher free:total ratio) may be found within prostate cancer cells. Bjork and colleagues found that prostate cancer cells produce not only prostate-specific antigen, but also ACT. This coexpression of prostate-specific antigen and ACT may allow for an increased likelihood of a prostate-specific antigen-ACT complex when prostate-specific antigen is expressed from a cancer cell as opposed to a benign cell. However, this is only speculative and the reason or reasons behind the observed free:total differences remain unknown.

Regardless of the explanation for the increased prostate-specific antigen-ACT complex in prostate-specific antigen expressed from prostate cancer cells (lower free:total ratios), free:total prostate-specific antigen ratios improve prostate-specific antigen specificity for patients with serum prostate-specific antigen levels in the 4 to 10 ng per mL range. The use of Hybritech’s free:total prostate-specific antigen has been granted approval from the Food and Drug Administration, and free:total ratios from other companies are expected to be approved in the near future. However, free:total prostate-specific antigen, like the other prostate-specific antigen derivatives, is not without controversy. A universal free:total prostate-specific antigen cutoff has yet to be established, and it appears that like Prostate-specific antigen density and age- and race-specific prostate-specific antigen, the resultant increases in specificity are at the cost of decreases in sensitivity.

There are reports that support the notion that since the introduction of prostate-specific antigen in the late 1980s, prostate-specific antigen-based prostate cancer screening has led to dramatic changes in the epidemiology of the disease, which are suggestive of effective screening. Data supplied by the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 1994 have shown a substantial increase in the number of newly diagnosed cases of prostate cancer. This trend accelerated when prostate-specific antigen use became widespread in the late 1980s. New prostate cancer cases peaked in 1992 and have since declined. However, the incidence has not fallen back to pre-prostate-specific antigen screening levels.

TABLE. Percent of Free to Total prostate-specific antigen Ratio and Cancer Probability

In addition to the drastic changes in the number of cases of prostate cancer during the prostate-specific antigen-testing era, there has been a downward shift in the age at which the disease is diagnosed. Perhaps more significant, however, is the increased proportion of tumors that are organ-confined at the time of diagnosis. Tumors diagnosed by prostate-specific antigen have a 70 to 80% chance of being organ-confined compared to only 20 to 30% in the pre-prostate-specific antigen era. A trend toward the diagnosis of moderately differentiated tumors has also become apparent. Indeed, organ-confined moderately differentiated disease now comprises 36% of tumors being diagnosed today. This is a significant increase from 22% prior to the prostate-specific antigen era.

Also consistent with, but not definite proof of, the introduction of effective screening is the reduction of mortality secondary to prostate cancer. In 1996, the National Center for Health Statistics reported a 6.3% decrease in prostate cancer mortality in the United States. This was the first time such a decline had been reported. Since then, the data coming out of Quebec and Canada have confirmed this trend. After 1991, prostate cancer mortality rates declined moderately until 1995, and then more dramatically in 1996. Age-standardized prostate cancer mortality rates declined by 23% in Quebec between 1991 and 1997, and by 9.6% in Canada between 1991 and 1996.

There are currently large well-designed, randomized, controlled trials underway both in the United States and Europe. The National Cancer Institute is running the Prostate, Lung, Colorectal, Ovarian (PLCO) screening trial that will last 16 years and involve 74,000 men who will be screened for prostate cancer with prostate-specific antigen and digital rectal examination at more than 10 screening centers across the country. The European Randomized Study of Screening for Prostate Cancer (ERSPC) will follow 172,000 men over 15 years. Preliminary data from these studies will not be available for 10 years, but they are anxiously awaited.

