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Efficacy of prostate cancer screening: Many questions remain
Ongoing trials and new screening tests could provide answers and improve treatment.
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When the U.S. Preventive Services Task Force published guidelines last fall recommending that men older than 75 not be screened for prostate cancer, the announcement generated a flurry of media attention and provoked controversy in the urologic community. Somewhat less controversial but equally important was the task force opinion that the paucity of data does not definitively indicate whether screening of men younger than 75 actually improves patient outcomes.
Controversy and uncertainty about the efficacy of prostate cancer screening, specifically PSA testing, was only further fueled last month when somewhat conflicting interim results of two highly anticipated prostate cancer screening trials — The European Randomized Study of Screening for Prostate Cancer and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial — were published in The New England Journal of Medicine.
Results from ERSPC indicated that PSA-based prostate cancer screening reduced the rate of death by as much as 20%; however, results from the PLCO trial show that there were more deaths among men screened with PSA and digital rectal exam than men in a usual care group. Neither set of results is a final analysis.
Despite differences of opinion about the efficacy of screening, most experts agree that additional data and screening tests for the detection of aggressive disease are essential. Informing patients of their options, making decisions based on patient information, and relying on factors other than PSA have become important tools for deciding which patients should be screened and treated.
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“The benefit of early detection is something that requires judgment all along the path,” said Oliver Sartor, MD, Gerald and Flora Jo Mansfield Piltz Endowed Professor in Cancer Research, departments of medicine and urology, Tulane Cancer Center, New Orleans.
According to Sartor, life expectancy plays a bigger role in the potential benefit of screening than patient age. “In fairness, the older the patient the more the comorbidities and the more limited the life expectancy.”
Unlike those issued by the USPSTF, recommendations from other organizations such as the American Cancer Society and the National Comprehensive Cancer Network emphasize the importance of contributing factors such as comorbidities and life expectancy when recommending or implementing an early detection program.
Conflicting recommendations
In its 2002 guidelines, the USPSTF did not have enough information to recommend for or against screening for prostate cancer. The 2008 update stated that the available evidence was still too little to promote screening among men aged younger than 75 years.
“The average age of death from prostate cancer in the United States is 80, which means that half of the men who die from the disease are over the age of 80,” said Ian Thompson Jr., MD, professor and chairman of the department of urology, The University of Texas Health Science Center at San Antonio.
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Photo by Lee Bennack |
“Against that context, the task force says that once you reach the age of 75, stop doing anything. And, if you are screened before 75, don’t be screened after age 75. What this ends up doing is creating a tendency to find in the young man the slow, potentially inconsequential cancer and, in the older man, the tendency to ignore a tumor that has the potential to take his life.”
Despite its controversial ruling, the USPSTF made an important and somewhat welcome change to the guidelines by recommending physician-patient discussion: “Given the uncertainties and controversy surrounding prostate cancer screening in men younger than age 75 years, a clinician should not order the PSA test without first discussing with the patient the potential but uncertain benefits and the known harms of prostate cancer screening and treatment. Men should be informed of the gaps in the evidence and should be assisted in considering their personal preferences before deciding whether to be tested.” Both the ACS and the NCCN also recommend this type of physician-patient discussion.
“As a routine policy recommendation, not screening men over the age of 75 makes sense because we haven’t proved the benefit of screening in anyone,” Eric Klein, MD, chairman, Glickman Urological and Kidney Institute at the Cleveland Clinic, told HemOnc Today. “On the other hand, there are a number of characteristics associated with prostate cancer in older men that make it potentially more lethal.
“In the absence of perfect tools to predict the lethality of a newly diagnosed cancer and the likelihood that someone else is going to die of another cause, it has to be an individual discussion,” Klein said.
In March 2008, the ACS revised its guidelines for the early detection of cancer. Its section on prostate cancer screening suggests physicians offer the PSA blood test and digital rectal exam each year beginning at age 50 to men with a life expectancy of at least 10 years, although it does not recommend routine screening.
According to the guidelines, men at high risk, including blacks and those with a strong family history, should begin testing at age 45. Additionally, all men should be informed of the known and unknown benefits, limitations and risks of screening and treatment.
Guidelines from the NCCN state that obtaining a baseline PSA test at the age of 40 is a reasonable option to assess the risk for subsequent prostate cancer detection. According to the recommendations, “the risk assessment might be useful in determining the most appropriate surveillance strategy for the individual, as well as whether or when a prostate biopsy should be recommended.”
William Catalona, MD, said that it is reasonable “for all men to begin PSA testing at age 40, not necessarily for the purpose of detecting prostate cancer — because the disease is very rare in men at age 40 — but to obtain some baseline measurements.”
Additionally, the NCCN recommends that physicians consider several factors when beginning an early-detection program: patient age, life expectancy, family history, race and previous early detection test results. The NCCN also encourages physician-patient discussion regarding known and unknown data.
