Keeping an active eye on prostate cancer

Dr. Hammond notes that the consensus document quantifies the risk of active surveillance. During radical prostatectomy, 35 percent of patients are found to have a higher Gleason score than at diagnosis. “However,” she notes, “active surveillance is useful because men with prostate cancer are very unlikely to die of their disease.” With surgery, the 20-year risk of prostate cancer-specific mortality for men with low-risk disease is 1.6 percent; among men on active surveillance, it is 2.8 percent. Curative treatment provides an average 1.8-month increase in life expectancy.

“The difference is not trivial,” Dr. Hammond acknowledges. “However, 97 percent of men with Gleason score six on cancer will not die of it while on active surveillance.”

In this context, Dr. Hammond says the consensus statement provides an important service by defining insignificant prostate cancer, “because that will not kill you.” Prostate cancer must meet three criteria to be deemed insignificant: only Gleason score six histology, organ confined tumor, and volume

The good prognosis for carefully selected patients on active surveillance and the surgical and radiation treatment-associated morbidity are why “it’s important that patients know they have another option besides radical prostatectomy or radiation therapy,” Dr. Hammond notes. And that brings up another area where pathologists need to play a role: supporting shared decision-making between clinicians and patients, with “patient preference as a way of defining treatment.

“The goal of all the work being done in prostate cancer is to get the most accurate evidence and information to present to a patient, so when the patient meets with a clinician they can together come up with the best treatment plan, including how the patient feels about various therapeutic options,” Dr. Hammond says. “Our information and evidence must be as accurate as possible. If you throw uncertainty about the value of the pathology information into the mix, it will be much more difficult for that conversation to be useful.”

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Tumor extent measurements

• Number of positive cores
• Fraction of positive cores
• Linear percentage × carcinoma in each site (core)
• Linear percentage carcinoma in core with the greatest amount of tumor
• Overall linear percentage of carcinoma across all sites (cores)
• Linear millimeters of carcinoma in each site (core)
• Linear millimeters of carcinoma in the core with greatest amount of tumor
• Total linear millimeters of carcinoma across all sites (cores)

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Several panel members discussed their institutions’ active surveillance programs. In the program at Johns Hopkins, Dr. Epstein says, “a somewhat complicated algorithm” is used. Basically, repeat biopsy is done every one to two years. “What has been found in virtually every study is that the only way to detect whether someone has worse disease is biopsy, not digital rectal examination or PSA,” Dr. Epstein says. “Those measures are not specific enough to identify men who should not be followed on active surveillance.”

Dr. Carter says about 1,400 men have been enrolled in the Hopkins active surveillance program at some time since 1995. “Some left the program, others were treated. We know that in the range of 40 percent of individuals who get diagnosed with prostate cancer have favorable disease features. Of those who come to our center who we think qualify for the program about 50 percent enter,” Dr. Carter says. Over the past 20 years, he adds, the proportion of men over age 65 who met the criteria for the program who underwent surgery is very small. “We have been very selective about who gets operated and who enters this program,” says Dr. Carter.

Asked why they have been more successful than some other urologists at getting men into active surveillance, Dr. Carter says, “It is hard to get into the mind of other people.” However, he did suggest that, in part, “There have been particular physicians’ concerns about losing an opportunity for cure. And obviously patients’ concerns as well. And that affects how physicians communicate the risks of both monitoring and treatment and the balance between the two.” Aside from stringent criteria for entry and monitoring, Hopkins has three full-time people who help run the program—a program administrator, a biostatistician, and a biorepository administrator, who manages blood, urine, and tissue.

What are the risks of radical prostatectomy? “Most people who do it all the time would probably conclude that 95 percent of individuals will recover urinary control completely,” Dr. Carter says. “Some may claim higher, but I think that’s a reasonable estimate.” Recovery of erectile function varies. “Under ideal circumstances, which means the patient has no preexisting problem with erectile function, is relatively young, doesn’t have extensive disease, and is operated on by someone experienced, I would estimate the chance of getting back to baseline function in the range of 70 percent to 80 percent.” Dr. Carter emphasizes the term baseline function. “To talk about the return of an erection strong enough for intercourse tells you nothing,” he says. That raises questions: Has it happened once? All the time? Are the patient and his partner satisfied with the quality of intercourse?

While the focus has been on urinary incontinence and loss of erectile function, the latter are not the only treatment-related complications, Dr. Carter points out. In a study of the men who underwent surgery or radiotherapy alone for prostate cancer between 2002 and 2009 in Ontario, Canada, almost one in five men were found to have been readmitted to the hospital with problems related to the surgery or radiation therapy (Nam RK, et al. Lancet Oncol. 2014;15:223–231). “Not all the surgeons in the survey met the ‘experienced’ criterion,” Dr. Carter explains. “In the real world most people don’t have access to a surgeon who has done thousands of these operations.”

In the Yale active surveillance program, Dr. Humphrey says, they are not enrolling patients with more than a (3+3) Gleason score. One change at the Yale program is that patients who are being considered for active surveillance undergo a new type of imaging called multiparametric MRI with fusion of ultrasound images. “We perform targeted biopsy of areas that this modality identifies as high-grade cancer,” Dr. Humphrey explains. “Often patients being seen here will already have had a systematic 12-core biopsy. To be sure they are candidates for active surveillance, with low tumor volume and low-grade disease, this multiparametric MRI imaging is done.”