A recent study by Labrie and colleagues was the first prospective, randomized, controlled prostate cancer screening trial published to date. The study enrolled 46,193 male voters from Quebec City aged 45 to 80. Screening invitations were mailed by random selection to 30,956 (67%) men. The remaining one-third of patients served as non-screened controls. Prostate cancer screening consisted of a serum prostate-specific antigen determination and digital rectal examination at the patient’s first visit with subsequent annual prostate-specific antigen tests. The transrectal ultrasound with prostate biopsy was performed if prostate-specific antigen exceeded 3.0 ng per mL or if digital rectal examination was suspicious. Appropriate treatment was initiated if prostate cancer was diagnosed. The prostate cancer death rates during the 8-year period were 48.7 and 15 per 100,000 man-years in the unscreened and screened groups, respectively (p < .01), a 69% difference in favor of screening and early treatment. The authors were criticized for selection bias because only 23% of men randomized to undergo screening actually agreed to undergo testing. A second point of contention was that the intent-to-screen analysis only revealed a 6% decrease of the prostate cancer death rate in favor of the group initially invited to be screened. These criticisms, however, do not completely invalidate the results of the study. The authors pointed out that there was a noncompliance rate of 77% in the original invited group and a contamination rate of 7% of the uninvited men. When statistical adjustments were made to account for these levels of noncompliance and contamination, the effect of screening was estimated to reduce the death rate from prostate cancer by 54 to 100%. Therefore, the authors felt the 69% benefit of screening shown in their report was consistent with the results of the intent-to-screen analysis.

Randomized, controlled trials currently taking place will all certainly be subject to some degree of selection bias. Additionally, any potential lack of survival differences in these ongoing trials will undoubtedly be influenced by the penetration of prostate-specific antigen determinations into the control unscreened populations. It will be difficult, if not impossible, to prevent these men from having prostate-specific antigen determinations performed by their primary care practitioners. As a result, men undergoing prostate-specific antigen screening outside of the study will infiltrate the nonscreened arm in any of these studies to various degrees.

Definition of Hispanics

The United States Bureau of the Census established the term “Hispanic” in 1970 to identify people of Spanish origin. The Hispanic population is very heterogeneous, including Mexicans, Puerto Ricans, Cubans, Dominicans, individuals from Central and South America within its subgroups, as well as those originating from the Iberian peninsula. Hispanics may be identified by their surnames as well as use of the Spanish language. However, Swallen and his colleagues demonstrated that this practice could potentially lead to ethnic misclassification which, in turn, could lead to false conclusions.

In spite of these limitations, when considering Hispanics as a distinct ethnic group, several generalizations can be made. Hispanics constitute one of the fastest growing minority groups in the United States, mostly due to high immigration and fertility rates. The number of Hispanics in the United States increased by 265% from 1950 to 1980, compared to a 50% increase in the general population. By 1990, Hispanics made up approximately 9% of the United States population and could potentially surpass other minority groups in numbers in the near future. The majority of Hispanics tend to live in major metropolitan areas with the largest concentrations seen in the southwestern and northeastern states of the United States as well as in Florida. The relatively lower education and income levels among Hispanics compared to the rest of the population may significantly influence this group’s overall access to health care, and general attitudes toward certain diseases, particularly cancer. These general characteristics among Hispanics may have a significant impact in the epidemiology and management of diseases within this group. Awareness among health care professionals of these demographic characteristics is essential if health care delivered to Hispanics is to be optimized.

Incidence

Although significant differences in the incidence, presentation, and mortality rates of prostate cancer have been noted between different ethnic groups, data concerning Hispanics are scarce. According to Surveillance, Epidemiology, and End Results (SEER) data, the percentage of Hispanics among all patients diagnosed with various types of malignancies ranges from 2.5 to 3.4%, depending on the site of the cancer. In 1990, approximately 2.5% of men diagnosed with prostate cancer in the United States were Hispanics. Gilliland et al. noted a sharp increase from 1969 to 1991 in the age-adjusted incidence rate of prostate cancer among New Mexico’s Hispanics. During this period, the age-adjusted incidence of prostate cancer among Hispanics grew by 75%, from 54.0 to 94.7 cases per 100,000.

This rise in the incidence of prostate cancer among Hispanics compared to an increase in the incidence of prostate cancer among non-Hispanic Caucasians of 87% and was felt to result from increased screening. The most significant increase was seen in the diagnosis of localized and regional disease as opposed to distant disease consistent with the phenomenon of stage migration. In contrast to Gilliland’s report, Danley et al. demonstrated that in spite of increased incidence rates of regional disease among all racial and ethnic groups in Los Angeles County between 1976 and 1988, only non-Hispanic Caucasians had a higher incidence of localized disease, suggesting a poorer prognosis for other groups, particularly African Americans and Hispanics. It is important to note that both these studies are based on data collected prior to the widespread availability of prostate-specific antigen screening.

