Screening for prostate cancer – The PSA controversy

Introduction

Prostate cancer is the most common non-skin cancer in men, with both physical and psychological symptomatology¹De Sousa A, Sonavane S, Mehta J. Prostate Cancer Prostatic Dis. 2012.  ; in India, it is one of the five leading sites of cancers among males in all the registries.²Ganesh B, Saoba SL, Sarade MN, et al. Indian J Urol. 2011;27(3):345-50.  

Screening constitutes an important method to check the progress of prostate cancer; the rationale is that early detection and treatment of asymptomatic cancers could extend life, as compared with treatment at the time of clinical diagnosis. Effective screening requires an accurate, reliable, and easy-to-administer test that detects clinically important cancers at a preclinical stage.

Prostate-specific antigen (PSA) testing has increased in the past as a widely adopted screening method based on its increased detection of early-stage cancer. About 90% of prostate cancers are detected by means of screening³Hoffman RM, Stone SN, Espey D, et al. BMC Cancer 2005;5:27.  ; nevertheless, screening still remains a contentious issue, and PSA appears to be the central element in this controversy since it is not cancer-specific and since prostate cancer’s aggressiveness varies widely.⁴Brett AS, Ablin RJ. N Engl J Med 2011;365(21):1949-51.   Yet, its introduction as a screening tool increased the lifetime risk of receiving a diagnosis of prostate cancer.

The diagnostic performance of PSA testing may vary according to the cutoff level.⁵Wolf AM, Wender RC, Etzioni RB, et al. CA Cancer J Clin 2010;60:70-98.   Initially, PSA values > 4.0 ng per milliliter were considered abnormal; however, lower cutoff levels have subsequently been proposed. While most abnormal PSA values are false positive results, a normal PSA value does not rule out prostate cancer.⁶Thompson IM, Pauler DK, Goodman PJ, et al. N Engl J Med 2004;350:2239-46. [Erratum, N Engl J Med 2004;351:1470.]  

Benefits of PSA Screening: The “yes-no” conflict

Although links have been suggested between PSA testing and a decrease in mortality from prostate cancer, the findings are conflicting and the value of PSA screening is not convincingly established.^7-117) Bartsch G, Horninger W, Klocker H, et al. BJU Int 2008;101:809-16.
8) Lu-Yao G, Albertsen PC, Stanford JL, et al. BMJ 2002;325:740.
9) Concato J, Wells CK, Horwitz RI, et al. Arch Intern Med 2006;166:38-43.
10) Collin SM, Martin RM, Metcalfe C, et al. Prostate-cancer mortality in the USA and UK in 1975-2004: an ecological study. Lancet Oncol 2008;9:445-52.
11) Etzioni R, Tsodikov A, Mariotto A, et al. Cancer Causes Control 2008;19:175-81.   While the European Randomized Study of Screening for Prostate Cancer (ERSPC) showed that screening resulted in a moderatelyreduced mortality from prostate cancer,¹²Schröder FH, Hugosson J, et al. N Engl J Med 2009;360:1320-8.   the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial showed no benefit.¹³Andriole GL, Grubb RL III, Buys SS, et al. N Engl J Med 2009;360:1310-9. [Erratum, N Engl J Med 2009;360:1797.]  

The ERSPC randomly assigned 182,160 men between the ages of 50 and 74 years to PSA screening every 4 years (or every 2 years) or usual care (no PSA screening). The initial mortality findings were based on data for 162,243 men between the ages of 55 and 69 years. The results showed that during a median follow-up of 9 years, prostate cancer was detected in 8.2% of the screened subjects as compared with 4.8% of the control subjects (a 71% increase). Also, mortality from prostate cancer was 20% lower in the screening group.

Nonetheless, the absolute difference that was only 0.7 deaths per 1000 men suggested that 1410 men would need to be screened about twice over nine years to prevent one death from prostate cancer. Besides, to prevent that 1 death prostate cancer would need to be diagnosed in 48 men. Interestingly, screening did not result in decreased mortality (overall or prostate-cancer) among men between the ages of 50 and 54 years or those between the ages of 70 and 74 years.

