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Keeping an active eye on prostate cancer

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William Check, PhD

April 2015—In December 2011, M. Elizabeth H. Hammond, MD, was a member of an expert panel for an NIH State-of-the-Science conference on the role of active surveillance in managing men with localized prostate cancer. At these public meetings patients can address the panelists. “There was a lot of concern among patients and some of the panelists that pathologists were not doing everything we could to support the concept of active surveillance,” says Dr. Hammond, a professor of pathology at the University of Utah School of Medicine. “Patients perceived pathologists as not being engaged in the treatment dilemmas they faced.

Dr. Jonathan Epstein (right) and Dr. H. Ballentine Carter were two members of the group that wrote the consensus statement on the role of pathologists in determining eligibility for active surveillance. Dr. Epstein and others are also proposing a new five-level grading system.

Dr. Jonathan Epstein (right) and Dr. H. Ballentine Carter were two members of the group that wrote the consensus statement on the role of pathologists in determining eligibility for active surveillance. Dr. Epstein and others are also proposing a new five-level grading system.

“Our inability to communicate to patients and clinicians about our diagnostic process was causing them to discount the biopsy as a way to determine whether they should be on active surveillance. It was a horrible experience for me to see how badly we pathologists were perceived,” she recalls.

Active surveillance is an important strategy for men with low-grade disease. “And we are in a pivotal place as far as this treatment is concerned,” Dr. Hammond says. “Our role as pathologists is critical in helping to define which prostate cancer patients are eligible and to determine whether a patient should continue to be followed on active surveillance or whether his disease has progressed.”

Dr. Hammond shared her concerns with Mahul Amin, MD, professor, medical director, and chairman of pathology at Cedars-Sinai Medical Center, who spearheaded an initiative by the CAP, other pathology organizations, and the Prostate Cancer Foundation to achieve consensus on the critical role of pathologists in determining eligibility for active surveillance.

“To bring greater credibility to the pivotal document and to reiterate that contemporary prostate cancer treatment is a team science,” Dr. Amin says, “it was important to assemble a multidisciplinary international team of pathologists, urologists, radiation oncologists, and scientists to coauthor this consensus paper.” Face-to-face meetings, numerous conference calls, and “passionate discussions through emails and personal communications” is what led up to its creation, he says.

Dr. Hammond adds, “The College has done everything it can to support the consensus statement, including provide financial support.”

Dr. Amin

Dr. Amin

The consensus statement was published last fall (Amin MB, et al. Arch Pathol Lab Med. 2014;138:1387–1405). “The goal of the document was to deal with aspects of diagnosis that were problematic and to give guidance to pathologists on how they could do a better job providing diagnostic information that would guide treatment options,” Dr. Hammond explains. One example: “The document talks about the definition of insignificant prostate cancer, which is only Gleason score six,” she says. “This should help a lot.”

To formulate the statement, a panel of primary pathologists, genitourinary pathologists, and urologists was assembled, one of whom was Lawrence True, MD, professor of pathology and chief of genitourinary pathology at the University of Washington. “It has become far more widely appreciated among all of us who deal with prostate cancer that there is overdiagnosis and consequent overtreatment,” Dr. True says. “To address this, we tried to get a consistent way of making the diagnosis and grading prostate cancers and characterizing other features that we think are associated with the behavior of the tumor, such as the amount of invasive cancer on needle biopsy.”

Consistent high-quality pathology is what is needed to increase the percentage of men on active surveillance, says Jonathan I. Epstein, MD, professor of pathology, urology, and oncology at Johns Hopkins School of Medicine, who was a member of the consensus panel. “Clinicians will trust pathologists more and rely more on our reports.”

“There is no question that certain well-known urologists in the U.S. do not support active surveillance,” Dr. Epstein says. Overall about 10 percent of men with prostate cancer who are eligible for active surveillance go on that regimen, compared with about 50 percent in Canada. A recently published study finds that about two-thirds of men newly diagnosed with prostate cancer are eligible for active surveillance (Overholser S, et al. J Urol. Epub ahead of print Jan. 27, 2015;doi: 10.1016/j.juro.2015.01.089). The authors concluded that “the majority of men in the US who are diagnosed with prostate cancer based on regular PSA testing are likely to be eligible for active surveillance and should be carefully counseled regarding the risk of their disease as well as the consequences of treatment.”

