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Carcinogenicity of some drugs and herbal products
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Carcinogenicity of some drugs and herbal products In June, 2013, 23 experts from nine countries met at the International Agency for Research on Cancer (IARC), Lyon, France, to assess the carcinogenicity of 14 drugs and herbal products (table). Some agents are discussed in more detail because of data complexity or the extent of human exposure. These assessments will be published as volume 108 of the IARC Monographs.1 Thiazolidinediones (eg, pioglitazone and rosiglitazone) have been used for the treatment of type 2 diabetes. Many patients might have received both drugs sequentially. Among ever-users of rosiglitazone, relative risks (RRs) of bladder cancer from two case–control studies and two cohort studies were close to null in all except for one study from the UK. Pioglitazone was assessed in an analysis of one large randomised controlled trial, four cohort studies, and three case–control studies. Everuse of pioglitazone was associated with an increased risk of bladder cancer in all except for one case– control study from Taiwan, and across all study designs and geographical regions, with RRs ranging from 1·2 in the observational studies to almost 3 in the randomised controlled trial. Dose–response associations were assessed in five studies, three of which were high-quality population-based studies. Increased risks were reported with higher dosage or longer use in one case–control study2 and in one cohort study.3 However, the Working Group was unable to consistently rule out confounding and bias related to disease severity and detection. Notably, pioglitazone induced an increased incidence of urinary bladder transitional cell carcinoma4 or papilloma in male rats in two individual gavage studies. Urolithiasis or peroxisome proliferator-activated receptor-mediated effects seemed to be the most likely mechanisms of carcinogenesis.5,6 Pioglitazone was classified as probably carcinogenic www.thelancet.com/oncology Vol 14 August 2013
to humans (group 2A), on the basis of limited evidence in humans that it causes urinary bladder cancer, and sufficient evidence in experimental animals. Rosiglitazone was assessed as not classifiable as to its carcinogenicity to humans (group 3), on the basis of inadequate evidence in humans and limited evidence in experimental animals. Digoxin, a widely prescribed drug that is extracted from the digitalis plant, shares structural homology with steroid hormones. An association with breast cancer was investigated in four case–control studies (including two studies in men) undertaken in Scandinavia, France, and Switzerland; in a nationwide records-based cohort study of women in Denmark; and in two cohort studies in the USA and Norway. All four case–control studies reported significant increases in the incidence of breast cancer; odds ratios were 1·3 in women and 2–4 in men. The largest study, which included all women using digitalis drugs in Denmark, reported an increased risk for current users only (hazard ratio 1·39, 95% CI 1·32–1·46).7 Although
no clear effects of duration or dose were recorded, detection of incident tumours decreased after cessation of exposure, which is consistent with a possible promoting effect of digoxin. The association was stronger for oestrogen receptor (ER)positive than for ER-negative breast tumours. Moreover, the incidence of cancers of the uterus was increased in current users in the cohort study in Denmark, and the risk of prostate cancer, another steroid hormonerelated cancer, was reduced in one high-quality cohort study from the USA.8 However, one cohort study reported a positive association (RR 1·25) for prostate cancer. Excess risk for male breast cancer provides further support for the association reported in women. Nonetheless, the record linkage studies that provided key evidence could not adjust for many of the recognised risk factors for female breast cancer, notably obesity and alcohol consumption. No carcinogenicity studies were done in experimental animals and only a few studies supported an ERmediated mechanism. Digoxin was
