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TUMORE POLMONARE DA FUMO PASSIVO. IL PRIMO CASO AMMESSO ALLINDENNIZZO DALLINAIL.
Autori: Carlo Enrico Manca (INAIL Direzione Regionale Sardegna), Sandro Pavanetto (INAIL Sede di Carbonia).
IL FUMO PASSIVO
Giΰ dallinizio degli anni 80 erano stati avviati molti studi2,8,9,10,11,12,13,14,15 rivolti a chiarire, dopo la classificazione, nel 1986, del fumo di tabacco in gruppo 1 dallo IARC1, le conseguenze del fumo sulla salute dei non fumatori, costretti a subire il fumo passivo.
Non pare fuori luogo ricordare in premessa che nei paesi industrializzati, dove il fumo di tabacco θ diffuso, labitudine al fumo θ stimata responsabile del 90% dei casi di tumore polmonare negli uomini e del 70% nelle donne. Inoltre, in questi paesi, al fumo viene attribuito il 56-80% di tutte le malattie croniche dellapparato respiratorio e il 22% delle malattie cardiovascolari.
In particolare in Italia hanno condotto uno studio Forestiere e Coll.2 nel quale gli Autori analizzano le conseguenze sulla popolazione italiana dellesposizione al fumo passivo distinguendo tra conseguenze sui bambini e conseguenze sugli adulti.
Per gli adulti, oggetto di attenzione di questo lavoro, gli Autori hanno analizzato il rischio relativo di ammalarsi di tumore del polmone per soggetti non fumatori esposti al fumo passivo in ambiente domestico (fumo del coniuge) ovvero in ambiente di lavoro (colleghi di lavoro). In ambiente di lavoro la stima del numero di maschi non fumatori esposti θ del 62,4%, contro il 38,5% delle donne. Lincremento di rischio associato ad esposizione nel posto di lavoro θ del 39%, contro il 24% in ambiente domestico. In base allo studio citato, in Italia si verificherebbero ogni anno 221 nuovi casi di tumore del polmone da fumo passivo in ambiente domestico e 324 casi da esposizione in ambiente lavorativo.
Del problema dellazione cancerogena del fumo passivo si θ occupato anche lo IARC, International Agency for Research on Cancer, di Lione. Lautorevole Agenzia, che opera allinterno dellOrganizzazione Mondiale della Sanitΰ, effettua ricerche per il controllo del cancro e, nellambito della sua attivitΰ, pubblica una collana di Monografie dedicate alla valutazione delle sostanze cancerogene per lessere umano. In esse, a cura di un gruppo internazionale di esperti, vengono prese in esame, per ciascuna sostanza o gruppo di sostanze o condizioni ambientali, linsieme delle evidenze pubblicate nelle riviste scientifiche piω autorevoli per giungere ad una classificazione che distingue 4 gruppi:
gruppo 1: sostanza cancerogena per luomo
gruppo 2a: sostanza probabilmente cancerogena per luomo
gruppo 2b: sostanza possibilmente cancerogena
gruppo 3: sostanza non classificabile come cancerogeno umano
Sul problema cancro da fumo di tabacco θ stato costituito un gruppo di lavoro, formato da 29 esperti provenienti da 12 nazioni diverse, coordinato dalla dr.ssa Annie J. Sasco, responsabile della Unit of Epidemiology for Cancer Prevention, IARC, che ha preso nuovamente in esame gli effetti cancerogenetici del fumo di tabacco, distinguendo questa volta fra effetti del fumo attivo e del fumo passivo. Il risultato del lavoro θ stato oggetto della Monografia IARC, Volume 83, 20023.
A distanza di 15 anni dalla prima pubblicazione, la lista degli organi, individuata nel 1986 come bersaglio del fumo attivo, nel 2002 θ risultata ampliata, infatti lassociazione θ risultata evidente non solo con il cancro del polmone, del cavo orale, della laringe, della faringe, dellesofago, della vescica urinaria e del bacinetto renale, giΰ riconosciuti a suo tempo, ma anche con il cancro dello stomaco, del fegato, del collo dellutero, del rene e con la leucemia mieloide.
Per quanto riguarda il fumo passivo (o involontario) la Monografia dello IARC θ rivolta a definire lassociazione del cancro nei soggetti non fumatori che sono esposti al fumo di tabacco prodotto da altri.
Il fumo passivo (detto anche fumo ambientale, environmental tobacco smoke degli anglosassoni) θ il risultato di una miscela con laria del fumo espirato dal fumatore attivo (tertiary smoke) e del fumo prodotto dalla sigaretta, o altro dispositivo per fumare il tabacco, e immesso direttamente nellambiente (sidestream smoking). Gli agenti cancerogeni giΰ noti che si ritrovano nel fumo di tabacco cosμ disperso nellaria includono il benzene, l1,3-butadiene, il benzo[α]pirene, il 4-(metilnitrosamino)-1-(3-piridil)-1-butanone e molti altri, alla stessa stregua del fumo attivo. Il fumo passivo θ formato da una parte gassosa e da una parte corpuscolata e la sua concentrazione θ variabile a seconda dellentitΰ della fonte e delle caratteristiche dellambiente dove viene disperso, nonchι della distanza del soggetto esposto dalla fonte di inquinamento.
Il gruppo di esperti dello IARC ha esaminato piω di 50 studi sul rapporto tra fumo passivo e rischio di tumore del polmone nei non fumatori, pubblicati negli ultimi 25 anni. Il rischio per il cancro del polmone θ risultato aumentato in modo significativo, specialmente per i soggetti con esposizione piω elevata, per intensitΰ e durata. In particolare, per quanto riguarda lesposizione in ambiente domestico θ stato calcolato un aumento di rischio di tumore del polmone del 30% per i mariti non fumatori e del 20% per le mogli non fumatrici. Per quanto riguarda gli ambienti di lavoro, lesposizione dei non fumatori al fumo passivo comportava un aumento del rischio di cancro del polmone del 16-19%.
Questi risultati sono stati giudicati adeguati dal gruppo di lavoro IARC per concludere che il fumo involontario θ una causa di cancro del polmone nei non fumatori e per inserire quindi tale condizione di rischio nel gruppo 1.
Queste autorevoli conclusioni scientifiche sono state condivise pure dalla Commissione Scientifica, costituita in base alla previsione dellart. 10 del D.L.vo 38/2000, che ha curato la stesura dellElenco delle malattie per le quali θ obbligatoria la denuncia in base allart. 139 del Testo Unico4. La Commissione ha incluso il fumo passivo come agente causale del tumore del polmone nella Lista III, Malattie la cui origine lavorativa θ possibile.