Subsequent analyses of these data suggest that the benefit of regular screening might be higher after adjustment for non-adherence and after additional adjustment for contamination (PSA screening in persons not randomly assigned to screening).¹⁴Roobol MJ, Kerkhof M, Schröder FH, et al. Eur Urol 2009;56:584-91.   However, these post hoc analyses were more susceptible to bias than the primary intentionto- treat analysis, and even suggested only a small absolute survival benefit.

The PLCO trial, in contrast, did not show any reduction in overall or prostate-cancer mortality with screening. The trial randomly assigned 76,693 men, between the ages of 55 and 74 years at enrollment, to annual PSA testing for 6 years and annual digital rectal examination for 4 years or to noscreening. The cancer detection rates increased significantly with screening; 22% more cancers were diagnosed in the screened group as compared to that in the control group (2820 vs. 2322) at 7-year follow-up. Furthermore, cancers in the screening group had more favorable tumor characteristics than cancers in the control group, including earlier stages and lower Gleason scores. However, prostatecancer mortality was not reduced in the screening group as compared with the control group.

It is proposed that several factors could have biased the results of the PLCO trial toward the null hypothesis, for instance: > 40% of enrolled subjects had undergone at least 1 PSA test in the 3 years before study enrollment; considering the long lead time associated with PSA testing, the 7-year follow-up might not have been sufficient to show a survival benefit; also, there was substantial contamination – > 50 % subjects in the control group reporting PSA testing in year 6.

Harms of screening

Men undergoing regular PSA screening are much more likely to receive a diagnosis of prostate cancer than unscreened men. However, a substantial proportion of PSA-detected prostate cancers are considered to be over-diagnosed considering life expectancy at the time of diagnosis and the natural history of the cancer and associated mortality in the absence of screening during the patient’s lifetime.

This over-diagnosis would lead to over-treatment; and aggressive treatment of these cancers may be associated with unnecessary risks of complications, adversely affecting the quality of life.¹⁵Wilt TJ, MacDonald R, Rutks I, et al. Ann Intern Med 2008;148:435-48. [Erratum, Ann Intern Med 2008;148:888.]   Furthermore, abnormal PSA tests lead to biopsies, which can infrequently lead to complications.⁵Wolf AM, Wender RC, Etzioni RB, et al. CA Cancer J Clin 2010;60:70-98.  

Risk stratification is the only mechanism to reduce overdiagnosis that can be applied before undertaking biopsies. Such risk stratification should be routinely used by clinicians until there are marker substances or imaging technologies that permit selective detection of aggressive cancers.²³McNaughton-Collins MF, et al. N Engl J Med 2011;365(21).1951-53.  

Informed decision making

PSA testing is often performed without discussing the benefits and harms of screening.¹⁶Hoffman RM, Couper MP, et al. Arch Intern Med 2009;169:1611-8.  ^,17Guerra CE, Jacobs SE, et al. A pilot study. J Gen Intern Med 2007;22:901-7.   However, considering the complexity of issues concerning prostate cancer screening, it is recommend that men receive support in making informed decisions.¹⁸Rimer BK, Briss PA, Zeller PK, et al. Cancer 2004;101:Suppl:1214-28.  ^,19Braddock CH III, Edwards KA, Hasenberg NM, JAMA 1999;282:2313-20.   It is important to share information on the options and outcomes relevant to an individual’s health status. This is a demanding issue, and competing clinical demands and the challenge of providing sufficient information to support informed decision making present important barriers to having this discussion.²⁰Barry MJ. Ann Intern Med 2002;136:127-35.   Further research is needed to determine the optimal formats, timing, and settings for this discussion.

What guidelines recommend?

Current guidelines appear considering the uncertainties regarding the outcomes of screening. Table 1 shows the American Urological Association (AUA) and American Cancer Society (ACS) guidelines, updated after the results of the ERSPC and PLCO trials.⁵Wolf AM, Wender RC, Etzioni RB, et al. CA Cancer J Clin 2010;60:70-98.  ^,21Greene KL, Albertsen PC, Babaian RJ, et al. J Urol 2009; 182:2232-41.   Both organizations recommend periodic PSA testing when the patient’s life expectancy is at least 10 years and encourage shared decision making between patients and clinicians. However, they differ about the recommended age at which to begin routinely discussing screening and the criteria for biopsy referral.