Published Online July 5, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70329-2 For more on the IARC Monographs see http:// monographs.iarc.fr/ Upcoming meetings Oct 8–15, 2013 Volume 109: Ambient air pollution Monograph Working Group Members B W Stewart (Australia)–Chair; R J Biggar (Australia); D W Lachenmeier (Germany); S Singh (unable to attend; India); H Tsuda (Japan); B Baguley (New Zealand); M M Marques (Portugal); C-H Tseng (Taiwan, China); T L Knight (UK); F A Beland, J M Betz, E J Carcache de Blanco, M L Cunningham, J K Dunnick, L Guo, C W Jameson, M Karagas, R M Lunn, D L McCormick, S Singh, K L Witt (unable to attend), S Zhou (USA)
Therapeutic or other use
Group
Pioglitazone Rosiglitazone
Type 2 diabetes
2A 3
Digoxin
Chronic heart failure and irregular heart rhythm
2B
Hydrochlorothiazide*
Hypertension, by diuresis
2B
Triamterene
Hypertension, by diuresis (combined with other drugs, including hydrochlorothiazide)
2B
Sulfasalazine
Autoimmune arthritis; inflammatory bowel disease
2B
Pentosan polysulfate sodium
Prevention of blood clots; interstitial cystitis
2B
Primidone
Essential tremor
2B
Methylene blue
Nitrate and cyanide poisoning antidote; methaemoglobinaemia; psychiatric disorders; disinfectant; microscopic staining agent
3
Whole leaf extract of Aloe vera
Laxative (latex component); food flavouring; in beverages and dietary supplements; cosmetics 2B
Ginkgo biloba extract
Food flavouring; in dietary supplements; medicinal products (peripheral arterial diseases and cerebral insufficiency)
2B
Goldenseal root powder
Prevention and reduction of inflammation and related diseases
2B
Kava extract
In beverages and dietary supplements; cosmetics; medicinal products (anxiety or insomnia)
2B
Pulegone
Component of pennyroyal oils (used to treat dyspepsia and menstrual disorders); and several species of mint (used in foods and beverages)
2B
*Previously assessed as “not classifiable as to its carcinogenicity to humans” (group 3).
Table: Agents assessed by the IARC Monograph Working Group
807
News
Invited Specialists R S Stafford (USA) Representatives None Observers A Bertocco (Herbalife Europe Ltd, UK); P Dolin (Takeda Global Research and Development Centre [Europe] Ltd, UK); O Kelber, E Koch (for the World Self-Medication Industry, France) IARC Secretariat M Arnold, R Baan, H Bailey, L Benbrahim-Tallaa, V Bouvard, F El Ghissassi, A Ghantous, Y Grosse, N Guha, B LaubySecretan, H-S Lee, D Loomis, H Mattock, D Puricelli Perin, M Sierra, K Straif, J Zavadil Conflicts of interest C-HT has received honoraria for attending advisory board meetings of Bristol-Myers Squibb, Eli Lilly, and Takeda pharmaceuctical companies. JMB is a volunteer member of the advisory board, American Botanical Council. RSS provided expert testimony in July, 2011, to Mylan Pharmaceuticals in a legal matter concerning doxycycline.
808
classified as possibly carcinogenic to humans (group 2B), on the basis of limited evidence in humans that it causes breast cancer. Some Working Group members supported a group 2A classification on the basis of the epidemiological evidence. Associations between use of hydrochlorothiazide (for hypertension) and squamous-cell carcinoma were assessed in two case–control studies in Denmark and the USA. In the Danish study, investigators reported an excess risk of squamous-cell carcinoma of the skin, with the risk increasing with higher dose. A records-based cohort study from the USA detected an excess risk of lip cancer and “other skin cancers”. A nested case–control study of lip cancer in the same population reported an adjusted odds ratio of 2·0 (95% CI 1·2–3·4) for three or more prescriptions, and increasing odds ratios with longer duration of use.9 Additionally, two other case–control studies in Europe and the USA reported increased odds ratios for squamouscell carcinoma of the skin associated with thiazide drug use. Although the data suggest that hydrochlorothiazide use is associated with squamous-cell carcinoma, the number of studies was small and not all studies assessed dose or duration effects, or controlled for sun exposure. A possible mechanism is hydrochlorothiazide-related photosensitisation, which induces DNA damage and could also lead to a chronic inflammatory reaction,10 since in the presence of ultraviolet A radiation, hydrochlorothiazide enhances the production of cyclobutane–pyrimidine dimers, both in isolated DNA and in the skin of DNA repair-deficient mice. Hydrochlorothiazide was classified as group 2B, on the basis of limited evidence in humans that it causes squamous-cell carcinoma of the skin and lip, and limited evidence for carcinogenicity in experimental animals.