LA TUTELA ASSICURATIVA INAIL PER LE MALATTIE NON TABELLATE
La tutela assicurativa delle malattie non ricomprese nella Tabella della Malattie Professionali (Allegato n. 4, D.P.R. n. 336/1994) e per le quali viene considerata ammissibile lipotesi si tratti di forme morbose secondarie allesposizione a rischi lavorativi ha trovato i presupposti legislativi nella sentenza della Corte Costituzionale n. 179 del 18 febbraio 1988 e n. 206 del 11 febbraio 1988.
In base ai principi enunciati dalla Suprema Corte lammissibilitΰ alla tutela assicurativa delle forme morbose non previste dalla Tabella allegata al Testo Unico richiede lonere della prova della natura professionale a carico del lavoratore. Non puς essere ammessa la presunzione legale dorigine, come per le forme tabellate, ma per ogni caso deve essere dimostrata la effettiva sussistenza e consistenza della causa lavorativa, invocata come responsabile, e ladeguatezza della stessa a produrre gli effetti dannosi per la salute del lavoratore, per i quali θ richiesta lammissibilitΰ alla tutela assicurativa INAIL.
Le norme di indirizzo emanate dalla Suprema Corte sono state oggetto di specifiche disposizioni attuative da parte dellINAIL che ha emesso al riguardo numerose circolari (circc. 23/1988, 65/1988, 35/1992, 80/1997, 81/2000, 71/2003 e 25/2004). Peraltro si θ formata nellarco di questi 15 anni una consistente dottrina e giurisprudenza che consentono di affrontare in modo adeguato tutte le fattispecie che di volta in volta giungono in esame.
Rispetto al problema dirimente della prova dellorigine professionale, lINAIL, giΰ con la circ. 80/1997, si θ attivato per svolgere un ruolo attivo nella acquisizione degli elementi probatori del nesso eziologico, svolgendo, se del caso, proprie indagini ispettive e tecniche per integrare i dati conoscitivi sul rischio.
Il PRIMO CASO DI CANCRO DEL POLMONE AMMESSO ALLINDENNIZZO INAIL.
Lassicurato: S.M. nato a Nulvi (Sassari) nel 1933, ma residente a Carbonia fin dal 1945, non presenta familiaritΰ per malattie tumorali. Non ha mai fumato. Tale circostanza, dirimente per li corretto inquadramento del caso, ha trovato conferma, oltre che nella dichiarazione rilasciata dal lavoratore, anche nella dichiarazione resa dal suo datore di lavoro e da quanto riportato nellanamnesi nelle cartelle cliniche.
Il rischio: il sig. S.M. ha sempre lavorato come banconiere di bar nei locali della cittΰ di residenza, fin dal 1948, svolgendo come minimo un orario di otto ore giornaliere. Ha lavorato continuativamente nello stesso locale dal 1961 al 1995, epoca del pensionamento.
I locali dove lassicurato ha svolto, nei diversi periodi, la propria attivitΰ erano ubicati al centro cittadino, con elevata frequenza di pubblico.
In particolare, per quanto riguarda la frequentazione, risulta che fino alla metΰ degli anni 70 il locale costituiva un notevole richiamo come sala TV, soprattutto in concomitanza di avvenimenti sportivi quali le partite del campionato di calcio, alle quali assistevano contemporaneamente non meno di 100-150 avventori. Parimenti si registrava un notevole afflusso di pubblico in occasione di frequenti ricevimenti, con un numero di invitati sempre tra i 100 e i 150. Il locale, nellarco degli anni qui in esame, era frequentato mediamente da non meno di 400 persone al giorno, prevalentemente di sesso maschile, e almeno il 40% si puς stimare fumasse almeno una sigaretta allinterno del bar (dati ISTAT sullabitudine al fumo di tabacco: nel 1980 il 54% degli uomini, nel 1986 il 40%, nel 1993 il 35%).
Per quanto riguarda la circolazione e il ricambio dellaria, occorre osservare che fino al 1988 la volumetria era limitata da una soppalcatura, i locali erano privi di ventilazione forzata e con scarsa aerazione naturale. Dal 1988 i nuovi locali avevano una volumetria maggiore e, dal 1992, erano muniti di impianto di aspirazione forzata.
Gli elementi di valutazione raccolti sono idonei ad ammettere che il sig. S.M. θ stato esposto in modo significativo allinalazione di fumo passivo per lintera vita lavorativa (47 anni), per una media di almeno 8 ore al giorno.
La malattia. Nel mese di maggio 1998 il lavoratore ha subito un ricovero presso la Divisione di Chirurgia Toracica dellOspedale Binaghi di Cagliari dove viene diagnosticata una neoplasia del polmone destro e, in data 25 giugno 1998, θ stato sottoposto ad intervento chirurgico di lobectomia superiore destra. La diagnosi istopatologica sul pezzo operatorio θ stata per: Carcinoma a cellule squamose non cheratinizzate, ben differenziato (G1), infiltrante; non superante la pleura viscerale.
Il rapporto di causalitΰ: la circostanza dirimente per ammettere la natura professionale della forma morbosa tumorale polmonare θ la condizione di non fumatore del paziente, come sopra evidenziata. Non θ, daltra parte, risultata familiaritΰ per patologia di natura tumorale Per contro appare ampiamente documentata una esposizione lavorativa a fumo passivo che, per durata ed intensitΰ, soddisfa i requisiti ammessi dalla Letteratura internazionale per configurare un rischio idoneo a determinare linsorgenza della neoplasia polmonare.
Sulla base di tali premesse il medico INAIL della Sede competente ha espresso un parere di indennizzabilitΰ del caso come malattia professionale non tabellata. Tali conclusioni sono state condivise dalla Sovrintendenza Medica Regionale INAIL e quindi dalla Sovrintendenza Medica Generale INAIL che ha pure acquisito parere specialistico pneumologico. In particolare la Sovrintendenza Medica Generale INAIL ha ritenuto che le condizioni suddescritte orientano a riconoscere nello specifico caso, con criterio di elevata probabilitΰ, lorigine professionale della malattia denunciata.
Il caso θ stato quindi sottoposto al definitivo parere della Direzione Centrale Prestazioni dellINAIL che si θ pronunciata con un giudizio di accoglimento, riconoscendo la effettiva sussistenza di un rischio oggettivo, rappresentato dal fumo passivo, cui lassicurato non poteva sottrarsi nello svolgimento del suo lavoro.
