Is There a Smarter Way to Diagnose and Manage Prostate Cancer?

Nurse taking man's blood at doctor's office
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When I was training to be a urologist in the 1980s, the PSA blood test we now use to screen for prostate cancer didn’t yet exist, and finding a prostate tumor was mostly a matter of chance.

Physicians either happened upon a suspicious lump while probing their patient’s prostate with an index finger during a routine checkup (the notorious digital rectal exam), or made the diagnosis after symptoms eventually prompted a man to schedule a doctor’s appointment to find out what was wrong.

Neither scenario was ideal for catching prostate cancer in its early, highly treatable stage.

Thirty years ago, half of newly-diagnosed cases involved prostate cancer that had already spread to other parts of the body by the time it was detected. The most common prostate cancer surgery I did as a urology resident was removing patients’ testicles—an attempt to treat advanced cancers by starving them of the testosterone that tumors use as fuel.

PSA Pluses

The advent of the PSA test in the 1990s allowed us to do widespread screening for prostate cancer in the same way that we look for high cholesterol levels as an early indicator of heart disease. Millions of men have been tested, and the results have helped us identify harmful tumors that can be successfully treated, as actor Ben Stiller’s experience showed.

A “benchmark” PSA test at age 50 can indicate a man’s lifetime risk of developing prostate cancer and help him and his doctor decide how often repeat tests should be done.

If the reading is less than 0.7 nanograms/milliliter (the population average for 50-year-olds), the lifetime risk of prostate cancer is less than 10 percent and future PSA screenings probably are only needed every five years. If the level is less than 2 nanograms/milliliter at age 60, the risk of getting life-threatening prostate cancer or dying of it is only about 2 to 3 percent, and follow-up PSA testing can be reduced or eliminated.

PSA Minuses

While the PSA test has value, it is hardly perfect. It measures the amount of a protein called prostate-specific antigen, or PSA, circulating in the bloodstream. PSAs are made by cells in the prostate gland. While an elevated PSA level may be due to cancer, the numbers also can be raised by other medical conditions, such as infections and the benign enlargement of the prostate that happens as men age. Even a sudden, large PSA increase from one test to the next—a measurement called PSA velocity—isn’t a reliable indicator by itself of the presence of prostate cancer.

In addition, there’s no clear-cut, universal “normal” PSA level. Many men with high levels of PSA in their blood don’t actually have prostate cancer, while some with low PSA levels do. There’s also evidence that PSA levels and other PSA characteristics are different in African-American men than in whites.

As a result of this imprecision, some men needlessly undergo a surgical biopsy of their prostate and may end up getting cancer treatments that aren’t necessary, while other men who need treatment aren’t promptly diagnosed.

The Prediction Problem

Finally, PSA results alone can’t predict prostate cancer’s future course. Many prostate tumors are low-risk, grow very slowly, cause few or no symptoms, and don’t require treatment. Other tumors are fast-growing and can aggressively spread to other areas of the body. Obviously we’d like to know which type of cancer a patient has so we can make the right treatment recommendations, but PSA levels don’t help us with that judgment.

A prostate biopsy, which samples tissue from suspicious areas for laboratory examination, can help classify tumors as low, medium, or high-risk using a ranking called a Gleason score, but it’s subjective and doesn’t always represent the cancer’s actual aggressiveness. And the point of a good screening test is to reduce the need for biopsies, since they’re uncomfortable, cause anxiety and can have side effects.

The good news is that improved screening tests and other diagnostic tools are becoming available, which should help us with the “cancer/not cancer” and “slow-growing/aggressive” determinations. Let’s take a look.

Smarter Screening Tests

Several screening tests on the market have been shown to be considerably more accurate than the PSA test at detecting the presence or absence of prostate cancer, and at detecting high-risk cancers that should be treated. They’re used in conjunction with—not instead of—PSA testing, and are meant to help patients and doctors decide whether a biopsy is needed after an elevated PSA test result.

The blood or urine tests include the 4Kscore, Prostate Health Index, Mi-Prostate Score, and ExoDx® Prostate (IntelliScore). Each analyzes a unique, proprietary combination of biomarkers, or biological indicators, of cancer. Some also measure PSA, but in different ways than the standard test. For example, a test (not yet commercially available) called IsoPSAdeveloped by Cleveland Clinic and Cleveland Diagnostics, Inc., looks for distinctive changes in the molecular structure of the PSA protein.

Although the new screening tests reduce unnecessary biopsies, neither Medicare nor private insurers currently will pay for them on a routine basis (some carriers may cover them in local markets)—a carryover, perhaps, from their previous concerns that the PSA test was finding too many low-grade cancers that didn’t need to be treated. Patients may have to bear the cost, which can be several hundred dollars.