Trapido et al. reviewed registries from geographic areas covering 68% of the United States Hispanic population. Although prostate cancer was the most common malignancy diagnosed in Hispanic males in most areas, Hispanic men had prostate cancer rates around 80% of those found in non-Hispanics. In another study, Trapido et al. also found a significantly lower incidence of prostate cancer among black Hispanic versus black non-Hispanics in South Florida. When stratifying the relative frequency of prostate cancer among different Hispanic subpopulations, Puerto Ricans and Cuban Americans had a higher incidence of prostate cancer than Mexican Americans, Central and South Americans, and other Hispanics.

Pathologic Outcome

Targeting the Hispanic Population

Attitudes and perceptions among Hispanics toward prostate or any other cancer may lead to scant participation in cancer screening programs as well as clinical trials. Perez-Stable et al. found that a larger proportion of Hispanic patients have a more fatalistic attitude toward cancer than do Anglo-Saxon patients. Under-representation of minorities in clinical trials may be due to “mistrust of white people” and the feeling of being treated like a “guinea pig,” as demonstrated by Roberson. Participation in quality-of-life studies may be hampered by methodologic problems with questionnaires encountered by a significant number of Spanish speaking patients.

Ramirez et al. have proposed several strategies to target the Hispanic population. These include focused epidemiologic and clinical research, recruitment of minorities into health professions, and improved access to health care for minorities. Zimmerman found several important factors influencing Hispanic male participation in prostate cancer screening programs, including availability of examinations at little or no cost. Various institutions have demonstrated the value of formal and informal support groups for Hispanic oncology patients.

Tejeda et al. recently reviewed the representation of non-Hispanic Caucasians, African Americans, and His-panics in National Cancer Institute (NCI) clinical trials. It is extremely encouraging that the relative number of minority patients enrolled in NCI trials between 1991 and 1994 is representative of the nation’s overall ethnic and racial groups. Active participation of Hispanic men in clinical trials for prostate cancer should provide more insight into the manifestation of this malignancy in one of the fastest growing segments of our population.

In a retrospective review of 336 men (24 Hispanics, 33 African Americans, 279 non-Hispanic Caucasians) who did not receive neoadjuvant hormonal therapy and were treated at the authors’ institution with radical prostatectomy for clinically localized prostate cancer, the incidence of extraprostatic extension of the disease was confirmed in the pathologic specimen of 67% of Hispanics, 61% of African Americans, and 52% of non-Hispanic Caucasians. The incidence of seminal vesicle involvement among Hispanics was 25%, compared to 12% and 11% in African American and non-Hispanic Caucasian patients, respectively. The status of lymphnode involvement was available for 226 patients (13 Hispanics, 24 African Americans, and 189 non-Hispanic Caucasians). Among these patients, 31% of Hispanics had positive lymph nodes on pathologic evaluation whereas no African Americans and only 3% of non-Hispanic Caucasians had evidence of nodal involvement.

Friedrichs and associates included patients from two additional institutions for a total of 1026 patients and found that, after controlling for grade, clinical stage, age, and prostate-specific antigen, Hispanic patients had a 321% greater risk of extraprostatic disease, a 247% greater risk of seminal vesicle involvement, and a 980% greater risk of nodal metastasis compared to non-Hispanic Caucasian patients. The risk of extraprostatic disease in African Americans in this study was intermediate to that of Hispanics and non-Hispanic Caucasians.

Other studies have also suggested a less favorable pathologic outcome in Hispanic patients with prostate cancer compared to non-Hispanic Caucasians. Villar demonstrated that Hispanics with prostate, stomach, colon, rectum, lung, breast, and cervical cancer presented at a more advanced stage of disease compared to non-Hispanic Caucasians, particularly those of moderate- to high-income. In this study, 39.9% of Hispanic men with prostate cancer presented with advanced disease versus 35.6% and 33.8% of low-income and moderate- to high-income non-Hispanic Caucasians, respectively. The 1994 National Cancer Data Base report on prostate cancer found Hispanic men to have a stage distribution between that of African American and non-Hispanic Caucasian patients, with 40.3% of Hispanic patients presenting with advanced disease compared to 41.6% of African Americans and 34.3% of non-Hispanic Caucasians. Unfortunately, while survival data were presented for African American and non-Hispanic Caucasian men, no data were presented for Hispanic men.

