Description
Insulin potentiation therapy (IPT) is a treatment regimen using insulin as an adjunct to conventional chemotherapy. It is claimed that insulin potentiates the effects of chemotherapy, which would enable a 75-90% reduction of the usual and customary doses of anticancer drugs thus reducing the risk of their adverse effects.
Although some hypotheses have been put forward, the mechanisms of the claimed insulin potentiation of chemotherapy remain unclear and the few published in vitro studies do not help to clarify this.
Efficacy
Clinical evidence is scarce, with only two small clinical trials and four cases published in peer-reviewed journals. Although they reported encouraging preliminary results on tumour growth, effects on patient survival or long-term effects have not been evaluated.
Safety
IPT is associated with risks such as hypoglycaemia, and the reduced anticancer effects of lower doses of chemotherapeutic drugs potentially leading to drug resistance. IPT might even promote tumour growth.Overall, due to a lack of information published in peer-reviewed journals, it is impossible to judge the efficacy and safety of IPT.
Citation
Wider B, CAM Cancer Consortium. Insulin potentiation therapy [online document], Sept 30, 2020.
Document history
Assessed as up to date in September 2020 and January 2019 by Barbara Wider. Summary first published in 2017, authored by Luc Geeraert. Next update due: September 2023
Scientific name(s)/brand name(s)/common name(s)/ingredient(s)
In IPT, insulin is used as an adjunct to conventional chemotherapy. It is claimed that insulin potentiates the effects of chemotherapy, enabling the use of lower doses of the latter1.
Insulin is a peptide hormone used as a conventional therapy for diabetes. Several medical preparations of insulin are available and sold under different brand names. Historically insulin was derived from animal sources (e.g., pig, cattle), although nowadays mainly human insulin (or very close analogues) manufactured by recombinant DNA technology is used2.
Application and dosage
Insulin is usually given subcutaneously, seldom intravenously, either by injections or by an insulin pump2.
In IPT, chemotherapeutic drugs are administered as in standard anticancer therapy, although at lower concentrations3.
In the only two IPT clinical trials published in a peer-reviewed journal4,5 cancer patients were given 0.3 to 0.4 units intravenous insulin per kg body weight followed by chemotherapy at lower doses than usual, starting 20 minutes after insulin administration or sooner if symptoms of hypoglycaemia were observed.
History/provider(s)
Insulin was first isolated by the Romanian scientist Nicolae Paulescu in 19216, the first successful application of insulin in the treatment of a diabetic patient was performed by the Canadian scientists McLeod, Banting, Best, and Collip in 19227.
IPT was developed by the Mexican medical doctor Donato Perez Garcia in the 1930s, originally for the treatment of syphilis1. Later on, he used IPT in the treatment of other diseases including arthritis, asthma, and colitis. Since 1947, Perez has also treated cancer patients with IPT, claiming positive results. However, as no clear scientific basis was provided for IPT and clinical trials were not reported in peer-reviewed journals, the therapy remained controversial.
Claims of efficacy/Mechanism(s) of action/Alleged indications
Insulin is a hormone that plays a pivotal role in regulating energy balances and the metabolism of glucose in the body2,8. When blood glucose levels are increased (e.g., after a meal), insulin is secreted by the pancreas. Most body cells possess insulin receptors; they capture this insulin signal and start to absorb glucose from the blood stream, lowering the blood glucose levels again. Uptake of glucose in liver, muscle and fat tissue is governed by insulin as well. Additionally, insulin plays a role in the stimulation of cell growth9,10.
It is claimed that insulin potentiates the effects of chemotherapy, enabling the use of lower doses of the latter1. Two hypothetic mechanisms for the potentiation of chemotherapy by insulin have been proposed3. On the one hand, insulin has been suggested to increase the permeability of the cell membrane for cytotoxic drugs, resulting in higher intracellular drug concentrations. On the other hand, influence of insulin on cell cycle kinetics has been proposed to play a part. In the latter hypothesis, insulin would increase the S-phase fraction of tumour cells, i.e., increase the number of cells with active DNA replication, hence making the tumour more vulnerable for the action of cytotoxic drugs, in particular cell-cycle-phase-specific agents. Moreover, IPT would differentiate between cancerous and normal cells based on the higher levels of insulin receptors on cancerous cells. Overall, it is claimed that drug potentiation by insulin enables a 75-90% reduction of the usual and customary doses of anticancer drugs, reducing the risk for their adverse-effects.
Prevalence of use / Legal issues
IPT is not endorsed by mainstream oncologists. It is usually provided by IPT clinics, making off-label use of approved drugs.
IPT inventor Perez and his successors claimed that several cancer patients were successfully treated with IPT1,3, though case reports or clinical trials to substantiate these claims have never been published in peer-reviewed journals.
