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News
www.thelancet.com/oncology
Vol 10 January 2009
13xx
In October, 2008, 21 scientistsfrom nine countries met at theInternational Agency for Researchon Cancer (IARC) and reaffi rmed theGroup 1 classification “carcinogenic tohumans” of 20 pharmaceutical agents(tables 1 and 2).IARC is compiling a review of themore than 100 Group 1 agents, manyof which were assessed more than20 years ago, before mechanisticstudies were prominent tools inassessments. Furthermore, additionaltumour sites and exposure scenariosmight be identified in the new review.For example, tobacco was firstidentified as a cause of lung cancer insmokers, and has since been shown tocause cancer at more than a dozensites, through smoking and smokelessforms
.
The assessments will be published asVolume 100 of the IARC Monographs,to be developed in six parts. Volume100 will include information on tumoursites and mechanisms of carcinogen-esis, although this does not precludethe possibility that an agent mightcause cancer at other sites or by othermechanisms. Volume 100 will provideinformation for two subsequent pub-lications: Tumour Site Concordancebetween Humans and Animals andMechanisms Involved in HumanCarcinogenesis. The major findingsof Volume 100 will also become thefirst entries of an enhanced electronicdatabase of Monograph findings.Five hormonal treatments werereassessed (table 1), two of whichincrease cancer risk at some sitesand decrease risk at others, actingthrough receptor-mediated eventsand genotoxic mechanisms.The Working Group concludedthat there is suffi cient evidence thatoestrogen-only menopausal therapyincreases the risk for ovarian cancer,whereas no definite association wasidentified in the IARC 1999 evalu-ation.
1
Two meta-analyses publishedsince then reported an increased riskfor ovarian cancer among womenwho used oestrogen-only therapy:the relative risks (RRs) for ever usewere significant and ranged from1·19 to 1·51.
2,3
Furthermore, a dose-dependent increase in risk was notedper year of use of oestrogen-onlytherapy (RR 1·07 [95% CI 1·06–1·08]).
3
 The Working Group also highlightedthe decrease in breast cancer incidenceafter the widespread reduction in the useof combined oestrogen-progestagenmenopausal therapy since 2003.
4
 Additionally, the Group confirmed thatcombined oestrogen-progestagen oralcontraceptives increase the risk forhepatocellular carcinoma,
5
stressingthat in populations where hepatitis Bvirus (HBV) infection is endemic, therisk is presumably masked by the higherrisk associated with HBV infection.A further 15 agents were reassessed,including some mixtures (table 2).The Working Group identified thespecific component most likely tobe responsible for cancer risk inthree mixtures, although it is not anexpressed intent of Volume 100 toidentify new carcinogenic agents.The Working Group reaffi rmed theGroup 1 classification of analgesicmixtures containing phenacetin, andfurther classified phenacetin itself in Group 1 (previously classified as“probably carcinogenic to humans”Group 2A, in 1987). The Group reachedthis decision because increased risksfor cancers of the renal pelvis and theureter could not be explained by othercomponents of the analgesic mixtures(ie, aspirin, codeine phosphate, andcaffeine) and noted that phenazone(sometimes added to these mixtures)was not a component of those mix-tures assessed in an influential study.
6
When reviewing antineoplasticdrugs, the Working Group noted that
Special Report: Policy
A review of human carcinogens—Part A: pharmaceuticals
Upcoming meetings
February 24–March 3, 2009Biological AgentsMarch 17–24, 2009Metals, Particles, and Fibres June 2–9, 2009RadiationSeptember 29–October 6, 2009Lifestyle FactorsOctober 20–27, 2009Chemical Agents and RelatedOccupationshttp://monographs.iarc.fr/
 
Group 1 agentCancer on which suffi cient evidence inhumans is basedSites where cancerrisk is reducedEstablished mechanisticeventsOther likelymechanistic events
DiethylstilbestrolBreast (exposure during pregnancy), vaginaand cervix (exposure in utero)Limited evidence: testis (exposure in utero),endometrium··Oestrogen receptor-mediated events (vagina,cervix), genotoxicityEpigeneticprogrammingOestrogen-only menopausaltherapyEndometrium, ovaryLimited evidence: breast··Oestrogen receptor-mediated eventsGenotoxicityCombined oestrogen–progestagen menopausal therapyEndometrium (risk decreases with numberof days/month of progestogen use), breast··Receptor-mediated eventsOestrogen genotoxicityCombined oestrogen–progestagen oral contraceptivesBreast, cervix, liverEndometrium,ovaryReceptor-mediated eventsOestrogen genotoxicity,hormone-stimulatedexpression of humanpapillomavirus genesTamoxifenEndometriumBreastOestrogen receptor-mediated events,genotoxicity··
Table 1:
Hormonal treatments assessed by the IARC Monograph Working Group
Published
Online
December 1, 2008DOI:10.1016/S1470-2045(08)70286-9
 
News
14
www.thelancet.com/oncology
Vol 10 January 2009
acute myeloid leukaemia induced byalkylating agents, such as busulfan,frequently exhibits clonal loss (partialor total) of either chromosome 5or 7, thereby distinguishing it fromacute myeloid leukaemia induced bytopoisomerase II inhibitors, such asetoposide. The latter shows clonalbalanced translocations involving the
MLL
gene on chromosome 11 (11q23).
