Postulate 1: detection through screening

Prostate-cancer screening results in the detection of disease that in many patients is not clinically significant. Screening for prostate cancer on the basis of prostate biopsy for men with elevated levels of serum PSA or an abnormal digital rectal examination results in many men whose lives are not at threat from prostate cancer being diagnosed with the disease. In the US, there are 2.74 million men who are aged 50–70 years and have a PSA level greater than 2.5 ng/ml. Catalona's group advocates using a PSA cut-off point of 2.5 ng/ml for biopsy in men aged 50 years or older. If all American men in this age-group with a PSA level greater than 2.5 ng/ml were subjected to a biopsy, 775,000 cases of prostate cancer would be diagnosed this year in the US alone. This is 543,000 more cases than the 232,000 diagnosed in 2005, and 25 times the 30,350 men expected to die of prostate cancer each year in the US. PSA screening has resulted in a progressive decrease in the extent of cancer present at the time of diagnosis (i.e. stage migration). As a consequence, the proportion of patients newly diagnosed with prostate cancer who fall into the 'favorable-risk' category has increased and now constitutes almost half of patients with the disease.

The aggressiveness of cancer can be predicted by the use of existing clinical parameters. The parameters most widely used are the tumor grade or Gleason score, PSA level, and tumor stage. Favorable-risk prostate cancer is characterized by a Gleason score of 6 or less, a PSA level of 10 ng/ml or less, and stage T1c–T2a disease Importantly, although patients with these characteristics have a much more favorable natural history and progression rate than those who have a higher Gleason grade or PSA level, in a few patients tumors will still progress to advanced, incurable prostate cancer and death.

Autopsy studies have demonstrated that prostate cancer typically begins in the third or fourth decade of life In most patients, this means that there is a period of slow subclinical tumor progression from a microscopic focus of disease, which lasts approximately 30 years, followed by a period of clinical progression (potentially, but not invariably, leading to metastatic disease and death), which lasts about 15 years. The implication is that most patients have a long window of curability. This is particularly true for patients with favorable-risk, low-volume disease.

Data on a large group of patients in Connecticut, US assessed by watchful waiting have been reported at 20 years. These data confirm the powerful predictive value of the Gleason score. In the pre-PSA screening cohort, 23% of untreated patients with a Gleason score of 6 died of prostate cancer within 20 years. Of the patients with a Gleason score of 7, about 65% died of prostate cancer within 20 years. In addition, the authors recently reanalyzed prostate pathology slides that were initially read between 1990 and 1992, using contemporary Gleason scoring. The study demonstrated clearly that there has been a shift in grade interpretation during the past 15 years. This shift is largely the result of the removal of Gleason scores 2–4 from the classification, the inclusion of small proportions of high-grade cancer into the grading system, and the reclassification of cribriform-pattern cancer from a Gleason score of 3 to a Gleason score of 4. Many cancers diagnosed 20 years ago as a Gleason score of 6 would be classified as a Gleason score of 7 today. The Connecticut study results probably represent a 'worst case' scenario for the expected mortality from untreated cancer with a Gleason score of 6. This means that the mortality from untreated, non-screen-detected prostate cancer in patients with contemporary Gleason scores of 6 might be as low as 10% at 20 years.