Il danno indennizzabile. Il caso θ stato poi ammesso alle prestazioni assicurative INAIL a cura della Sede competente in base alle previsioni del D.L.vo 38/2000, con valutazione del grado della menomazione dellintegritΰ psico-fisica nella misura del 57% e con coefficiente dindennizzo del 0,8.
CONCLUSIONI
Coerentemente con il progredire delle conoscenze in campo epidemiologico che hanno portato lo IARC a riconoscere il fumo passivo come cancerogeno inserito nel gruppo 1, lINAIL, in presenza di elementi oggettivi che consentivano di riconoscere in modo inequivoco il rischio lavorativo specifico e dopo lesclusione di altre possibili cause extralavorative, ha ammesso alla tutela assicurativa il primo caso di cancro del polmone da fumo passivo.
Θ il primo caso in Italia e, per quanto riguarda la specifica forma tumorale (polmone), non risultano in Letteratura altri casi in altri Paesi.
Il caso in esame θ il risultato dello sforzo che lINAIL, attraverso tutte le sue articolazioni a livello centrale e periferico, compie per far emergere dal sommerso le forme morbose per le quali viene spesso misconosciuta lorigine professionale.
BIBLIOGRAFIA
1. IARC Monographs (Vol 38) Tobacco Smoking (1986).
2. Forastiere F., Lo Presti E., Agabiti N., Rapiti E., Perucci Ca., Health impact of exposure to environmental tobacco smoke in Italy, Epidemiol. Prev. 2002; 26(1):18-29.
3. IARC Monographs (Vol 83) Tobacco Smoke and Involuntary Smoking (June 2002).
4. Decreto Ministeriale del Ministro del Lavoro, del 27 aprile 2004, G.U. Serie Generale, 10 giugno 2004; n.134: 16-45.
5. Cameron, P., J. S. Kostin, et al. (1969). "The health of smokers' and nonsmokers' children." Journal of Allergy 43(6): 336-41.
6. Colley, J. R., W. W. Holland, et al. (1974). "Influence of passive smoking and parental phlegm on pneumonia and bronchitis in early childhood." Lancet 2(7888): 1031-4.
7. Repace, J. L. and A. H. Lowrey (1980). "Indoor air pollution, tobacco smoke, and public health." Science 208(4443): 464-72.
8. Wells, A. J. (1988). "An estimate of adult mortality in the United States from passive smoking." Environ. Int. 14: 249-265.
9. Glantz, S. and W. Parmley (1991). "Passive Smoking and Heart Disease: Epidemiology, Physiology, and Biochemistry." Circulation 83(1): 1-12.
10. Fontham, E. T., P. Correa, et al. (1994). "Environmental tobacco smoke and lung cancer in nonsmoking women: A multicenter case-control study." JAMA 271: 1752-1759.
11. Glantz, S. A. and L. R. A. Smith (1994). "The Effect of Ordinances Requiring Smoke-Free Restaurants on Restaurant Sales." American Journal of Public Health 84: 1081-1085.
12. Hirayama, T. (1981). "Non-smoking wives of heavy smokers have a higher risk of lung cancer: a study from Japan." British Medical Journal (Clinical Research Ed.) 282(6259): 183-5.
13. Klonoff-Cohen, H., H. Edelstein, et al. (1995). "The effect of passive smoking and tobacco exposure through breast milk on sudden infant death syndrome." JAMA 273: 795-798.
14. Barnes, D. and L. Bero (1998). "Why review articles on the heath effects of passive smoking reach different conclusions." JAMA 279: 1566-1570.
15. Chapman, S., R. Borland, et al. (1999). "The impact of smoke-free workplaces on declining cigarette consumption in Australia and the United States." American Journal of Public Health 89(7): 1018 - 1023
http://www.inail.it/cms/Medicina_Riabilita...ssivo_Manca.doc
Tumore del colon-retto: il fumo aumenta il rischio di incidenza e di mortalitΰ
Il fumo aumenta del 18% il rischio di sviluppare un tumore del colon e del retto e del 25% il rischio di morire per questo tumore: θ quanto emerge dallo studio, pubblicato su JAMA.
Edoardo Botteri, epidemiologo, Ricercatore presso lIstituto Europeo di Oncologia ( IEO ) di Milano, insieme ad alcuni colleghi ha condotto per la prima volta un lavoro di revisione e sintesi dei dati giΰ esistenti sul legame tra incidenza e mortalitΰ per il carcinoma del colon-retto e il fumo.
Sebbene il fumo di tabacco sia responsabile di circa 5,4 milioni di morti nel 2005, nel mondo ci sono ancora circa 1 miliardo e 300 milioni di fumatori. Il fumo θ giΰ stato riconosciuto come la causa di alcune forme di tumore, tuttavia negli studi condotti finora il legame tra la sigaretta e il tumore del colon-retto θ sempre apparso poco significativo.
Poichι labitudine al fumo potenzialmente puς essere tenuta sotto controllo con interventi a livello sia individuale che sociale, identificare una relazione tra fumo e cancro del colon-retto puς aiutare a ridurre le vittime di questo tumore, il terzo piω diffuso nel mondo e che attualmente causa ogni anno 500mila morti.
Secondo gli Autori dellarticolo si stima che, solo negli Stati Uniti, nel 2008 le morti per tumore del colon-retto siano 50.000.
I Ricercatori hanno preso in esame 106 studi osservazionali per un totale di circa 40 mila nuovi casi di tumore del colon-retto. Per quanto riguarda lincidenza, il fumo θ stato associato a un aumento del 18% del rischio di sviluppare un tumore.
I Ricercatori inoltre hanno rilevato lesistenza di un rapporto significativo tra casi di tumore e dose di tabacco, con un aumento dei casi in proporzione al numero di pacchetti di sigarette consumati ogni anno ( numero di pacchetti di sigarette fumate al giorno moltiplicato per gli anni in cui si ha fumato ) e numero di sigarette fumate ogni giorno. Il rapporto θ comunque risultato statisticamente rilevante solo dopo 30 anni di fumo.
Per lanalisi della mortalitΰ sono stati esaminati 17 studi che hanno indicato che i fumatori hanno un rischio maggiore del 25% di morire per tumore del colon-retto rispetto alla popolazione che non ha mai fumato. Θ stato inoltre rilevato un aumento del rischio di morte per tumore del colon-retto proporzionale al numero di sigarette fumate al giorno e alla durata del periodo in cui si ha fumato. Il rischio sia di incidenza che di mortalitΰ θ risultato maggiore per il tumore del retto rispetto a quello del colon.