Although there is debate about whether the benefits of early detection outweigh the associated risks, some physicians argue that screening can save lives.
Weighing the risks, benefits
“In the United States alone, during the PSA era, the age-adjusted death rate from prostate cancer decreased by 37% and now by more than a third,” said Catalona, professor of urology at the Feinberg School of Medicine at Northwestern University.
“Additionally, the death rate is dropping by about 4% per year, so when you weigh those risks and benefits, in the hands of good, competent doctors the benefits greatly outweigh the risks.”
According to Klein, indirect evidence supports the benefits of screening; namely, its ability to detect prostate cancer in its early stages while it is still curable. More direct evidence in the form of stage migration is also apparent.
“Before PSA came along, about half of the patients newly diagnosed with prostate cancer — either because they had a lump that could be felt on DRE or they presented with symptoms of urinary obstruction or metastatic disease — were incurable at diagnosis. Within about five years of the advent of PSA, almost all of the cancers that were diagnosed were contained within the prostate, and only about 5% were incurable at the time of diagnosis,” Klein said.
According to the ACS, there were approximately 186,320 new prostate cancer cases diagnosed in 2008 with only about 28,660 deaths.
“That suggests that we may be finding, on average, over 100,000 new cases per year that are not destined to harm or kill the patient and that those patients would be better off not knowing they have prostate cancer,” he said.
A study published in the April issue of The Journal of Urology reported that men aged between 75 and 80 years who have PSA levels <3 ng/mL are not likely to experience or die of aggressive prostate cancer during the remainder of their life.
The longitudinal cohort study included 122 men with prostate cancer and 727 without the disease who had serial PSA measurements taken as part of the Baltimore Longitudinal Study of Aging. The primary outcome was the proportion of men by PSA and age who died of prostate cancer or developed aggressive disease.
No men aged between 75 and 80 years with a PSA level <3 ng/mL died of prostate cancer; however, men of all ages with a PSA >3 ng/mL had a continued increase in the probability of death from prostate cancer (P<.001), according to the researchers.
After age 75, the time-to-death or aggressive disease diagnosis did not differ between PSA categories of 3 ng/mL to 3.9 ng/mL and 4 ng/mL to 9.9 ng/mL (P=.634). However, the researchers reported that PSA category <3 ng/mL had a longer time-to-death or diagnosis of aggressive disease (P=.019).
“Our findings suggest that men 75 to 80 years old who have a PSA less than 3 ng/mL are unlikely to be diagnosed with high-risk prostate cancer during life,” the researchers wrote. “Therefore, these men may represent an ideal target group for discontinuation of PSA testing, which could dramatically reduce the costs associated with screening, as well as the potential morbidity of additional evaluations and/or treatment in a population unlikely to experience benefit.”
Detection vs. treatment
The detection of potentially “harmless” cancers can have negative effects on the patient’s health and psychological status, according to some experts. Though most agree this is a problem, some believe it is one that could be minimized if detection were no longer equated with treatment.
According to Sartor, equating early detection with early treatment has played a role in the controversy surrounding prostate cancer screening.
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Peter R. Carroll, MD, MPH, professor and chair of urology at The University of California at San Francisco, agrees. Carroll argues for early detection coupled with selective treatment. “The new paradigm would be to advocate early detection in healthy, well-informed patients at risk but at the same time advocate more selective treatment.
“Men identified to have low-volume, low-grade cancers should be considered for active surveillance, and those men identified to have higher-grade, higher-volume cancers caught early may be ideal candidates for treatment with surgery, radiation or a variety of other things,” he told HemOnc Today.
Sartor considers five factors: patient age, comorbidities, PSA, Gleason score and clinical stage.
Fritz H. Schröder, MD, professor of urology, Erasmus Medical Center, the Netherlands, said he also considers family history. “If someone has a strong family history of prostate cancer, I would be likely to recommend earlier screening,” he said. “If someone comes to my office at age 75 and says their father died at age 102 and their mother died at age 98 and they’re extremely healthy and just want to know [their risk] and want to be screened, I can’t refuse it.”
Awaiting final data
In 1993, Schröder and colleagues initiated the ERSPC trial. The main endpoint of the ongoing study is prostate cancer mortality associated with screening.
“We hope to also answer several questions: What age limits or age cutoffs make a lot of sense? How should we best screen to find prostate cancer that will, at the end, contribute to a decrease in prostate cancer mortality?”
The study, which takes place in eight European countries, currently includes about 260,000 men who are randomly assigned to prostate cancer screening or a control arm, according to Schröder. An update on the current status of the trial that was published last year in Urologic Oncology indicated that about 30% of all screen-detected prostate cancers are identified as indolent due to the validity of the nomogram for the identification of indolent disease.