In the absence of adequate epidemiological studies, the other assessments relied mainly on animal carcinogenicity bioassays. From Aloe vera leaves, four products are processed: the whole leaf and decolourised whole leaf extracts, gel, and dried latex. Decolourisation by activated carbon removes the toxic anthraquinones from the latex in the whole leaf extract. Exposure data do not identify the type of product used by the many consumers. In a 2-year study in rats, drinking-water containing whole leaf extract induced, in both sexes, increased incidences of adenoma and carcinoma of the large intestine—tumours that occur rarely in rats.11 The anthrone C-glycosides aloin A and aloin B, found in the latex, are converted to aloe-emodin9-anthrone by bacteria present in the gastrointestinal tract of rats and humans, and sequentially oxidised to aloe-emodin, which is genotoxic and could be responsible for the reported tumours. All the other herbal products and drugs (except for methylene blue) caused liver tumours in mice (and in rats, in the case of goldenseal root powder and triamterene), and often tumours at other sites. These agents and whole leaf extract of Aloe vera were classified as group 2B, on the basis of sufficient evidence in experimental animals. Methylene blue was classified as group 3, on the basis of limited evidence in experimental animals.
We declare that we have no conflicts of interest. 1
2
3
4
5
6 7
8
9
10
11
IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Volume 108. Some drugs and herbal medicines. Lyon: International Agency for Research on Cancer (in press). Azoulay L, Yin H, Filion KB, et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested casecontrol study. BMJ 2012; 344: e3645. Lewis JD, Capra AM, Achacoso NS, et al. Thiazolidinedione therapy is not associated with increased colonic neoplasia risk in patients with diabetes mellitus. Gastroenterology 2008; 135: 1914–23. US Food and Drug Administration. Review and evaluation of pharmacology and toxicology data: pioglitazone. Pharmacology reviews application number: 021073. Center for Drug Evaluation and Research. 1999. http://www. accessdata.fda.gov/drugsatfda_docs/ nda/99/021073A_Actos.cfm (accessed July 2, 2013). Sato K, Awasaki Y, Kandori H, et al. Suppressive effects of acid-forming diet against the tumorigenic potential of pioglitazone hydrochloride in the urinary bladder of male rats. Toxicol Appl Pharmacol 2011; 251: 234–44. Smith U. Pioglitazone: mechanism of action. Int J Clin Pract Suppl 2001; 121: 13–18. Biggar RJ, Wohlfahrt J, Oudin A, et al. Digoxin use and the risk of breast cancer in women. J Clin Oncol 2011; 29: 2165–70. Platz EA, Yegnasubramanian S, Liu JO, et al. A novel two-stage, transdisciplinary study identifies digoxin as a possible drug for prostate cancer treatment. Cancer Discov 2011; 1: 68–77. Friedman GD, Asgari MM, Warton EM, et al. Antihypertensive drugs and lip cancer in non-Hispanic whites. Arch Intern Med 2012; 172: 1246–51. Jahan-Tigh RR, Huen AO, Lee GL, et al. Hydrochlorothiazide and cutaneous T cell lymphoma: prospective analysis and case series. Cancer 2013; 119: 825–31. National Toxicology Program. Toxicology and carcinogenesis studies of a nondecolorized whole leaf extract of aloe barbadensis miller (aloe vera) in F344/N rats and B6C3F1 mice (drinking water studies). 2013. http://ntp. niehs.nih.gov/Ntp/About_Ntp/Trpanel/2011/ April/DraftTR577.Pdf (accessed July 2, 2013).