7,8
 Following this line of reasoning, theWorking Group classified etoposideitself in Group 1 (previously classifiedin Group 2A, in 2000).When reviewing plants containingaristolochic acid, the Working Groupreviewed new evidence that DNAadducts and A:T→T:A transversions in
TP53
induced by aristolochic acid werefound in patients with nephropathyor urothelial tumours after ingestionof  material from
 Aristolochia
plantspecies.
9,10
As a result, aristolochic acidwas classified in Group 1 (previouslyclassified in Group 2A, in 2002). In just 6 years, mechanistic studiesconvincingly showed that aristolochicacid was responsible for the high risk forcancer and nephropathy in individualswho ingested material from
 Aristolochia
 plants—in the form of weight-loss pillsin Belgium and from cereal fields in theBalkans where
 Aristolochia
plants weregrowing as weeds.
10,11
This shows how mechanistic datacan help identify carcinogenic hazards.It is encouraging to think that otherenvironmental or occupational cancersmight be investigated and resolvedwith similar confidence.
Yann Grosse, Robert Baan,Kurt Straif, Béatrice Secretan,Fatiha El Ghissassi, Véronique Bouvard,Lamia Benbrahim-Tallaa, Neela Guha,Laurent Galichet, Vincent Cogliano, onbehalf of the WHO International Agencyfor Research on Cancer MonographWorking Group
International Agency for Research onCancer, Lyon, France
The IARC authors declared no conflicts of interest.1 IARC. IARC Monographs on the evaluation of carcinogenic risks to humans. Volume 72.Hormonal contraception and post-menopausalhormonal therapy. Lyon: International Agencyfor Research on Cancer 1999.2 Zhou B, Sun Q, Cong R, et al. Hormonereplacement therapy and ovarian cancer risk:a meta-analysis.
Gynecol Oncol
2008;
108
: 641–51.3 Greiser CM, Greiser EM, Dören M. Menopausalhormone therapy and risk of ovarian cancer:systematic review and meta-analysis.
Hum Reprod Update
2007;
13
:
 
453–63.4 Jemal A, Ward E, Thun MJ. Recent trends inbreast cancer incidence rates by age and tumorcharacteristics among U.S. women.
Breast Cancer Res
2007;
9
: R28.5 IARC. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91.Combined estrogen-progestogen contraceptivesand combined estrogen-progestogenmenopausal therapy. Lyon: International Agencyfor Research on Cancer 2007.6
 
McCredie M, Stewart JH, Day NE. Differentroles for phenacetin and paracetamol in cancerof the kidney and renal pelvis
. Int J Cancer 
 1993;
53
: 245–49.7 Pedersen-Bjergaard J, Christiansen DH, Desta F,et al. Alternative genetic pathways andcooperating genetic abnormalities in thepathogenesis of therapy-relatedmyelodysplasia and acute myeloid leukemia.
Leukemia
2006;
11
: 1943–49.8 WHO classification of tumours of haematopoietic and lymphoid tissues.Swerdlow SH, Campo E, Harris NL, et al, eds.Lyon: WHO Press, 2008.9 Lord GM, Hollstein M, Arlt VM, et al. DNAadducts and p53 mutations in a patient witharistolochic acid-associated nephropathy.
 Am J Kidney Dis
2004;
43
: e11–17.10 Grollman AP, Shibutani S, Moriya M, et al.Aristolochic acid and the etiology of endemic(Balkan) nephropathy.
Proc Natl Acad Sci USA
 2007;
93
: 12129–34.11 Nortier JL, Martinez MC, Schmeiser HH,
 
et al.Urothelial carcinoma associated with the useof a Chinese herb (
 Aristolochia fangchi
).
N Engl J Med
2000;
342
: 1686–92.