More recently, two small clinical studies and four cases have been published in peer-reviewed journals.
Clinical trials
In a small uncontrolled study4, 16 patients with castration-resistant tumours were treated with insulin (0.4 units per kg body weight at 5-day intervals) in combination with goserelin depot (3.6 mg) and low-dose chemotherapy, i.e., eight patients with: cyclophosphamide (0.10–0.15 g/m2) + epirubicin (3 mg/m2) + vinblastine (0.5 mg/m2), and eight patients with docetaxel (3.6 mg/m2). Overall prostate-specific antigen (PSA) results after the sixth course of IPT showed partial effect in eight patients, stabilization in four patients, and disease progression in four patients; the median survival for all treated patients was 11.7 months. During the treatment no significant side effects were observed, and no lethal cases occurred.
In a small prospective, controlled, randomized clinical trial5, IPT was tested in 30 women suffering from metastatic breast cancer resistant to 5-fluorouracil + doxorubicin + cyclophosphamide and to hormone therapy with measurable lesions4. Patients were divided in three groups of ten: a group receiving only the anticancer drug methotrexate (2.5 mg/m2 every other day), a group receiving only insulin (0.3 units per kg body weight every other day), and a group receiving a combination of both. Drugs were given in two 3-week courses with a 1-week interval in-between. After 8 weeks, the sizes of the target tumours were measured and compared to the respective sizes before treatment. Progressive disease was less frequently observed in the group treated with the combination of methotrexate and insulin, and in this group the median increase in tumour size was found to be significantly lower than in the groups where drugs were used separately. Quality of life, patient survival, or lasting effects were not evaluated.
Case studies
Three cases of IPT in patients with advanced metastatic cancer and failure of preceding standard conventional treatment have been described: two women with breast cancer, and one man with prostate cancer13. The initial 4 to 6 IPT courses (insulin + patient-specific chemotherapy) were repeated weekly after which a maintenance schedule at several-week intervals was started. The treatment was well tolerated. Laboratory examinations showed no significant toxicity. Remission was achieved for 15 months (after which the patient was lost to follow up), and 21 and 8 months (publication time of results).
In another case study, a woman with breast cancer was treated with IPT14. Treatment (insulin + chemotherapy) was repeated twice-weekly for 3 weeks, and then weekly for 5 weeks. After 8 weeks, the breast mass was no longer palpable, and no evidence of tumour was found on a xeromammogram at 3 months.
Pre-clinical trials
Tumour-bearing rats were found to have a significantly more reduced tumour size after treatment with doxorubicin (one single dose) and insulin (once-daily, starting 1 day after doxorubicin administration) than after being treated with doxorubicin alone15. Insulin also led to a marked improvement in food intake and host weight.
In several human cancer cell lines, insulin enhanced the cytotoxic effect of chemotherapeutics16-19. Testing a broad range of human tumours20, insulin increased significantly the colony formation in about half of the tested tumour cells, but only little difference in the sensitivity to cytotoxic agents was observed.
Adverse events
The main risk of insulin administration is hypoglycaemia or low blood glucose levels. In a small prospective, randomized clinical trial of IPT5, toxicities recorded with methothrexate alone, at a lower dose (2.5 mg/m2) than the conventional one, were considered non-relevant (WHO grades 1 or 2). Toxicities in the methotrexate/insulin treated group (IPT) were even lower (only WHO grade 1).
Contraindications
The use of certain types of insulin is contraindicated in people having allergic reactions to them21. IPT during pregnancy may harm the foetus.
Interactions
Low blood sugar caused by IPT may have more severe effects in diabetics treated with pills to lower the blood sugar21. Beta-blockers can mask the symptoms of low blood sugar, making it harder to detect low blood sugar before dangerously low levels are being reached. Sulfa antibiotics and excessive amounts of alcohol can make the blood sugar levels go even lower.
Warnings
The use of chemotherapeutic drugs at only 10%-25% of the recommended dose is a concern21. There is no evidence that such low doses of chemotherapy in combination with insulin can produce the same anticancer effect as the recommended doses. Moreover, the use of lower doses of chemotherapeutic drugs may promote drug resistance.
It is important to note that insulin may actually promote tumour growth22,23. Multiple and complex mechanisms are potentially responsible for this tumour growth promoting effect. Most cancer cells express receptors for insulin and the insulin-like growth factor (IGF), via which insulin can directly stimulate cell division, proliferation, and metastasis. Apart from this direct effect, insulin increases the levels of circulating IGF-I, which has more potent effects on promotion of cell division and against apoptosis than insulin itself. It is still unclear how these effects translate into the clinic, but in some cancers (e.g., breast and colon cancer) data indicating a possible link between high insulin levels and poor outcomes in cancer are accumulating24,25.
- 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. Accessed 8th of September 2020.