Recently, the U.S. Preventive Services Task Force attempted to balance the risks and benefits of screening against those of treatment, and decided to recommend against screening for PSA, concluding that there is moderate

or high certainty that the service has no net benefit or that the harms outweigh the benefits. This recommendation is meant to apply to the general population of men who might be at risk for clinically relevant prostate cancer and applies to healthy men of all ages, irrespective of race or family history; and contradicts the view that PSA-based screening saves lives by reducing the risk of death from prostate cancer. ²²McNaughton-Collins MF, et al. N Engl J Med 2011;365(21).1951-53.  ^,23Schröder FH. N Engl J Med 2011;365(21): 1953-55.   However, the report has a number of key weaknesses, and it is quite subjective to decide the benefit of cancer screening with regards to decrease in mortality; weighing the pros and cons to make a decision about PSA screening is an individual process, and different well-informed men will make different decisions. Watchful waiting and active surveillance may help prevent the conversion of over-diagnosis to over-treatment, mitigating the harms of screening.²³Schröder FH. N Engl J Med 2011;365(21): 1953-55.  

Conclusion

Ironically, PSA testing became widespread before any data supported the benefit of aggressively treating early-stage cancer. Nevertheless, while initial trial results might have underestimated the potential benefit of screening with respect to prostate cancer mortality, the small absolute disease-specific survival benefit must be balanced against the potential harms of over-diagnosis and complications of treatment.

In conclusion, despite different evidences and recommendations, it is still unlikely to end the PSA controversy, and it may be suggested that PSA screening should not be dismissed as uniformly non-beneficial. Rather, decisions should be made on an individual basis, by an informed patient and clinician, after weighing patient’s particular risk factors.²³Schröder FH. N Engl J Med 2011;365(21): 1953-55.  

References

1. De Sousa A, Sonavane S, Mehta J. Prostate Cancer Prostatic Dis. 2012.
2. Ganesh B, Saoba SL, Sarade MN, et al. Indian J Urol. 2011;27(3):345-50.
3. Hoffman RM, Stone SN, Espey D, et al. BMC Cancer 2005;5:27.
4. Brett AS, Ablin RJ. N Engl J Med 2011;365(21):1949-51.
5. Wolf AM, Wender RC, Etzioni RB, et al. CA Cancer J Clin 2010;60:70-98.
6. Thompson IM, Pauler DK, Goodman PJ, et al. N Engl J Med 2004;350:2239-46. [Erratum, N Engl J Med 2004;351:1470.]
7. Bartsch G, Horninger W, Klocker H, et al. BJU Int 2008;101:809-16.
8. Lu-Yao G, Albertsen PC, Stanford JL, et al. BMJ 2002;325:740.
9. Concato J, Wells CK, Horwitz RI, et al. Arch Intern Med 2006;166:38-43.
10. Collin SM, Martin RM, Metcalfe C, et al. Prostate-cancer mortality in the USA and UK in 1975-2004: an ecological study. Lancet Oncol 2008;9:445-52.
11. Etzioni R, Tsodikov A, Mariotto A, et al. Cancer Causes Control 2008;19:175-81.
12. Schröder FH, Hugosson J, et al. N Engl J Med 2009;360:1320-8.
13. Andriole GL, Grubb RL III, Buys SS, et al. N Engl J Med 2009;360:1310-9. [Erratum, N Engl J Med 2009;360:1797.]
14. Roobol MJ, Kerkhof M, Schröder FH, et al. Eur Urol 2009;56:584-91.
15. Wilt TJ, MacDonald R, Rutks I, et al. Ann Intern Med 2008;148:435-48. [Erratum, Ann Intern Med 2008;148:888.]
16. Hoffman RM, Couper MP, et al. Arch Intern Med 2009;169:1611-8.
17. Guerra CE, Jacobs SE, et al. A pilot study. J Gen Intern Med 2007;22:901-7.
18. Rimer BK, Briss PA, Zeller PK, et al. Cancer 2004;101:Suppl:1214-28.
19. Braddock CH III, Edwards KA, Hasenberg NM, JAMA 1999;282:2313-20.
20. Barry MJ. Ann Intern Med 2002;136:127-35.
21. Greene KL, Albertsen PC, Babaian RJ, et al. J Urol 2009; 182:2232-41.
22. McNaughton-Collins MF, et al. N Engl J Med 2011;365(21).1951-53.
23. Schröder FH. N Engl J Med 2011;365(21): 1953-55.