In early July, both the FDA(1) and Health Canada(2) released statements concerning Lantus (insulin glargine), the latest long-acting insulin analogue injection made by Sanofi-Aventis. These regulatory bodies are both initiating an ongoing safety review on this product in light of recent evidence related to a possible increased risk of cancer in human. ﾠThey are also reviewing all available evidence, recent and older, concerning Lantus insulin and it’s potential cancer risk.

Insulin is a medication that is essential in diabetes management. ﾠEspecially in type-1 diabetics, since its the main therapy option for these patients. Insulin is an incredibly effective, safe and commonly used drug. It’s benefits include: control of blood sugars to target levels, prevention of microvascular complications (ie: small blood vessel damage to eyes, kidneys), prevention of macrovascular complications (ie: heart attacks, bypass surgeries, strokes), prevention of hyperglycemia (high blood sugar) symptoms (ie: diabetic coma), near normal quality of life. ﾠKnown risks of insulin and it’s various forms (ie: human vs. analogue) have been well known for years, and include: hypoglycemia (low blood sugar), weight gain, fluid retention and rare anaphylaxis (severe allergy), etc.

However, recent data shows conflicting results of blood sugar lowering regimens (ie: intensive vs. conventional) and their benefit versus risk profile – where one trial (3) opposes the results of another (UKPDS).  Newly published studies have looked at whether certain formulations of insulin – human compared to analogues, long acting to short – have any cancer-causing effects (4,5,6,7). ﾠThe new studies being looked at by FDA and Health Canada have all been published in a european scientific journal, Diabetologia, online in june of this year (8). ﾠLet’s take a closer look at this recent information.

Background
There are various brands and types of insulin available for treatment of diabetes; type 1 and sometimes in type-2 diabetes (aka adult or late-stage diabetes). In type-2 diabetics, their blood sugar levels are usually controlled by an oral medication (ie: metformin tablets) or a combination of different oral drugs. Sometimes, insulin will eventually be added to oral medications to get patients’ blood sugars under control.

The different brands are mainly based on 3 clinically important factors, first the insulin source (ie: animal, human or analog…that’s right, you heard me: a…ni…mal insulin!), the dosage form (ie: multidose vial, pen fill cartridges, pre-filled disposable pens, insulin pump, etc.) and their pharmacokinetics (ie: how fast and how long they work). The specific insulin type and the regimen (ie: how many times and when in the day you inject insulin) are carefully determined by your physician in order to best control your blood sugars, to prevent diabetes complications (ie: macro and microvascular), all the while minimizing side-effects.

In this case, the new studies have all looked into a specific analog insulin called Lantus. This insulin is considered a long acting insulin and is typically taken once daily (mourning, evening or bedtime) (9). There have been some cancer concerns with some insulin products in the past, such as inhaled insulin. Remember Exubera, the inhaled insulin released in US? I vaguely do.

Turns out, after company data revealing 5- to 6-fold increase (11) in lung cancer (6 cases vs. 1 in 3800 patient-years) rates in people who used Exubera, Pfizer sold the rights to Nektar in november of 2007 (13), who six months later abandoned marketing of the insulin inhaler (12).

On a funny note: check out ridiculously long patient manual and Trek-ish inhaler design, starting at page 35 of ref(11)… They really could have gone with a little less Original Series and a little more Deep Space 9 on the inhaler concept…

What do These New Studies Show?
The folks over at the Diabetologia Journal seem to have been the first to publish online human evidence (observational studies) of a German insurance study (cohort study) where they found a dose-dependant (risk increases with dose) excess risk of cancer (malignant neoplasm) in patients taking insulin glargine (Lantus) for a few years (mean: 1.4yrs) compared to insulin aspart or lispro (4).