In New Mexico, which has the highest percentage of Hispanics of all states in the nation, the 5-year relative survival rate for patients with prostate cancer of all stages between 1980 and 1990 was 57.4% for African Americans, 78.5% for Hispanics, and 82.3% for non-Hispanic Caucasians. In a more recent study, Gilliland et al. found that the unadjusted relative risk of death after prostate cancer diagnosis was higher for Hispanic than for non-Hispanic Caucasians. However, after adjusting for age, stage, histologic grade, year of diagnosis, and initial treatment, there was no significant difference in the risk of death between both groups. The authors suggested that the difference in outcome between Hispanics and non-Hispanic Caucasians may be the result of delayed detection and differences in treatment among Hispanics.

Danley and associates concluded that Hispanic men were at a significantly higher risk for advanced disease at the time of prostate cancer diagnosis than were non-Hispanic Caucasian patients. In this study, African American men had a higher risk for advanced disease at diagnosis than did Hispanic men. Despite these findings, Danley did not find a significant difference in the age-adjusted mortality rates between different ethnic and racial groups. Based on all these studies, it appears that being Hispanic is an indicator of poorer pathologic outcome with prostate cancer.

The etiology of the poorer outcome observed in Hispanic men with prostate cancer is unclear. Various demographic characteristics of Hispanics as a group may play a significant role. Poverty and lower levels of education are more prevalent in this segment of the United States population. Access to health care may be limited by lack of health insurance, cultural and language differences, and the relative lack of Hispanic health care providers.

Hispanics may be more likely to underutilize preventive health care services, which may contribute to the presence of more advanced disease at diagnosis. However, some investigators have suggested that Hispanics may be subcategorized into two different groups depending on their degree of acculturation, with significant differences in behaviors related to cancer risk. Those Hispanics with a high acculturation index were more likely to participate in cancer screening programs than those with a low acculturation index. Taken as a whole, however, Hispanics are somewhat less likely than Anglo-Saxons to obtain selected recommended cancer screening tests, as demonstrated by Perez-Stable et al. In their study of Hispanics and Anglo-Saxons in a prepaid health plan, 67% of Hispanic men reported having at least one digital rectal examination compared to 80% of Anglo-Saxons. Reasons frequently cited for Hispanics not making appropriate use of cancer screening tests included forgetfulness, lack of transportation, long wait for appointments, and the need for child care.

Recently, Shibata and Whittemore reviewed the literature on ethnic variation in genetic susceptibility to prostate cancer. In their review, they identified ethnic variation in polymorphic alleles that may be related to a moderately increased risk, and ethnic variation in the prevalence of rare mutation in major genes associated with a significantly higher risk. Further studies including large numbers of Hispanic men are warranted to determine if genetic factors play a role in the poorer outcome of Hispanics compared to non-Hispanic Caucasians.

Overview.

Several hormonal therapies are in development for CaP. Baxter Oncology’s D-63153 and teverelix (Ardana’s Antaralix) are decapeptide luteinizing hormone-releasing hormone (LHRH) antagonists in Phase II development. Lack of data precludes further discussion of them. Toremifene (GTx’s Acapodene) is a nonsteroidal selective estrogen-receptor modulator (SERM) in Phase Ilb / III development. It is being tested for the prevention of CaP among patients with high-grade prostatic intraepithelial neoplasia and for the prevention and treatment of osteoporosis caused by adjuvant LHRH analogues. This agent falls outside the scope of this study. In late-stage development for CaP are finasteride.

Mechanism Of Action.

Finasteride is a steroid analogue of testosterone that treats benign prostatic conditions by blocking the activity of the enzyme 5-alpha reductase and obstructing the conversion of testosterone to dihydrotestosterone, a hormone that plays a role in benign prostatic growth and is believed to contribute to the development of CaP.

Histrelin hydrogel implant is an LHRH antagonist. Unlike LHRH analogues (e.g., goserelin, leuprorelin [leuprolide acetate]), which produce their effect by activating and then desensitizing androgen-producing cells to LHRH, histrelin hydrogel implant directly blocks the effect of the releasing hormone.

Finasteride.

