"" Ralph Moss—Cancer Consultant: 2016-09-11

Sunday, September 11, 2016

DOES INSULIN POTENTIATED THERAPY WORK?


“Insulin potentiation therapy” (IPT) is a very popular form of cancer treatment. Also called insulin-potentiated targeted low-dose (IPTLD) therapy, it is very attractive to patients, since it promises to attain the beneficial effects of full-strength chemotherapy, but with virtually no toxicity. The efficacy of the chemotherapy is allegedly greatly enhanced by co-administration of the hormone insulin. The dose of “chemo” given in IPT is typically in the 10 to 15 percent of normal range, sometimes with shorter-than-normal intervals between treatments.

According to proponents:

“Insulin is truly a ‘magic bullet’ cancer treatment, meaning it allows chemotherapy to target cancer cells and results in far less side-effects.” (http://www.cancertutor.com/ipt/)
The administration of insulin will lower blood sugar. Depending on the dose, this will put some people at risk of hypoglycemia. In the worst case scenario, this cut cause insulin shock, in which case the patient becomes unconscious due to a too low blood sugar level. You may think this is unlikely to happen, but in 2000 I actually saw patients being put into insulin shock at a Tijuana cancer clinic. Thankfully, within days the Mexican health authorities permanently shut down that clinic. 

All sorts of claims are made for the efficacy of IPT or IPTLD, but where is the proof? I was on the NIH panel (the Cancer Advisory Panel on Complementary and Alternative Therapies, or CAPCAM) to which the proponents of IPT submitted some of their best cases on September 18, 2000. In my opinion, the presentation was a failure, since they did not present a single case in which a remission from cancer could reasonably be ascribed to IPT. At the time I pointed out that I, and the other members of the panel, had every reason to want them to give a successful presentation, but that they had failed to do so. 

According to the theory, insulin makes cancer cells responsive to small doses of chemotherapy because of the presence of insulin-like receptors on the cells. This does not necessarily follow. In general, the presence of elevated insulin levels in the body is not a good thing. Insulin levels, for instance, are generally elevated in cases of type 2 diabetes and pre-diabetes. Yet diabetes and pre-diabetes correlate with an increased risk of cancer, probably because cancer cells thrive in a high-glucose environment. If you are unaware of this connection, let me quote from “The Diabetes-Cancer Connection,” from the American Institute for Cancer Research (AICR):

“A growing body of evidence is finding that having diabetes or signs of insulin resistance may lead to an increased risk of certain cancers. The connection is strongest among certain types of cancers, including kidney, pancreatic and colorectal.

“The trend emerging [in this area] is that the type 2 diabetes associated with high insulin levels is the biggest problem relating to cancer risk,” said Michael Pollak, M.D., a professor at the Department of Oncology and Director of the Cancer Prevention Research Unit at McGill University. But it’s not just type 2 diabetes, he added, this link is evident for everyone with pre-diabetes, which is a much larger group.”
(http://preventcancer.aicr.org/site/News2?page=NewsArticle&id=13631&news_iv_ctrl=0&abbr=res_)

It is true (as proponents say) that cancer cells frequently have insulin-like growth factor 1 (IGF-1) receptors on their cell surfaces. But why would one assume that it is a good thing to stimulate these receptors? Again to quote the AICR article:

“High levels of insulin, independent of body fat, are linked to increased production of insulin-like growth factor 1 (IGF-1). And IGF-1, which shares a similar structure to insulin, plays a key role in cell growth, proliferation and inhibiting apoptosis” [none of which are good things!]

There are scientific studies on the effects of “exogenous” insulin (that is, insulin injected to control the patient’s hyperglycemia) and insulin-like drugs (analogs) on cancer. None of this is good for the IPT argument:

  • Studies have shown an increase in cancer-related mortality in patients with type 2 diabetes (T2D) treated with insulin. Bowker concluded: “Patients with type 2 diabetes exposed to…exogenous insulin had a significantly increased risk of cancer-related mortality….”
    (Bowker SL, Majumdar SR, Veugelers P & Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 2006;29 254–258)
  • Currie reported that patients treated with insulin had an increased risk of colorectal and pancreatic cancers compared with patients treated with metformin.
    (Currie CJ, Poole CD & Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52 1766–1777; Yang Y-X, Hennessy S, Lewis JD. Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology 2004;127:1044–1050)
  • A German study showed increased cancer risk in patients treated with insulin analogs. There was a a dose-dependent increase in cancer risk in patients treated with the insulin analog, glargine, compared with human insulin.
    (Hemkens LG, Grouven U, Bender R, Gunster C, Gutschmidt S, Selke GW & Sawicki PT. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 2009;52 1732–1744)
  • There was a positive association with breast cancer incidence in Swedish women using the insulin analog glargine.
    (Jonasson JM, Ljung R, Talback M, Haglund B, Gudbjornsdottir S & Steineck G. Insulin glargine use and short-term incidence of malignancies – a population-based follow-up study in Sweden. Diabetologia 2009;52 1745–1754; Others have disputed that there is a greater risk with glargine than with human insulin.)
This hardly covers the full extent of the evidence of an increased risk of cancer associated with the use of insulin and insulin-like factors. Why then would one suppose that insulin administered alongside chemotherapy would exert a beneficial effect on cancer?

WHERE IS THE EVIDENCE?

If we take insulin out of the equation, what evidence is there that giving, say, 15 mg of the drug cisplatin will be as effective as 150 mg? 

