2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

OVERDIAGNOSIS AND OVERTREATMENT OF PROSTATE CANCER
undergoes prostate biopsy; if there is evidence of development
of a more aggressive or larger tumor, treatment can
then be instituted. Thus, AS seeks to reserve treatment for
patients in whom there is evidence of a developing risk of an
aggressive tumor.
Many early series of WW attested to the fact that even
tumors detected with DRE (often large and extraprostatic
tumors), could be observed and, with extended follow-up,
most patients did not develop metastases nor did they die
as a result of prostate cancer. 12 Since the advent of PSA
testing, there has been growing evidence that these lowergrade,
lower-volume tumors can be watched carefully,
treated only in the event of evidence of a more aggressive or
larger tumor, thus avoiding treatment in many patients and
still showing low rates of metastasis and cancer death.
There are many examples of these series, including that of
Klotz and colleagues. 13 In their series, the risk of prostate
cancer death at 5 years was 0.3% and at 10 years was 2.8%.
It was important to recognize in this series as well that 17%
of the patients undergoing AS actually had cancer with a
Gleason score of 7.
Sealing the evidence of overtreatment are the data from
the CAPSURE prostate cancer registry, a collection of a
range of urologic practices designed to evaluate practice
patterns related to prostate cancer. In one of their studies,
Cooperberg and colleagues found that 92% to 98% of patients
who had the lowest tumor risk scores (and presumably
were eligible for AS) were treated with radical surgery,
radiation, or hormone therapy. 14 This stunning observation
that at least 92% of men who had a 10-year risk of prostate
cancer death of 2.8% received aggressive management,
strongly suggests that overtreatment is indeed occurring in
this disease. On the other hand, it is certain that some of
these men are making an individualized decision that this
risk is high enough to justify treatment.
What Is the Solution to Overdiagnosis and
Overtreatment in Prostate Cancer?
Prostate Cancer Prevention
Many institutions are increasingly focusing on methods to
reduce these problems in the U.S. population that cause
substantial resources to be expended unnecessarily and that
lead to substantial morbidity including sexual dysfunction,
urinary obstruction or incontinence, as well as GI complications.
Certainly, one of the methods to reduce this problem is
through prostate cancer prevention. Currently available are
two agents that have been clearly demonstrated to reduce a
man’s risk of detection of a low-grade prostate cancer:
dutasteride and finasteride, members of the class of five
alpha reductase inhibitors. These two agents have been
tested in phase III trials and have been found to reduce the
risk of prostate cancer by between 22% and 25%. 15,16 Patients
in both studies who received active treatment were,
however, more commonly found to have high-grade cancer.
Although the interpretation of some parties has been that
the agents induce high-grade cancer, substantial data show
that both agents facilitate the detection of cancer and
high-grade cancer. This occurs in, for example, the case of
finasteride, through an improved sensitivity of PSA for
overall cancer detection, improved sensitivity of DRE for
overall cancer detection, and likely through a reduction in
prostate volume leading to a greater likelihood of detection
Table 2. Potential Benefits and Harms of Prostate Cancer
Chemoprevention
Benefit Harm
Reduction in morbidity of
treatment
Reduction in cost of
treatment
Reduction in psychologic
burden of diagnosis
Unnecessary exposure to preventive drug of healthy
subjects who will never develop prostate cancer.
Side effects of chemoprevention agent. In the
example of finasteride and dutasteride, these
include gynecomastia, decreased libido, loss of
ejaculate, erectile dysfunction, and potential
increase in risk of high-grade cancer.
Increase in cost. (It is not known whether
chemoprevention would increase or decrease total
cost of the disease to society.)
of high-grade cancer at the time of prostate biopsy by more
comprehensive sampling of a smaller prostate. 17,18,19 Multiple
studies have demonstrated that, when these biases
increasing cancer detection with finasteride are taken into
account, the overall impact on the entire range of high-grade
tumors (Gleason scores of 7–10) is a reduction in risk with
finasteride. Clearly, then, one option for reducing the risk of
overtreatment through a reduction in overdetection is
through chemoprevention. Table 2 lists the potential benefits
and harms of chemoprevention of prostate cancer.
Screening and Biopsy of Men Who Are Most Likely to Harbor
Consequential Prostate Cancer
Through the use of risk assessment tools that provide
physicians with not only the risk of cancer detection but the
risk of detection of a high-grade cancer, it is possible to do a
better job of identifying the man who more likely has a
high-grade cancer. It is these men who have the greatest
potential for disease progression and death, best illustrated
by the work of Albertsen and colleagues, who examined the
outcomes of prostate cancer by age and grade. 20 Let’s examine
these risks in two men using the Prostate Cancer
Prevention Trial Risk Calculator (www.prostate.cancer.
risk.calculator.com), which was developed based on PCPT
data and has been validated in a number of external
populations. 21-23 Mr. Smith went to see his primary care
physician who felt a prostate nodule and sent him to his
urologist. Every single guideline in urology at this time
recommends biopsy for such a man, regardless of any other
risk factors. If this man is 55 and white, has a PSA of 0.5
ng/mL, has no family history of prostate cancer, and had a
biopsy of the nodule last year, his risk of low-grade cancer is
11.9% and his risk of high-grade cancer is 0.8%. Thus, there
is a 15-fold greater likelihood of finding an inconsequential
cancer in this man and his risk of having an aggressive
cancer is about 1 in 125. Because the detection of a lowgrade
cancer probably has a net negative impact (the bulk of
these tumors are of low malignant potential and, even with
surveillance, there is a substantial degree of morbidity,
anxiety, and cost of this strategy), in this particular man,
the net potential benefit (probably 1 in 125) is likely to be far
outweighed by the net potential harm (about 1 in 8). Conversely,
Mr. Jones, a healthy 73-year-old black man with no
other comorbidities who had a father with prostate cancer, is
found to have a new prostate nodule and whose PSA is 5.8
ng/mL, has a 56% risk of high-grade disease and a 15% risk
of low-grade disease. In this particular man, his risk is 1 in
2 that he may benefit from detection of an aggressive cancer,
whereas his risk of potential overdetection of a low grade
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