Finasteride (Merck’s Proscar) was approved in 1992 for the treatment of benign prostatic hypertrophy (BPH) and is being tested as both a preventive and a therapeutic agent for CaP. In patients with BPH, finasteride can reduce prostate volume by 25-30%; in preclinical experiments, it has been shown to inhibit CaP cell-line growth. The focus here is on finasteride as a therapy to treat CaP; discussion of it as a preventive agent falls outside the scope of this study. Finasteride is in Phase II development for the treatment of CaP.

A Phase II trial involving 71 patients with biochemical recurrence of CaP after primary therapy received finasteride (5 mg twice daily) and flutamide (125 mg twice daily). At a mean of 44 months’ follow-up, 38% had no evidence of PSA progression (and continued on treatment), 8% had greater than 50% reduction in PSA, and 29% had PSA progression.

Efficacy was greatest in men who achieved a PSA nadir of 0.1 ng / mL or less after starting treatment (58% of patients). Major side effects were breast tenderness (90%), gynecomastia (72%), and gastrointestinal disturbances (22%). According to investigators, the side effects were well tolerated by most patients.

Histrelin Hydrogel (now launched for Valera Pharmaceuticals). Histre-lin hydrogel implant (Valera Pharmaceuticals’ Vantas, formerly SPD-424) is a 12-month LHRH analogue implant approved by the FDA for the palliative treatment of advanced prostate cancer in November 2004.

A Phase III open-label trial was completed in September 2003, and in December of the same year, Valera submitted an NDA to the FDA. The original developer, Shire, retains a marketing option outside of the United States. Few data have been made publicly available regarding histrelin hydrogel implant, although company-reported early data show that its efficacy is comparable to that of other LHRH agonists.

Histrelin hydrogel implant presumably has the same side effects as other, marketed LHRH analogues (e.g., impotence, gynecomastia, hot flashes).

Overview.

A vast amount of R&D has been committed to the study of epidermal growth factor receptor (EGFR) inhibition. Although several EGFR inhibitors have been launched for other solid tumor types, results for CaP have been very disappointing. The two main approaches researchers have investigated are the specific inhibition of EGFR tyrosine kinase (e.g., gefitinib [AstraZeneca's Iressa]) and MAbs directed at the external domain of the EGFR (e.g., trastuzumab [Genen-tech / Roche's Herceptin] and, initially, panitumumab). Both approaches have failed to deliver results in CaP. The following sections discuss only trastuzumab and gefitinib because of their success in treating other tumor types.

Please note that Panitumumab, has now been discontinued. One

agent targeting the EGFR pathway that is in earlier-stage development is pertuzumab (Genentech / Roche / Chugai’s Omnitarg). This next-generation, humanized, anti-HER / neu MAb is in Phase II development. Enrollment for the trial, which recruited men with hormone-refractory CaP who had received a taxane or epothilone, has been completed. In a Phase I trial, pertuzumab achieved a partial response in a single patient with CaP. The lack of published clinical data precludes further discussion of this agent.

Mechanism Of Action.

The precise role of EGFR inhibition is not fully understood because some EGFR inhibitors are active in EGFR-negative patients as well as in EGFR-positive patients.

Conflicting results on EGFR family expression in CaP have been reported, likely because of differences in testing technologies, lack of standardization of immunohistochemical assays, or different scoring systems. Estimates of the prevalence of HER-2 (ErbB-2) range from 6% to 60% (Gray CR, 2001). Several recent studies have found evidence of a role of HER-2 in the progression of CaP to hormone-refractory status, but other studies have found very low levels of HER-2 expression even in metastatic disease.

Estimates of the prevalence of overexpression of EGFR, also known as HER-1, are wide-ranging (40-80%). Its expression is often raised in metastases compared with its expression in the primary tumor, and expression is increased in hormone-refractory CaP. Overexpression of EGFR is associated with de-differentiation, so the expression of EGFR rises along with the Gleason score.

Investigators have proposed that EGFR family receptors and androgen receptors function synergistically in the absence of androgen, suggesting cross-talk between the ErbB-2 and androgen-receptor pathways. According to recent studies, mitogen-activated protein kinase and phosphatidylinositol 3-kinase can be considered the transduction pathways.

Trastuzumab.

