In a lively session featured at the 32nd Annual Meeting of the American Society of Clinical Oncology (ASCO), Jerome P. Richie, 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 January issue, E. David Crawford, MD, University of Colorado Health Sciences Center, Denver, framed the debate by exploring the issues surrounding the screening and early detection of prostate cancer. This month, Dr. Richie presents data supporting the value of screening. In a subsequent issue, Dr. Woolf will argue against routine screening.
Many different requirements must be met to justify the use of screening for any disease, Dr. Richie said. "First of all, you have to show that early treatment is more effective than later treatment. And I think with prostate cancer we can show that."
Also, it must be shown that the disease is serious from a health standpoint. The lifetime risk of a man age 50 developing prostate cancer is about 10%, Dr. Richie noted, and his risk of dying from prostate cancer is about 3%. Given these "sobering statistics," prostate cancer does qualify as a serious health problem.
Other requirements for screening must also be met. "You have to have effective treatments, testing must be safe and inexpensive, and there should be acceptable sensitivity, specificity, and positive predictive value," Dr. Richie said.
"There are a variety of biases that are introduced when one screens, including length-time and lead-time bias, so that you ultimately need to have a randomized study to prove whether screening will be beneficial or not," he added. Another important issue is the impact of screening on patients' quality of life. Most important, however, in the current era of health-care cost consciousness, is the cost of screening. A critical question is, how much can we afford to do?
Yet another key issue specific to prostate cancer is its unpredictable natural history. "We don't really know in an individual patient whether that cancer will progress and compete as a cause of death. And so we're lacking the true markers to really know about biologic predictability."
Studies Present Conflicting Views of Natural History
Several papers have dominated the literature on the natural history of prostate cancer over the last 5 to 10 years, Dr. Richie said. In a study of 120 patients with prostate cancer published in 1988, George found that only about 4% of patients died of prostate cancer, whereas about 40% died of other causes. Similarly, a 1991 paper by Adolffson and colleagues with a median follow-up of about 8 years showed that only a small percentage of patients died of prostate cancer.
One of the most widely quoted series in the literature, Dr. Richie noted, is a study of 223 Swedish prostate cancer patients by Johansson and associates. This study reported a 5-year cancer-specific survival rate of 94% and a 10-year survival rate of 89%. "The clear implication of this study was that most of these patients have indolent disease, they don't need to be treated, and therefore, we are overtreating or trying to diagnose patients who won't need treatment."
Closer examination of these data reveal, however, that only about 10% of the patients died of prostate cancer, Dr. Richie noted. The majority of the patients (148 of 223) had very well-differentiated tumors (grade 1[Swedish system]; approximately equivalent to Gleason score 2-4), whereas only 66 patients had grade 2 tumors (equivalent to Gleason 5-7) and 9 patients had grade 3 tumors (equivalent to Gleason 8-10).
Furthermore, in the first 2 years, only patients with very well-differentiated disease were accrued to the study. "This skews the data and stacks the odds in favor of patients with very well-behaved disease," Dr. Richie said. Such patients have low rates of progression and of death due to cancer. In contrast, most patients detected by screening have grade 2 or 3 disease, which has a higher mortality.
Dr. Richie added that most of the patients in the study by Johansson et al were elderly. No patient was less than 60 years of age, two-thirds of the patients were older than 70, and almost 20% were over 80. Prostate cancer was diagnosed by transurethral resection, and one-third of the patients had one focus or a very small microscopic focus of well-differentiated disease. Thus, Dr. Richie asserted, "in any series in any country" such patients would be followed conservatively. Progression was determined by rectal or bone scan, and a quarter of the patients were treated with hormonal therapy.
Many subsequent studies, as well as some of the data analysis by Markov modeling, rely predominantly on the study by Johansson et al to determine whether prostate cancers are likely to progress, Dr. Richie noted. "And in any of these models, if you put in data that are spurious, the answer that comes out is also spurious."
Another study published in 1994 by Gronberg and colleagues seems to counter the data of Johansson's group, Dr. Richie said. Gronberg et al compared close to 7,000 prostate cancer patients in northern Sweden with age-matched controls. The relative survival of the men with prostate cancer was about 50% at 10 years, with younger men experiencing an even greater decrease in survival. "Another way of looking at this is average loss of life expectancy, and the men with prostate cancer lost an average of 40% of their expected life," Dr. Richie said.
In 1995, Gann and associates reported on data from the Physician's Health Study. In this group of 22,000 male physicians who were followed and whose sera were stored, 2% developed clinical prostate cancer, detected either on the basis of symptoms or a digital rectal examination. The researchers then compared each physician with two age-matched controls. This comparison revealed a very high excess mortality in the study population. Furthermore, "three quarters of the deaths in men with prostate cancer were caused directly by prostate cancer. So I think we can't assume that this is an indolent disease that will not progress," Dr. Richie said.
PSA as a Screening Tool
The beginning of screening for prostate cancer can be dated back to a 1991 study by Catalona and colleagues at Washington University in St. Louis, Dr. Richie noted. These researchers performed the then relatively new prostate-specific antigen (PSA) test in 1,600 men over 50 years of age. If the patient's PSA was abnormal, a digital rectal examination and an ultrasound scan were performed, and if either of these was abnormal, a biopsy was done.
This study showed the importance of PSA as a screening tool. Of the patients in this series, 6.5% had a PSA between 4 and 10 ng/mL, and about one-fifth of these men had a positive biopsy for prostate cancer. Approximately 2% of the men had a PSA over 10 ng/mL, and two-thirds of them had prostate cancer.
A second large, multicenter study done at Washington University, Brigham and Women's Hospital, and four other institutions involved over 6,000 asymptomatic men over age 50. All of these men were screened with both a PSA and digital rectal examination and underwent an ultrasound scanning and biopsy if either screening test was abnormal.
In the initial screening, approximately 15% of the men had an abnormal PSA and a similar percentage had a suspicious digital rectal examination (Table 1). Of the patients with abnormal screening tests who were found to have prostate cancer and underwent surgery, about three-quarters had pathologically organ-confined disease. This is "extremely discordant" with the rate of organ-confined disease among men whose prostate cancer was discovered prior to the advent of PSA screening, Dr. Richie noted. At best, approximately 35% of those men had organ-confined disease.
An important issue is whether prostate tumors detected by screening are significant cancers or whether they are indolent cancers that won't progress. Defining "significant" cancers as moderately or poorly differentiated tumors or large-volume disease, Catalona et al found that 93% of patients who underwent radical prostatectomy had significant disease. These data suggest that "we're not detecting the indolent cancers, but we're detecting cancers that are likely to progress," Dr. Richie concluded.