Spontaneous remission in low-risk forms of prostate cancer

The issue of spontaneous remission of low-risk forms of prostate cancer came up yesterday during a meeting of Prostate Cancer International’s Active Surveillance Virtual Support Group (ASVSG).

Your sitemaster is aware of just one reported case of spontaneous remission in a high-risk form of prostate cancer. In the report of this case, Lee et al. describe a high-risk patient with apparent biochemical recurrence of prostate cancer after radical prostatectomy and a clear finding of a single, large, positive lymph node prior to and at the time of surgery. His PSA level immediately post-surgery was > 2.0 ng/ml and slowly climbed to 3.86 ng/ml. Because his PSA was climbing so slowly, he was given no further treatment. Then, at about 2 years post-surgery, his PSA level dropped into the undetectable range (< 0.1 ng/ml) and remained there. At 4 years post-surgery, his PSA level was 0.02 ng/ml and his serum testosterone level was within the normal range.

By contrast, it appears that spontaneous remission of low-risk prostate cancer in men on active surveillance may not be anything like as rare. The classic and very public example is that of Howard Wolinsky, who has been writing about the management of low-risk prostate cancer for several years now on the MedPage Today web site. Howard was initially diagnosed in 2010 with a very small amount of Gleason 3 + 3 = 6 disease in one of 14 biopsy cores. He has been on active surveillance ever since. In 2011, at an early follow-up evaluation, he had a positive MRI that showed two suspicious areas on his prostate. However, at a repeat, MRI-guided biopsy in early 2012, there was no sign of any cancer at all. Despite the fact that his PSA had risen to about 9 ng/ml by December 2013, when Howard had his fourth biopsy, there was still no sign of cancer on that biopsy. His PSA subsequently started to decline, and there has been no further signal indicating prostate cancer since.

But unlike the single case of spontaneous remission described above in the case of high-risk prostate cancer, Howard is far from being alone. Both Howard himself and another patient with a very comparable story were on the ASVSG call yesterday, and your sitemaster has come across  several other similar cases (although he hasn’t been counting). Perhaps he should have been.

It makes perfect sense that prior to the modern “active surveillance era” reports of cases of spontaneous remission of low-risk prostate cancer would have been non-existent. Prior to the availability of the PSA test, most such patients would never have been diagnosed at all. After the availability of the PSA test in the 1980s, and for the following 20 or so years, nearly every man who was diagnosed with low-risk prostate cancer was told he needed immediate treatment, and so there was no chance that he could have gone into spontaneous remission because his cancer had been eliminated (albeit, in many cases, unnecessarily).

However, as of today, it is beginning to seem like a really good idea for us to start carefully tracking the incidence of apparent spontaneous remission of prostate cancer in men on active surveillance. Just how many of these men are there? Is it 1 percent of all the men with very low-risk disease, like Howard? Or might it be 5 percent of all the men with low- and favorable intermediate-risk prostate cancer? We don’t currently have a clue.

What we do know is that if it is a significant and meaningful number of patients, these patients might be able to offer us greater insights into exactly why such spontaneous remissions occur, and that could be very important.

For those who are interested in reading more about spontaneous remission in cancer generally, try these two relatively recent articles by Eldridge and by Pukel. Your sitemaster is aware that spontaneous remission is an area of research interest at the National Cancer Institute, and he was under the impression that there was a small group of researchers trying to build a database of confirmable cases. However, so far he has been unable to identify that research team. One of the most widely held hypotheses is that such spontaneous remissions may occur most commonly when a patient’s immune system is stimulated by certain types of infection. This hypothesis was first proposed by the late Dr. Lloyd Old and it does correlate with other recent information about the use of immunotherapeutic approaches to cancer treatment (e.g., checkpoint inhibition and CAR-T). Dr. Old himself died of prostate cancer at the age of 78.

9 Responses

  1. All very exciting but not really central to the thrust of AS. Possibly relevant to the development of a new cure based on an infective agent I suppose (viz: phages).