Dr. Humphrey doesn’t have data on how often patients are reclassified at his center on the basis of the new technique, but he refers to published data on this question. At the National Cancer Institute, 1,003 men underwent concurrent MR/ultrasound fusion-guided biopsy as well as standard ultrasound-guided biopsy. “The new method detected 30 percent more high-risk cancers and about 20 percent fewer low-risk cancers, which is exactly what you want,” Dr. Humphrey says (Siddiqui MM, et al. JAMA. 2015;313:390–397). “It is not perfect,” he adds, but it could increase accuracy in selecting men for active surveillance programs.

In the University of Washington program, Dr. True says, the criteria for active surveillance are a tumor with no higher Gleason score than (3+4) (more than 95 percent of those in the UW program have Gleason score six cancer) and cancer present in no more than two or three cores of a routine 12-core biopsy. As for how much cancer is present, Dr. True says: “For well over 10 years we have been assessing the amount of cancer by measuring the total amount of parenchyma in which there is cancer with or without intervening tissue. So if there is a focus of cancer at each end of a core, we would say the whole core is positive for cancer.” However, he says, “Gleason score and the number of cores involved are the most important criteria for entry to active surveillance.”

Dr. True says all of his urologic colleagues discuss the active surveillance option with patients and enter patients in the program. “Nonetheless, I know some patients seen here with a diagnosis of prostate cancer, even though they have a minimal-volume tumor and as low grade as it can be, they or their family members are concerned about not treating the cancer and they are reluctant to enter into an active surveillance trial.” There may be uncertainty about how predictive the criteria for entering patients into active surveillance are, he speculates, particularly in the community.

The consensus document cites a half-dozen trials supporting the value of active surveillance. Dr. True points to a multidisciplinary trial headed by urologist Daniel Lin, MD, of the University of Washington, with more than 1,000 patients and follow-up approaching five years that asks an important question: How many patients have a tumor that progresses to a cancer that is found clinically? “I’m not aware of any patient in whom that occurred,” Dr. True says.

“In our active surveillance group, we do have patients who have had prostatectomy and in some of them there are histological features that it is of higher grade or higher stage,” Dr. True says. “But I am not aware of any of those patients having metastases.”

Dr. True has talked with colleagues who themselves have been diagnosed with minimal-risk prostate cancer. “We talked about the fact that you can’t be 100 percent sure the tumor won’t progress,” he says. “On the other hand, there are side effects, and some are severe enough that the patient should be aware of them. It is a tough decision. Among the colleagues he has talked to, he says, “Some decide to have intent-to-cure therapy; others decide to be followed on active surveillance.” It’s likely there will always be those who demand action. Even so, the current level of participation in active surveillance can be increased.

“We all recognize we need better tools to distinguish cancers that will not progress if not treated from those that will progress if not treated,” Dr. True says.
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Molecular markers to lessen the uncertainty

Dr. Lawrence True, a professor of pathology at the University of Washington and a member of the consensus panel’s subgroup on biomarkers, says he is “enthusiastic” about biomarker potential. However, he notes, “We don’t have outcomes data to know whether differential expression of markers is associated with different behavior [of prostate cancer] or response to therapy.

“One big advance last year—outside the context of active surveillance—is the discovery of variants of the androgen receptor gene that allow activation of androgen pathways independent of ligand binding to the receptor,” Dr. True says. About 10 percent of patients with primary prostate cancer express one of those variants, though at very low levels. Perhaps metastases with those variants will be less responsive to androgen deprivation therapy.

The University of Washington is one of nine centers in a consortium that is looking for biomarkers that correlate with aggressive prostate cancers. Samples taken at radical prostatectomy are examined by tissue microarrays for numerous possible signals. “Two potential markers that have come out so far are loss of PTEN and a high frequency of Ki-67 tumor cells,” Dr. True says.

Dr. E. David Crawford, professor of surgery/urology/radiation oncology and head of urologic oncology at the University of Colorado School of Medicine, calls “extremely valuable” a number of prostate cancer markers that have come out in the last few years. He has been using one commercial panel, ConfirmMDx, in the context of patients with a negative biopsy. There are 1.2 to 1.4 million prostate biopsies each year in the U.S. but only about 250,000 cases of prostate cancer.
“Concern about prostate cancer doesn’t go away with a negative biopsy,” Dr. Crawford says. “If you are biopsied once, you have a 50 percent probability of being biopsied again. And often the second biopsy is negative as well. We want a test that, if it is negative, the patient has a very low probability of having prostate cancer.”

Two studies have showed that the ConfirmMDx screen, which measures methylation of three molecules, has a 90 percent negative predictive value. That is, 90 percent of the samples that were negative on this test did not have cancer on subsequent surgery. Both studies were retrospective reviews. Of the 10 percent of patients who were falsely negative, Dr. Crawford says, “Most were Gleason score six.”

Dr. Jonathan Epstein, professor of pathology, urology, and oncology at Johns Hopkins, was a co-investigator on one of the studies. He and colleagues recently began to use ConfirmMDx in men with a negative biopsy or high-grade prostatic intraepithelial neoplasia.

“Clinicians are trying to decide whether to leave the patient alone because they have a low risk of cancer or do repeat biopsy,” he says. —William Check, PhD
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William Check is a writer in Ft. Lauderdale, Fla.