Hemkes et al. found: “After adjusting for dose, a dose-dependent increase in cancer risk was found for treatment with glargine compared with human insulin (p < 0.0001): the adjusted HR was 1.09 (95% CI 1.00 to 1.19) for a daily dose of 10 IU, 1.19 (95% CI 1.10 to 1.30) for a daily dose of 30 IU, and 1.31 (95% CI 1.20 to 1.42) for a daily dose of 50 IU. No increased risk was found for aspart (p = 0.30) or lispro (p = 0.96) compared with human insulin”.

This trial has many limitations, namely; nuanced statistical calculations used to estimate the real cancer risks (when adjusting for factors like rate of cancer diagnosis, all-cause mortality between insulin groups); the issue of implausability because the short duration of treatment (1.3 to 1.4 years), widely encompassing outome (looked at all cancer instead of focusing on specific cancers that might more be affected by insulin or diabetes, ie: colon, pancreas, breast)

A Swedish study (5) analysis of registry data cancer patients using insulin, taken in 2005 and lasting for 2 years, answered some of the questions raised by the German one. They found that women using Lantus only, compared to women using other insulin combination, had a doubling of their risk of breast cancer (adjusted RR= 1.99%, 95% CI 1.31–3.03). However, no significant increases in gastro-intestinal (GI), prostate, or all type cancers were found. This study also showed no significant risk increase in people using combination of insulin (ie: Lantus + fast-acting, human insulin).

Jonasson et al. concludes that the duration of their study and the unavailability of actual rates of breast cancer suggest that the increase rate seen may have been due to random fluctuations (ie: chance). This second trial also has limitations, for example: relatively low cases of cancer (25 cases out of nearly 6000 glargine users), no increased risk in Lantus+ other insulin combination groups, potential indication bias, limited information on breast cancer risk factors that may affect results.

Another trial by Coulhoun et al. (6) did not find an increase in all-type cancer for patients using Lantus +other insulin as compared to patients not using Lantus at all. A small subset of Lantus-only versus non-Lantus patients, found a small, yet significant increased risk of cancer in the Lantus-only group. This last finding was barely significant (HR= 1.55, 95%CI 1.01–2.37, p=0.045).

Finally, a Scottish, 5 year, randomized study (7) followed more than a thousand patients and found no significant difference in cancer rates (all types, or specific).

Conclusion and Recommendations

Considering the well established cancer risks (especially colon, breast, pancreas) of diabetes in humans, and the fact that a UK study (albeit, far from conclusive) found some oral medications for diabetes may increase (or decrease less?) the risk of certain types of cancer (16), the overall picture can be hard to figure out. As of this posting, the evidence on Lantus, or any other Insulin is considered preliminary. In other words, it is something worth looking at close (ie: with mora and better studies) as such that the FDA and Health Canada are doing just that. An editorial posted online adresses these studies and puts this new data in context (17)
“The evidence presented in this set of papers is sufficient to establish that there is a case to answer, but is entirely insufficient to bring in a verdict”
Furthermore (18):
“…since Lantus does not offer better overall glucose control than human insulin in type 2 diabetes, patients can consider alternatives.”

From the FDA (1):
“Based on the currently available data, the FDA recommends that patients should not stop taking their insulin therapy without consulting a physician, since uncontrolled blood sugar levels can have both immediate and long-term serious adverse effects.”

From Health Canada (2):
“At this time, Health Canada recommends that patients should not stop taking their insulin therapy without first consulting their physician...”

From the Canadian Diabetes Association:

In closing, it is recommended that patients taking Lantus talk to their physician or pharmacist in order to talk about the risks and benefits of changing insulin therapy, since the evidence to support this is presently based on preliminary data. Further studies are needed to guide further recommentations, precautions or warnings relating to Lantus, or any other insulin analogs, and specific cancer risks.

