Is prostate cancer overtreated?

Issues of screening, epidemiological shifts and mortality risk have complicated prostate cancer treatment.

It is hard to imagine that the second leading cause of cancer deaths in U.S. men is in the midst of a wait-and-see approach treatment controversy. However, whether to treat prostate cancer is often a hot topic among oncologists.

Prostate cancer will be discovered in an estimated 186,320 men this year and about 28,660 will die from the disease, according to the ACS. More than 60% of all prostate cancers are diagnosed in men aged 65 and older.

Andrew K. Lee, MD, inspects a compensator’s plunge depths. Photo by Barry Smith

Some research has indicated that although prostate cancer is on the rise, this may likely be the result of increased screening for the disease rather than an epidemiological shift.

One in six men will develop prostate cancer during his lifetime, but only one in 35 will die from the disease; mortality rates have taken a decline during the past decade, according to the National Cancer Institute.

Results of studies have shown that older men with early-stage prostate cancer may not be taking a big risk if they wait to treat the disease instead of treating it right away. These men are more likely to die from another cause during the first 20 years after their diagnosis.

In addition, treating prostate cancer with surgery or radiation can lead to such complications as urinary incontinence, erectile dysfunction and bowel difficulties.

With all of this being considered, HemOnc Today spoke with a number of experts in the field of prostate cancer treatment and research and asked the question: Is prostate cancer being overtreated or overemphasized?

With the widespread adoption of the PSA test in the United States, the incidence of prostate cancer rose sharply a decade ago. However, is this because of increased screening for the disease or an epidemiological shift?

David Penson

“There’s no doubt in my mind that the increase in prostate cancer diagnosis we saw in the early- and mid-1990s was due to increased screening for the disease,” David Penson, MD, MPH, an associate professor of urology and preventive medicine at University of Southern California/Norris Comprehensive Cancer Center, told HemOnc Today. “There is simply no other explanation.”

Penson said the real question is whether these screen-detected cases were destined to become clinically meaningful cancers, or, conversely, were physicians detecting indolent disease that would not have caused problems.

“The answer to this question is very complex,” Penson said. “Some cases were probably overdiagnosed, but other cases were probably clinically meaningful and likely benefited from earlier detection.”

Andrew K. Lee, MD, MPH, associate professor at The University of Texas M.D. Anderson Cancer Center, agreed that increased screening has likely led to more cases being diagnosed earlier, but the number of cases is also a function of the aging population.

“Prostate cancer is primarily a disease of older men, and there are more men over 60 years of age now than 15 to 20 years ago,” Lee said in an interview. “This trend will continue as the baby boomers turn 60.”

Mortality rates

Are mortality rates for prostate cancer on the decline?

According to the NCI, the most recent report available on cancer mortality shows that in 2004 the overall death rate from prostate cancer among American men was 25 per 100,000, meaning that the rate had decreased by an average of 4% each year during the previous decade. In addition, the NCI estimated that there are currently 2 million prostate cancer survivors in the United States.

“I would argue strongly that prostate cancer mortality has declined considerably since 1993,” Penson said. All eight physicians interviewed by HemOnc Today agreed.

The reasons for the decline in mortality remain uncertain. Monique Roobol, PhD, researcher in Erasmus Medical Centre, Rotterdam, Netherlands, said that it is not quite clear whether it is a result of improved treatment or early detection.

“Some claim that this is for sure the result of early detection; however, I feel that this is too soon,” Roobol said in an interview. “A few more years and we will be able to see whether early detection indeed has an influence on declining mortality rates.”

Howard Sandler, MD, a radiation and prostate specialist at University of Michigan, said that the evidence of prostate cancer death rates declining could be due to several factors.

“This could be due to better treatments, earlier detection and effective therapy of small tumors or due to detection of insignificant cancer due to sensitive screening tests, like PSA,” Sandler told HemOnc Today.

“I hope, and believe, that numbers one and two are correct, but three is still possible.”

Although only one in 10,000 men aged younger than 40 will be diagnosed with prostate cancer, the rate increases to one in 38 for ages 40 to 59, and one in 15 for ages 60 to 69, according to the Prostate Cancer Foundation.

Researchers of a study considered to be the largest to look at prostate cancer since PSA tests became popular found that older men with early-stage prostate cancer are not taking a big risk if they keep an eye on the disease instead of going through treatment immediately.

The researchers studied 9,018 men (average age 77) diagnosed from 1992 to 2002 with early-stage prostate cancer who did not get surgery, radiation or hormone therapy for at least six months. Most patients never received any treatment. A decade later, the researchers found that 3% to 7% of those with low- or moderate-grade tumors had died of prostate cancer compared with 23% of those with high-grade tumors.