Fino ad oggi il fumo non θ mai stato considerato un fattore significativo per determinare le fasce di popolazione che necessitano dello screening per tumore del colon-retto, spiegano. Tuttavia molti studi hanno dimostrato che questo tumore compare piω precocemente nei fumatori, e in particolare nei forti fumatori, e i dati raccolti sia in passato che oggi forniscono prove evidenti di quanto il fumo di sigaretta abbia un effetto determinante sullo sviluppo dei polipi adenomatosi ( tumori benigni ) e del tumore vero e proprio. Riteniamo che il fumo sia un fattore importante da tenere in considerazione quando si debba determinare letΰ in cui iniziare lo screening: puς determinare sia unetΰ inferiore nei fumatori che unetΰ maggiore nei non fumatori. ( Xagena2008 )
Fonte: Istituto Europeo di Oncologia, 2008
Onco2008
www.xapedia.it/oncologia/show.php?a=14780&l=f&w=Fumo+tumori
Finalmente levidenza scientifica: il fumo e responsabile di 9 casi di cancro al polmone su 10
Posted by admin on 03 Sep 2009
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Morte per cancro, nuovi dati
Individuate tre aree del Dna collegate al pericolo di tumore ai polmoni nei fumatori. Due di queste aree influenzerebbero il tipo di cancro che si sviluppera. La scoperta e dovuta a un gruppo di ricercatori dellInstitute of Cancer Research e lo studio e stato pubblicato sulla prestigiosa rivista Cancer Research.
Il fumo e responsabile di 9 casi di cancro al polmone su 10.
I ricercatori hanno confrontato il Dna di circa 1.900 pazienti affetti da tumore al polmone con quello di 1.400 soggetti sani. Le informazioni raccolte sulle aree a rischio genetico sono state poi esaminate su altri 2 mila pazienti con il cancro al polmone e su altrettanti individui sani.
I ricercatori hanno trovato specifiche differenze, associate con il rischio cancro al polmone, sul cromosoma 5, 6 e 15. In particolare, quelli che hanno presentato differenze genetiche sul cromosoma 5 sono risultati piu a rischio di sviluppare un tipo di cancro chiamato adenocarcinoma. La regione del cromosoma 6, invece, sembra determinare lo sviluppo di un adenocarcinoma o di un altro tipo di tumore chiamato carcinoma a cellule squamose. Infine, sul cromosoma 15, sono stati individuati due siti indipendenti che avrebbero un ruolo nello sviluppo o meno del cancro ai polmoni nei fumatori. Queste aree del genoma contengono una famiglia di geni che influenzerebbe il comportamento dei fumatori, ma anche la crescita delle cellule tumorali e delle cellule morte. I fumatori e gli ex fumatori che hanno una copia di ciascuna di queste varianti genetiche hanno il 28 per cento delle probabilita in piu di sviluppare il cancro al polmone. Una percentuale che sale all80 per cento nei fumatori portatori di due copie. Invece, coloro che hanno queste mutazioni genetiche, ma che non fumano,Β non hanno avuto alcun aumento del rischio cancro. Il prossimo passo ha detto Richard Houlston, che ha coordinato lo studio e quello di scavare piu a fondo per individuare quale gene o quali geni in queste regioni causano laumento del rischio di sviluppare il cancro al polmone e il modo in cui innescano effettivamente questo aumento -Β Fonte:Β AGI Salute www.agi.it
http://www.exfumatore.com/2009/09/03/final...-polmone-su-10/
www.icr.ac.uk/research/research_profiles/2761.shtml
Professor Richard Houlston
Professor of Molecular and Population Genetics
Tel: (020) 8722 4175
Tel: (020) 8722 4011
[email protected]
Location: Brookes Lawley Building, Sutton
Section: Section of Cancer Genetics
Research Interests
Molecular and Population Genetics
Software and Databases
National Interobserver Agreement in Colorectal Cancer (NIACC) Study
View Publications from Dr Richard Houlston.
A Genome-wide Association Study of Lung Cancer Identifies a Region of Chromosome 5p15 Associated with Risk for Adenocarcinoma
Landi, M. T., Chatterjee, N., Yu, K., Goldin, L. R., Goldstein, A. M., Rotunno, M., Mirabello, L., Jacobs, K., Wheeler, W., Yeager, M., Bergen, A. W., Li, Q., Consonni, D., Pesatori, A. C., Wacholder, S., Thun, M., Diver, R., Oken, M., Virtamo, J., Albanes, D., Wang, Z., Burdette, L., Doheny, K. F., Pugh, E. W., Laurie, C., Brennan, P., Hung, R., Gaborieau, V., McKay, J. D., Lathrop, M., McLaughlin, J., Wang, Y., Tsao, M., Spitz, M. R., Wang, Y., Krokan, H., Vatten, L., Skorpen, F., Arnesen, E., Benhamou, S., Bouchard, C., Metsapalu, A., Vooder, T., Nelis, M., Vaelk, K., Field, J. K., Chen, C., Goodman, G., Sulem, P., Thorleifsson, G., Rafnar, T., Eisen, T., Sauter, W., Rosenberger, A., Bickeboeller, H., Risch, A., Chang-Claude, J., Wichmann, H. E., Stefansson, K., Houlston, R., Amos, C. I., Fraumeni Jr., J. F., Savage, S. A., Bertazzi, P. A., Tucker, M. A., Chanock, S., Caporaso, N. E. (2009) A Genome-wide Association Study of Lung Cancer Identifies a Region of Chromosome 5p15 Associated with Risk for Adenocarcinoma. AMERICAN JOURNAL OF HUMAN GENETICS, 85 (5). pp. 679-691. ISSN 0002-9297
Full text not available from this repository.
Abstract
Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of king cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four Studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SQ. In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR] = 1.23, 95% confidence interval [CI] = 1.13-1.33, p = 3.02 x 10(-7)), but not with other histologic types (OR = 1.01, p = 0.84 and OR = 1.00, p = 0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR = 1.24, 95% CI = 1.17-1.31, p = 3.74 x 10(-14) for AD; OR = 0.99, p = 0.69 and OR = 0.97, p = 0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.