Monograph Working Group
MembersA B Miller—Co-Chair (Canada),D H Phillips—Co-Chair (UK); J Kaldor (Australia); J H Olsen(Denmark); M R Berger,H H Schmeiser (Germany);H Tsuda (Japan); S H Kim (unableto attend, Republic of Korea);B C Baguley (New Zealand);M Marques (Portugal); P Karran(UK); E Barrett-Connor,F A Beland, J L Bolton (unable toattend), M C Bosland, J F Buell,D Eastmond, C J Jameson,D G Kaufman, A A Molinolo,C A Schiffer, L Titus-Ernstoff,D B Thomas (USA)
Conflicts of interest
DE has previously receivedfunding from, and acted asconsultant to, Johnson & Johnson. He currently receivesfunding from Pfizer. Both of these companies manufacturehormone-based contraceptives. JK is deputy director of the Centrein HIV Epidemiology and ClinicalResearch, University of NewSouth Wales, Australia, whichreceives partial funding fromHoffman-La Roche, Bristol-MyersSquibb, Pfizer, and Johnson & Johnson. All of these companiesmanufacture drugs, oralternatives to drugs, mentionedin this articleInvited SpecialistsNone
Representatives
 None
Observers
M G Bird (ExxonMobil Corp, USA)
Group 1 agentCancer on which suffi cientevidence in humans is basedEstablished mechanistic events
BusulfanAcute myeloid leukaemiaGenotoxicity (alkylating agent)ChlorambucilAcute myeloid leukaemiaGenotoxicity (alkylating agent)CyclophosphamideAcute myeloid leukaemia,bladderGenotoxicity (metabolism to alkylatingagents)MelphalanAcute myeloid leukaemiaGenotoxicity (alkylating agent)Semustine(methyl-CCNU)Acute myeloid leukaemiaGenotoxicity (alkylating agent)ThiotepaLeukaemiaGenotoxicity (alkylating agent)TreosulfanAcute myeloid leukaemiaGenotoxicity (alkylating agent)MOPP combinedchemotherapyAcute myeloid leukaemia, lungGenotoxicityEtoposide in combinationwith cisplatin andbleomycinAcute myeloid leukaemiaGenotoxicity; translocations involving
MLL
gene (etoposide)Etoposide (Group 2A in2000)··Genotoxicity, translocations involving
MLL
geneChlornaphazineBladderGenotoxicity (alkylating agent,metabolism to 2-naphthylaminederivatives)AzathioprineNon-Hodgkin lymphoma, skinGenotoxicity, immunosuppressionCiclosporinNon-Hodgkin lymphoma, skin,multiple other sitesImmunosuppressionMethoxsalen+ultravioletlightSkinGenotoxicity following photo-activationPlants containingaristolochic acidRenal pelvis, ureterGenotoxicity, DNA adducts in humans,A:T→T:A transversions in
TP53
inhuman tumoursAristolochic acid(Group 2A in 2002)··Genotoxicity, DNA adducts in animalsare the same as those found in humansexposed to plants, A:T→T:Atransversions in
TP53
,
RAS
activationAnalgesic mixturescontaining phenacetinRenal pelvis, ureter(See phenacetin)Phenacetin(Group 2A in 1987)Renal pelvis, ureterGenotoxicity, cell proliferation
MOPP=chlormethine (mechlorethamine), vincristine (oncovin), procarbazine, and prednisone
Table 2
: Antineoplastic drugs and other drugs evaluated by the IARC Monograph Working Group
 
News
www.thelancet.com/oncology
Vol 10 April 2009
321
Special Report: Policy
A review of human carcinogens—Part B: biological agents
In February, 2009, 36 scientists from16 countries met at the InternationalAgency for Research on Cancer (IARC)to reassess the carcinogenicity of the biological agents classified as“carcinogenic to humans” (Group 1)and to identify additional tumour sitesand mechanisms of carcinogenesis(tables 1 and 2). These assessments willbe published as part B of Volume 100of the IARC Monographs.
1
Hepatitis B virus (HBV) and hepatitisC virus (HCV) infect, respectively, over300 million and 170 million peopleworldwide, mainly in Asia and Africa.Chronic infection with these virusesis known to cause hepatocellularcarcinoma.
2
Suffi cient evidence isavailable to conclude that chronicinfection with HCV can also causenon-Hodgkin lymphoma, especiallyB-cell lymphoma. In an interventionstudy, patients with HCV infection andsplenic lymphoma who were given theantiviral agent, interferon, showedregression of the lymphoma.
3
 Epstein–Barr virus (EBV) infectsalmost everyone and causes severaltypes of cancer, including naso-pharyngeal carcinoma, one of the mostcommon cancers in southeastern Asia,and Burkitt’s lymphoma in childrenin Africa. New evidence points toa role for EBV in 5–10% of gastriccarcinomas worldwide.