“Our data showed that the majority of patients — about 85% — had less than a 10% risk for dying of prostate cancer 10 years after cancer diagnosis, and the risk of late-stage cancer-related complications were relatively low,” researcher Grace Lu-Yao, PhD, from UMDNJ/Robert Wood Johnson Medical School, said in an interview.

Lu-Yao said the misconceptions about prostate cancer risk is common among physicians. The misconceptions may be based on current literature and interactions with patients and other physicians.

“The deep-rooted fear about cancer may drive the decision-making process, rather than scientific evidence,” Lu-Yao said.

Low-risk cancers

Research has shown that the classification of cancer has changed significantly over time, perhaps having a profound impact on treatment decisions, according to Lu-Yao.

“A patient classified as having a ‘low-grade cancer in the 1990s and early 2000s is likely to be classified as having a ‘moderate-grade cancer nowadays,” Lu-Yao said.

“Although most physicians agree that men with ‘low-grade cancer are good candidates for watchful waiting, very low percentages of new cases are in this category.”

Less than 3% of the population in Lu-Yao’s study was classified as having ‘low-grade cancers; the majority of patients (83%) have ‘moderate grade’ cancers.

“As noted, few men with newly diagnosed prostate cancer are left untreated [via] watchful waiting, even though the recent evidence suggests that they have a low risk for death from the cancer at 10 years if left untreated,” said Timothy Wilt, MD, MPH, professor of medicine at the Minneapolis VA Center for Chronic Disease Outcomes Research, referring to Lu-Yao’s study.

Wilt said that additional information suggests that treatment recommendations are influenced by a practitioner’s specialty. For example, “urologists more commonly recommend surgery, whereas radiation oncologists more commonly recommend radiation therapy. Few of these practitioners recommend watchful waiting, even among older men with low-risk cancers.”

Active surveillance

Although many physicians support the concept of watchful waiting, the term itself is not as favored.

“I much prefer the term ‘active surveillance,’ because watchful waiting seems much more passive, almost like we’re waiting for the cancer to spread, which is not the case,” said Penson, who noted that it is an important distinction.

“What we’re doing is actively following patients with low-risk cancers and if their PSA values increase or the cancer appears to be worse than originally thought, then we’re making early interventions and hopefully impacting the course of the disease.”

Penson said that in an unpublished review of his experience with patients at USC/Norris Cancer Center who had low-risk disease on biopsy and had undergone surgery, roughly a third had “intermediate- or high-risk” disease on surgical pathology.

“The problem is that I can’t pick this third out immediately after diagnosis,” Penson said.

That is why patients who are newly diagnosed with low-risk disease may be able to safely avoid aggressive therapies like surgery or radiation but still need to be followed closely, he said.

“And if there is the slightest hint of worsening of disease on PSA follow-up or repeat biopsy, the patient needs to be treated aggressively,” Penson said.

Researchers in the Netherlands showed that screening at increased intervals does not reduce the rate of detection of interval and aggressive interval prostate cancers, according to study results published in the Journal of the National Cancer Institute several months ago.

Roobol and colleagues found that a larger number of prostate cancers were identified in patients who were screened every two years as opposed to those screened every four years, but more frequent screenings did not decrease the number of aggressive cancers detected.

The researchers concluded the results did not seem to justify annual PSA testing, except “in men at high risk of prostate cancer, who may be identifiable at secondary screening using recently developed algorithms.”

“Having a far advanced prostate cancer, which will kill you, is a terrible way of dying and this should be avoided if possible,” Roobol said. “However, there must be a balance between avoiding these deaths and on the other side [creating] unnecessary costs and anxiety caused by the detection of cases that would never have become life threatening.”

Michael LeFevre

Michael LeFevre, MD, MSPH, professor of family and community medicine at University of Missouri-Columbia, said that it is simply unknown whether screening finds the aggressive cancers in time to prevent morbidity and mortality or how often physicians find and treat disease that would never have caused any problems.

“Treatment is not benign; we take healthy men and make them suffer or die as a consequence of the treatment,” LeFevre said in an interview. He said that some men may have lengthened their lives through treatment; others may have suffered needlessly.

“Unfortunately, we do not have the science that tells us how many men will fall into each of these groups. The harder you look for prostate cancer, the more you will find.”

PSA testing common

PSA testing and early intervention is common, according to Wilt, even in men with relatively short life expectancy and even though there are few reliable data indicating that PSA testing improves length or quality of life.