Internal Authors or Editors: Authors (ICR Faculty only) Email Address
Houlston, Richard [email protected]
All Authors: Landi, M. T., Chatterjee, N., Yu, K., Goldin, L. R., Goldstein, A. M., Rotunno, M., Mirabello, L., Jacobs, K., Wheeler, W., Yeager, M., Bergen, A. W., Li, Q., Consonni, D., Pesatori, A. C., Wacholder, S., Thun, M., Diver, R., Oken, M., Virtamo, J., Albanes, D., Wang, Z., Burdette, L., Doheny, K. F., Pugh, E. W., Laurie, C., Brennan, P., Hung, R., Gaborieau, V., McKay, J. D., Lathrop, M., McLaughlin, J., Wang, Y., Tsao, M., Spitz, M. R., Wang, Y., Krokan, H., Vatten, L., Skorpen, F., Arnesen, E., Benhamou, S., Bouchard, C., Metsapalu, A., Vooder, T., Nelis, M., Vaelk, K., Field, J. K., Chen, C., Goodman, G., Sulem, P., Thorleifsson, G., Rafnar, T., Eisen, T., Sauter, W., Rosenberger, A., Bickeboeller, H., Risch, A., Chang-Claude, J., Wichmann, H. E., Stefansson, K., Houlston, R., Amos, C. I., Fraumeni Jr., J. F., Savage, S. A., Bertazzi, P. A., Tucker, M. A., Chanock, S., Caporaso, N. E.
Item Type: Article
Uncontrolled Keywords: TELOMERASE REVERSE-TRANSCRIPTASE; IDIOPATHIC PULMONARY-FIBROSIS; SUSCEPTIBILITY LOCUS; FAMILY-HISTORY; MUTATIONS; VARIANTS; POPULATION; EXPRESSION; TERT; METAANALYSIS
Sections and Clinical Units: Cancer Genetics Section
Cancer Genetics Section > Molecular & Population Genetics (Prof R Houlston)
ID Code: 9102
Deposited By: Ashley Cousins
Deposited On: 04 Dec 2009 09:58
Last Modified: 10 Feb 2010 11:49
http://publications.icr.ac.uk/9102/
Tumori maschili causati in maggioranza dal fumo
IL FUMO ATTIVO E PASSIVO Θ RESPONSABILE DELL'INSORGENZA DELLA MAGGIOR PARTE DI TUMORI MASCHILI, E DI 7 DECESSI SU 10 PER CANCRO
I ricercatori dellUniversitΰ della California, coordinati da Bruce Leistikow, hanno esaminato i dati relativi alla mortalitΰ per tumore degli uomini del Massachusetts nel periodo compreso tra il 1979 e il 2003 scoprendo che maggior parte dei tumori maschili, non solo ai polmoni, θ direttamente o indirettamente causato dal fumo.
Nell'ambito della ricerca sono stati analizzati migliaia di dati che han evidenziato come nel range di etΰ 30 / 74 anni lincidenza del tumore ai polmoni e di altre neoplasie salga notevolmente, e come il fumo sia correlato a 7 decessi su 10
A causare questi effetti sarebbe sia il fumo attivo che quello passivo, precedentemente sottovalutato.Uno studio risalente al 2001, infatti, aveva fissato al 34% lincidenza del fumo attivo e passivo sul numero di decessi legati al cancro, una stima che θ stata quasi raddoppiata in questa ultima ricerca.
Redazione MolecularLab.it (28/01/2009)
Male tobacco smoke load and non-lung cancer mortality associations in Massachusetts
Leistikow BN, Kabir Z, Connolly GN, Clancy L, Alpert H. . 8:341 www.biomedcentral.com/1471-2407/8/341
BMC Cancer. 2008. 8:341.
www.biomedcentral.com/1471-2407/8/341 Abstract (provisional) Background Different methods exist to estimate smoking attributable cancer mortality rates (Peto and Ezzati methods, as examples). However, the smoking attributable estimates using these methods cannot be generalized to all population sub-groups. A simpler method has recently been developed that can be adapted and applied to different population sub-groups. This study assessed cumulative tobacco smoke damage (smoke load)/non-lung cancer mortality associations across time from 1979 to 2003 among all Massachusetts males and ages 30-74 years, using this novel methodology. Methods Annual lung cancer death rates were used as smoke load bio-indices, and age-adjusted lung/all other (non-lung) cancer death rates were analyzed with linear regression approach. Non-lung cancer death rates include all cancer deaths excluding lung. Smoking-attributable-fractions (SAFs) for the latest period (year 2003) were estimated as: 1- (estimated unexposed cancer death rate/observed rate). Results Male lung and non-lung cancer death rates have declined steadily since 1992. Lung and non-lung cancer death rates were tightly and steeply associated across years. The slopes of the associations analyzed were 1.69 (95% confidence interval (CI) 1.35-2.04, r=0.90), and 1.36 (CI 1.14-1.58, r=0.94) without detected autocorrelation (Durbin-Watson statistic = 1.8). The lung/non-lung cancer death rate associations suggest that all-sites cancer death rate SAFs in year 2003 were 73% (Sensitivity Range [SR] 61-82%) for all ages and 74% (SR 61-82%) for ages 30-74 years. Conclusions The strong lung/non-lung cancer death rate associations suggest that tobacco smoke load may be responsible for most prematurely fatal cancers at both lung and non-lung sites. The present method estimates are greater than the earlier estimates. Therefore, tobacco control may reduce cancer death rates more than previously noted.
http://leistikow.ucdavis.edu/
Fumare provoca cancro mortale ai polmoni
In Svizzera, il cancro ai polmoni θ di gran lunga la principale causa di morte per cancro negli uomini; nelle donne θ la terza causa di morte dopo il tumore al seno e il cancro del colon e del retto(1). L85 % dei casi di cancro ai polmoni θ riconducibile al tabagismo(2). In altre parole, oltre 2'100 persone si ammalano in Svizzera di tumore ai polmoni dovuto al consumo di ta-bacco(3).
Il rischio di sviluppare un tumore ai polmoni aumenta in modo significativo in base alla quantitΰ di sigarette fumate al giorno e ancor piω al numero di anni in cui si sono consumati prodotti del tabacco4,5. Il tabacco θ quindi di gran lunga la principale causa del cancro ai polmoni. L80 % delle persone che ne θ colpito muore in meno di tre anni.
Si stima che, nel corso della propria vita, rischia di ammalarsi di tumore ai polmoni e di morirne un uomo su 11, rispettivamente uno su 12, e una donna su 21, rispettivamente una su 226.
La pipa e il sigaro possono anchessi provocare il cancro ai polmoni, ma i rischi sono inferiori alla sigaretta, dato che numerosi fumatori di pipa e sigaro non ne inalano il fumo7,8.
Smettere di fumare permette di ridurre in misura considerevole il rischio di sviluppare un tumore ai polmoni8,9.
Riferimenti bibliografici:
1. ASSOCIAZIONE SVIZZERA REGISTRI TUMORI, Cancer in Switzerland, Volume 2 - Statistics of Mortalitΰ 1985-2003, p. 5; URL: http://asrt.ch/asrt/newstat/m2003ch.pdf.
