News

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 casecontrol
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 casecontrol 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 12 in
the observational studies to almost
3 in the randomised controlled trial.
Doseresponse associations were
assessed in ve studies, three of which
were high-quality population-based
studies. Increased risks were reported
with higher dosage or longer use in
one casecontrol 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 eects seemed
to be the most likely mechanisms of
carcinogenesis.5,6 Pioglitazone was
classied 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
sucient evidence in experimental
animals. Rosiglitazone was assessed as
not classiable 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 casecontrol 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 casecontrol studies
reported signicant increases in the
incidence of breast cancer; odds ratios
were 13 in women and 24 in men.
The largest study, which included
all women using digitalis drugs in
Denmark, reported an increased risk
for current users only (hazard ratio
139, 95% CI 132146).7 Although

no clear eects of duration or dose

were recorded, detection of incident
tumours decreased after cessation
of exposure, which is consistent
with a possible promoting eect
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
125) 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 815, 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; inammatory 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

Whole leaf extract of Aloe vera

Laxative (latex component); food avouring; in beverages and dietary supplements; cosmetics 2B

Ginkgo biloba extract

Food avouring; in dietary supplements; medicinal products (peripheral arterial diseases and
cerebral insuciency)

2B

Goldenseal root powder

Prevention and reduction of inammation 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 classiable as to its carcinogenicity to humans (group 3).

Table: Agents assessed by the IARC Monograph Working Group

807

News

Invited Specialists
R S Staord (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
Conicts 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

classied 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 classication on the basis of
the epidemiological evidence.
Associations between use of hydrochlorothiazide (for hypertension)
and squamous-cell carcinoma were
assessed in two casecontrol 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 casecontrol study
of lip cancer in the same population
reported an adjusted odds ratio of
20 (95% CI 1234) for three or more
prescriptions, and increasing odds
ratios with longer duration of use.9
Additionally, two other casecontrol
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 eects, or controlled for
sun exposure. A possible mechanism
is hydrochlorothiazide-related photosensitisation, which induces DNA
damage and could also lead to a chronic
inammatory reaction,10 since in the
presence of ultraviolet A radiation,
hydrochlorothiazide enhances the production of cyclobutanepyrimidine
dimers, both in isolated DNA and in
the skin of DNA repair-decient mice.
Hydrochlorothiazide was classied
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
intestinetumours 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 classied as group 2B, on
the basis of sucient evidence in
experimental animals. Methylene blue
was classied as group 3, on the basis
of limited evidence in experimental
animals.

We declare that we have no conicts of interest.

1

6
7

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: 191423.
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
eects of acid-forming diet against the
tumorigenic potential of pioglitazone
hydrochloride in the urinary bladder of male
rats. Toxicol Appl Pharmacol 2011; 251: 23444.
Smith U. Pioglitazone: mechanism of action.
Int J Clin Pract Suppl 2001; 121: 1318.
Biggar RJ, Wohlfahrt J, Oudin A, et al. Digoxin
use and the risk of breast cancer in women.
J Clin Oncol 2011; 29: 216570.
Platz EA, Yegnasubramanian S, Liu JO, et al.
A novel two-stage, transdisciplinary study
identies digoxin as a possible drug for
prostate cancer treatment. Cancer Discov 2011;
1: 6877.
Friedman GD, Asgari MM, Warton EM, et al.
Antihypertensive drugs and lip cancer in
non-Hispanic whites. Arch Intern Med 2012;
172: 124651.
Jahan-Tigh RR, Huen AO, Lee GL, et al.
Hydrochlorothiazide and cutaneous T cell
lymphoma: prospective analysis and case
series. Cancer 2013; 119: 82531.
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,

Batrice Lauby-Secretan,
Fatiha El Ghissassi, Vronique 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