Despite decades of research, multinational clinical trials, regular guideline updates by the U.S. Preventive Services Task Force, and coordinated efforts by ASCO and other major oncology organizations, the management strategy for prostate cancer remains controversial. To keep the oncology community updated on the current clinical discussions that are trying to shape a cohesive approach to prostate cancer detection and treatment, The ASCO Post recently spoke with Bert Vorstman, MD, MS, FAAP, FRACS, FACS, a urologic surgeon who has, along with his clinical surgical practice, been a keen observer of the state of prostate cancer.
Progress in Detection and Treatment
The U.S. prostate cancer mortality data remain fixed at about 30,000 per year. Please shed some light on that number within the context of our progress in detection and treatment.
As you noted, the annual U.S. death rate is about 30,000 and slowly decreasing as each decade passes. Surprisingly, this improvement in mortality is probably not based on early detection and treatment, but rather on the effect of a gradual increase in life expectancy due to better treatment of infections and comorbidities. In fact, to hammer home this point, the 5-year survival for prostate cancer is estimated to be 100%, and the 10-year survival is estimated at about 98%, whereas the 15-year survival is estimated to be about 96%, regardless of the type of treatment. Even more stunning is the revelation that, for patients with low-stage disease, no treatment yields a similar 10-year survival as treatment.
Bert Vorstman, MD, MS, FAAP, FRACS, FACS
Gleason 6 Controversy
Gleason 6 remains a point of contention with those in the community, with many insisting it be not classified as a “cancer.” What’s your opinion on this issue?
Laurence Klotz, MD, and others have determined some time ago that the grade 3 in the Gleason 3+3 = 6 lacks the hallmarks of a cancer on the basis of its clinical outcome and its molecular biology. This stunning revelation meant that the Gleason 6 tumor should not be labeled a cancer, should not be detected, should not be treated, and should not be included in prostate cancer statistics. The inclusion of Gleason 6 tumors in prostate cancer statistics has grossly misrepresented the significance of prostate cancer.
Are we in a better scientific place to determine which are the potentially lethal prostate cancers?
So, which prostate cancers are potentially lethal and responsible for the 30,000 annual deaths in the United States? The answer is essentially those diagnosed with Gleason grades 4+3, 4+4, and anything with 5s. On the other hand, those with 3+4s, and particularly those with low amounts of pattern 4 disease (the critical amount is yet to be established), seem to have a natural history similar to the bogus Gleason 6 disease previously described.
However, because of the complexity and subjectivity of the Gleason grading and scoring system, errors of interpretation and incorrect diagnoses of Gleason grades and scores are frequent. In fact, Swedish pathologists appeared to disagree about Gleason grades a staggering 60% of the time.1 Therefore, from a patient perspective, because a diagnosis portends invasive treatments and complications, this grading and scoring system is unreliable.
Additionally, not only do prostate cancers exhibit different degrees of aggressiveness, but they are affected by the phenomenon of field effects, which may occur through genetic or epigenetic changes. This situation is common in the prostate (as in the bladder), and it explains why cancer may be detected in more than one area of the prostate or develop in another part and be of a different grade at a later date during surveillance. This knowledge also underscores why relying upon the prostate needle biopsy for detection is grossly unscientific.
Core-Needle Biopsy
The core-needle biopsy remains the mainstay for detecting prostate cancer. Some in the community believe it is an outdated detection method. What is your opinion?
The transrectal, ultrasound-guided, 12-core prostate needle biopsy component of prostate-specific antigen (PSA)-based screening randomly samples only about 0.1% of the prostate gland (the total volume of the 12-core samples taken by an 18-gauge needle compared with the size of an average prostate is easily calculated). Not only is this test uncomfortable (despite local anesthetic), but it carries a significant risk for sepsis, rectal bleeding, erection issues, and depression. Shockingly, the grossly unscientific 0.1% hit-or-miss biopsy means that there is 0 knowledge about the remaining 99.9% of the prostate. Yet more than one million core-needle biopsies are ordered in the United States each year, with costly complications.
“The inclusion of Gleason 6 tumors in prostate cancer statistics has grossly misrepresented the significance of prostate cancer.”— Bert Vorstman, MD, MS, FAAP, FRACS, FACS
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Radical Prostatectomy
Please share your opinion on radical prostatectomy, given that surgical techniques have improved over the past decades.