**For more information: Patients should visit FDA or Health Canada websites (1,2) for more information or telephone numbers to report adverse-effects to these agencies.  Biochem majors and geeks alike can check out reference 17 for possible physiological theories for insulin and carcinogenesis**

REFERENCES
1)Food and Drug Agency, Postmarket Drug Safety Information for Patients and Providers, Early Communication About Safety of Lantus (insulin glargine), 7/1/2009 – available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm169722.htm
2)Health Canada, Advisories, Warnings and Recalls, Health Canada Update About Safety of Lantus (Insulin Glargine), July 9, 2009 – Available at http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2009/2009_115-eng.php
3)The Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD). Effects of Intensive Glucose Lowering in Type 2 Diabetes. NEJM Volume 358:2545-2559 June 12, 2008 Number 24
4)4)L. G. Hemkens, U. Grouven, et al., ﾠRisk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study, Diabetologia,
5)5)Jonasson JM, Ljung R, et al,, Insulin glargine use and short-term incidence of malignancies a population-based follow-up study in Sweden. ﾠDiabetologia
6)6) Colhoun H on behalf of SDRN (2009) Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Network Epidemiology Group. Diabetologia
7)7)Currie CJ, Poole CD, Gale EAM (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia doi:10.1007/s00125-009-1440-6
8)8) Diabetologia Journal Online, Press Release: Lantus insulin: a possible link with cancer which requires further investigation, available at: ﾠhttp://www.diabetologia-journal.org/cancer.html
9)Rxfiles, Diabetes Charts -www.RxFiles.ca-Oct 2008
10)FDA, Dear Doctor Letter, April 9, 2008

http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm126610.pdf

11)http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021868s016s017lbl.pdf
12)http://www.fiercebiotech.com/story/inhaled-insulin-lung-cancer-warning-riles-investors/2008-04-09?utm_medium=nl&utm_source=link
13)http://www.fiercebiotech.com/story/pfizer-gives-nektar-135m-exubera-settlement/2007-11-13
14)http://www.fiercebiotech.com/story/inhaled-insulin-lung-cancer-warning-riles-investors/2008-04-09?utm_medium=nl&utm_source=link
15)L. G. Hemkens, U. Grouven et al., Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study, Diabetologia,June2008 DOI :10.1007/s00125-009-1418-4
16)C. J. Currie, C. D. Poole, E. A. M. Gale, The influence of glucose-lowering therapies on cancer risk in type 2 diabetes, Diabetologia, online publication
17)U. Smith, E. A. M. Gale, Editorial: Does diabetes therapy influence the risk of cancer?
Diabetologia.
18)http://www.diabetologia-journal.org/cancer.html#published

History tells us of nurse Renée Caisse’s discovery, promotion, and subsequent investigation, that an unproved native North American herbal mixture has been used by patients for prevention or treatment of serious conditions such as cancer. Essiac is a herbal mixture – a complementary or alternative medicine, or CAM – that has been said to be formulated by an Ojiwan healer to “to purify the body and put it back in balance with the great spirit.” (1) and it’s recipe obtained by Caisse from a woman who claimed it cured her breast cancer (1).

In 1938, the Cancer Commission, established under the Cancer Remedies Act of Ontario, lead an investigation after growing concerns and questions about the use of Essiac. (2) Commission members concluded that there was limited evidence for the mixture’s effectiveness and were concerned about Caisse’s unwillingness to divulge Essiac’s composition. (2)

In fact, Caisse has reported to have used Essiac as a tea and administered one ingredient intravenously in her clinic to hundreds of patients for over 40 years. (1,3) Caisse reportedly worked on a formulation with physicians, namely with Dr. Charles Brusch, in order to modify the formula and to arrive at a final oral product (1). Both eventually sold rights in 1977 of the formulation to a Toronto based corporation, Resperin co. Limited (4). The following year, the Department of National Health and Welfare of Canada allowed Resperin to conduct studies on Essiac’s safety and effectiveness, but withdrew its permission four years later because the corporation was not proceeding with the studies as planned (1,5).