“For example, nearly 80% of men age 50 or greater have had a PSA test, and up to 40% of men in their 80s have had a PSA test within the past year — even among these elderly men with a life expectancy less than five years due to comorbidities,” Wilt said.

“These are higher rates than exist for colorectal cancer screening, where early detection has shown benefit in reducing cancer specific but not overall mortality,” Wilt said.

Widespread PSA testing, use of lower PSA thresholds to label someone as abnormal, as well as a greater number of prostate gland “cores” obtained at biopsy have been associated with an increase in the number of men being diagnosed with prostate cancer, according to Wilt.

“It is likely that many of these cancers are found serendipitously and if left untreated would not cause any health problems,” Wilt said.

Autopsy reports

Lee said that he agrees that a portion of low-risk patients may not need definitive therapy in their lifetime but is not sure that this is a valid reason for not treating patients.

“This is similar to saying that some men shot with .22 caliber bullets do not die from their gunshot wound but rather from other causes, and, therefore, we do not need to provide medical care for men shot with .22 caliber bullets,” Lee said.

E. David Crawford, MD, head of urologic oncology at the University of Colorado Health Sciences Center, said that autopsy reports do show that low-risk prostate cancer possibly could be a disease that can be lived with under watchful waiting rather than treatment, “but up until recently, most cases found and treated were significant with more biopsies,” he said in an interview.

“Prostate cancer is 20% to 40% overtreated, and it is underemphasized,” Crawford said. “And there’s not enough research support on the topic.”

Overtreated and overemphasized?

Results of a recent study conducted at the University of Michigan showed that more than half of men with low-risk prostate cancer are overtreated with surgery or radiation therapy.

Analyzing NCI data on 24,405 men with lower-risk prostate cancer, the research team found that 55% underwent surgery or radiation treatment within a year of diagnosis.

Penson said he believes that about 20% to 30% of patients undergoing aggressive therapy for newly diagnosed localized disease have clinical indolent disease that could be followed with active surveillance. Again, his numerical estimation for the percentage of patients overtreated fell in line with many of the physicians interviewed.

“But I don’t think it can be overemphasized because it’s still the most common solid tumor among American men, and, more importantly, it is still the leading cause of cancer death among American men in the U.S.,” Penson said.

Physicians need to emphasize prostate cancer awareness even further, Penson said. “Only through awareness can men make informed decisions about this important public health condition.”

Sandler said he also thinks that although there are cases of prostate cancer that are overtreated, he wishes patients with prostate cancer could be accurately divided into two groups: “those with cancer who need treatment right away and those who can be safely monitored.

“But the state of science does not allow us to make that distinction with precision,” Sandler said.

Cavalier decision-making

“I do not think we have enough knowledge about who can be treated and who cannot be treated with enough certainty to be cavalier with this level of medical decision-making,” Lee said.

Choosing not to have definitive therapy for prostate cancer may be too anxiety-provoking for some patients, despite a physician’s best attempts to educate and reassure them, according to Lee.

“Asking men not to have their cancer treated without understanding the full implications of this decision — physically, psychologically and emotionally — is somewhat disingenuous,” Lee said.

“A significant portion of the aging population will face this diagnosis at some point, and, as a field, oncologists need to be ready to not only provide the best care in terms of cure but also in terms of quality of life after treatment,” Lee said. – by Angelo Milone

Prostate cancer – Is it overtreated?

For more information:

• Gelmann EP. Complexities of prostate cancer risk. N Engl J Med. 2008;358:961-963.
• Lu-Yao G. Prostate disease trajectory of untreated localized prostate cancer in elderly men: a population-based study. Presented at: the 2008 Genitourinary Cancers Symposium; Feb. 14-16, 2008; San Francisco.
• Miller DC, Gruber SB, Hollenbeck BK, et al. Incidence of initial local therapy among men with lower-risk prostate cancer in the United States. J Natl Cancer Inst. 2006;98:1134-1141.
• Roobol MJ, Grenabo A, Schroder FH, et al. Interval cancers in prostate cancer screening: comparing 2- and 4-year screening intervals in the European randomized study of screening for prostate cancer, Gothenburg and Rotterdam. J Natl Cancer Inst. 2007;99:1296-1202.
• Walsh PC, DeWeese TL, Eisenberger MA. Localized prostate cancer. N Engl J Med. 2007;357:2696-2705.
• Welch HG, Schwartz LM, Woloshin S. Prostate-specific antigen levels in the United States: implications of various definitions. J Natl Cancer Inst. 2005;97:1132-1137.