Trastuzumab (Genentech / Roche / Chuga’s Herceptin) is already marketed in the United States and Europe for the treatment of advanced-stage breast cancer. It has undergone Phase II trials in the United States for patients with recurrent or hormone-refractory CaP. Researchers hypothesize that trastuzumab blocks the tumor growth stimulus delivered via the EGFR HER-2.

In general, studies of trastuzumab in CaP have been disappointing. Preliminary results from a Phase II trial published at ASCO 2000 found that trastuzumab alone was ineffective in HER-2-negative, androgen-independent tumors. In 2002, investigators reported results from a failed trial combining trastuzumab with the farnesyl transferase inhibitor tipifarnib (Janssen / Johnson & Johnson’s Zarnestra).

A U.S. multicenter Phase II trial set out to compare trastuzumab and docetaxel, followed by a combination of both agents, in 160 patients with hormone-refractory CaP. Investigators screened hormone-refractory patients for HER-2 positivity and treated HER-2-positive patients with trastuzumab (4 mg / kg IV week one, 2 mg / kg thereafter) or docetaxel (30 mg / m² weekly for six weeks followed by a two-week break). After two eight-week cycles, nonresponding patients received the combination of trastuzumab and docetaxel. Of 100 patients screened, only seven patients had 3+ or 2+ HER-2 by immunohistochemistry (IHC), and no correlation between IHC, fluorescent in situ hybridization (FISH), or enzyme-linked immunosorbent assay occurred. Of the seven eligible patients, only four agreed to participate, so the trial was closed early for nonfeasibility. No patient responded to trastuzumab alone.

Gefitinib.

Gefitinib (AstraZeneca’s Iressa, previously ZD-1839) is a once-daily oral EGFR tyrosine kinase inhibitor that acts on a range of other kinases. It does not require high levels of EGFR (HER-1) expression to be active. Gefitinib has been approved in Japan and the United States for non-small-cell lung cancer. It is in Phase II development for CaP.

In Phase I trials, the compound showed signs of activity as a monotherapy for late-stage CaP, but the results of Phase II monotherapy trials and Phase II combination therapy trials have been disappointing. A Phase I / II trial in the United States will investigate gefitinib in combination with the sirolimus analogue everolimus (Novartis’s Certican) to treat progressive, metastatic CaP.

The final analysis of a Phase II trial that randomized 58 men with hormone-refractory CaP to gefitinib (500 mg daily) or placebo had disappointing results. Comparison of PSA slopes revealed doubling times of 3.9 months for the placebo arm and 5.0 months for the gefitinib arm. No significant differences in progression rates, time to progression, and overall survival were observed.

In 2002, at the 27th European Society of Medical Oncology Congress, the disappointing results of two Phase II trials investigating gefitinib in combination with chemotherapy in patients with hormone-refractory CaP were presented. The first, 21-patient trial evaluated gefitinib in combination with mitoxantrone and prednisone. Patients received 12 mg / m² mitoxantrone on day 1 of a 21-day cycle to a maximum cumulative dose of 140 mg / m², 10 mg / day prednisone, and 250 or 500 mg / day of gefitinib. Five patients (two of eight patients receiving low-dose gefitinib and three of 13 receiving high-dose gefitinib) experienced a PSA response (a decline of at least 50% lasting for at least four weeks).

The second trial evaluated gefitinib in combination with estramustine and docetaxel in 30 chemotherapy-naive patients. Patients received up to six 21-day cycles of treatment comprising 840 mg / day estramustine on days one through

five, docetaxel 60 mg / m² on day 2 as a one-hour infusion, and gefitinib as a once-daily oral dose of 250 or 500 mg from day 3 onward. Four patients experienced a reduction in bone pain at each dose level, and 10 of the 30 patients demonstrated a PSA response.

Gefitinib is not associated with the side effects usually seen with chemotherapy (myelosuppression, alopecia). Its side effects in the CaP trials are consistent with those recorded in the large non-small-cell lung cancer Phase II trials (IDEAL I and II). They were generally mild; the most common were grade 1-2 rash, diarrhea, pruritus, and dry skin.

Gefitinib’s principal shortcoming is its failure to demonstrate clinical benefit either alone or in combination with chemotherapy.

Overview.

