Should All Colorectal Cancer Patients Over Age 60 Be Screened for Prostate Cancer?
Should All Colorectal Cancer Patients Over Age 60 Be Screened for Prostate Cancer?
ABSTRACT: Two large, randomized studies have demonstrated a prostate cancer–specific survival benefit to prostate cancer screening using the prostate-specific antigen (PSA) assay. Yet, the US Preventive Services Task Force recently recommended against PSA-based screening for prostate cancer, claiming it results in more harm than good, given concerns regarding overtreatment. The purpose of this article is to characterize the patients with colorectal cancer who are most likely to benefit from PSA-based screening for prostate cancer. Because the survival benefit due to PSA-based screening does not manifest until 7 years after screening is initiated, we conclude that PSA screening is most appropriate for men with a remaining life expectancy of at least 10 years. Accordingly, younger men with stage I–II colorectal cancers at diagnosis (or stage III colorectal cancer that has not recurred 5 years after treatment) who have no or minimal comorbidities and who are at increased risk for either a diagnosis of prostate cancer or mortality secondary to prostate cancer (patients who have a positive family history or are African-American, respectively) are most likely to experience more good outcomes than harmful ones as a result of undergoing PSA-based screening.
Recommendations for PSA-Based Screening for Prostate Cancer Among Patients With Colorectal Cancer
Our results suggest that whether or not men over 60 years of age with colorectal cancer should be considered for prostate-specific antigen (PSA)-based screening depends on the presence and stage of the colorectal cancer, as well as patient age, comorbidities, race, and family history of prostate cancer. Men who are appropriate candidates for a discussion of the risks and benefits of PSA-based screening for prostate cancer include those with newly diagnosed stage I colorectal cancer who are healthy (with a life expectancy > 10 years), African-American, or who have a first-degree relative with prostate cancer. Men who may be appropriate candidates for such screening include those who have newly diagnosed stage II colorectal cancers, who are in good health (with a life expectancy > 10 years), and who are African-American or have a first-degree relative with prostate cancer.
Newly diagnosed stage III colorectal cancer patients are generally not appropriate candidates for screening for prostate cancer. However, if such patients attain a disease-free interval of 5 years after treatment of their colorectal cancer, they should be considered for PSA-based screening for prostate cancer if their remaining life expectancy is at least 10 years and they are either African-American or have a first-degree relative with prostate cancer.
The time to initiate PSA-based screening for prostate cancer would be at the time of diagnosis of stage I or II colorectal cancer and after a 5-year disease-free interval in men with stage III colorectal cancer, assuming that they have at least a 10-year remaining life expectancy and have been counseled about the potential risks and benefits of PSA-based screening. Patients with metastatic colon cancer are not appropriate candidates for PSA-based prostate cancer screening.
Once a patient has been appropriately educated by the primary care physician about the possible benefits and risks of PSA screening, then patient preference, as part of shared decision making regarding PSA screening, should be considered in all cases.
Randomized trials and consensus statements relating to PSA-based screening for prostate cancer
In 2012, the US Preventive Services Task Force (USPSTF) recommended against PSA-based screening for prostate cancer. In assigning such practice a grade D recommendation, the USPSTF indicated that they believed that there was moderate to high certainty that PSA-based screening had no benefit or that the harms outweighed the benefits. The recommendation applied to men in the general population, regardless of their age, remaining life expectancy, risk of developing an aggressive prostate cancer, and comorbidities.
Several randomized trials have evaluated the role of PSA-based screening for prostate cancer. In the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial, conducted in the United States at 10 centers between 1993 and 2001, a total of 76,685 men aged 55 to 74 years were randomized to annual PSA screening for 6 years and an annual digital rectal exam for 10 years vs “usual care.”[2,3] With a follow-up of up to 13 years in the updated analysis, a 12% relative increase in the incidence rate of prostate cancer was noted in the intervention arm (relative risk [RR] = 1.12; 95% confidence interval [CI], 1.07–1.17), although no differences were seen in prostate cancer–specific or all-cause mortality between the two arms. At 13 years, 158 and 145 deaths due to prostate cancer had occurred in the intervention and control arms, respectively, a difference that was not statistically significant (RR = 1.09; 95% CI, 0.87–1.36). However, significant limitations of this trial—including the fact that 44% of patients had had at least one PSA test in the 3 years preceding randomization, and that in the control arm the rate of having had at least one PSA screening was estimated to be 85%—hinder the ability to draw any firm conclusions about the value of PSA screening in this setting.
Between 1991 and 2003, the European Randomized Study of Screening for Prostate Cancer (ERSPC), which enrolled men from eight European countries, randomized 162,388 men in the “core age group” of 55 to 69 years to PSA-based screening (median screening interval, 4.02 years) vs no screening.[5,6] With a follow-up of 11 years, a total of 6,963 and 5,396 cases of prostate cancer were diagnosed in the screening and control groups, respectively (RR = 1.63; 95% CI, 1.57–1.69). There were 299 and 462 deaths from prostate cancer in the screening and control groups, respectively, corresponding to a 21% reduction of prostate cancer–specific mortality with screening (RR = 0.79; 95% CI, 0.68–0.91; P = .001). The number needed to screen to prevent one death from prostate cancer was 1,055; the corresponding number needed to treat was 37. Relative to the PLCO trial, the rate of PSA screening in the control group of the ERSPC trial was lower, being 24% in the Rotterdam cohort of the ERSPC study vs 85% in the PLCO study, and the upper age of the core group analyzed in the ERSPC study was lower as well, increasing the likelihood that men would die of prostate cancer vs a comorbid condition; these differences potentially account for the variation in the outcomes of these two trials.
