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Post by Allen on Jul 29, 2014 20:35:34 GMT -8
Metformin
The anti-diabetic drug metformin may have an anti-PC effect. It is believed to act on AMPK, a substance that decreases insulin levels that might encourage cancer feeding and castrate resistance. It may inhibit the mTOR cancer growth pathway as well (see thread below). It may work synergistically with bicalutamide and with statins. It may preferentially kill cancer stem cells and radiosensitizes cancer cells. There is a randomized clinical trial comparing metformin+Lupron to Lupron alone ( NCT01620593). Results of studies so far have been equivocal. Metformin effective• A study of health records at the Mayo Clinic was published this week. It found that PC mortality was reduced by 61% among diabetics who took metformin vs insulin, by 45% vs those taking other diabetic meds, and by 31% compared to non-diabetics. Validating drug repurposing signals using electronic health records: a case study of metformin associated with reduced cancer mortality• In 2901 consecutive patients at MSK, metformin reduced the 10-yr PC mortality by 88% compared to diabetics taking other drugs, and by 67% vs non-diabetics, with significant decreases in other signs of PC progression. There was a 15-fold decrease in castrate resistance among metformin users vs diabetics who took other drugs. Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality.• Among 3,857 older, diabetic men, metformin use was associated with a 34% reduction in PC mortality for every 6 months of use. Metformin Use and All-Cause and Prostate Cancer–Specific Mortality Among Men With DiabetesMetformin ineffectiveSeveral studies have failed to show any survival benefit for prostate cancer: The use of metformin in patients with prostate cancer and the risk of death.Association of diabetes mellitus and metformin use with biochemical recurrence in patients treated with radical prostatectomy for prostate cancerMortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival.Association Between Metformin Use and Risk of Prostate Cancer and Its GradeMetformin does not affect risk of biochemical recurrence following radical prostatectomy: results from the SEARCH database.Effect of metformin on prostate cancer outcomes after radical prostatectomy.Metformin Does Not Affect Cancer RiskSafety
Whatever its efficacy may turn out to be, at least metformin is a relatively safe drug for both diabetics and non-diabetics when taken moderately.
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Post by lupronjim on Aug 1, 2014 10:57:17 GMT -8
Thanks for starting the thread Allen.
Your timing is good since my wife who was pre-diabetic and taking Metformin, was recently put on a blood thinner that means she can no longer take the Metformin. So I have a supply on hand.
So I will have the discussion with Dr Jeffrey Turner, but not until I qualify for Provenge with two consecutive increasing PSA's.
You are very familiar with my case since you have been my mentor with Dr Chris King and very high dose SBRT. Will include some background for others ...
My PSA test yesterday where I was trying to show an increase from <0.04 was inconclusive @ =0.03 but established a more quantitative baseline 0.03. Dr Turner suggested I may want to try another assay to see if it comes out >=0.04 rather than waiting 2 more weeks and then another 2 weeks for presumably second PSA increase, thus further delaying my radiation to prostate, prostate bed, and pelvic girdle.
So while the Metformin may be beneficial, I will keep it on hold as I am doing with the Zytiga until I qualify for Provenge to leverage the so-called abscopal effect during SBRT.
If the timing works out rightly, I will have the first week of SBRT Mon-Wed-Fri the week before the big PCRI conference at LAX Marriott first week of Sept and the second Mon-Wed (or Tue-Thur due to Labor Day holiday) the week after PCRI and stay in LA for the PCRI conference. I already paid the $60 to get the lower rate.
The placement of fiducials and CT scan needed to do the detailed planning for optimal dosage by Dr King would then be two weeks before the PCRI conference.
LupronJim
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Post by Josh Denny on Aug 15, 2014 19:25:55 GMT -8
I was asked to reply as one of the authors of one of the studies above (the Mayo and Vanderbilt study, in which we saw that metformin reduced cancer rates for many types of cancer compared to other diabetic medications and when compared to non-diabetics). The post above is an excellent summary. You will notice that most of the studies performed so far use retrospective reviews, and they define cancer patients, diabetes, and exposures to metformin in different ways. Also, they have different study sizes, and some of the studies that don't show a benefit may be underpowered to show an effect.
As a general internist (not an oncologist), my take on the field is that if you have diabetes and cancer, one should consider with their doctor if metformin makes sense as part of a antidiabetic regimen. I am not aware of solid data to suggest to use of metformin for non-diabetics, since metformin can itself cause risk because it lowers your blood sugar, which certainly can be harmful.
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Post by Tony Crispino on Aug 15, 2014 19:52:32 GMT -8
Dr. Denny, Thank you so kindly for coming to us and replying. Allen is a terrific patient advocate who just continues to amaze me with his efforts. I started this website with the support of my SWOG colleagues to try to help bridge the researchers and physicians with the patients and patient advocates. You are most welcome.
We are seeing a lot of discussion online about the use of Metformin in the prostate cancer arena. A friend of mine at Mount Sinai, Dr. Matt Galsky, has been working on a trial for prostate cancer with Metformin that I think is very much needed to help define it's role for patients with or without diabetes and have prostate cancer. Dr. Snuffy Myers in Virginia, a well known specialist in prostate cancer, has in his own vision suggested that Metformin can play an important role in controlling prostate cancer progression for patients with or without diabetes.
Again, thank you for this very valuable input.