In addition, evidence suggests that most of the indolent cancers are found in low PSA ranges. According to the paper, “longer screening intervals are applicable and details can be worked out. Many aspects of future screening are still uncertain.”
More recent results published last month show that at nine years follow-up, 8.2% of the screening group was diagnosed with prostate cancer and only 4.8% of the control group had been diagnosed. As of Dec. 31, 2006, the researchers confirmed 214 prostate cancer-related deaths in the group screened with PSA compared with 326 deaths in the control group.
PSA-based screening for prostate cancer reduced the rate of death by 20% (95% CI, 0.65-0.98). When researchers looked at only those men who were actually screened during the first round, the rate ratio for death from prostate cancer was 0.73, or a 27% reduced rate of death (95% CI, 0.56-0.90). Final trial results are expected in 2010.
The PLCO cancer screening trial began randomly assigning patients to a screening or control arm in 1993. Like the ERSPC trial, the goal is to determine whether annual screening with PSA and DRE reduces prostate cancer-specific mortality.
The trial compared men randomly assigned to screening with PSA and DRE (n=38,349) and those assigned to ‘usual’ medical care. According to the 2008 update published in BJU International, 1,902 cancers were diagnosed. Cancers detected at baseline (n=549) were more likely to be clinical stage III or IV (5.8%) and have a Gleason score of between seven and 10 (34%) compared with screen-detected cancers during subsequent screening rounds (1.5% to 4.2% stage III/IV and 24% to 27% Gleason score between seven and 10 among 1,054 cases).
Updated results from this trial indicated that the increased number of cancer diagnoses did not result in a lower mortality rate.
At seven years follow-up, there were 50 prostate cancer deaths in the screening group compared with 44 in the control group (rate ratio=1.13; 95% CI, 0.75-1.70). At 10 years, there were 92 prostate cancer deaths in the screening group and 82 in the control group (rate ratio=1.11; 95% CI, 0.83-1.50).
“Regardless of the outcome [of the ERSPC and PLCO trials], we’ll learn a great deal by the systematic study of prostate cancer screening in large numbers of men,” Sartor said.
New markers needed
Most physicians agree that PSA and DRE tests are helpful tools but additional assays are needed to diagnose aggressive disease. “What we really need is a way of determining — ideally noninvasively — who has aggressive prostate cancer and who doesn’t,” Sartor said.
“If we know how aggressive the disease is, we have some degree of confidence in our ability to make predictions in terms of the cancer prognosis, and then we have a very powerful tool that we can use to exercise judgment about how individual patients are treated.”
Thompson and Schröder have designed two prostate cancer risk calculators to identify men at risk for indolent and aggressive disease. Although different, each calculator asks questions based on age, family history and PSA level.
“Ideally we’d like to find the aggressive cancers, and this risk calculator is a tool that helps you discriminate the man who is at risk for those aggressive cancers,” Thompson said.
Other efforts include the development of blood and urinary assays, tests that detect the presence of gene fusion proteins and additional markers designed solely for the detection of cancer.
“There are some new tests coming along that have not yet been widely validated. I don’t know if any single one of them will ever replace the PSA test, but it’s likely that there will be other tests that can be used in conjunction with the PSA test that will make it more accurate,” Catalona said.
Thompson said that it continues to be the responsibility of both the physician and organized medicine “to educate the patient that we don’t know [everything about screening] and that there are potential advantages and disadvantages.
“The important thing is that, like most things in life, it’s not so simple; it sounds simple, but it’s not,” he said. – by Stacey L. Adams
I am strongly in favor of screening. Why age 75? Why not 76 or 70? Although it is true that prostate cancer in most men older than 75 is indolent, the point is that it is not in others, and a simple test can be life saving. Once prostate cancer is metastatic, cure is not possible and a life on antiandrogens has its problems. Men older than 70 with urinary difficulties or inability to have erections do not necessarily run to their doctor to have a PSA done. Therefore, waiting for symptoms may not be the answer.
– Joseph R. Bertino, MD
HemOnc
Today Associate Medical Editor
For more information:
- American Cancer Society Guidelines for the Early Detection of Cancer. American Cancer Society website. www.cancer.org. Accessed January 19, 2009.
- Barry MJ. N Engl J Med. 2008;359:2515-2516.
- Grubb RL. BJU International. 2008;102:1524-1530.
- Logothetis CJ. Cancer Prev Res. 2008;1:151-152.
- Practice Guidelines in Oncology – v.2.2007. National Comprehensive Cancer Network website. www.nccn.org. Accessed January 20, 2009.
- Schröder FH. Urol Oncol: Seminars and Original Investigations. 2008;26:533-541.
- U.S. Prevention Services Task Force. Ann Intern Med. 2008;149:185-191.