Yann Grosse, Dana Loomis, Béatrice Lauby-Secretan, Fatiha El Ghissassi, Véronique Bouvard, Lamia Benbrahim-Tallaa, Neela Guha, Robert Baan, Heidi Mattock, Kurt Straif, on behalf of the International Agency for Research on Cancer Monograph Working Group International Agency for Research on Cancer, Lyon, France
www.thelancet.com/oncology Vol 14 August 2013
Carcinogenicity of some drugs and herbal products In June, 2013, 23 experts from nine countries met at the International Agency for Research on Cancer (IARC), Lyon, France, to assess the carcinogenicity of 14 drugs and herbal products (table). Some agents are discussed in more detail because of data complexity or the extent of human exposure. These assessments will be published as volume 108 of the IARC Monographs.1 Thiazolidinediones (eg, pioglitazone and rosiglitazone) have been used for the treatment of type 2 diabetes. Many patients might have received both drugs sequentially. Among ever-users of rosiglitazone, relative risks (RRs) of bladder cancer from two case–control studies and two cohort studies were close to null in all except for one study from the UK. Pioglitazone was assessed in an analysis of one large randomised controlled trial, four cohort studies, and three case–control studies. Everuse of pioglitazone was associated with an increased risk of bladder cancer in all except for one case– control study from Taiwan, and across all study designs and geographical regions, with RRs ranging from 1·2 in the observational studies to almost 3 in the randomised controlled trial. Dose–response associations were assessed in five studies, three of which were high-quality population-based studies. Increased risks were reported with higher dosage or longer use in one case–control study2 and in one cohort study.3 However, the Working Group was unable to consistently rule out confounding and bias related to disease severity and detection. Notably, pioglitazone induced an increased incidence of urinary bladder transitional cell carcinoma4 or papilloma in male rats in two individual gavage studies. Urolithiasis or peroxisome proliferator-activated receptor-mediated effects seemed to be the most likely mechanisms of carcinogenesis.5,6 Pioglitazone was classified as probably carcinogenic www.thelancet.com/oncology Vol 14 August 2013
to humans (group 2A), on the basis of limited evidence in humans that it causes urinary bladder cancer, and sufficient evidence in experimental animals. Rosiglitazone was assessed as not classifiable as to its carcinogenicity to humans (group 3), on the basis of inadequate evidence in humans and limited evidence in experimental animals. Digoxin, a widely prescribed drug that is extracted from the digitalis plant, shares structural homology with steroid hormones. An association with breast cancer was investigated in four case–control studies (including two studies in men) undertaken in Scandinavia, France, and Switzerland; in a nationwide records-based cohort study of women in Denmark; and in two cohort studies in the USA and Norway. All four case–control studies reported significant increases in the incidence of breast cancer; odds ratios were 1·3 in women and 2–4 in men. The largest study, which included all women using digitalis drugs in Denmark, reported an increased risk for current users only (hazard ratio 1·39, 95% CI 1·32–1·46).7 Although
no clear effects of duration or dose were recorded, detection of incident tumours decreased after cessation of exposure, which is consistent with a possible promoting effect of digoxin. The association was stronger for oestrogen receptor (ER)positive than for ER-negative breast tumours. Moreover, the incidence of cancers of the uterus was increased in current users in the cohort study in Denmark, and the risk of prostate cancer, another steroid hormonerelated cancer, was reduced in one high-quality cohort study from the USA.8 However, one cohort study reported a positive association (RR 1·25) for prostate cancer. Excess risk for male breast cancer provides further support for the association reported in women. Nonetheless, the record linkage studies that provided key evidence could not adjust for many of the recognised risk factors for female breast cancer, notably obesity and alcohol consumption. No carcinogenicity studies were done in experimental animals and only a few studies supported an ERmediated mechanism. Digoxin was