- Joshi SR, Parikh RM, Das AK. Insulin--history, biochemistry, physiology and pharmacology. J. Assoc. Physicians India. 2007 Jul;55 Suppl:19-25. Accessed 8th of September 2020.
- Ayre SG, Garcia y Bellon DP, Garcia DP Jr. Insulin, chemotherapy, and the mechanisms of malignancy: the design and the demise of cancer. Med. Hypotheses. 2000 Oct;55(4):330-334. Accessed 8th of September 2020.
- 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. Accessed 8th of September 2020.
- Lasalvia-Prisco E, Cucchi S, Vázquez J, Lasalvia-Galante E, Golomar W, Gordon W. Insulin-induced enhancement of antitumoral response to methotrexate in breast cancer patients. Accessed 8th of September 2020.Cancer Chemother. Pharmacol. 2004 Mar;53(3):220-224.
- Murray I. Paulesco and the isolation of insulin. J. Hist. Med. Allied Sci. 1971 Apr;26(2):150-157. Accessed 8th of September 2020.
- Bliss M. The history of insulin. Diabetes Care. 1993 Dec;16 Suppl 3:4-7. Accessed 8th of September 2020.
- De Meyts P. Insulin and its receptor: structure, function and evolution. Bioessays. 2004 Dec;26(12):1351-1362. Accessed 8th of September 2020.
- Sandow J. Growth effects of insulin and insulin analogues. Arch. Physiol. Biochem. 2009 May;115(2):72-85. Accessed 8th of September 2020.
- Straus DS. Growth-stimulatory actions of insulin in vitro and in vivo. Endocr. Rev. 1984 Spring;5(2):356-369. Accessed 8th of September 2020.
- Arizona Center for Advanced Medicine. Frequently Asked Questions About IPTLD. Available online. Accessed 8th of September 2020.
- Baratz R, Why you should stay away from insulin potentiation therapy. Quackwatch.org. August 2013. Available online. Accessed 8th of September 2020.
- 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(4):711–715. Accessed 8th of September 2020.
- Ayre SG, Perez Garcia y Bellon D, Perez Garcia D Jr. Neoadjuvant low-dose chemotherapy with insulin in breast carcinomas. Eur. J. Cancer. 1990;26(11-12):1262-1263. Accessed 8th of September 2020.
- Peacock JL, Gorschboth CM, Norton JA. Impact of insulin on doxorubicin-induced rat host toxicity and tumor regression. Cancer Res. 1987 Aug 15;47(16):4318-4322. Accessed 8th of September 2020.
- Oster JB, Creasey WA. Enhancement of cellular uptake of ellipticine by insulin preincubation. Eur. J. Cancer Clin. Oncol. 1981 Oct;17(10):1097-1103. Accessed 8th of September 2020.
- Alabaster O, Vonderhaar BK, Shafie SM. Metabolic modification by insulin enhances methotrexate cytotoxicity in MCF-7 human breast cancer cells. Eur. J. Cancer Clin. Oncol. 1981 Nov;17(11):1223-228. Accessed 8th of September 2020.
- Jiao SC, Huang J, Sun Y, Lu SX. [The effect of insulin on chemotherapeutic drug sensitivity in human esophageal and lung cancer cells]. [Article in Chinese]. Zhonghua Yi Xue Za Zhi. 2003 Feb 10;83(3):195-197.
- Zou K, Ju JH, Xie H. Pretreatment with insulin enhances anticancer functions of 5-fluorouracil in human esophageal and colonic cancer cells. Acta Pharmacol. Sin. 2007 May;28(5):721-730. Accessed 8th of September 2020.
- Kern DH, Chien FW, Morton DL. Selective effects of insulin and hydrocortisone on colony formation and chemosensitivity of human tumors in soft agar. Int. J. Cancer. 1984 Jun 15;33(6):807-812. Accessed 8th of September 2020.
- Memorial Sloan Kettering Cancer Center. Insulin Potentiation Therapy. Available online. Accessed 8th of September 2020.
- Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus report. CA Cancer J. Clin. 2010 July-August;60(4):207-221. Accessed 8th of September 2020.
- Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. Diabetes and cancer. Endocr. Relat. Cancer. 2009 December;16(4):1103-1123. Accessed 8th of September 2020.
- Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madarnas Y, Hartwick W, Hoffman B, Hood N. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J. Clin. Oncol. 2002 January 1;20(1):42-51. Accessed 8th of September 2020.
- Wolpin BM, Meyerhardt JA, Chan AT, Ng K, Chan JA, Wu K, Pollak MN, Giovannucci EL, Fuchs CS. Insulin, the insulin-like growth factor axis, and mortality in patients with nonmetastatic colorectal cancer. J. Clin. Oncol. 2009 Jan 10;27(2):176-185. Accessed 8th of September 2020.