Radical prostate surgery was particularly deadly in its early years, mainly from blood loss. Over time, there has been human experimentation with different approaches to the prostate trying to gain better control of blood loss. Also, because of a host of other complications, such as bladder neck contracture and urinary and erectile issues, various techniques such as “nerve sparing” were developed to decrease the chance of these problems impacting recovery. Even when robotics managed to become mainstream, there was still no proof that complications were fewer nor that the procedure was safe, effective, and saved significant numbers of lives.
Further doubts about the usefulness of surgical treatment came from the PIVOT study. Published in The New England Journal of Medicine, the report concluded: “Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not substantially reduce all-cancer or prostate cancer mortality, as compared with observation [active surveillance], through at least 12 years of follow up. Absolute differences were less than 3 percentage points [statistically insignificant].”2
Another study conducted by urologists and taken out over 29 years implied that 2.9 years of life was “gained” with radical prostatectomy.3 However, the results of this study were also skewed, because it included men with Gleason 6 pseudocancer and treated other participants with testosterone suppression, which itself can produce life extension. At best, the study provided only a semblance of cure.
Adding to the confusion, surgical studies typically included patients with a mix of Gleason grades, scores, and tumor volumes. Also, prostate cancer was commonly staged on the basis of CT scans and bone scans, both highly undependable, as these technologies are not sensitive enough to detect small-volume cancer spread. This particular concern has been underscored by bone marrow aspiration studies and the use of sophisticated staining techniques demonstrating cells in the bone marrow of men with negative staging studies.
MRI: Best Screening Tool We Currently Have?
About 15% of detected prostate cancers are potentially lethal. Detecting and treating those malignancies continue to be problematic. Is there any light at the end of this tunnel?
There is no reliable blood or urine indicator that can detect only the high-grade potentially lethal prostate cancers. The PSA value is highly unreliable and is associated with a false-positive rate of about 78%. Even alternative biomarkers, such as PSA derivatives (such as the percent-free PSA), PCa3, “score” tests, genome tests, and urine tests, are not foolproof.
The best screening tool we currently have appears to be MRI. Unlike the hit-or-miss prostate needle biopsy, sampling randomly about 0.1% of the prostate, the MRI evaluates the whole prostate. And, based upon imaging details in a properly conducted study, By using the Prostate Imaging Reporting and Data System (PI-RADS) 4 and 5 features, MRI is able to identify reliably almost all high-grade cancer anywhere within the prostate while ignoring the Gleason 6. Uncommonly, some intermediate-risk cancers may show PI-RADS 4 features.
The PI-RADS is a complex MRI scoring system, and patients may be misinformed and harmed because of observer error and inadequate knowledge among some radiologists. These errors may be compounded if the technique undertaken to perform the MRI is also substandard or the MRI is supported by outdated software.
Not all prostate MRIs are equal. Although most newer-generation MRIs are suitable, many radiologists are not skilled in prostate MRIs. Additionally, other MRI “detection” options using endorectal coil MRI or office-based “fusion” techniques are not reliable. The MRI images for any “fusion” study are not in real-time during the ultrasound study. Worse, placement of the transrectal ultrasound can distort the shape of the prostate, making alignment with the old MRI image unreliable.
There is a lot of work ahead of us. Before we can make substantial progress in identifying only potentially lethal prostate cancers, we need to closely review procedures in detection and treatment that have no proven value for patients.
This article is dedicated to Anthony Horan MD, a urologist who challenged fearlessly the culture and the business of prostate cancer. He was always on the right side of what should never have been a controversy.
DISCLOSURE: Dr. Vorstman owns shares in health-care mutual funds.
REFERENCES
1. Horan A: The Big Scare: The Business of Prostate Cancer. Sterling House Books, 2009.
2. Wilt TJ, Brawer MK, Jones KM, et al: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 367:203-213, 2012.
3. Bill-Axelson A, Holmberg L, Garmo H, et al: Radical prostatectomy or watchful waiting in prostate cancer: 29-Year follow-up. N Engl J Med 379:2319-2329, 2018.