2. U.S. Department of Health and Human Services, Reducing the Health Consequences of Smoking: 25 Years of Progress. A Report of the Surgeon General, U.S. Department of Health and Human Services, Public Health Service, DHHS Publication No. (CDC) 89-8411, 11 gennaio 1989.
3. Ufficio federale di statistica (2009). La mortalitΰ da fumo in Svizzera, stima per gli anni 1995-2007.
4. Y. T. Gao, W. J. Blot, W. Zheng et al., Lung Cancer and smoking in Shanghai, in «Int J Epidemiol», 17, 1988, pp. 277-280.
5. R. Doll, J. Peto, Cigarette smoking and bronchial carcinoma;dose and time relationships among regular smokers and life-long nonsmokers, in «J Epidemiol Community Health», 32, 1978, pp. 303-313.
6. Institut national du cancer du Canada, Statistiques canadiennes sur le cancer 1999, Toronto, 1999, p. 45.
7. W. J. Blot, J. F. Fraumeni Jr, Cancers of the lung and pleura, in Cancer epidemiology and prevention, a cura di D. Schottenfeld, J. F. Fraumeni Jr., 2nd ed., New York, Oxford University Press, 1996, pp. 637-665.
8. Santι Canada, Actualitιs sur le cancer. Le cancer du poumon au Canada; (http://www.hc-sc.gc.ca/hl-vs/tobac-tabac/b...ie/index_f.html).
9. IARC, Tobacco smoking. Monographs on the evaluation of carcinogenic risk of chemicals to man, vol. 38, Lione, IARC, 1986.
http://www.bag.admin.ch/themen/drogen/0004...ex.html?lang=it
MORTALITY FROM SMOKING IN DEVELOPED COUNTRIES 1950-2000
(2nd edition: updated June 2006)
Richard Peto, Alan D. Lopez, Jillian Boreham and Michael Thun
For 45 'developed' countries or groups of countries, smoking-attributed deaths are estimated indirectly from national vital statistics,
as in Peto, Lopez et al, 1992, 1994 (but now updated with year 2000 national data).
To sample the tables of tobacco deaths presented for each geographic area, click EU25 and review the 6 pairs of pages, or go to CONTENTS, click "Specific country ...." and choose one.
To sample choosing one particular pair of pages for all 45 areas click Main tables (and wait for downloading), or go to CONTENTS,
click "Specific pair ...." and choose to download one particular type of table or figure.
For four former Yugoslav republics, where historical trends may be unreliable or are unavailable, pages showing trends are omitted.
Minor differences between this and the 1994 (1st) edition are due to the use of slightly different population estimates and use of actual
(instead of projected) national mortality data for 1995.
The material presented is preliminary (last updated June 2006) and will change slightly, especially when actual year 2000 mortality data
replaces the estimates that had to be made for two countries, Belgium and Turkmenistan (the latter incorporated into Central Asia).
Copyright waiver: Any part may be reproduced without seeking permission.
CONTENTS
AUTHOR AFFILIATIONS
RICHARD PETO
Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU)
Nuffield Department of Clinical Medicine, University of Oxford
Richard Doll Building, Old Road Campus
Roosevelt Drive, Oxford OX3 7LF, UK
ALAN D LOPEZ
School of Population Health, University of Queensland
Herston Road, Herston
Brisbane Qld 4006, Australia
JILLIAN BOREHAM ([email protected])
CTSU
Nuffield Department of Clinical Medicine, University of Oxford
Richard Doll Building, Old Road Campus
Roosevelt Drive, Oxford OX3 7LF, UK
MICHAEL THUN
Department of Epidemiology and Surveillance Research
American Cancer Society
1599 Clifton Road NE
Atlanta, GA 30329-4251, USA
www.ctsu.ox.ac.uk/~tobacco/
www.airc.it/tumori/tumore-al-polmone.asp
piω importante fattore di rischio nel tumore del polmone θ rappresentato dal fumo di sigaretta: esiste infatti un chiaro rapporto dose-effetto, e questo vale anche per il fumo passivo, tra questa abitudine e la neoplasia. Ciς significa che piω si θ fumato (o piω fumo si θ respirato nella vita), maggiore θ la probabilitΰ di ammalarsi. Questa relazione vale in particolare per alcuni sottotipi di cancro al polmone: il carcinoma spinocellulare e il microcitoma.
Il fumo di sigaretta contiene numerose sostanze che agiscono direttamente (cioθ con lesioni immediate) o indirettamente (cioθ con lente modificazioni nel corso del tempo) a livello dei bronchi. Per fare un esempio, sono cancerogeni diretti gli idrocarburi aromatici policiclici (cioθ i prodotti della combustione, tra cui il ben noto benzopirene) e le nitrosamine (derivati dell'ammoniaca usati nella lavorazione delle sigarette); invece i fenoli e le aldeidi (contenuti per esempio nella carta) si sono dimostrati fattori indiretti, cioθ sono in grado, col tempo, di promuovere la trasformazione delle cellule in senso tumorale.
Esistono poi altri cancerogeni chimici come l'amianto (asbesto), il radon, i metalli pesanti, il catrame e gli oli minerali, che provocano il tumore del polmone soprattutto in quella parte di popolazione che viene a contatto con queste sostanze per motivi di lavoro: si parla in questo caso di esposizione professionale.
Infine non bisogna dimenticare alcune alterazioni genetiche che predispongono a questa malattia: le piω importanti sono quelle che avvengono a carico del gene p53 o del gene FHIT, che comunque sono causa di un numero molto ridotto di casi.
Il fumo in cifre
Il fumo di sigaretta θ oggi ritenuto il fattore causale piω importante del tumore polmonare. Θ stato dimostrato che un uomo dell'etΰ di 35 anni, che fuma 25 o piω sigarette al giorno, ha un rischio di morire di cancro del polmone prima dei 75 anni pari al 13 per cento.
Il rischio aumenta in relazione a:
1. numero di sigarette fumate
(in modo proporzionale diretto: piω sono, piω sale il rischio);
2. etΰ di inizio dell'abitudine al fumo (piω si θ giovani, piω rischi si corrono);
3. assenza di filtro nelle sigarette
(i prodotti della combustione, come i catrami, contribuiscono in modo rilevante alla patologia).
Nei soggetti che smettono di fumare il rischio si riduce nel corso dei 10-15 anni successivi, fino a eguagliare quello di chi non ha mai fumato, se si riesce a smettere per tempo. Anche il fumo passivo aumenta il rischio di sviluppare il carcinoma polmonare (ovvero aumenta del 19 per cento il rischio dell'individuo non fumatore di ammalarsi di cancro al polmone).
http://it.wikipedia.org/wiki/Carcinoma_del_polmone
Carcinoma del polmone
Da Wikipedia, l'enciclopedia libera.