Published Online July 5, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70329-2 For more on the IARC Monographs see http:// monographs.iarc.fr/ Upcoming meetings Oct 8–15, 2013 Volume 109: Ambient air pollution Monograph Working Group Members B W Stewart (Australia)–Chair; R J Biggar (Australia); D W Lachenmeier (Germany); S Singh (unable to attend; India); H Tsuda (Japan); B Baguley (New Zealand); M M Marques (Portugal); C-H Tseng (Taiwan, China); T L Knight (UK); F A Beland, J M Betz, E J Carcache de Blanco, M L Cunningham, J K Dunnick, L Guo, C W Jameson, M Karagas, R M Lunn, D L McCormick, S Singh, K L Witt (unable to attend), S Zhou (USA)
Therapeutic or other use
Group
Pioglitazone Rosiglitazone
Type 2 diabetes
2A 3
Digoxin
Chronic heart failure and irregular heart rhythm
2B
Hydrochlorothiazide*
Hypertension, by diuresis
2B
Triamterene
Hypertension, by diuresis (combined with other drugs, including hydrochlorothiazide)
2B
Sulfasalazine
Autoimmune arthritis; inflammatory bowel disease
2B
Pentosan polysulfate sodium
Prevention of blood clots; interstitial cystitis
2B
Primidone
Essential tremor
2B
Methylene blue
Nitrate and cyanide poisoning antidote; methaemoglobinaemia; psychiatric disorders; disinfectant; microscopic staining agent
3
Whole leaf extract of Aloe vera
Laxative (latex component); food flavouring; in beverages and dietary supplements; cosmetics 2B
Ginkgo biloba extract
Food flavouring; in dietary supplements; medicinal products (peripheral arterial diseases and cerebral insufficiency)
2B
Goldenseal root powder
Prevention and reduction of inflammation and related diseases
2B
Kava extract
In beverages and dietary supplements; cosmetics; medicinal products (anxiety or insomnia)
2B
Pulegone
Component of pennyroyal oils (used to treat dyspepsia and menstrual disorders); and several species of mint (used in foods and beverages)
2B
*Previously assessed as “not classifiable as to its carcinogenicity to humans” (group 3).
Table: Agents assessed by the IARC Monograph Working Group
807
News
Invited Specialists R S Stafford (USA) Representatives None Observers A Bertocco (Herbalife Europe Ltd, UK); P Dolin (Takeda Global Research and Development Centre [Europe] Ltd, UK); O Kelber, E Koch (for the World Self-Medication Industry, France) IARC Secretariat M Arnold, R Baan, H Bailey, L Benbrahim-Tallaa, V Bouvard, F El Ghissassi, A Ghantous, Y Grosse, N Guha, B LaubySecretan, H-S Lee, D Loomis, H Mattock, D Puricelli Perin, M Sierra, K Straif, J Zavadil Conflicts of interest C-HT has received honoraria for attending advisory board meetings of Bristol-Myers Squibb, Eli Lilly, and Takeda pharmaceuctical companies. JMB is a volunteer member of the advisory board, American Botanical Council. RSS provided expert testimony in July, 2011, to Mylan Pharmaceuticals in a legal matter concerning doxycycline.
808
classified as possibly carcinogenic to humans (group 2B), on the basis of limited evidence in humans that it causes breast cancer. Some Working Group members supported a group 2A classification on the basis of the epidemiological evidence. Associations between use of hydrochlorothiazide (for hypertension) and squamous-cell carcinoma were assessed in two case–control studies in Denmark and the USA. In the Danish study, investigators reported an excess risk of squamous-cell carcinoma of the skin, with the risk increasing with higher dose. A records-based cohort study from the USA detected an excess risk of lip cancer and “other skin cancers”. A nested case–control study of lip cancer in the same population reported an adjusted odds ratio of 2·0 (95% CI 1·2–3·4) for three or more prescriptions, and increasing odds ratios with longer duration of use.9 Additionally, two other case–control studies in Europe and the USA reported increased odds ratios for squamouscell carcinoma of the skin associated with thiazide drug use. Although the data suggest that hydrochlorothiazide use is associated with squamous-cell carcinoma, the number of studies was small and not all studies assessed dose or duration effects, or controlled for sun exposure. A possible mechanism is hydrochlorothiazide-related photosensitisation, which induces DNA damage and could also lead to a chronic inflammatory reaction,10 since in the presence of ultraviolet A radiation, hydrochlorothiazide enhances the production of cyclobutane–pyrimidine dimers, both in isolated DNA and in the skin of DNA repair-deficient mice. Hydrochlorothiazide was classified as group 2B, on the basis of limited evidence in humans that it causes squamous-cell carcinoma of the skin and lip, and limited evidence for carcinogenicity in experimental animals.