These tests are useful in cases where it isn’t clear if a rising PSA is indicative of cancer, and in patients with a rising PSA and a previously negative biopsy.

A Better Biopsy Method

For men with abnormal results from any of these tests, the next step is a biopsy. In this procedure we take samples of prostate tissue for a pathologist to examine under a microscope to determine if cancer is present. There have been recent, welcome advances here, too.

To get the tissue samples, we poke a series of needles (from 12 to 24) into different parts of the gland, guided by an ultrasound scan. We’ve used this method since the 1980s. The prostate is small, about the size of a walnut, so ultrasound images help us place the needles properly. But the images aren’t detailed enough for us to tell suspicious, potentially cancerous areas from normal tissue.

The truth is that we’re using a scattershot technique, hoping that, if a tumor is present, at least one of the needles will encounter it. These random biopsies can miss some harmful tumors, while revealing others that are inconsequential and may end up being treated unnecessarily.

Fortunately, a souped-up MRI scan called multiparametric MRI can distinguish between malignant and benign prostate tissue.

It would be difficult to do the biopsy while the patient is inside the MRI scanner. But we don’t have to. New software lets us combine, or fuse, those detailed multiparametric MRI scans with live, real-time ultrasound images to guide the biopsy needles. The patient first undergoes the MRI. A radiologist reviews it and highlights suspicious areas. Later, in an outpatient surgery setting, we insert an ultrasound probe into the patient’s rectum, next to the prostate.

The fusion software blends the pre-existing MRI and live ultrasound images. As we move the ultrasound probe around the prostate, the software shifts the MRI image accordingly, giving us a detailed, 3-D view. We can used this fused image to target the biopsy needles to the lesion we want to sample instead of poking around and hoping we find something. It’s like using your smartphone’s GPS to reach a destination rather than driving without directions.

The challenge with this approach, called MRI/transrectal ultrasound (TRUS) fusion-guided biopsy, again is cost. The scan is about $1,500 and insurance companies generally won’t pay for it in patients who are having their first biopsy. They will cover it if used for a repeat biopsy or in patients who’ve previously been diagnosed with prostate cancer.

Fusion-guided biopsy isn’t perfect. One study found that it misses almost as many prostate tumors as does standard biopsy. But the cancers it misses are far more likely to be clinically insignificant ones that don’t need to be treated. And fusion-guided biopsy is very good at spotting potentially aggressive tumors.

Predicting Aggressive Cancers

To help us even more with that assessment, there are newer tests that can analyze biopsy tissue for signs of high-risk cancers. These genomic tests—Oncotype DX® Genomic Prostate Score, Decipher® Prostate Cancer Classifier, ProMark® Proteomic Prognostic Test and the Prolaris® test—look for DNA instability that is a hallmark of aggressively growing tumors.

In addition, the Oncotype DX and ProMark tests can predict whether there is high-risk cancer hiding elsewhere in the prostate, in areas that weren’t sampled with the biopsy needles. (Cleveland Clinic helped develop Oncotype DX and participated in research that validated Decipher and ProMark.)

Medicare and some insurance companies cover the cost of these predictive tests for patients whose pathology results (the Gleason scores I mentioned earlier) indicate the presence of very low- or low-risk tumors. They typically don’t pay for predictive testing in cases where Gleason scores show intermediate- or high-risk tumors.

With the results of these genomic tests, doctors and patients can make more informed decisions about how to proceed—either immediate treatment such as surgical removal of the prostate, or active surveillance, which means periodic checkups and re-evaluation of the cancer’s status.

Dr. Klein is Chairman of Cleveland Clinic’s Glickman Urological & Kidney Institute, the nation’s No. 2 urology program as ranked by U.S. News & World Report.

Sources:

de Rooij M, Hamoen EH, Fütterer JJ, et al. Accuracy of multiparametric MRI for prostate cancer detection: a meta-analysis. AJR Am J Roentgenol. 2014 Feb;202(2):343-51.

Klein EA, Cooperberg MR, Magi-Galluzzi C, et al. A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur Urol. 2014 Sep;66(3):550-60.

Hegde JV, Mulkern RV, Panych LP, et al. Multiparametric MRI of prostate cancer: an update on state-of-the-art techniques and their performance in detecting and localizing prostate cancer. J Magn Reson Imaging. 2013 May;37(5):1035-54.

Brawley OW, Thompson IM Jr, Grönberg H. Evolving Recommendations on Prostate Cancer Screening. Am Soc Clin Oncol Educ Book. 2016;35:e80-7.

Loeb S, Catalona WJ. The Prostate Health Index: a new test for the detection of prostate cancer. Ther Adv Urol. 2014 Apr;6(2):74-7.

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