In a lively session at the 32nd Annual Meeting of the American Society of Clinical Oncology (ASCO), Jerome P. Ritchie, MD, Brigham and Women's Hospital, Boston, and Steven H. Woolf, MD, MPH, Medical College of Virginia, Fairfax, debated the merits of screening for prostate cancer. In the first of a three-part report on that session, E. David Crawford, MD, University of Colorado Health Sciences Center, Denver, frames the debate by exploring the issues surrounding the screening and early detection of prostate cancer. Dr. Ritchie's and Dr. Woolf's remarks will be featured in subsequent issues of ONCOLOGY.
"Prostate cancer is the most common cancer diagnosed in men, and it's the second leading cause of death, but more people die with prostate cancer than of prostate cancer," Dr. Crawford said. That is the crux of the dilemma facing clinicians.
Some 317,000 new cases of prostate cancer will be diagnosed in 1996, and 41,000 men will die of prostate cancer. Also, the past 15 years have witnessed a dramatic increase in both the incidence of and deaths from this cancer--almost a 500% rise in the number of new cases and nearly a 200% increase in prostate cancer deaths. Given the graying of the US population, the fact that men are living longer, and the association of prostate cancer with aging, these trends are likely to continue into the first few decades of the 21st century.
Faced with a cancer that is rising in both incidence and mortality, clinicians have three options, according to Dr. Crawford. "The first thing we can do is try to prevent it," he said. The second approach--to find prostate cancer early, treat it, and cure it--has both pros and cons. Third, if a cure for advanced prostate cancer existed, clinicians could wait until people developed advanced disease and then cure them.
Is Prevention Feasible?
"There is an opportunity over a long period of time to try to prevent prostate cancer or just delay its progression," Dr. Crawford said. First, prostate cancer has a high prevalence, slow growth rate, and genetic heterogeneity. Another helpful feature is that prostate cancer is androgen-dependent. Also, there are some accepted precursors of prostate cancer, particularly prostatic intraepithelial neoplasia, that can serve as markers. Lastly, like many tumors, prostate cancer has a long history before metastatic disease and death of the patient occur.
If a chemoprevention strategy is to be effective, several criteria must be met, Dr. Crawford asserted. First, the strategy must interfere with a critical step in carcinogenesis. It should also interfere with tumor growth itself and have minimal toxicity.
With regard to chemoprevention and prostate cancer specifically, there are many things we know, but a great deal that we don't know, Dr. Crawford commented. For example, "we know that retinoids promote cancer differentiation, [and] there is some evidence in prostate cancer that they may ameliorate incidence." It is also known that red meat increases incidence. On the other hand, the effect of beta-carotene is unclear, with some studies showing that it increases prostate cancer risk, others indicating no effect, and a recent study demonstrating that it decreases risk.
Recent studies also have shed some light on the relationship between testosterone and dihydrotestosterone (DHT) and prostate cancer, Dr. Crawford said. Testosterone and DHT drive the cell cycle and may shorten it. In the presence of high testosterone levels, DNA repair may be altered, leading to genetic alterations. Some studies have substantiated that African-American men have higher baseline testosterone levels than white men, and this may be one explanation for the higher incidence of prostate cancer in African-Americans.
In a rat model, Boslan from NYU found that testosterone and estrogens(Drug information on estrogens) (E2), together, were the most mitogenic compounds, whereas DHT, by itself, did not produce much tumor growth. Thus, methods to interrupt testosterone may be important, Dr. Crawford said.
Finasteride (Proscar) is another potential approach to chemoprevention. This drug is an 5-alpha-reductase inhibitor and inhibits the conversion of testosterone to DHT. "We know that DHT...has the most affinity for the receptor. And so this may be a way to prevent prostate cancer because we know that men who are congenitally deficient in 5-alpha-reductase have no prostate development or develop prostate cancer," Dr. Crawford said.
Although finasteride(Drug information on finasteride) decreases serum DHT by 75% and decreases intraprostatic DHT by 80%, it also increases serum testosterone by 10%. Its effects on serum testosterone may be problematic, given Boslan's findings that serum testosterone and estrogens are the most potent drivers of prostate cancer. In the presence of higher serum levels, testosterone is aromatized to estrogens.
The soon-to-be completed NCI Chemoprevention Trial "should add a lot of information on various aspects of prostate cancer--not just the effects of finasteride, but natural history and so forth," Dr. Crawford noted. In this trial, 18,000 men being between the ages of 55 and 70 with no evidence of prostate cancer were randomized to finasteride or placebo for 10 years. At the end of the treatment period, all patients will undergo a biopsy of the prostate.
Rationale for Early Detection
There are several reasons why early detection of prostate cancer is desirable, Dr. Crawford said. First, "men die from prostate cancer and we can't cure advanced disease, and we know that most cancers start microscopically." A number of surgical series indicate that if a patient has organ-confined disease and the prostate is removed, he can be cured.
Second, even if the chemopreventive agents under investigation, such as finasteride and retinoids, do, in fact, prevent prostate cancer, it would be years before such a benefit could be shown. With a cancer that is increasing in mortality, one cannot afford the luxury of waiting for those results, Dr. Crawford argued. "What's at stake here is the patient's life, and I think we have some good tools...to at least detect prostate cancer earlier."