In the absence of adequate epidemiological studies, the other assessments relied mainly on animal carcinogenicity bioassays. From Aloe vera leaves, four products are processed: the whole leaf and decolourised whole leaf extracts, gel, and dried latex. Decolourisation by activated carbon removes the toxic anthraquinones from the latex in the whole leaf extract. Exposure data do not identify the type of product used by the many consumers. In a 2-year study in rats, drinking-water containing whole leaf extract induced, in both sexes, increased incidences of adenoma and carcinoma of the large intestine—tumours that occur rarely in rats.11 The anthrone C-glycosides aloin A and aloin B, found in the latex, are converted to aloe-emodin9-anthrone by bacteria present in the gastrointestinal tract of rats and humans, and sequentially oxidised to aloe-emodin, which is genotoxic and could be responsible for the reported tumours. All the other herbal products and drugs (except for methylene blue) caused liver tumours in mice (and in rats, in the case of goldenseal root powder and triamterene), and often tumours at other sites. These agents and whole leaf extract of Aloe vera were classified as group 2B, on the basis of sufficient evidence in experimental animals. Methylene blue was classified as group 3, on the basis of limited evidence in experimental animals.
We declare that we have no conflicts of interest. 1
2
3
4
5
6 7
8
9
10
11
IARC. IARC monographs on the evaluation of carcinogenic risks to humans. Volume 108. Some drugs and herbal medicines. Lyon: International Agency for Research on Cancer (in press). Azoulay L, Yin H, Filion KB, et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested casecontrol study. BMJ 2012; 344: e3645. Lewis JD, Capra AM, Achacoso NS, et al. Thiazolidinedione therapy is not associated with increased colonic neoplasia risk in patients with diabetes mellitus. Gastroenterology 2008; 135: 1914–23. US Food and Drug Administration. Review and evaluation of pharmacology and toxicology data: pioglitazone. Pharmacology reviews application number: 021073. Center for Drug Evaluation and Research. 1999. http://www. accessdata.fda.gov/drugsatfda_docs/ nda/99/021073A_Actos.cfm (accessed July 2, 2013). Sato K, Awasaki Y, Kandori H, et al. Suppressive effects of acid-forming diet against the tumorigenic potential of pioglitazone hydrochloride in the urinary bladder of male rats. Toxicol Appl Pharmacol 2011; 251: 234–44. Smith U. Pioglitazone: mechanism of action. Int J Clin Pract Suppl 2001; 121: 13–18. Biggar RJ, Wohlfahrt J, Oudin A, et al. Digoxin use and the risk of breast cancer in women. J Clin Oncol 2011; 29: 2165–70. Platz EA, Yegnasubramanian S, Liu JO, et al. A novel two-stage, transdisciplinary study identifies digoxin as a possible drug for prostate cancer treatment. Cancer Discov 2011; 1: 68–77. Friedman GD, Asgari MM, Warton EM, et al. Antihypertensive drugs and lip cancer in non-Hispanic whites. Arch Intern Med 2012; 172: 1246–51. Jahan-Tigh RR, Huen AO, Lee GL, et al. Hydrochlorothiazide and cutaneous T cell lymphoma: prospective analysis and case series. Cancer 2013; 119: 825–31. National Toxicology Program. Toxicology and carcinogenesis studies of a nondecolorized whole leaf extract of aloe barbadensis miller (aloe vera) in F344/N rats and B6C3F1 mice (drinking water studies). 2013. http://ntp. niehs.nih.gov/Ntp/About_Ntp/Trpanel/2011/ April/DraftTR577.Pdf (accessed July 2, 2013).
Yann Grosse, Dana Loomis, Béatrice Lauby-Secretan, Fatiha El Ghissassi, Véronique Bouvard, Lamia Benbrahim-Tallaa, Neela Guha, Robert Baan, Heidi Mattock, Kurt Straif, on behalf of the International Agency for Research on Cancer Monograph Working Group International Agency for Research on Cancer, Lyon, France
www.thelancet.com/oncology Vol 14 August 2013