    But for AS the whole point is that, by definition, treatment is deferred because the cure is worse than the disease. If the disease gets better, that equation does not change and as Howard shows, “They’ll never spontaneously stop mucking you about with needles. My next one is on Monday week.” I’d love my cancer to go away but if it just sits there and stops growing I’m not sure there’s much difference.

  2. Dear SUM:

    Twenty years ago there was a very small number of people who believed that some form of monitoring was potentially the right way to initiate management for a lot of people with low-risk prostate cancer. Everyone else was having their prostate either removed or radiated (or was a physician doing the surgery or the radiation). Those of us arguing that there was potentially “another way” were regularly vilified on line.

    Twenty years from now we might be able to show that a single injection of a relatively benign form of treatment might be able to put 90% of low-risk men into long-term remission, if we can work out what that sort of injection should be.

    The “central thrust” of AS today is monitoring patients to ensure sufficiently early treatment if treatment appears to be needed. Some of us, however, are already working on the central thrust of how to manage men with low-risk disease tomorrow — just as 20 years ago were were arguing that we were over-treating low-risk prostate cancer.

    How will we ever get to tomorrow if we only talk about what seems to be important today?

  3. Yes, sorry: should not overweight the AS element. It is a fact that all of this is observed in patients on AS due to the obvious sample bias and there is nothing we can do about that. Obviously I appreciate the broader applications.

  4. Dear SUM: You are duly forgiven! :O)

  5. It is not that rare. In this study they report:

    “A remarkable observation was the fact that 35% of patients undergoing surveillance experienced spontaneous PSA declines without receiving any therapy (Figs 4A and 4B).”

  6. Dear George:

    Please understand that there is a huge difference between “spontaneous” decreases in a man’s PSA level while he is on AS and the actual disappearance of any signs of the tumor after multiple MRIs and biopsies (true spontaneous remission of cancer).

    Also … The study you provided a link to had nothing to do with low-risk men on AS. This was a study in high-risk men who had oligometastatic prostate cancer after first-line treatment, and the study was looking at when such men should be started on some form of metastasis-directed therapy (MDT). That is a very different group of patients, and absolutely none of them had spontaneous remission of their cancer.

  7. I’ve been doing some research on prostate cancer gene therapy. One of the genes that has garnered some attention is TP53 or tumor protein p53 (or p53). This protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing (proliferating) too fast or in an uncontrolled way.

    This led me to do some research to determine if there is any research on “prostate cancer elite suppressors”. The term “elite suppressor” is normally used in the context of HIV-positive patients who are able to reduce HIV or eliminate it completely. It has something to do with the fact that they have “super” T cells that hunt down and eradicate HIV.

    So, I’m wondering if there is any prostate cancer research that is looking for patients that may present as “prostate cancer elite suppressors” who turn TP53 genes into super TP53 genes. They would then be able to keep prostate cancer under check or eradicate it.

    I only bring this up because synthesizing an existing super TP53 gene from a “prostate cancer elite suppressors” would be a promising way to jump start gene therapy for prostate cancer patients.

    So has anyone heard of any research in this area?

  8. Dear Carl:

    I am certainly not aware of any such research.

    I would bring to your attention that the way that the immune system works in the management of infectious disorders like HIV is very different to the way it works in cancer. In cancer the cancer itself is able to naturally suppress the immune system as a way to allow the cancer to develop and spread (which is why we are seeing the enormous interest in the checkpoint inhibitors like Opdivo and Keytruda to reverse that process). Interestingly, to date, there are very limited data to suggest that these drugs will have beneficial effects in the treatment of prostate cancer.

    So, while your hypothesis is certainly not impossible, I have my doubts about whether it is relevant to prostate cancer (but I am more than willing to be proven wrong).

  9. Here’s a report on interesting case of advanced prostate cancer that went into spontaneous regression:

    Case: Spontaneous regression of post-radical prostatectomy prostate-specific antigen elevation without adjuvant therapy in a patient with lymph node metastasis

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