Polishing the Gold Standard in Prostate Cancer

When Howard Wolinsky, 72, received a prostate cancer diagnosis in 2010, the urologist at a community hospital wasted no time in presenting him with a range of treatment options: surgery, radiation and cryotherapy (freezing tissue to destroy it). The biopsy had revealed just a small lesion of low-grade cancer in one of 12 zones, or sectors, of the prostate gland, but Wolinsky’s doctor was among many at the time who did not yet recommend active surveillance as a less-invasive alternative for men with low-risk prostate cancer.

Fortunately, Wolinsky, a Chicago journalist, was well-informed and knew that the University of Chicago had an active surveillance program. Typically, men in these programs are monitored carefully through routine prostate-specific antigen (PSA) testing and periodic biopsies. PSA is a normal protein produced by the prostate gland, which is located below the bladder and makes some of the fluid found in semen. Levels of PSA are often elevated in men who have prostate cancer. Men in active surveillance do not undergo traditional treatment, such as surgery to remove the prostate or radiation, until it’s warranted — if ever. Wolinsky said that his urolo- gist called him “a poster boy for active surveillance” and he immediately signed on. Today, almost 10 years later, he is still in active surveillance. His cancer has not progressed.

Jim Cassell*, 72, of Silver Spring, Maryland, received a similar diagnosis in 2011. In early 2012, he was accepted into a clinical trial at the National Cancer Institute that was testing the diagnostic effectiveness of multiparametric MRI, which merges ultrasound with MRI to reveal details about anatomy and function. Although the MRI continued to show no cancer progression, a targeted biopsy conducted in 2016 found that Cassell’s cancer had spread to eight of the 14 prostate sectors tested, with some tumors classified as intermediate-risk disease. Cassell had little choice but to be treated, and he selected to have his prostate surgically removed. However, over the course of the following year, cancer cells were still detected, requiring radiation. Today, Cassell is cancer-free, but unlike Wolinsky, he lives with side effects from both surgery and radiation.

These two patients illustrate the promise and the limitations of active surveillance. Why did Wolinsky’s cancer remain indolent (slow growing), whereas Cassell’s progressed? Could additional screening tools have led to a different outcome for Cassell? Questions like these remain unanswered.

The good news is that ongoing research may better illuminate the biology of prostate cancer and the reasons for progression. What’s more, oncologists have become more aware of what variables require close attention when evaluating men for active surveillance. “Looking at the quality of the biopsy, the quality of the pathology report, the quality of the MRI and how it was read, as well as asking important questions, such as the man’s age, his overall health, his family history and his projected life span, are all important factors to take into account,”says Dr. Oliver Sartor, medical director of the Tulane Cancer Center in New Orleans. “By paying close attention to these nuances, we have a much better chance of selecting the right candidates.”

WHY ACTIVE SURVEILLANCE?

Active surveillance is a minimally invasive treatment method that the National Comprehensive Cancer Network (NCCN) recommends for men with low-risk prostate cancer who are expected to live at least 10 more years. However, men with local or regional prostate cancer who have a five-year survival rate of nearly 100% are generally considered good candidates for active surveillance, too. Those with low-risk disease but shorter anticipated life spans might instead be assigned to even less invasive watchful waiting, which isn’t meant to be curative and involves fewer tests, instead focusing on treating symptoms as they arise.

Active surveillance became more popular in response to a wave of overdiagnosis and overtreatment of prostate cancer. Because of routine PSA testing in older men, cancers that might have gone undetected without ever causing health problems were identified and treated. The test measures the amount of PSA in the blood, and it was widely thought that if the number rose above 4, a man could have cancer.

Typically, the next step involved taking 10 to 12 biopsies, or cores, each from a different one of the prostate’s 14 zones. During this invasive procedure, the physician takes tissue samples that can then be analyzed and assigned a grade from 1 to 5, with 1 indicating slightly abnormal cells and 5 indicating very abnormal cells with potential to grow aggressively. Adding the two grades that represent the largest portion of cancerous tissue generates a Gleason score. For instance, if the dominant pattern is 3 and the secondary pattern is also 3, the tumor is assigned a 3 + 3 = 6 score. The higher the score, the more aggressive the tumor. The highest it can be is 10.

