Sunday, April 28, 2019

If you are using PSA to monitor your cancer, you may want to avoid curcumin (and some other supplements)

Curcumin (a turmeric extract) is one of the most popular natural substances subjected to pre-clinical research. Based on mouse and lab studies, it has been touted as the cure to cancer and just about everything else, with reports of activity including anti-inflammatory, anti-HIV, antibacterial, antifungal, nematocidal, antiparasitic, antimutagenic, antidiabetic, antifibrinogenic, radioprotective, wound healing, lipid lowering, antispasmodic, antioxidant, immunomodulating, anticarcinogenic, and Alzheimer’s disease, among others. This "panacea" and the low level evidence behind it are satirized in this amusing video.

It is one of the most widely researched supplements - in mouse and lab studies. In spite of its spectacular success with mice, randomized clinical trials in humans have been lacking. Choi et al. reported on a double-blinded randomized clinical trial of curcumin on 82 evaluable men who completed one treatment cycle of intermittent hormone therapy. They were then given 1440 mg/day of curcumin or a placebo for 6 months. The goal of the study was to see whether curcumin could extend their time off of hormone treatment.
  • Those taking curcumin were able to avoid hormone therapy for 16.3 months
  • Those taking the placebo were able to avoid hormone therapy for 18.5 months
  • The difference was not statistically significant
  • 10% of patients taking curcumin had PSA progression during the curcumin treatment period vs 30% of those taking the placebo.
The fact that those taking the placebo had an insignificantly longer break from hormone therapy in spite of the fact that their PSA progression was greater than those who were taking curcumin in the first 6 months, indicates that curcumin may have interfered with the PSA tests while they were taking it. Clearly, curcumin did not delay clinical progression.

Ide et al. found in a small (n=85) double-blind randomized clinical trial that a mixture of soy isoflavones and curcumin suppressed the serum PSA readings of men with high PSA (>10 ng/ml) who were confirmed by biopsy to not have prostate cancer. The curcumin mixture suppresses the PSA reading independent of prostate cancer.

Fabiani et al. reported on 50 consecutive patients with PSA over 4.0 ng/ml or PSA velocity > .75 ng/ml/year. They were given curcumin for 30 days.
  • Baseline % free PSA was 17%
  • After 30 days of curcumin, % free PSA was 20%
  • The changes in PSA and % free PSA were statistically significant
It seems that curcumin suppressed PSA. Although it is possible that 30 days of curcumin reversed the prostate cancer, that is unlikely. It is more plausible that curcumin affected the PSA assay.

This effect has been noted in the literature. The authors of this analysis and this one label curcumin as a Pan-Assay Interference Compound (PAINS), which means that it is known to interfere with assay readouts. Curcumin particularly confounds tests of molecules, like prostate specific antigen (PSA) and prostate-specific membrane antigen (PSMA), that penetrate the cell wall. According to this analysis, other common supplements that may interfere with the integrity of the cell wall without actually binding to a site on the proteins (which would be a real drug effect) include genistein (a soy isoflavone), EGCG (green tea), resveratrol (grapes),  and capsaicin (chili peppers).  Some of these compounds, including curcumin, are capable of forming stable metal ion complexes and should be scrupulously avoided by patients taking Ga-68-PSMA-11, Lu-177-PSMA-617, technetium bone scan, or gadolinium MRI contrast agent.

There are other supplements that may mask PSA readings without affecting progression. These include saw palmetto, pygeum, and beta-sitosterol. 5-alpha-reductase inhibitors (Proscar and Avodart) affect PSA in men with BPH and prevent the occurrence of prostate cancer. Because they affect PSA in a known way in men with BPH, we are able to correct for the PSA aberration (by doubling the PSA reading). The FDA has warned that biotin, in many multivitamin preparations, may interfere with many laboratory blood tests. Men taking statins should also be aware that it may produce artificially low PSA readings (see this link and this one). Statins, which seem to be beneficial in some observational studies but not in others, may only have an apparent benefit because of masking of PSA, as in this study and this study.

In designing future clinical trials on curcumin, like this one or this one that tests its benefit as an adjuvant therapy to active surveillance, it is important that the measured endpoint not be dependent on PSA. PSA doubling time, biochemical recurrence-free survival, and time before ADT is initiated (which is usually given as a result of increasing PSA) are artificially increased by curcumin. Only endpoints like radiographic progression-free survival and metastasis-free survival are useful. Incidentally, this is also why those endpoints must be chosen when evaluating the effectiveness of metastasis-directed therapy, which will lower PSA arising out of macroscopic metastases but may or may not slow the cancer's progression.