4
EBV-positivegastric carcinoma develops early inlife and has distinct histopathology,therefore it might belong to a separateclinical entity.
5
In this subset of gastrictumours, presence of the viral genomein a monoclonal form and expression of EBV-transforming proteins are strongevidence for the involvement of EBV.
6
 Data from 22 cohort studies and80 case–control studies show anassociation between Kaposi’s sarcomaherpes virus (KSHV) and Kaposi’ssarcoma, with relative risks higherthan 10. Most studies are of transplantrecipients and people infected withHIV-1. In both patients who are and arenot infected with HIV-1, risk of Kaposi’ssarcoma increases relative to increasingtitre of antibodies directed againstKSHV, which are markers of the viralload.
7,8
Evidence is suffi cient to showthat KSHV causes primary effusionlymphoma, a rare subgroup of B-cellnon-Hodgkin lymphoma. Mechanisticdata support an oncogenic role for KSHVin Kaposi’s sarcoma and in primaryeffusion lymphoma—in individuals whoare immunocompromised and in thoseapparently immunocompetent. KSHVis also associated with multicentricCastleman’s disease.Individuals who are infected withHIV-1 have a high risk of cancer. HIV-1infection, mainly through immuno-suppression, leads to increased repli-cation of oncogenic viruses such asEBV and KSHV. Although antiretroviraltherapy lowers the risk of many cancersassociated with HIV-1, risks remainhigh.
9
 Cervical cancer is caused by typesof human papillomavirus (HPV) thatbelong to a few phylogenetically related“high-risk” species (alpha-5, 6, 7, 9, 11)of the mucosotropic alpha genus.
10,11
Thetypes found most frequently in cervicalcancer (HPV-16, 18, 31, 33, 35, 45, 52,58) and four types less constantly found(HPV-39, 51, 56, 59) were classified in
Group 1 agentCancers for which there is suffi cient evidence in humansOther sites with limited evidence in humansEstablished mechanistic events
Epstein–Barr virus (EBV)Nasopharyngeal carcinoma, Burkitt’s lymphoma, immune-suppression-related non-Hodgkin lymphoma, extranodalNK/T-cell lymphoma (nasal type), Hodgkin’s lymphomaGastric carcinoma,* lympho-epithelioma-likecarcinoma*Cell proliferation, inhibition of apoptosis, genomicinstability, cell migrationHepatitis B virus (HBV)Hepatocellular carcinomaCholangiocarcinoma,* non-Hodgkin lymphoma*Inflammation, liver cirrhosis, chronic hepatitisHepatitis C virus (HCV)Hepatocellular carcinoma, non-Hodgkin lymphoma*Cholangiocarcinoma*Inflammation, liver cirrhosis, liver fibrosisKaposi‘s sarcoma herpesvirus (KSHV)Kaposi’s sarcoma,* primary effusion lymphoma*multicentric Castleman’s disease*Cell proliferation, inhibition of apoptosis, genomicinstability, cell migrationHuman immunodeficiencyvirus, type 1 (HIV-1)Kaposi’s sarcoma, non-Hodgkin lymphoma, Hodgkin’slymphoma,* cancer of the cervix,* anus,* conjunctiva*Cancer of the vulva,* vagina,* penis,* non-melanoma skin cancer,* hepatocellularcarcinoma*Immunosuppression (indirect action)Human papillomavirustype 16 (HPV-16)†Carcinoma of the cervix, vulva, vagina, penis, anus, oralcavity, and oropharynx and tonsilCancer of the larynxImmortalisation, genomic instability, inhibition of DNA damage response, anti-apoptotic activityHuman T-cell lymphotrophicvirus, type-1 (HTLV-1)Adult T-cell leukaemia and lymphoma..Immortalisation and transformation of T cells
Helicobacter pylori
Non-cardia gastric carcinoma, low-grade B-cell mucosa-associated lymphoid tissue (MALT) gastric lymphoma*..Inflammation, oxidative stress, altered cellular turn-over and gene expression, methylation, mutation
Clonorchis sinensis
Cholangiocarcinoma*....
Opisthorchis viverrini
Cholangiocarcinoma..Inflammation, oxidative stress, cell proliferation
Schistosoma haematobium
Urinary bladder cancer..Inflammation, oxidative stress
*Newly identified link between virus and cancer. †For other types, see table 2.
Table 1:
Biological agents assessed by the IARC Monograph Working Group
See
From the Archives
page 430
Upcoming meetings
 June 2–9, 2009RadiationSeptember 29–October 6, 2009Lifestyle FactorsOctober 20–27, 2009Chemical Agents and RelatedOccupationshttp://monographs.iarc.fr/
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