On Guard: Gauging Aggressiveness of Prostate Cancer Aids Decision Making

The story unfolds in a way familiar to many men: A routine blood test brings news of an elevated prostate-specific antigen (PSA) level. It’s nothing alarming, until infection and benign prostatic hyperplasia are ruled out. Then a biopsy reveals a small tumor that probably won’t endanger health in the long run, but it brings a long consultation with a urologist and a list of treatment options that carry a payload of worrisome long-term side effects.

That’s how Jim Cassell of Silver Spring, Md., learned of his prostate cancer. In 2011, his primary care physician noticed a rise in the level of PSA in Cassell’s blood compared with the previous year and suggested he have a follow-up PSA test. Subsequent levels measured over the next few months showed another increase, sending Cassell to a urologist, who ordered a biopsy. The results showed a very small tumor in one area of his prostate and undetermined “suspicious” activity in two other areas. Fortunately, Cassell was considered low-risk, meaning his cancer would be unlikely to shorten his life. Still, he says, “just the idea that you have cancer is kind of a blow.”

Diagnosed with a small, localized tumor in his prostate, Jim Cassell weighed numerous treatment options before choosing active surveillance. [Photo by Daniel Peck, Peck Studios]

He needed to make a decision. One urologist recommended brachytherapy, a type of internal radiation treatment. Cassell, 64 at the time, wanted to wait; his wife was less certain. He contacted the National Cancer Institute (NCI) about a clinical trial testing magnetic resonance imaging (MRI) scans as part of a surveillance program that keeps an eye on men who have low-risk cancers to help them stave off surgery, perhaps forever. Cassell liked the idea, but couldn’t get an appointment for months. He sought out another practitioner, a urologic oncologist at Johns Hopkins Hospital in Baltimore; this one suggested that surgery might be the best approach. Physicians worried that the rapid change in his PSA level — something called PSA velocity — might point to an aggressive tumor. Still, the tumor was small and confined to one area, so he did more research. “I put two and two together and thought, ‘This is cancer, and it’s not good news, but it’s not like I have to do something tomorrow.’”

A member of a local prostate cancer support group encouraged Cassell to pursue the NCI trial, even though there was a wait. Cassell did, and underwent an MRI scan and a biopsy, both of which confirmed a very small tumor in one section of his prostate. The areas previously deemed “suspicious” showed nothing.

Low Risk, High Anxiety

Cassell has been participating in the active surveillance program at the NCI for several years. A yearly PSA test and a multiparametric, or extra-sensitive, MRI monitor his tumor. “My last MRI in early 2015 showed no change in the lesion from the previous year,” Cassell says.American men face a 15.3 percent lifetime risk of developing prostate cancer, but the risk of dying from the disease is only 2.7 percent. Men with localized disease enjoy a nearly 100 percent survival rate over five years. In fact, a study published in 2012 in the New England Journal of Medicine concluded that among men with localized cancer — most of whose cancers were diagnosed after PSA testing — removing the prostate made them no less likely to die from prostate cancer within 10 years than had they done nothing more than active surveillance. Prostate removal did benefit the subset of men who had aggressive disease.

The numbers are less encouraging, however, for men with aggressive disease based on the histological grade (Gleason score) and sites of spread. Once prostate cancer spreads, the five-year survival drops to 31.9 percent. Doctors have a growing number of tools that can help identify “advanced” cancers, which in turn can help them predict outcomes and offer patients an array of treatment alternatives. Yet the most widely used tool, the PSA test, is also the most controversial because of its high rate of false positives.

PSA levels can fluctuate, and levels that go up and down like a roller coaster don’t necessarily point to prostate cancer, explains Herbert Ballentine Carter, a professor of urology and oncology at Johns Hopkins University in Baltimore. But because rapidly rising PSA levels can flag an aggressive cancer after benign causes have been ruled out, doctors can use that PSA velocity to the patient’s advantage.

“I don’t think any urologist in the U.S. is going to ignore a PSA that’s exponentially increasing,” Carter says.

Other tests can be added to the PSA test to ensure a more accurate diagnosis. Researchers are working to find a noninvasive way to detect prostate cancer by looking for biomarkers in seminal fluid or urine. These biomarkers may help identify cancers that are less or more aggressive and, perhaps, eliminate the need for biopsies.

The Prostate Health Index is a blood test, approved by the FDA in 2012, that takes into account subtypes or variations of PSA to help determine whether biopsies are warranted in men with PSAs between 4 and 10 ng/mL. 4KScore is another system for checking blood to help determine which men with elevated PSAs, if biopsied, will turn out to have high-grade disease.

In 2012, the FDA also approved the PCA3 (prostate cancer gene 3) gene test. Prostate cancer cells overexpress PCA3 RNA, which can be detected with a urine test. The test can be used, for example, if the PSA level is high but a biopsy is negative. Another genetic test of urine carries the long name TMPRSS2:ERG. In some cancers, genetic material rearranges itself and then fuses together. The unhealthy combination of TMPRSS2:ERG genes wreak havoc in the prostate because they spark a cascade of events that lead to the development of prostate cancer. Yet even that test is imprecise.

Also available to help men discern whether they might benefit from repeat biopsies are ConfirmMDX, the Prostate Core Mitomic Test and the PTEN prognostic assay, which look differently at tissue collected in an initial biopsy.