A second product, Flor-Essence (Flora Manufacturing and Distributing Ltd), contains the original 4 herbs in Essiac but with 4 additional ingredients, which are supposedly based on a formulation developed by Caisse and Brusch. (1,3,5,6). These products are available for purchase online and at health food stores. Essiac is available through Health Canada’s emergency release program. Purported use of Essiac and FlorEssence include treatment of cancer, quality of life, cancer-related mortality, chronic GI diseases (Ulcerative and inflammatory conditions), reduction in pain, increase in appetite, strengthening the immune system, treatment of HIV and diabetes. (1,3,5)

Since CAM (specifically vitamin-herbals) use in cancer patients is quite common (7) and especially since 1 in 7 (14.8%) Canadian breast cancer patients have reported to use Essiac (8), this article will review Essiac and Flor-Essence and their purported use in cancer treatment, prevention and quality of life.

Formulation and Mechanism(s) of Action(s)

Although good manufacturing practices are reportedly followed and dosage information is available (4), Currently, Essiac does not have a natural product number (NPN) that certifies the product’s standardisation of active ingredients (AI), nor has the FDA or Health Canada evaluated any health claim related to this product.

Today, Essiac products are manufactured and distributed by Essiac Canada International (ECI), who’s products contain the original 4 herb mixture formulation (4). These ingredients include:
-Arctium lappa L. (burdock root),
-Rheum palmatum L. (Turkish rhubarb),
-Rumex acetosella L. (sheep sorrel) and
-Ulmus fulva or U. rubra Muhl (the inner bark of slippery elm) (1,3,4)

Recommended at twice daily dosage for 12 week duration treatment of capsules, powder or tonic with price ranging from 200 to over 350 (CD|USD) dollars (4).

Flor-Essence contains the same 4 ingredients as Essiac, but with 4 additional ingredients, including:
-Nasturtium officinale R. Br (watercress),
-Cnicus benedictus L. (blessed thistle),
-Trifolium pratense L. (red clover) and
-Laminaria digitata Lmx. (kelp) (1,3,6)

Essiac’s mechanism(s) of action and Pharmacology

A few preliminary in vitro trials have suggested various physiological activities of Essiac or Flor-Essence and include antiproliferative, immunomodulatory, fibrinolysis inhibition and antioxidant activity (AA, BB,CC). One study did note an inhibition of mice-derived prostate cancerous cell lines by Essiac (CC), while another noted antiproliferative activity in a human breast cell line (DD). However, these results conflict with unpublished studies conducted by The Memorial Sloan-Kettering Cancer Center (EE) (which are reviewed here (FF)), and a controlled (paclitaxel as comparator) in vitro study on prostate cancer cell lines (GG). In another study, Flor-Essence and Essiac has been shown to stimulate breast cancer cell lines, both through estrogen-dependant and estrogen-independent mechanisms. (HH)

Because these studies are mostly preliminary and conflicting, we cannot postulate a coherent mechanism of action of active ingredients for treatment of human diseases. Little, if anything, is known about Essiac’s or Flor-Essence’s administration, distribution, metabolism or elimination (3).
Since these two CAM products contain multiple ingredients , it is important consider evidence about the herbal mixture products (Essiac or FlorEssence) instead of looking at studies on the seperate ingredients (ie: Slippery Elm, Red Clover) since this would make it very hard to assess the added effects in the body.

Clinical evidence in Humans

To date, there exists no randomized, controlled trials (RCTs) published – in peer-reviewed journals or otherwise – studying Essiac or Flor-Essence in the treatment or prevention of any cancer. Most human evidence on the mixture consist of subjective surveys (i.e: patients said they “felt better”) (II,JJ,KK) or case series which have resulted in inconclusive results on cancer mortality (FF). A retrospective cohort study involving 510 women with diagnosed breast cancer found that Essiac does not improve quality of life, nor does it improve mood states (LL).

