By: Dan Sperling, MD
While PSA screening has undeniably lowered the death rate from prostate cancer, there is another side to the coin. Screening has led to the overdetection of Gleason 6 (3+3) prostate cancers that are so slow growing as to be considered indolent. Without the tools to determine with confidence which cell lines will pose no long-term threat, medicine has erred to the side of caution, because untreated malignancies are assumed to proliferate and colonize other structures and organs. Therefore, the standard of care has been to treat all prostate tumors aggressively. Countless patients have thus been overtreated; for many this has resulted in impaired personal quality of life due to urinary, sexual or bowel side effects. With increasing evidence that certain Gleason 6 cell lines do not appear to progress to Gleason 7, some experts are asking whether they are true malignancies. Lepor and others suggest, “It is time to reappraise whether these indolent abnormalities should be labeled with the term ‘cancer.’”[i]Throughout the centuries, cancer has been viewed as an encroaching disease that progresses from a cluster of deviant cells into an uncontrollable monster that ravages the body. Although a diagnosis of prostate cancer (PCa) may still catalyze this fear in a patient, the antidote lies in reassuring messages that have blossomed since the beginning of PSA screening: “It’s a slow-growing disease;” “More men die with prostate cancer than from it;” and “Don’t worry, we caught it early while it’s still curable.”
At issue is whether Gleason 6 prostate cancer has the potential to become more aggressive to the point where the cells can proliferate locally and metastasize to remote locations, and if so, how soon will this occur after the initial biopsy. For this reason, patients who go on AS have PSA tests at regular intervals within a year and are urged to have undergo repeat TRUS biopsy (at least at the end of the first year) to monitor for progression. At the first sign of progression, patients will be offered treatment—though not all will pursue it at that point. Here are examples from the published literature illustrating various aspects of the dilemma:
- An Italian case study is a cautionary tale that begins by acknowledging the debate on Gleason 6 being labeled as cancer. The patient described in the study was TRUS biopsy-proven to have Gleason 6 PCa and other low risk factors (PSA 5 ng/mL, stage T2a). He was treated with prostatectomy. The specimen initially showed organ confined Gleason 3+3 PCa. However, the pathologist also found cancer cells in nearby blood and lymph vessels (lymphovascular invasion) and one positive lymph node close to the prostate gland. Most clinicians consider this a poor prognostic factor because the tumor is aggressively invasive and has left the gland. When the pathologist made deeper section cuts in the specimen slices, <5% of the tumor showed Gleason pattern 4 cells and had penetrated the capsule. His disease was upstaged to T3a and the tumor upgraded to reflect a tertiary Gleason pattern 4.[ii]
- An interesting study by Hussein et al. examined a group of 219 patients on active surveillance (AS) in order to observe rates of cancer progression and learn whether adverse outcomes were associated with delaying treatment until progression.[iii] The cohort of 219 men were initially qualified for AS based on Gleason 3+3 disease, and they underwent routine surveillance biopsies while enrolled in the study. All of the patients were eventually upgraded, average follow-up 23 months. 150 (68%) were upgraded to 3+4 and 69 (32%) to >4+3. The number of those who sought treatment at the time of upgrade was 163 men (74%) with the majority (69%) choosing radical prostatectomy. At 5 years, the treatment-free survival for the Gleason 3+4 patients was 22%, whereas for those with >4+3 it was 10%. Of special note, when the prostate specimens were analyzed by a pathologist, 34% of the cancers were downgraded while only 6% were further upgraded; and after surgery, the larger the tumor volume, the greater the correlation with adverse surgical outcomes, suggesting that the size of the tumor—not necessarily the grade—was significant factor associated with poor surgical results. The authors concluded since very few men were further upgraded at surgery, delaying treatment was not associated with adverse outcomes. However, the Hussein et al. paper points to a common problem with TRUS biopsies, that is, inaccurate or inconsistent biopsy results. The next study is testing a way to qualify patients for AS with greater confidence.
- The research by Arsov et al. reports on 9 patients who were part of a larger study on MRI-guided biopsy, additional TRUS biopsy, and genomic analysis involving a novel RNA expression signature derived from 31 cell-cycleprogression (CCP) genes.[iv] The 9 patients were placed on AS, and the authors designed “a qualitative pilot study to evaluate the prognostic value of the CCP-score (CCP-S) for the first time in men managed with AS after MRI-guided prostate biopsy (MRI-GB).” When used in conjunction with the initial MRI-guided biopsy, which tends to be more accurately diagnostic than conventional TRUS biopsy, the CCP-S values predict the 10-year mortality risk. The authors found that the CCP-S “confirms accurate staging of AS patients detected by MRI-based biopsy strategies and may significantly reduce inaccurate staging of AS patients and subsequent unnecessary re-biopsies. The CCP score may help to more accurately select for active surveillance candidates.”
Looking at the three diverse studies above, it becomes obvious that conclusive evidence as to whether Gleason 3+3 cancer behaves like cancer is not yet to be had. It is clear that a significant number of patients whose first biopsy is 3+3 go on to a higher grade of cancer. Is this due to inaccurate biopsy results the first time, or did the tumor actually mutate in a more aggressive direction? Since there’s no definitive answer, it seems that ongoing work such as the Arsov study is aimed at better identification of which patients can defer treatment because their tumor has favorable genetic markers.
One final publication sheds light on focal treatment as a middle ground between radical therapy (with the risk of urinary and sexual side effects) and AS (with the risk of tumor progression and possibly missing a treatment window). In their review paper, Klotz & Emberton point out, “Approximately 30% of men diagnosed with low-risk disease harbour high-grade cancer that is unrepresented on the biopsy. Moreover, a small percentage of low-grade cancers have molecular alterations that result in progression to aggressive disease.”[v] Because of the inability today to identify such patients, they caution that while AS is an appropriate choice for patients with apparent low risk PCa, they should be carefully followed-up and monitored. However, focal therapy represents a middle ground that complements AS, especially for men with higher disease risk factors.
Focal therapy technologies include cryotherapy (freezing), HIFU and laser, as well as some novel technologies mostly used in countries other than the U.S. (Despite lack of long term data, focal laser ablation appears to offer competitive cancer control while having the least risk of side effects.) Therefore, until there is greater certitude about which lines of Gleason 3+3 cancer will not progress, a precise focal treatment in addition to AS promises to offer the best of all worlds.
[i] Lepor H, Donin N. Gleason 6 Prostate Cancer: Serious Malignancy or Toothless Lion? Cancer Network Review Article. Jan. 15, 2014. http://www.cancernetwork.com/oncology-journal/gleason-6-prostate-cancer-serious-malignancy-or-toothless-lion/page/0/1
[ii] Montironi R, Scarpelli M, Mazzucchelli R, Lopez-Beltran A et al. Does prostate acinar adenocarcinoma with Gleason Score 3 + 3 = 6 have the potential to metastasize? Diagn Pathol. 2014 Oct 18;9(1):190.
[iii] Hussein A, Welty CJ, Ameli N et al. Untreated Gleason grade progression on serial biopsies during prostate cancer active surveillance: clinical course and pathological outcomes. J Urol. 205 Jan 23. pii: S0022-5347(15)00167-6. doi: 10.1016/j.juro.2015.01.077. [Epub ahead of print]
[iv] Arsov C, Jankowiak F, Hiester A et al. Prognostic value of a cell-cycle progression score in men with prostate cancer managed with active surveillance after MRI-guided prostate biopsy–a pilot study. Anticancer Res. 2014 May;34(5):2459-66.