An Active Eye

Men can also get hung up on their numbers by thinking that a higher PSA level always means a worse cancer, but that’s a false assumption. “You can have a PSA of 50 from a bad prostate infection and a bad type of prostate cancer with a PSA of 1.5,” says Oliver Sartor, medical director of Tulane Cancer Center in New Orleans, adding that he gets his own PSA levels checked even though the test “is far from perfect.”In recent years, there’s been a rise in the percentage of men with low-risk prostate cancer who initially opt for active surveillance.

Of men with low-risk disease tracked in two large U.S. databases, between 13 and 21 percent chose active surveillance in 2004; those percentages rose to between 20 and 32 percent in 2010.

Yet once a PSA test leads to a biopsy and then to a low-grade cancer diagnosis, some men want that cancer removed, and removing only part of the prostate is not an option.

“Men are not comfortable with doing nothing when faced with a cancer diagnosis,” says Richard Hoffman, a professor of internal medicine at the University of New Mexico in Albuquerque, which is why the phrase “watchful waiting” is problematic. “Patients don’t want to hear, ‘You have prostate cancer, but don’t worry. If it looks like it’s going to cause problems, we’ll do something to treat your symptoms,’” he adds. “‘Active surveillance’ seems more acceptable because we’re not ignoring the cancer.”

In response to the trend toward overdiagnosing and potentially unnecessarily treating some cancers, a working group of the NCI recently published recommendations on the definition of cancer. It suggested that many lesions detected during prostate cancer screenings should be referred to as “indolent lesions of epithelial origin,” not “cancer.”

Deciding whether to choose active surveillance is something doctors and patients should accomplish through a dialogue, suggests Mitchell C. Benson, the Herbert and Florence Irving Professor at Columbia University Medical Center, New York- Presbyterian Hospital.

He said he goes through a PowerPoint presentation with his patients to help them understand the factors in choosing active surveillance versus active treatment, including their biological and chronological age and the details of their disease. “Going on active surveillance is a risk assessment,” Benson says. “Active surveillance doesn’t mean no treatment ever. It just means no treatment now, and that’s an important thing for the patient to understand.”

Indeed, although they are not immediately treating cancer, active surveillance programs have the intent of still being able to cure the disease by providing treatment if necessary. Hoffman says sometimes the program is dubbed “proactive” to give men an even higher comfort level. The type and frequency of monitoring varies. In general, men are monitored via frequent PSA tests, perhaps every six months, possibly with MRIs and biopsies conducted every couple of years. A change for the worse in any of these tests can reclassify cancer to the intermediate or high-risk category. Even this treatment option comes with issues that need to be considered.

One criticism of active surveillance is that men might worry more between testing, knowing that the cancer is still there. Cassell hasn’t found that to be the case.

“I don’t dwell on it, but I do think about it,” he says. “Is there any certitude in life about anything? I have as much information as I can get at this point, given what we know about these things.”

If any of his test results worsen, Cassell says he will come out of active surveillance, and he’s emotionally ready for that, as well. “I’ll say, ‘We do what we’ve got to do here.’”

Another issue for men on active surveillance is that every biopsy raises the risk of serious infection because prostate tissue is sampled close to the anus. Men might have previously taken antibiotics, increasing the chances that bacteria in their stool have developed a resistance to a common antibiotic. Puncturing the prostate could then carry resistant bacteria into the gland, making the men sick enough to be hospitalized.

Because biopsies give a limited view of the prostate, some medical centers are using powerful MRIs to confirm or monitor the size of the tumor or for preoperative staging. An emerging trend is the use of multiparametric MRI, in which imaging is done in several sequences that allow physicians to see the prostate, blood flow and water movement, increasing the accuracy of the test and, ideally, reducing the number of false positives; this is the type of MRI Cassell receives when he’s screened by the NCI. Not all men have access to a medical center with that type of MRI scanner or to radiologists trained to interpret the images, but the technology is becoming available at more centers all the time.

Genetic Markers

As MRI techniques improve, calling for an MRI rather than a biopsy might be “the preferred way of evaluating a guy with elevated PSA,” says Gerald Andriole Jr., a urologic surgeon at Washington University School of Medicine in St. Louis.Evaluating biopsy tissue for gene mutations might help physicians predict which tumors will spread. GenomeDx launched a new genetic test called Decipher. Other tumor genetic tests include Myriad Genetics’ Prolaris and the Oncotype DX test from Genomic Health. In addition, ProMark, which uses immunofluorescent imaging to classify tumors, entered the market in 2014. These tests analyze tissue from prostate biopsies for gene activity that points to how aggressive the cancer might be. Doctors can use the tests in several ways. For men on active surveillance, the tests might be able to help determine whether to keep a patient in a particular treatment program. The tests also can be used on prostate tissue following radical prostatectomy to help physicians evaluate the risk of whether the cancer will recur.

Out-of-pocket costs for such tests can range from $375 to around $3,800. Coverage depends on insurance plans, but companies offer assistance with appeals and also patient financial assistance. “It’s hopeful that these tests, if they show that cancer is aggressive, could be enough to switch a guy from active surveillance to treatment,” Andriole says. “If it confirms it’s not aggressive, then everybody sleeps a bit better knowing that we’re not undertreating the issue.”

The most important thing to remember about prostate cancer is to keep the disease in perspective, Carter says. “Prostate cancer is not the most common cause of death in men — it is below cardiovascular disease and diabetes,” he adds. “People are afraid when they hear the word ‘cancer’ because they think it’s automatically deadly and want aggressive treatment. So, we work with patients to help them make a careful decision.”