Adverse Effects and Safety

Since no RCTs exist in humans, side effects (SE) of Essiac or Flor-Essence have not been adequately studied. Anaphylaxis (severe allergy), hyponatremia (low sodium in blood), nausea, vomiting, fatigue and diarrhea has been reported (3,NN). Furthermore, individual components of the mixtures have been reported to cause allergic dermatitis and laxative effects (1). Potential drug interactions theoretically could be of concern since it has been shown that Essiac, in vitro, can inhibit liver enzymes (CYP1A2, 2C19) (AA) and interact with an experimental chemotherapeutic agent (MM). Theoretical contraindications include children, pregnancy, renal and hepatic insufficiency (00).

There is a hypothetical risk of major bleeds due to the potential anti-inflammatory or blood thinning effects of Essiac/Flor-Essence. Patients on blood thinners should avoid avoid these two products and include people taking such drugs as (including but not restricted to): salisylic acide (ASA, Aspirin, Entrophen, Novasen), clopidogrel (Plavix), dipyridamol (Aggrenox), warfarin (Coumadin) and heparin-like injections.

Again, most of the evidence for safety comes from surveys taken by current or former cancer patients where they would report side-effects. Even if a particular this survey (JJ) showed 7% of patients reported “ill- effects” attributed to Flor-Essence, surveys typically misrepresents actual medical ouctomes; they are not adequate to really know if a particular side effect is really caused by a drug or natural health product (NHP). In other words, because surveys do not prove that a reported SE happens more oftenly with a NHP than in adummy pill (aka: placebo), we cannot accurately say that it does.

Conclusions and Recommendations

An important safety issue concerning any alternative medicine in cancer is the possibility of delayed conventional treatment. Certain cancers develop rapidly, so forestalling medical treatment in order to try Essiac, or any other CAM, to prevent the disease from growing or returning should never be attempted without medical supervision. Cancer is a serious disease that necessitates proper care by medical doctors and specialists (ie: Oncologist), and good physician-patient communication in order to receive quality health care.

Neither Essiac or Flor-Essence has any convincing evidence – or even promising – about it’s role in cancer management. Considering these facts; using an expensive treatment, duration of 12 weeks, mild digestive systems SE, some rare but serious SE (ie: anaphylaxis) and absolutely no reliable human data (not one RCTs on human cancer outcomes); the use of these two mixtures in prevention, treatment or cancer-related complication (i.e: mood, quality of life) have very limited role in cancer care.

This reviewer does aknowledge the issue of compassionate care in situations where patients are in terminal phase, or who have failed therapy or otherwise used all medical treatments or procedures to no avail. Situations like these are indeed complex and should always be directed under medical supervision and agreed upon after a good discussion between the patient and physician.

Other reviews:
Kaegi (1) concluded:
“ (Essiac use in cancer has)…some weak evidence of its effectiveness.. the nature and quality of studies reporting benefit are such that the findings can only be regarded as preliminary.”

The U.S. National Cancer Institute (5) says:
“At this time, evidence does not support the use of either Essiac or Flor•Essence in the treatment of cancer patients…”

The FDA
“Studies performed on the preparation of
Essiac in Canada and by the National Cancer Institute found that the product had no anti-tumor activity.”(9)
“Essiac… a fake cancer cure”(10)