PSA is currently the best marker for early detection of prostate cancer, but the test has numerous drawbacks. “For one thing, the test cannot distinguish between indolent and aggressive cancer,” says Dr. Richard Ablin, professor of pathology at the University of Arizona College of Medicine in Tucson and the pioneer who discovered PSA. “What’s more, there’s no level of PSA that’s truly diagnostic. A man can have a PSA of 11 and not have cancer, (whereas) another man with a PSA of 0.5 can have aggressive cancer.”

Nonetheless, the PSA test remains a key element of active surveillance that has gained traction over the past decade. According to data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), between 1990 and 2009, just 6.7% of men who received diagnoses of low-risk prostate cancer were on active surveillance; between 2010 and 2013, that number soared to 40.4%. This increase can be partly attributed to mounting evidence that there is little difference in overall survival rates between men with low-risk disease who are in active surveillance and those who receive more invasive treatment.

Case in point: The Prostate Cancer Intervention Versus Observation Trial (PIVOT). Published in the New England Journal of Medicine in 2017, the 20-year study followed 731 men with localized prostate cancer who were randomly assigned to either radical prostatectomy or observation.

The results showed no significant difference in mortality between the two groups. Disease progression, however, was higher in the observation group, pointing to one reason some men may opt for treatment immediately following diagnosis.

The reason the active surveillance rate among eligible men isn’t 100% may be related to the belief among some men and their partners that forgoing definitive treatment will breed constant worry. As a result, some choose more invasive treatment even when surveillance is an option. Those who do choose surveillance may find it desirable for an important reason: It delays, either temporarily or permanently, living with incontinence and erectile dysfunction, the main side effects of surgery and radiation.

PERSONALIZING THE PROGRAMS

With active surveillance now established as the gold standard for low-risk disease, the next challenge is determining what diagnostic tools to use. Most programs incorporate PSA testing every three to six months and a digital rectal exam, performed manually by a doctor, with similar frequency. The differences lie in whether MRI is part of the protocol and how often biopsies are done. Some may also recommend a 5-alpha-reductase inhibitor, which prevents testosterone from converting into the more potent androgen dihydrotestosterone and reduces prostate cancer risk. The physician’s personal preference also plays a role in how the program is executed.

The Johns Hopkins Hospital in Baltimore, a pioneer in active surveillance, has a reputation for running a rigorous program. The Hopkins program looks for patients with a Gleason score of 6 or lower and cancer in just one or two cores, with a small amount of cancer in each. The physicians also pay close attention to PSA density, determined by dividing the PSA by the volume of the prostate. This test adjusts for men with larger prostate glands, who tend to have higher PSA levels, giving a truer picture of their levels.

“We think density is a better measurement of risk than the PSA score alone,” says Dr. Jonathan Epstein, director of surgical pathology at Johns Hopkins and an early advocate for active surveillance. “The grade of the tumor is also a red flag. It correlates with the risk of the tumor spreading locally.”

Epstein adds that they do a biopsy each year during the early years, a practice in alignment with NCCN guidelines. Over time, however, biopsies are conducted less often, a recent adjustment to the program.

Dr. Greg Auffenberg, an assistant professor of urology at Northwestern Medicine in Chicago, also follows the NCCN guidelines, but he stresses the importance of a confirmatory biopsy after the initial diagnosis. Before Auffenberg does that, he often has his patient undergo an MRI.

“For the confirmatory biopsy, I’ll use MRI fusion technology, which overlays the ultrasound images in real time over the MRI,” Auffenberg explains. “If a patient has an area of concern usually not biopsied, I find this strategy helpful in targeting that area, ensuring that we’re evaluating the patient’s risk accurately.”