Despite its promise, no antisense therapy for the treatment of cancer has yet been approved. Genta (in collaboration with Sanofi-Aventis) and Isis are the main players in antisense approaches. This section focuses on Genta’s agent, oblimersen (Genasense), because it has been the most extensively investigated for CaP. Another antisense oligonucleotide in development is Lorus Therapeutics’ GTI-2501, which is targeted to the Rl component of ribonucleotide reductase, a highly regulated enzyme in the cell cycle of mammalian cells that plays an essential role in DNA synthesis and cell proliferation. The lack of published data precludes further discussion of it.

Antisense oligonucleotides are short sequences of single-stranded DNA that can bind to a specific region of corresponding messenger RNA (mRNA) sequence, thereby blocking both the expression and translation of the mRNA itself and the generation of the corresponding protein encoded by the mRNA. In this way, antisense molecules can block the expression of undesirable genes and their proteins.

Mechanism of Action.

Oblimersen.

Oblimersen (Genta’s Genasense, formerly G-3139) is an antisense oligonucleotide designed to block the production of the Bcl-2 protein from bcl-2 (a protooncogene). In November 2004, Sanofi-Aventis terminated its agreement with Genta for the development of oblimersen. The drug entered Phase II trials for CaP in 1997, but despite demonstration of activity, it has not yet entered Phase III trials. In fact, in April 2004, oblimersen received a negative recommendation for malignant melanoma from the FDA’s Oncologic Advisory Committee. The committee stated the data presented did not provide substantial evidence of oblimersen’s efficacy, as measured by response rate and progression-free survival, to outweigh the increased toxicity endured by the patients receiving it. Genta subsequently announced it was withdrawing the NDA for malignant melanoma.

TABLE: Findings of Key Trials Investigating Thalidomide for Prostate Cancer

Bcl-2 is an apoptosis regulator that, when overexpressed, inhibits the process of natural cell death that should occur when cells are damaged—for example, by chemotherapy. Bcl-2 is located in the mitochondrial membrane and prevents the release of cytochrome c, protecting the cell from entering the intrinsic apoptotic pathway and promoting survival. Inhibition of Bcl-2 allows cells to progress through the cell death pathway. CaP patients with hormone-sensitive disease have low levels of bcl-2 expression, whereas patients with hormone-refractory disease have high levels of bcl-2 expression. Bcl-2 is overexpressed in virtually all hormone-refractory, metastatic CaPs. Bcl-2 overexpression also correlates with resistance to chemotherapy. Like taxanes, oblimersen interacts with Bcl-2 to overcome this mechanism of drug resistance.

At ASCO 2003, investigators reported preliminary findings from a nonrandomized Phase II trial combining oblimersen with docetaxel to treat 29 patients with metastatic, hormone-refractory CaP (Chi KN, 2003). The median age was 66, and the median time from diagnosis to study entry was 5.8 years. Eight of the patients had undergone chemotherapy. Patients received 7 mg / kg / day oblimersen by continuous infusion over 8 days and 75 mg / m² docetaxel IV on day 6 every 21 days until progression or toxicity. The median number of cycles of docetaxel / oblimersen was four (range one to ten); 20 patients were continuing treatment at the time of presentation. Twenty-seven percent of the patients achieved a partial response and 48% achieved a greater than 50% reduction in PSA. Grade 3-4 neutropenia occurred in 42% of patients (18% of cycles). The PSA response rate was the same as that achieved by docetaxel / prednisone. Five patients had grade 3-4 febrile neutropenia. The most common grade 1-2 side effects were fatigue (35%) and non-neutropenic fever (31%). Because the trial was nonrandomized, it is difficult to distinguish the activity of oblimersen from that of docetaxel.

A Phase I dose-finding trial investigating oblimersen in combination with mitoxantrone in 26 patients with hormone-refractory CaP found the combination was well tolerated (Chi KN, 2001). Patients were treated at seven dose levels ranging from 0.6 to 5.0 mg / kg / day by 14-day continuous infusion every 28 days and mitoxantrone from 4 mg / m² to 12 mg / m² as an IV bolus on day 8. Two patients experienced greater than 50% reductions in PSA, and one patient had symptomatic improvement in bone pain. The researchers did not observe any dose-limiting toxicities, and hematological toxicities (including neutropenia, thrombocytopenia, and lymphopenia) were transient. Nonhematological toxicities included fatigue, fever, nausea, arthralgias, myalgias, and transient elevations in serum creatinine, none of which were severe.