A 1989 survey showing that men didn't know great deal about prostate cancer or screening for that cancer was the impetus for the public education and research campaign begun by the Prostate Cancer Education Council in the United States. "Our goals were to increase public awareness, to encourage early detection and diagnosis and conduct community-based screening studies," Dr. Crawford said.
Calling the success of these efforts "phenomenal," Dr. Crawford noted that over 2-1/2 million men have been screened since 1989, and records are available on 300,000 men at some 800 sites around the United States. One of the first findings to emerge from this work was the value of prostate-specific antigen (PSA). In particular, the advent of PSA enabled clinicians to identify a new group of prostate cancer patients--those with an elevated PSA and a normal digital rectal examination (DRE). "PSA has made a big splash in the early detection of prostate cancer and it's here to stay around the world, but it's also controversial."
Other important pieces of information coming out of the Prostate Cancer Education Council's efforts include the following:
- The age-related increase in PSA
- The higher incidence of prostate cancer in African-American males
- The positive predictive value of PSA testing
- The lack of an association between vasectomy and prostate cancer
In 1992, in the context of Prostate Cancer Awareness Week, a multicenter longitudinal study was begun in 1992 that followed 120,000 participants to chart yearly changes in PSA, age ranges, and so forth. This study captured data on about 50,000 patients each year and now has serial records from 3 years of screening. The average positive biopsy rate is about 25%, he added.
What have we learned from this study? First, Dr. Crawford cited age-specific PSA reference ranges developed on the basis of a few hundred thousand PSAs obtained during Prostate Cancer Awareness Week. Dr. Osterling was one of the first to report the relationship of age and PSA based on data from 1,000 men in Olmstead County, Minnesota. These data indicate that PSA increases with age.
"We think this is important because if you see a 40 year old man who has a PSA above 2 that is abnormal, whereas a 75-year-old man is allowed to have a PSA of above 5," Dr. Crawford said, adding that PSA varies by race and age.
Also, some new data have been generated based on a comparison of prostate cancers that were detected at the initial screening vs subsequent screenings at years 2, 3 and 4 (Figure 1). This comparison shows that the majority of prostate cancers--70%--were detected at the initial screening. The detection rate in the second year is approximately 25%, and then it drops off substantially in serial screening.
Dr. Crawford also highlighted several other interesting findings that have emerged from this large body of data. "If we look at age when the number of positive biopsies occurred in those that had prostate cancer, there is a large difference in men ages 40-49 in the first second year of screening compared to men in their 50s and 60s. This suggests that men with risk factors (ie, family history, African-American race) should have a PSA determination earlier than age 40 in order for the test to have an impact (Figure 2)."
Also, close examination of the initial, second, third, and fourth year screenings for prostate cancer shows that advanced (D2) prostate cancer has been eliminated. "And if you believe that that may be valuable, then serial screening has been effective in eradicating advanced prostate cancer, which, in fact, the majority of patients presented with several years ago," Dr. Crawford said.
Determining free and total PSA also is important. It is known that approximately 85% of PSA in the serum is bound to alpha-1-antichymotrypsin, whereas the remainder is either free in the serum (the active form) or completely surrounded by macroglobulin. It is also known that the ratio of free to total PSA is lower in patients with prostate cancer. Several studies have shown that if a man has a PSA ratio less than .18, he has a higher risk of prostate cancer. This has increased the specificity of the test, according to Dr. Crawford.
Based on present knowledge, Dr. Crawford proposed that "after an initial negative screen, you don't need to test for prostate cancer every year in all patients. Maybe...every other year or every third year [will suffice]."
Why the Controversy?
"I think that we can clearly show that the [PSA] test is effective in detecting prostate cancer...But why is it controversial?" Dr. Crawford asked. "The screening skeptics say that our diagnostic methods are unreliable...that treatment isn't effective (radical prostatectomy, radiation, implants)." The PSA test also has been criticized on the grounds that it is unethical to create anxiety, and that the test poses too great an expense to society to be recommended on a widespread basis.
On the plus side, screening can detect more localized cancers, and has eliminated metastatic prostate cancer. However, part of the controversy stems from the fact that more men die with, rather than of, prostate cancer. Particularly "eye-opening" in this regard, said Dr. Crawford, is the work of Wael Sakr from Wayne State. In a study of young men who died of trauma at a young age, Dr. Sakr found that 31% of men between the ages of 30 and 39 have prostate cancer.
"We don't want to find those prostate cancers in all those men," Dr. Crawford asserted. "We want to find it in men [in whom] we can interfere with the disease in such a way as to increase the survival rate."
When one looks at the results of screening over time, some important findings emerge, said Dr. Crawford. First, the initial year yields the highest results (Figure 3). He emphasized that what is being seen is the prevalence, which is the incidence times the number of years the patients lives with the disease. Second, with serial screening, metastatic prostate cancer is definitely on the decline. "And hopefully with effective treatments, we're going to see the mortality fall. And, in fact, in some of the SEER data, we're seeing that."
Dr. Crawford concluded by noting that physicians need to keep in mind what patients with prostate cancer actually want. Several surveys indicate that patients want the cancer to be slowed, their lives extended, and their quality of life improved.