Some 18 months ago we had written about the possible occurrence of spontaneous remissions in men on active surveillance (AS) for low-risk forms of prostate cancer. We were therefore very interested in a recent article closely related to this topic.
Chu et al. have just published an article in the Journal of Urology entitled, “The clinical significance of multiple negative surveillance prostate biopsies for men on active surveillance — does cancer vanish or simply hide?” Although only the abstract of this paper is available on line, we have been able to access the full text.
So, first and foremost, we should be clear that it wasn’t really going to be possible (at least, not yet) to answer the question that Chu et al. posed. The only way that it would be possible to answer that question would be to examine, pathologically, the prostates of numerous men on AS with serially negative prostate biopsies after an initially positive prostate biopsy. And that would have to await the demise of the serially negative patients from other causes. That could take several decades, even if the patients were willing to give permission for removal of their prostates post mortem.
However, what Chu et al. were able to do was carry out a detailed analysis of data from 514 men with low-risk prostate cancer, initially managed on AS, in the University of California, San Francisco, AS database.
Here are some of the key things that they found:
- 484/514 men (94.2 percent) had Grade Group 1 disease and 30/514 (5.8 percent) had Grade Group 2 disease.
- Average (median) PSA level at diagnosis was 5.2 ng/ml.
- Median PSA density was 0.12.
- Median time between biopsies was 16 months
- Median total follow-up time was 112 months (i.e., just over 9 years)
- 133/514 men (25.9 percent) had a negative confirmatory biopsy (i.e., after an initial positive biopsy, their biopsy to confirm that they were good candidates for inclusion on the UCSF AS protocol was negative).
- 74/514 men (14.4 percent) had at least two consecutive negative biopsies.
- 36/514 men (7.0 percent) had three or more consecutive negative biopsies.
In a conversation with Dr. Carissa Chu, the lead author of this paper, yesterday, she further informed us that:
- All patients who were included in this study were either initially diagnosed at UCSF or had their original biopsy specimens reviewed at UCSF to confirm their diagnosis.
- A least some of the patients who went on to have serial negative biopsies had a second, confirmatory diagnostic biopsy at UCSF that was positive before they started to have serial negative biopsies.
We can therefore be confident that all these patients did indeed have an accurate, initial diagnosis of prostate cancer and that least some of them had a second, positive confirmatory biopsy.
In this group of patients, what Chu and her colleagues focused their analysis on was the relationships between clinically evident risk factors, subsequent negative biopsies, and lower risks of active treatment. So, for example, they were able to show that:
- Average (median) PSA density (PSAD) was lower for men with one negative biopsy (median PSAD = 0.11) and consecutively negative biopsies (median PSAD = 0.10) compared to men who never had a negative biopsy (median PSAD = 0.13; p < 0.01).
- Higher PSAD levels (OR = 1.68) and suspicious MRI findings (OR = 2.00), were associated with a higher likelihood of detecting cancer on a fourth biopsy.
- One negative biopsy (OR = 0.22) and consecutively negative biopsies (OR = 0.12) were associated with a lower likelihood of detecting subsequent cancer.
- Of the 74 men with consecutively negative biopsies after diagnosis,
- 32/74 (43 percent) had a negative biopsy at their fourth (outcome) biopsy.
- 42/74 (57 percent) had a positive biopsy at their fourth (outcome) biopsy.
- 7/74 men (9 percent) had a biopsy-based pathological upgrade to prostate cancer with a Grade Group of 2 or higher at that fourth (outcome) biopsy.
- 10-year treatment-free survival was highest for patients with consecutively negative biopsies (84 percent) and 1 negative biopsy (74 percent) than for patients who never had a negative biopsy (66 percent).
The authors concluded that, in this group of 514 men with low-risk prostate cancer, initially managed on AS:
Consecutively negative surveillance biopsies are correlated with favorable clinical risk factors and independently associated with subsequent negative biopsy and lower risks of active treatment.
They drew no conclusions about the possibility of spontaneous remission of low-risk prostate cancers.