I spent a very short career as a chemist developing radioimmunoassays for biological substances, like PSA, that were only detected in serum in nanomolar and picomolar amounts. I can attest that even small amounts of impurities that adsorb, quench fluorescence, or react with the protein or its antibody can completely invalidate a test. Curcumin seems to do this.

The biggest problem with curcumin as a medication is its oral bioavailability, which is less than 1% and its elimination half-life, which is about a half hour in rats. It is doubtful that enough is bioavailable to have any therapeutic effect. This is true in spite of substances like piperine that aid passage through the gut wall. It is metabolized very quickly by the liver. Moreover, what is actually in a pill labeled as curcumin is highly variable, and curcumin is chemically unstable.

Many men rely on PSA to monitor prostate cancer progression. It may be misleading to use a supplement that may invalidate this important test. If there were any valid clinical studies indicating a true benefit, the corruption of a biomarker might be forgivable. But curcumin has only shown a benefit to mice so far. Patients must be wary of any supplement whose benefit is only supported by mouse/lab studies, and which only seems to affect PSA measurements. It is entirely possible to treat PSA without actually treating the cancer.

11 comments:

  1. From the Italian group:
    "PSA elevation is associated with prostate cancer and it is used in screening programs for its diagnosis."

    "Conclusions: Use of the Curcuma extract is able to lower the PSA value after a 30-day intake period. We are not able to state that the reduction of PSA after intake of this Curcuma extract may exclude a prostate cancer. We need further studies to evaluate that."

    So, Andrea Fabiani's study indicated that taking something to reduce or maintain PSA levels interferes with the true value of PSA measurements. This should be a caution for prostate cancer patients and their doctors.

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  2. Some of these compounds, including curcumin, are capable of forming stable metal ion complexes and should be scrupulously avoided by patients taking Ga-68-PSMA-11, Lu-177-PSMA-617, technetium bone scan, or gadolinium MRI contrast agent.

    Why would someone who has gadolinium in their system want to avoid a chelation agent? Aren't they looking for something to remove the gadolinium?

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    1. Gadolinium is given with MRIs for contrast-enhancement. Removing it negates its purpose.

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  3. At a PC site a question arose whether finasteride (to prevent hair loss) would suppress (mask)PSA in a man without a prostate following RP. The answer, as I recall, was that finasteride would mask PSA only in a man WITH a prostate - not without. The claim was that if PSA continued to rise in a man on finasteride who had his prostate intact - it would be a stronger indication Pca was present. Yet the commenter alluded that finasteride would not produce a masking effect on Pca progression in an RP patient without a prostate. What is your opinion on this? Thank you.

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    1. Finasteride and dutasteride (5-alpha-reductase inhibitors) prevent the conversion of testosterone into the more powerful androgen DHT. DHT is known to encourage benign prostatic hyperplasia (BPH) and male pattern baldness. So 5-αRis reduce the PSA that comes from BPH, but does nothing to reduce the PSA that comes from prostate cancer. After a prostatectomy, there is no BPH, so a 5-αRi does not have any effect on PSA. PSA from benign tissue left behind vanishes quickly as its blood supply ends. Any significant PSA (over 0.03 ng/ml) after prostatectomy comes from malignant sources that are not reduced by a 5-αRi.

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    2. Thank you for your informative response.

      The curcumin/IAD study did not indicate whether the subjects w/ Pca on hormone treatment were with or without prostates (or were a mixture).

      Are the noted supplements suspected to interfere (suppress) all PSA testing in Pca patients regardless of whether their prostates are intact or not?

      Thank you.

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  4. Great article. How long does one have to abstain from curcumin, pomegranate juice, to obtain a true reading? There is a lot of hyoe about modifued citrus pectin as a chelation agent that aids preventing metastasis. Is the same psa altering issue valid there?

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  5. They should clear your system in a couple of days. Avoid chelation agents before scans.

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  6. Can you provide a source to support that Saw Palmetto increases PSA Levels. My research shows that it doesn't. https://nccih.nih.gov/health/palmetto/ataglance.htm

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