REFERENCES

1) E. Kaegi and Institute. Task Force on Alternative Therapies of the Canadian Breast Cancer Research
Unconventional therapies for cancer: 1. Essiac, Can. Med. Assoc. J., Apr 1998; 158: 897 – 9022)Cancer 2) Commission Reports, Record Group 10, Series 106, at the Archives of Ontario, Toronto
3) Essiac Product Monograph, CAMline. Accessed 03-04-09 : http://www.camline.ca/professionalreview/pr.php?NHPID=17
4) Essiac Canada International Website : http://essiacproducts.com/
5) US National Institute of Health, National Cancer Institute, Essiac – Flor-Essence PDQ summary : http://www.cancer.gov/cancertopics/pdq/cam/essiac/HealthProfessional/page1
6) Flora Health, Flor-Essence Herbal Tea Blend : http://www.florahealth.com/Flora/Home/canada/Products/R8070.asp
7)Richardson et al., Complementary/alternative medicine use in a comprehensive cancer center and the implications for oncology, J Clin Oncol. 2000 Jul;18(13):2505-14.
8) Use of complementary/alternative medicine by breast cancer survivors in Ontario: prevalence and perceptions. Boon H, Stewart M et al., J Clin Oncol. 2000 Jul;18(13):2515-21.
9) FDA, Drug Import Alert : http://www.accessdata.fda.gov/ImportAlerts/ora_import_ia6664.html
10) FDA, News release June 2008, FDA Warns Individuals and Firms to Stop Selling Fake Cancer ‘Cures’ : http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116913.htm
AA) Seely D, Kennedy DA et al., In vitro analysis of the herbal compound Essiac.
Oncol Rep. 2004 Feb;11(2):471-6.
BB) Leonard SS. Et al, Essiac tea: scavenging of reactive oxygen species and effects on DNA damage, J Ethnopharmacol. 2006 Jan 16;103(2):288-96. Epub 2005 Oct 13.
CC) Ottenweller J, Putt K, Blumenthal EJ, et al.: Inhibition of prostate cancer-cell proliferation by Essiac. J Altern Complement Med 10 (4): 687-91, 2004
DD) Tai J.,et al. In vitro comparison of Essiac and Flor-Essence on human tumor cell lines., Oncol Rep. 2004 Feb;11(2):471-6.
EE) Hutchison, D.J., Experimental Chemotherapy, Memorial Sloan-Kettering Cancer Center, Rye, NY, personal communication, September 26, 1988 and March 1989
FF) OTA UCOOTA. Essiac. Unconventional cancer treatments. Washington, D.C.: US Congress Office of Technology Assistance (OTA). US Government Printing Office.; 1990 1990.
GG) Eberding A et al., Evaluation of the antiproliferative effects of Essiac on in vitro and in vivo models of prostate cancer compared to paclitaxel, Nutr Cancer. 2007;58(2):188-96.
HH) Kulp KS, et al., Essiac and Flor-Essence herbal tonics stimulate the in vitro growth of human breast cancer cells, Breast Cancer Res Treat. 2006 Aug;98(3):249-59. Epub 2006 Mar 16.
II)Karn H, Moore, M. The use of the herbal remedy ESSIAC in an outpatient cancer population. In: American Society of Clinical Oncology: Meeting Program Proceedings; 1997: American Society of Clinical Oncology; 1997.
JJ)Richardson M, Sanders, T, Tamayo, C, Perez, C, Plamer, JL. Flor Essence Herbal Tonic Use in North America: A profile of general consumers and cancer patients. Herbalgram 2000;50:40-46.
KK) Project OBCIE. A guide to unconventional cancer therapies. 1st ed. Toronto, ON: Ontario Breast Cancer Information Exchange Project; 1994
LL) Zick SM, Sen A, Feng Y, et al. Trial of Essiac to ascertain its effect in women with breast cancer (TEA-BC). J Altern Complement Med 2006 Dec;12(10):971-80.
MM) Geyer C, et al. Dose-schedule optimization the hexacyclic camptothecin (CPT) analog dx-8951f: a phase I and pharmacokinetic study with escalation of both treatment duration and dose (meeting abstract). Proc Annu Meet Am Soc Clin Oncol 1999;18.
NN) Oncolink, Abramson Cancer Center of the University of Pennsylvania, NCI/PDQ® Health professionals: Essiac/FlorEssence (PDQ®), accessed 04-05-09
00) Memorial Sloan-Kettering Cancer Center, Essiac Healthcare Professional Monograph : accessed 04-05-09