We, on the other hand, would observe that, in our opinion, the data reported by Chu et al. further suggest:
- The possibility that spontaneous remissions of low-risk prostate cancers could well be “real”.
- The possibility that such spontaneous remissions might occur in as much as 3 or 4 percent of men initially diagnosed with low-risk prostate cancers
- The likelihood that if this were to be the case, such spontaneous remissions would be most likely to occur in men with low PSA densities (e.g., < 0.12) and no suspicious findings on MRI.
On the other hand, we suspect that, even among men with multiply serially negative biopsies, after an initial diagnosis with low-risk prostate cancer, compared to men who have never been diagnosed with prostate cancer, these men may well be at heightened risk for a completely new diagnosis of clinically significant cancer. We suggest this (on the basis of no actual data) because if you have developed cancer of the prostate once, it is not unreasonable to think you might do it again.
We therefore suggest that anyone who is initially diagnosed with low-risk prostate cancer and subsequently has multiple negative findings on appropriate MRIs, biopsies, and other tests, may need to have annual urologic evaluations and relevant tests for risk of a new occurrence of prostate cancer (in addition to the risk from the original diagnosis), at least until they believe their life expectancy is of the order of 10 years or less.
Exactly why might spontaneous emissions occur in men with an evident diagnosis of prostate cancer? That is still to be elucidated. However, our suspicions remain that such remissions would have to be driven in some way by an immunological response to the cancer, although other factors may also be important.
Editorial note: Our thanks to one of our regular readers for providing us with the full text of this article, and our thanks to Carissa Chu, MD, of the University of California, San Francisco, for her time in talking with us about this paper. its findings, and its potential implications.
Filed under: Diagnosis, Living with Prostate Cancer, Management, Risk | Tagged: active, biopsy, negative, remission, serial, spontaneous, surveillance |
THE "NEW" PROSTATE CANCER INFOLINK 
Dr. Peter Carroll, senior author, mentioned this study when he spoke to the ANCan/UsTOO webinar in July. You might be interested to know that you indirectly triggered this when you wrote earlier about my case and that of another patient. I wrote about this in MedPageToday.
I found doctors are split on the idea of remission of low-risk prostate cancer. But some powerful, experienced voices, such as Dr. Laurence Klotz, think remission is possible.
Carroll said one of his patients read the article and asked about remission. The UCSF team decided to look into UCSF data.
I “celebrate” 10 years on AS in December. My cancer was seen but once, 10 years ago, in a biopsy in a single core and never again. Should low-risk, low-volume Gleason 3 + 3 even be called cancer?
A significant question is whether or not the biopsies in this study were ‘random’ needle biopsies or image-targeted biopsies. If random, a confounding factor in repeat biopsies is whether or not they actually sample the same tissues.
I take it we are talking saturation biopsies? Even then I have direct experience of this and no belief at all that my “index node” has downgraded itself. Biopsies have error bands.
Dear Jon and SUM:
(1) Most of the initial diagnostic biopsies were probably standard, TRUS-guided biopsies since they date back at least 10 years.
(2) Many of the more recent confirmatory and repeat biopsies (all done at UCSF) would probably have been mpMRI/TRUS fusion-guided biopsies, but the paper does not provide specific information about this.
(3) It is highly unlikely that any of these patients would have been having “saturation” biopsies (usually meant to imply 20 or more biopsy cores).
(4) It is almost impossible to prove a “negative” biopsy, which was exactly why I made the point about the only way to “prove” spontaneous remission would be to remove the prostate after the patient’s death and then look for prostate cancer.
The only point I am making here is that in my entirely personal opinion the concept of spontaneous remission of low-risk prostate cancers is perfectly reasonable (based on all sorts of evidence of the spontaneous remission of more advanced cancers — at least one case of prostate cancer included) and supported by the data in this paper. If someone knows of another way to prove or disprove this hypothesis, please don’t hesitate to speak up!
My first biopsy was done 13 years ago when my PSA went up to about 4.2. A 3 + 3 “tumor” of about 0.5 mm was found in a single 20 mm core. Fortunately my urologist suggested I discuss the AS program at UCSF Urology.