Auffenberg joins a growing field of urologists and oncologists who use MRI increasingly for both diagnosis and surveillance. “It’s a game changer,” Ablin says. “It enables urologists to go back to the same area biopsied previously so that they compare apples to apples instead of apples to oranges. It’s a very big deal.”

Sartor agrees but adds that, in his view, MRI enables physicians to forgo biopsies unless there are indications that they are necessary. “If you look at the MRI and it is stable from year to year, you’re looking at a small chance of finding significant cancer,” he says. “We think this approach saves unnecessary biopsies, especially since there’s a 3% to 4% risk of infections or other complications.”

But in Cassell’s case, the MRI missed the spread of cancer, which was revealed only by biopsy. In fact, the literature is mixed as to the percentage of false negatives and false positives that emerge from MRIs and the subsequent role of biopsies.

Patient selection is also very important. Sartor carefully assesses all available evidence before admitting men into his program. “I look at the number of cores, the percentage of involvement of each core, how big each core is and whether there is cancer on both sides of the prostate,” he says. “I also have numerous conversations with the patient and his family. I often find that spouses are reluctant to go along with active surveillance. Their feeling is that if their husband has cancer, it should be treated. In those instances, I gently remind the spouse what active surveillance is and why it works for prostate cancer.”

Sartor and Auffenberg both estimate that 30% of the men in their active surveillance programs experience disease progression and need treatment over a five- to 10-year period. Research corroborates that: A 2010 study by Dr. Laurence Klotz of Toronto, one of the leaders in the field, found that over about a seven-year period, 30% of 450 men in an active surveillance program progressed to definitive treatment.

IMPROVING ACCURACY OF ACTIVE SURVEILLANCE

Although active surveillance has come a long way, most physicians agree that there is room for improvement. Better tools are needed to, as Klotz says, “find the wolf in sheep’s clothing”: About 25% of men in active surveillance for low-risk cancer turn out to have hidden pockets of higher-grade disease.

In a paper published in Translational Andrology and Urology in 2018, Klotz writes: “Nomograms incorporating MRI and/or biomarker findings to predict the risk of co-existent higher-grade cancer are urgently needed.” Using complex math, nomograms predict risk based on data from a large number of men. An emerging field called radiogenomics is working on ways to combine data from genomic testing and multiparametric MRI on large numbers of patients followed for long periods to more accurately identify patients for active surveillance.

The role of the genomic markers currently available, however, is questionable. “I’m not convinced that genomic markers are helpful, except perhaps in further analyzing borderline cases,” Sartor says. “I don’t get genomics on every patient.”

Epstein agrees with that approach. “The tests are very expensive and are usually done at the request of a patient,” he adds.

Another ongoing debate in the field is whether active surveillance is a viable option for men with intermediate- risk disease (Gleason score of 3 + 4 = 7). “This is a controversial area,” Epstein acknowledges. “I would consider this more for older men, but for younger men with a longer life span, I wouldn’t recommend that route.”

Although he wasn’t able to remain on active surveillance, Cassell says he’s grateful he participated for a few years. “I only wish that the progression had been detected sooner,” he says, “through a biopsy done earlier.”

Wolinsky, by all accounts an active surveillance success story, says he feels lucky that he has what one of his doctors called a “lame cancer.” But over the years, he has felt like a pincushion, given how often his prostate has been probed during biopsies. An MRI, too, is not without consequences. He has tinnitus, a ringing or buzzing in the ears, from loud clanging during one of his first MRIs. Wolinsky adds that there is emerging concern about the safety of gadolinium, a contrast dye used during an MRI. Some studies suggest that it may stay in the body longer than previously thought, posing risks for people with impaired kidney function.

“Men should be aware that active surveillance is not a stroll in the park,” Wolinsky says. “It definitely has down- sides. But at this point, active surveillance should be on the table for all men diagnosed with low-risk prostate cancer.”