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Post by Allen on Aug 16, 2014 9:44:01 GMT -8
Dr. Denny, Thanks for your reply, and for the study you did. I think you are on the forefront of two important new trends in medicine. Drug repurposing has the potential to vastly change the trajectory of health care costs. With new drugs costing upwards of $2B for development and testing, and a very lengthy approval process, it pays to look at what we already have in our armamentarium. Last month, the 3rd Annual Drug Repositioning, Repurposing, and Rescue Conference was held in Boston. Patient advocates on this site may notice that one of the stated themes this year was "Emphasis on and engagement with patient advocacy groups, who are investing in drug repositioning efforts to an unprecedented degree." The other interesting trend you evidenced is the rising use of electronic health record data mining. Because the government has provided incentives, establishing standards for this, and setting universal requirements for it over time, this has the potential to vastly increase our medical knowledge. However, Big Data is useless without the pioneering efforts of researchers like you who are able to extract meaningful information from it.
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Post by Tony Crispino on Aug 21, 2014 15:21:17 GMT -8
Allen, do you have any questions to frame on this one? I think after reading it, we have what we knew we have, a need for trials to be completed.
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Post by Allen on Aug 21, 2014 18:51:03 GMT -8
Tony, my question for clinicians is whether they are using them in their practice off label, and what kind of results they are seeing; e.g., a slowing in PSADT or other measure of progression. I know, for example, that Dr. Scholz is prescribing metformin (and several others) off label for non-diabetic men. The point of repurposing is that we don't have to wait for clinical trials. With some drugs, like metformin, statins, and Celebrex, for example, the risk is low and manageable, so clinicians are already using them.
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Post by Tony Crispino on Aug 21, 2014 21:47:11 GMT -8
That's an interesting poll. And from a clinical researcher probably very few would generously be prescribing drugs off label except in trials. My concerns about metformin are the contradictions and adverse effects. Additionally compliance issues are common. Wiki on MetforminThe three retrospective looks that propose a positive roll for metformin and cancer in your post are all retrospective with interesting inclusion criteria. Just pennies... The first one, Xu et al, is not prostate cancer specific. In the conclusion Xu states that "This study serves as a model for robust and inexpensive validation studies for drug repurposing signals using EHR data." A reasonable conclusion but defining this conclusion in a prostate cancer specific study would clearly be more than inexpensive and seeing that this drug is off patent and therefore would require a funding from a major public institution or the NCI which has been cut in cancer research dollars by 25% this next year. But some trials have been started...
The second one, Spratt et al, is straight forward in suggesting that "The retrospective study design was the primary limitation of the study." however the conclusion gives us further validation that more research is needed. And finally the third study, Margel et al, has more interesting features but the also linked Penney & Stampfer paper (which says Margel et al shows a 24% reduction for every 6 months), brings up some interesting points: Were these diabetes patients, which are more prone to heart disease, [and] on other drugs like statins and such? What were the risk stratifications of these patients in the study (Gleason Grade and stage for example)? Still the call for clinically trials is reasonable. Until such time, prescribing metformin, which has it's share of co-morbidity, is educated opinion and not much more than that. So to Scholz, and Myers prescribing it I would ask a question: for which patients? Advanced? A G6 on AS? A man treated with low risk and has already been treat successfully? It would seem the latter would be unnecessary. Especially given the 53% of men that experience gastrointestinal disorder on metformin. Should I keep my pennies on my pocket?
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Post by Allen on Aug 22, 2014 9:17:28 GMT -8
I don't know that your guess that very few are prescribing it outside of trials is true. In fact, based on anecdotal evidence from my support groups, it seems to be widely prescribed.
The Xu study actually did look at prostate cancer specifically and breaks out the data separately for that subgroup. The large mortality reduction I showed here was for prostate cancer patients. Their call is for validation studies using electronic health record data at other institutions (They looked at Vanderbilt and Mayo). This kind of research is at the forefront of investigation because of the new Federal laws being phased in and already in place in many large institutions, and the comparatively low cost of such studies compared to RCTs. The use of Big Data will become increasingly important to medicine.
I titled these threads "for advanced PC" because that is the group most interested in such adjuvant therapies, and the evidence I gave has relevance to them. I know that Scholz gives it to high risk patients. I assume Myers does as well, since he prescribes drugs with much inferior safety records to his patients. Compliance would not be much of an issue for this group, as the GI SEs are manageable.
If there were prospective data from randomized clinical trials there would be no need to prescribe any of these drugs off label - for some, the manufacturer could extend his patent by applying for and getting FDA approval to market them for the new use. For the drugs that are already generic, there is, as you say, no incentive to finance clinical trials, and with NIH cutbacks, they will rarely get financing. The point of these posts is that these drugs are or may be used legally off label, (1) now, without waiting, and (2)without adding the enormous cost (or the convincing data) of a long term RCT. For advanced cancer patients, metformin offers enormous potential benefit with very little risk.
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Post by houseboy on Aug 23, 2014 12:40:02 GMT -8
Hi:
Just started Metformin under Dr. Myers after agreement with Sunnybrook Hospital in Toronto. Query though, Dr. Myers prescribes one 500 mg tablet daily (time release)for first month, then two for next month, then four a day - all with meals. A friend I know was prescribed just one daily. Does it vary according to the individual' condition? Anyone having SEs, and if so, at what dosage?
Houseboy
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Post by tarhoosier on Aug 24, 2014 6:39:08 GMT -8
My experience with Metformin is that 1000mg twice a day caused gastric distress. Hard to separate from other OTC used but seemed to be Met. I cut to 500, 2xday and after 2-3 weeks of improvement then went to 1000mg, 2xday. I think his gradual dosage is for this reason.
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