Starting in 1995, the Göteborg prostate cancer screening trial randomized 20,000 men aged 50 to 64 years and living in Göteborg, Sweden, to PSA-based screening every 2 years vs no screening. The study was ongoing at the time of analysis in 2008. Men in the screening arm had PSA levels obtained until they reached (on average) 69 years of age. With a median follow-up of 14 years, prostate cancer was identified in 1,138 and 718 men in the screening and control arms of the study, respectively. At 14 years, the cumulative incidence of prostate cancer was 12.7% in the screening group and 8.2% in the control group (hazard ratio [HR] = 1.64; 95% CI, 1.50–1.80; P < .0001). In the intervention and control groups, 44 and 78 men, respectively, died of prostate cancer. The relative risk of PSA-screened men dying of prostate cancer was 0.56 (95% CI, 0.39–0.82; P = .002). The number needed to screen to prevent one death from prostate cancer was 293; the corresponding number needed to treat was 14. Given the sometimes indolent nature of prostate cancer, and that the rate of death due to prostate cancer increases 15 to 20 years after the diagnosis, the number needed to screen and treat in order to save one life will likely decrease with further follow-up. Assuming overdiagnosis and screening efficacy consistent with results of the ERSPC, investigators have estimated that the number needed to screen and treat to avoid one prostate cancer death at 25 years will be 262 and 9, respectively.
There are a number of possible reasons that the Göteborg study yielded a larger survival benefit with PSA screening than the ERSPC study and the PLCO study (the latter of which did not identify such a benefit). Notably, the median age of 56 years for men in the Göteborg study was lower than the median ages of men in the PLCO and ERSPC studies (with the median in both studies being greater than 60 years), increasing the likelihood that men would die from prostate cancer rather than from the effects of a competing risk factor. The threshold for biopsy (PSA > 2.5–3.0 ng/mL) was also lower in the Göteborg study than in the PLCO study (PSA > 4 ng/mL) and the ERSPC study (PSA generally > 3 ng/mL). Moreover, a higher percentage of patients with a positive screening result underwent a prostate biopsy in the Göteborg trial relative to the PLCO study (93% vs 30% to 40%[8,11]). In addition, only 3% of patients in the Göteborg study had PSA level measured before the start of the study (while up to 45% of patients in the PLCO study had PSA level assessed in the 3 years before study initiation). Last, the Göteborg study possesses the longest follow-up period of any of the randomized studies for prostate cancer screening. For these reasons, the Göteborg study is likely the most rigorously conducted PSA-screening trial to date and most accurately reflects the magnitude of the prostate cancer–specific mortality benefit seen with PSA screening.
It is important to note that in addition to improving prostate cancer–specific survival, PSA-based screening for prostate cancer reduces the likelihood of metastatic disease. In the ERSPC study, 0.67% and 0.86% of men in the screening and control arms, respectively, developed metastatic disease by 12 years; the HR for the association between screening and development of distant metastases was 0.70 (95% CI, 0.60–0.82; P = .001). Low-risk patients managed with radical prostatectomy or radiation therapy display lower rates of distant metastatic disease than those managed expectantly. The physical and psychological suffering that follows a diagnosis of metastatic prostate cancer can have a significant impact on quality of life. Also, the management of patients with metastatic disease results in significant cost to the US healthcare system. Therefore, as other authors have suggested, survival may not be the only pertinent metric when evaluating the utility of PSA-based screening for prostate cancer.
The Prostate Cancer Intervention Versus Observation (PIVOT) trial, published in 2012, did not identify differences in prostate cancer–specific mortality between low-risk patients managed conservatively vs definitively. However, the PIVOT trial was designed to accrue 2,000 men, but only 731 men enrolled in the study before it was closed. In addition, approximately 20% of patients in the observation arm received definitive therapy. Together these factors render the study markedly underpowered to measure a difference in death from prostate cancer in the men randomized to treatment vs observation, although this comparison did approach statistical significance (P = .09). Moreover, 4-year all-cause mortality estimates in patients managed with curative vs non-curative intent in the PIVOT trial were 9.6% and 14.2%, respectively; these rates are significantly higher than estimates among the general population (mortality of 4.33% and 9.27% for men managed with curative vs non-curative approaches, respectively), suggesting that men in the PIVOT study represent a less healthy cohort compared with the general population. Therefore, the results may not be generalizable to the US population at large. For these reasons, and because another randomized trial did demonstrate a survival benefit to prostatectomy vs observation, it is still not clear whether definitive treatment improves survival for all patients or only for select patients with favorable-risk prostate cancer.
Many expert consensus groups do not concur with the recommendations of the USPSTF. The American Urological Association (AUA) states that “shared decision-making is recommended for men age 55 to 69 years [who] are considering PSA-based screening,” stating that this population is “a target age group for whom benefits may outweigh harms.” Based on the available evidence, routine PSA-based screening could not be recommended by the AUA for patients 40 to 54 years old and those over 69 years of age. The European Association of Urology guidelines recommend a baseline PSA test at age 40 to 45 years, with follow-up testing starting at age 45 for all men with a life expectancy greater than 10 years.