Carcinoma del polmone
Sezione di polmone colpito da carcinoma a cellule squamose (area solida biancastra).
La zona a valle del bronco colpito ha limiti sfrangiati ed irregolari, con aspetto cotonoso; quest'ultimo reperto identifica un'area di consolidamento pneumonico post-ostruttivo.
Sezione istologica di un carcinoma polmonare a cellule squamose. Il tessuto θ composto da cellule squamose e non sono piω presenti le caratteristiche della mucosa e della sottomucosa bronchiale normale.
Tipo Maligno
Cellula di origine
Epitelio bronchiale
Cellule APUD
Fattori di rischio
Fumo
Radon
Amianto
Inquinamento atmosferico
Incidenza
60-90/100 000
Etΰ media alla diagnosi 60 - 80 anni
Rapporto M:F 4-5:1
ICD-9-CM
(EN) 162
ICD-10
(EN) C33-C34
Con la locuzione carcinoma del polmone si fa riferimento ad una categoria diagnostica che comprende l'insieme delle neoplasie maligne che originano dai tessuti epiteliali (carcinomi) che compongono i bronchi e il parenchima polmonare.[1]
Per questo, i sarcomi e i linfomi che originano nel contesto delle strutture polmonari devono essere distinti da questa categoria.
La maggior parte (oltre il 95%) delle neoplasie polmonari maligne θ rappresentato dal carcinoma del polmone, mentre i sarcomi e linfomi costituiscono meno dello 0,5% di questa casistica.[2] Meno del 5% delle neoplasie polmonari θ invece rappresentato da tumori benigni (amartoma) o a basso grado di malignitΰ (carcinoidi).[3]
Un'ulteriore distinzione deve essere operata tra neoplasie primitive e neoplasie secondarie; infatti, mentre le prime originano dalle strutture polmonari, le seconde sono rappresentate da metastasi di neoplasie che si originano in altri organi come, ad esempio, il rene, il fegato, la mammella e la prostata.
Storia [modifica]
Il carcinoma del polmone era poco comune prima della diffusione dell'abitudine al fumo di tabacco e fino al 1791 non era considerato un'entitΰ patologica con dignitΰ propria.[4] I differenti aspetti del carcinoma del polmone vennero descritti nel 1819.[5] Nel 1878 i tumori maligni del polmone costituivano solo l'1% delle neoplasie osservate in corso di autopsia, ma la percentuale salμ fino al 10-15% nella prima parte del 1900.[6] I dati riportati nella letteratura medica riferiscono solo 374 casi in tutto il mondo nel 1912,[7] ma lo studio dei dati derivati dai referti autoptici ha dimostrato che l'incidenza aumentς dallo 0,3% nel 1852 al 5,66% nel 1952.[8]
In Germania, nel 1929, il medico Fritz Lickint riconobbe la connessione tra il fumo di sigaretta e il carcinoma del polmone,[6] evento che portς ad un'imponente campagna anti-fumo nella Germania nazista.[9] Il British Doctors Study, uno studio iniziato negli anni cinquanta, costituμ la prima solida evidenza epidemiologica della connessione tra il fumo e il carcinoma del polmone.[10] Come risultato, nel 1964, il Surgeon General of the United States raccomandς a tutti i fumatori di interrompere l'abitudine al fumo.[11]
La connessione con il radon venne riconosciuta per prima tra i minatori delle riserve metallifere intorno a Schneeberg, nella zona di confine tra la Baviera (Germania) e la Boemia (Repubblica Ceca). Questa regione θ molto ricca in fluorite, ferro, rame, cobalto e argento, quest'ultimo raccolto fin dal 1470. La presenza di notevoli quantitΰ di uranio e radio si tradusse in un'intensa e continuativa esposizione al radon, gas radioattivo ritenuto responsabile della carcinogenesi (vedi eziologia).
I minatori svilupparono una quantitΰ sproporzionata di affezioni polmonari, ricondotte nel 1870 ai poliedrici quadri clinici sostenuti dalle neoplasie polmonari. Θ stato stimato che circa il 75% di questi minatori morirono per carcinoma del polmone.[12] Nonostante questa scoperta l'estrazione di uranio continuς anche durante gli anni cinquanta, a causa della continua richiesta da parte dell'Unione Sovietica.[13]
Il primo intervento riuscito di pneumectomia per carcinoma del polmone θ stato effettuato nel 1933.[14] La radioterapia palliativa θ stata usata sin dagli anni quaranta,[15] mentre la radioterapia radicale (ad alti dosaggi) cominciς ad essere presa in considerazione dagli anni cinquanta in poi come presidio terapeutico nei soggetti con carcinoma del polmone limitato, ma inadatti all'intervento chirurgico.[16] Nel 1997 la radioterapia continua accelerata iperfrazionata (CHART) soppiantς la convenzionale radioterapia radicale per la cura delle neoplasie polmonari.[17]
Per quanto riguarda il carcinoma polmonare a piccole cellule, gli iniziali approcci chirurgici nel 1960[18] e la radioterapia radicale[19] furono infruttuosi. Regimi chemioterapici soddisfacenti vennero sviluppati solo a partire dagli anni settanta.[20]
Nel mondo [modifica]
Il carcinoma del polmone θ la neoplasia con il maggior tasso di incidenza e di mortalitΰ nel mondo (1,35 milioni di nuovi casi all'anno e 1,18 milioni di morti), con la massima frequenza negli Stati Uniti d'America e in Europa.[21] Negli Stati Uniti, nel 2006, il carcinoma del polmone θ stato diagnosticato in circa 60 persone ogni 100 000 abitanti; nello stesso periodo sono morte per questa neoplasia circa 52 persone ogni 100 000 abitanti.[2]
Vengono colpiti prevalentemente soggetti di etΰ superiore a 50 anni che abbiano fatto uso di tabacco. Le misure di prevenzione per il fumo di sigaretta prese dal 1960 in poi hanno portato a una lenta ma costante diminuzione del tasso di mortalitΰ negli individui di sesso maschile nella prima parte di questo secolo, benchι non si sia ancora osservata una diminuzione significativa nelle donne.[22] In particolare θ stato rilevato che mentre nell'Europa orientale il tasso di mortalitΰ θ maggiore negli uomini, nell'Europa settentrionale (vedi epidemiologia in Europa) e negli Stati Uniti il tasso di mortalitΰ θ maggiore nelle donne.[23]