Leaving aside all theoretical considerations, what clinical data exists to support the safety and efficacy of IPT? If we put the phrase “insulin potentiation therapy” into the PubMed index of 26 million medical journal articles, we come up with four ‘hits.’ 

The first of these was a theoretical article in the journal Medical Hypotheses, dated June 1986, in which the late Steven G. Ayre, MD, the late Donato Perez Garcia y Bellon, and Dr. Donato Perez Garcia, Jr. put forward the concepts of IPT. Over the intervening 30 years this article has only been cited once—by the Damyanov article below.
(Ayre SG, Perez Garcia y Bellon D, Perez Garcia D Jr. Insulin potentiation therapy: a new concept in the management of chronic degenerative disease.   Med Hypotheses. 1986 Jun;20(2):199-210)

A second study, of a bladder leiomyoma from Turkey, contains a passing mention of IPT, but then says nothing further about it.
(Goktug, Goksel Hasan, Ufuk Ozturk, Nevzat Can Sener, Can Tuygun, Hasan Bakirtas, and Abdurrahim Muhammet Imamoglu. “Transurethral Resection of a Bladder Leiomyoma: A Case Report.” Canadian Urological Association Journal = Journal De l’Association Des Urologues Du Canada 8, no. 1–2 (February 2014): E111-113)

There is an article on IPT from Christo Damyanov, MD, of the “Medical Center ‘Integrative Medicine,’” on Deliiska Vodenitza Street, Sofia, Bulgaria. Dr. Damyanov appears to be a urologist affiliated with the University of Sophia, who has been practicing IPT since 2006. His medical center is otherwise unknown to me. This study involved a total of 16 patients with advanced,  “castration-resistant,” prostate cancer. However, this paper only compares two different low-dose chemotherapy regimens. There were objective responses in about one-third of patients, and some improvement in quality of life, but there was no comparison of low-dose vs. normal dose treatments. Thus I cannot see how this helps solve the question of whether or not low-dose IPT chemotherapy is really effective in such situations. 
(Damyanov C, Radoslavova M, Gavrilov V. Stoeva D. Low dose chemotherapy in combination with insulin for the treatment of advanced metastatic tumors. Preliminary experience. J. BUON. 2009;14:711–715; Damyanov C, Gerasimova D, Maslev I, Gavrilov V. Low-dose chemotherapy with insulin (insulin potentiation therapy) in combination with hormone therapy for treatment of castration-resistant prostate cancer. ISRN Urol. 2012;2012:140182; see also: See http://www.whatclinic.com/doctors/bulgaria/sofia/medical-center-for-integrative-medicine)

The most recent of these articles is a description of the practice of James Forsythe, MD, but contains no abstract and does not even provide a contact email for the doctor. The article has yet to be cited by a single other study.
(Forsythe J, Gustafson C. James Forsythe, MD, HMD: the success of integrative cancer therapy based on chemosensitivity testing and insulin potentiation therapy. Altern Ther Health Med. 2015 Mar-Apr;21(2):54-9)

There is also a single trial listed at clinicaltrials.gov of IPT that was initiated in 2015 by the Best Answer for Cancer Foundation. It is scheduled to run until 2020. The title of the trial is self-explanatory:

“A Quality of Life Study Using Insulin Potentiation Targeted LowDose (IPTLD) Chemotherapy and Nutrition Therapy in the Treatment of Cancer (IPTLDAZCAM).”

The Best Answer for Cancer Foundation (whose founding director is Ms. Annie Brandt), has expanded their focus beyond IPT or IPTLD, but still promotes this treatment concept at their website. Their slogan is “IPTLD: Targeting the Cancer Cells… Not the Patient!™”

Their website contains some statements about the action of IPT that I do not find to be supported by any of scientific articles on the topic:

“IPTLD, however, penetrates easily through the cell membrane because it goes in hand-in-hand with sugar (glucose). Cancer cells, unlike healthy cells, need lots of glucose for fuel. Without it, they die. The membrane of a cancer cell is designed to take in a lot more glucose than healthy cells. In medical parlance we say cancer cells are equipped with many more insulin receptors. So, what if we pair a small dose of chemo drugs with the glucose? Yes, the cancer cell takes in the chemotherapy drugs in its effort to get at the sugar. Using insulin allows us to differentiate the cancer cells from the normal cells. This is a significant advantage.”

This is a simplification of the relationship of insulin and glucose to cancer. It is true that cancer cells in general consume much more glucose than normal cells. That is because they utilize fermentation for much of their energy needs. But cancer cells also generally retain about 40 to 50 percent of their mitochondria and of their normal energy-generating capacity, per a lifetime of scientific work of Peter L. Pedersen, PhD, of Johns Hopkins Medical Institution, Baltimore, and many others. 

Thus when cancer cells are deprived of the excessive amount of glucose that “aerobic glycolysis” (fermentation even in the presence of oxygen) requires, they do not die, but become more dormant. Incidentally, healthy cells also need glucose to generate energy, although they use it more efficiently than most cancer cells (per the citric acid, or Krebs, cycle). But what evidence is there that when one co-administers insulin with chemotherapy one is “pairing” the drug with glucose, or that “the cancer cell takes in the chemotherapy drugs in its effort to get at the sugar”? (One wonders why you need insulin to allegedly do that? Why not just co-administer glucose?)

IPT and IPTLD are interesting ideas, but I am unaware of any experimental evidence that co-administering insulin makes chemotherapy so much more effective that it can be given at 10 to 15 percent of the normal dose. 

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