A second biopsy several months later found nothing. I participated in the MENS study and the CANARY study, which involved several repeat biopsies over a period of years. None were positive, and none of the MRIs revealed anything. I began to think of myself as a member of the “worried well” club, and it was suggested that I might have gone into spontaneous remission. This view of things felt pretty good but I still considered that first biopsy as a warning shot across the bow. So I stayed with the AS protocol, and then sure enough an MRI revealed a PI-RADs 3 area and subsequent biopsy found a very small 3 + 4. I’m still on AS and believe that once diagnosed, don’t go to sleep.
Dear Bob:
Thank you for this information. Can you tell us whether the second positive (3 + 4) biopsy specimen was in the same area of your prostate as the original (3 + 3) specimen? Also, how long was it between your original positive 3 + 3 biopsy and the new 3 + 4 biopsy?
My diagnostic biopsy in 2009 found three cores of Gleason 3 + 3 = 6 at 10 percent. An MRI found two PI-RADS 3 and one PI-RADS 4.
There have been five later biopsies, one negative. My MRI in 2019 found one PI-RADS 2 lesion. A Precision Point biopsy found one core at 5 percent.
Don’t claim spontaneous remission, but my pathology is certainly less than in 2009.
Thanks for your interest. The original 3 + 3 was 0.5 mm in two cores (30 mm) from the left apex. This biopsy totaled 18 cores and found a single 2 mm tumor in two cores (30 mm) from left apex; 10% of this 2 mm was 3 + 4 = 7. It is possible that the original tumor was in fact 3 + 3 containing a tiny bit of 3 + 4 missed by the needle. I’ve assumed that grade-progression doesn’t happen with 3 + 3 prostate cancer cells, but the tumors may not be homogeneous in cell type. The 3 + 4 here is fused gland.
A new 1 mm 3 + 3 was found in two cores (40 mm) from left mid-gland. The first biopsy was done in 2007. This is the first positive biopsy since then, with re-biopsies and mpMRI done every other year. A housecat instead of a tiger, so far anyway. Doing AS does require surveilling.
There is the small but always possible chance of specimen provenance error to explain the “disappearing tumor” scenario — which has lead many practices to employ DNA confirmation of biopsy specimens.
Dear Paul:
Indeed, that is certainly true.
For those who aren’t aware of the term “specimen provenance error”, Dr. Schellhammer is referring to the possibility that the biopsy tissue analysis is mistakenly assigned to the incorrect patient — which has been said to occur in between about 0.28 and 0.17 percent of prostate cancer patients, i.e., about 2 in 1,000 (see here). By cross-checking the patient’s DNA against the DNA of the biopsy sample, the risk for this error can be completely eliminated.
Dear Bob:
According to the expert pathologists at Johns Hopkins (as I suspect you know) Gleason 3 + 3 = 6 never progresses to Gleason 3 + 4 = 7, but they have observed at least one case in which a Gleason 3 + 3 = 6 was later re-assessed and found (as you suggest) to be a Gleason 3 + 4 = 7, with only a very tiny amount of Gleason pattern 4. Thus it does appear likely that your biopsies between 2007 and the most recent biopsy had simply “missed” your original small tumor.
On the other hand, as I had also suggested in the article above, a man like you who has already been diagnosed with prostate cancer can also be found to have a “new” lesion (the one in your left mid-gland). Luckily that one seems to be benign, so you should be good on AS for quite a while yet. But you are right, “Doing AS does require surveillance”. Clearly you are not a case demonstrating spontaneous remission, although it might have looked like it for a while.
Any new research on vitamin D3 and prostate cancer? It was looking promising.
Not that I am aware of.
“Vitamin D may influence prostate cancer risk, but evidence is inconsistent.” Some say increases incidence, decreases PCSM.
https://www.nature.com/articles/s41598-020-62182-w
http://ar.iiarjournals.org/content/40/1/491.short
https://www.tandfonline.com/doi/abs/10.1080/0284186X.2020.1837391
https://journals.physiology.org/doi/abs/10.1152/ajpcell.00522.2019
https://cancerpreventionresearch.aacrjournals.org/content/13/6/521.abstract