In addition to recommendations in the consensus statement, Dr. Epstein says, “We are proposing a new five-level grading system. In the near future it may replace the Gleason grade.” One of the problems with the current scoring system, he says, is that “it can instill fear in patients.

“If a patient is told he has a Gleason score of six, he may go to the Internet and see that six is in the middle of the scoring range. However, it is the lowest score you can get these days. Perhaps a revised scoring system would help alleviate some patient concerns,” Dr. Epstein says.

One of the urologists on the panel was H. Ballentine Carter, MD, professor of urology and oncology at Johns Hopkins. “Good pathology is vitally important” for active surveillance programs, says Dr. Carter, who worked with the subgroup that addressed clinical perspectives on active surveillance. Two randomized trials addressed this question, he says. “Both suggested that for men who are older—and older is a somewhat subjective term, most would agree age 55 or over—with favorable disease, active surveillance is a safe management option over at least 10 to 15 years. My own opinion is that a man over age 65 with favorable-risk disease ought to ask himself not which treatment he needs but whether he needs treatment.”

Dr. Humphrey

Dr. Humphrey

Panelist Peter A. Humphrey, MD, PhD, calls the consensus statement “a really important initiative by CAP and other pathology organizations” and “a strong response from our specialty speaking of the importance of what we do as far as getting patients into active surveillance.”

Dr. Humphrey, a professor of pathology and director of genitourinary pathology at Yale School of Medicine, was a member of the subgroup that addressed tumor quantification. “In our recommendations we listed factors related to how to quantify the amount of cancer,” he says. “We surveyed a wide variety of methods. A real strength of this paper is the summary in Table 5 of the variety of tumor extent measurements from the literature. We analyzed which are most powerful in predicting clinical outcomes.” (See “Tumor extent measurements,” page 42.)

In addition to traditional measures to qualify newly diagnosed patients for active surveillance, Dr. Humphrey and his colleagues are using a new imaging tool called multiparametric MRI with fusion of ultrasound images and biopsy. “Emerging data suggest this method better helps identify high-grade cancer,” he says.

Biomarkers are another possible adjunctive method for classifying tumor invasiveness. “I have been interested in molecular markers for several years,” E. David Crawford, MD, says. “I believe that if we had these biomarkers several years ago, we wouldn’t have had this backlash about overdiagnosis and overtreatment and repeat biopsy.” Dr. Crawford is a professor of surgery/urology/radiation oncology and head of urologic oncology at the University of Colorado School of Medicine. (See “Molecular markers to lessen the uncertainty,” page 46.)

Recommendations on quantifying cancer in biopsy cores are to report the number of cores submitted and the number of positive cores, Dr. Humphrey says. In addition, the recommendation is to always provide the linear percentage of cancer in the core that has the greatest amount of cancer. This last criterion is not so simple. Two methods are commonly used when a core contains foci of cancer separated by benign tissue—to sum only the cancer foci or to incorporate the benign stroma. It’s not clear which approach is more predictive. “We need more data with hard clinical endpoints,” Dr. Humphrey says.

Which method you use can be crucial. Many active surveillance programs exclude a patient who has more than 50 percent cancer in the core with the greatest amount of cancer. “So how you measure these foci could have a huge impact on whether the patient is eligible for active surveillance,” Dr. Humphrey says. The consensus recommendation strikes a compromise. One might report “two discrete foci involving 10% of the core but spanning 70% of the length.” Currently Dr. Humphrey incorporates benign stroma in his report, using the term “discontinuous involvement.”

At Johns Hopkins, Dr. Epstein says, “We only get the length of cancer from one end to the other. An increasing number of studies show it is more accurate to include benign tissue in the estimate.” What is most important is to make sure the clinician knows how you are measuring.

Even more important in determining eligibility for active surveillance than percent of cancer involvement in cores is Gleason grade. “Grade inflation” has complicated this measure since 2005, when the International Society of Urological Pathology (ISUP) reclassified prostate biopsy cores containing cribriform adenocarcinoma as high grade; now they are automatically Gleason pattern four.

Abbreviations: NR, not reported; PSA, prostate-specific antigen; PSAD, prostate-specific antigen density. aBiopsy code: A, percentage of positive cores; B, percentage of cores; C, percentage of any core; D, No. of cores.  bMean  cMedian. In “Source” column, reference numbers are as listed in Arch Pathol Lab Med. 2014;138:1387–1405. Reproduced with permission.

Abbreviations: NR, not reported; PSA, prostate-specific antigen; PSAD, prostate-specific antigen density. aBiopsy code: A, percentage of positive cores; B, percentage of cores; C, percentage of any core; D, No. of cores. bMean cMedian. In “Source” column, reference numbers are as listed in Arch Pathol Lab Med. 2014;138:1387–1405. Reproduced with permission.

“ISUP formally recommended what a lot of us had already been doing,” Dr. Humphrey says. “This has created a pure category for Gleason pattern three, which is now a relatively indolent cancer with little to no chance of metastasis.”

Dr. Humphrey cites a large study of more than 14,000 radical prostatectomies in which no patient with true Gleason score of six or less had lymph node metastasis (Ross HM, et al. Am J Surg Pathol. 2012;36:1346–1352). Conversely, a report early this year from the University of Toronto active surveillance program on 993 patients found that almost all patients with metastases had high-grade disease (Klotz L, et al. J Clin Oncol. 2015;33:272–277).

Dr. Epstein was in the subgroup that discussed Gleason grading. While Gleason described five patterns, Dr. Epstein notes that pattern one is virtually nonexistent. “In practice, six is the lowest score you get,” he says. So although there are 25 possible scores (including permutations), most scores are not used. “There are five distinct grades,” Dr. Epstein says. “That’s why we have come up with a five-level grading system.”

In the system Dr. Epstein and others are proposing, scores (3+3) or below are called Grade Group 1; (3+4) is Grade Group 2; (4+3) is Grade Group 3; Gleason score eight (by any permutation) is Grade Group 4; and Gleason scores nine and 10 are Grade Group 5. The new system separates the two types of Gleason score seven (3+4) from (4+3) because the latter has a more severe prognosis.

Support for the proposed new system comes from a retrospective review of more than 21,000 prostate cancer patients who had radical prostatectomy and 5,000 who had radiation therapy at five institutions—Hopkins, Cleveland Clinic, University of Pittsburgh, Memorial Sloan Kettering Cancer Center, and Karolinska Institute—as part of an ongoing trial. “We started with 2005 to make sure we had contemporary grading,” Dr. Epstein says. The study was submitted recently for publication.

“In general, we found we can distill prostate cancer into five distinct grades for a simplified system that is accurate and reflects disease better and is less worrisome for patients than the way grades are currently reported,” he says.

Dr. Epstein calls men with Grade Group 1 (Gleason score six) cancers “excellent candidates” for active surveillance. “In addition, there may be some men with Grade Group 2—(3+4)—tumors who could also be candidates for active surveillance, depending on factors such as cancer extent on biopsy, percentage of pattern four, age, comorbidity, and patient preference. That will be an area of additional investigation in the future.” Three of the seven major active surveillance programs listed in Table 1 of the consensus document include men with (3+4) prostate cancers; they will provide information on the prognosis of these patients. (See “Participant characteristics and inclusion criteria for several large active surveillance cohorts.”)

Even with good classification parameters, active surveillance has risks. “With needle biopsy, about 20 percent of the time when a patient has a Gleason score of six, there may be higher-grade tissue present in the rest of the prostate,” Dr. Epstein says, noting there will always be some sampling error. “That is why we repeat the biopsy every year, not so much for progression but in case we missed high-grade tissue on the initial biopsy.”

Even so, active surveillance can never be 100 percent safe. “No matter how much we follow and re-biopsy, relatively rare patients on active surveillance will have bad disease and have potentially lost their window of curability,” Dr. Epstein says. “Some urologists want it to be 100 percent safe. But that is not viable. There is a balance of benefit. Overtreating many men to save the exceptional patient does more harm than good.”

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