Altri studi epidemiologici si sono concentrati nella valutazione di altri fattori di rischio per lo sviluppo di tumori polmonari, rivelando un maggiore tasso d'incidenza nelle popolazioni esposte all'inquinamento proveniente dalle emissioni di automobili, industrie e centrali termoelettriche, come nel Texas,[24] a Taiwan[25] e nelle zone limitrofe a Dublino.[26] Dai dati provenienti da questi studi θ risultato evidente il ruolo delle misure preventive focalizzate sulla riduzione dell'esposizione soprattutto ai fumi provenienti dalla combustione del gasolio e dei carburanti derivati dal petrolio.[27]
Il carcinoma del polmone θ meno comune nei paesi in via di sviluppo, benchι sia stato rilevato un notevole aumento di incidenza e di mortalitΰ nei paesi in cui θ subentrata l'abitudine al fumo di sigaretta, in particolare in Cina[28] e in India.[29]
L'incidenza (per ogni paese) di neoplasie polmonari ha una relazione inversa con l'esposizione alla luce solare e ai raggi ultravioletti: una possibile spiegazione del fenomeno puς essere connessa al ruolo anti-tumorale svolto dalla vitamina D, che si origina dalla pelle in seguito all'esposizione solare.[30]
Un dato degno di nota θ un aumento dell'incidenza, dal 1950 in poi, della variante adenocarcinoma,[31] tumore che interessa soprattutto le regioni periferiche del polmone. Il fenomeno θ essenzialmente dovuto all'introduzione del filtro nelle sigarette, in grado di intrappolare le particelle piω grandi (che si depositerebbero nei bronchi prossimali) e di lasciar passare invece le particelle piω piccole, che si depositano nei bronchi distali. La presenza del filtro, inoltre, induce il fumatore a fare inspirazioni piω profonde per ricevere la stessa quota di nicotina, con maggiore deposizione delle sostanze tossiche nelle regioni polmonari piω periferiche.[32] Negli Stati Uniti d'America, tuttavia, l'incidenza di adenocarcinoma sta diminuendo dal 1999: questo dato sembra essere dovuto alla diminuzione dell'inquinamento ambientale.[31]
In Europa [modifica]
In Europa (2006) il carcinoma del polmone costituisce la piω comune causa di morte per cancro.[33]
Nella tabella e nelle carte tematiche sono riportati i relativi dati di incidenza e mortalitΰ in Europa nello stesso periodo.[33] L'incidenza nelle femmine, in assoluto, θ minore di quella nei maschi, in accordo con la tendenza mondiale. In particolare, l'incidenza nei maschi risulta essere particolarmente elevata negli stati dell'Europa orientale (Ungheria, Polonia, Russia e Bielorussia), mentre negli stati scandinavi e negli stati dell'Europa settentrionale (Svezia, Finlandia, Norvegia, Gran Bretagna, Islanda e Irlanda) l'incidenza θ molto minore. Per le femmine la situazione θ quasi opposta: negli stati dell'Europa settentrionale l'incidenza θ massima, con un sorpasso sul sesso maschile in Islanda, mentre θ minima nell'Europa orientale.
Elaborando queste informazioni si ricava che l'assetto della distribuzione dell'incidenza prevede una discrepanza minima tra il sesso maschile e quello femminile negli stati del nord e massima negli stati dell'est. Allo stesso modo si puς constatare che, in linea generale, a mano a mano che per ogni paese scende l'incidenza per i maschi quella per le femmine aumenta fino ad equipararsi. La mortalitΰ segue strettamente la tendenza mostrata dall'incidenza, con picchi nei paesi dell'est per i maschi e nei paesi del nord per le femmine.
In Italia [modifica]
Incidenza e mortalitΰ in Italia per carcinoma del polmone nel periodo 1998-2002
In Italia nel 2004 sono morte 32 840 persone per carcinoma del polmone.[34] Nel periodo compreso tra l'anno 1998 e il 2002, nell'area AIRT (localitΰ italiane analizzate nei grafici a destra) il carcinoma del polmone ha rappresentato per frequenza la 3ͺ neoplasia diagnosticata nel sesso maschile e la 4ͺ nel sesso femminile.[35] Per quanto riguarda la mortalitΰ, il carcinoma del polmone rappresenta la prima causa di mortalitΰ per cancro nell'uomo e la seconda nella donna (dopo il cancro della mammella).
I tassi relativi sono stati elaborati ed inseriti nel grafico a destra, dalla cui osservazione θ possibile ricavare una serie di informazioni. In primo luogo, come in Europa, l'incidenza di carcinoma del polmone in Italia θ caratterizzata da un rapporto maschi:femmine di circa 5-4:1, benchι queste differenze si stiano completamente annullando per quanto riguarda l'incidenza in soggetti di etΰ compresa tra i 20 e i 44 anni.[36] L'incidenza per il sesso maschile θ massima a Genova, in Veneto, a Ferrara e a Napoli, mentre θ minima nell'Alto Adige; nelle femmine l'incidenza θ massima nel Veneto e a Parma mentre θ minima in alcune cittΰ del Sud come Salerno e Ragusa. La mortalitΰ per i maschi θ massima in Veneto, Napoli e a Varese mentre θ minima in Umbria, a Macerata e a Ragusa. Nelle femmine la mortalitΰ θ massima a Ferrara ed in Veneto mentre θ minima a Ragusa, Salerno e Macerata.
Un'ulteriore osservazione puς essere fatta confrontando i dati di incidenza con quelli di mortalitΰ per uno stesso luogo, ricavando che, comunque sia, il carcinoma del polmone ha un bassissimo indice di sopravvivenza sia nei maschi che nelle femmine. Inoltre, per entrambi i sessi, in luoghi come Ferrara e Genova dove θ massimo il tasso di incidenza vi θ un indice di sopravvivenza maggiore rispetto a luoghi come l'Alto Adige in cui l'incidenza θ minima. Questo significa che ad esempio a Genova, benchι il tasso di mortalitΰ sia in assoluto maggiore rispetto a quello dell'Alto Adige, vi θ una maggiore possibilitΰ di sopravvivenza nei soggetti cui viene diagnosticato il carcinoma del polmone. Nello stesso periodo gli istotipi (vedi classificazione istologica) piω frequenti nel sesso maschile sono il carcinoma polmonare a cellule squamose (32%) e l'adenocarcinoma polmonare (23%), mentre il carcinoma polmonare a piccole cellule rappresenta circa l'8% di questa casistica.[35] Nelle femmine l'adenocarcinoma polmonare rappresenta l'istotipo piω frequente (33%), seguito dal carcinoma polmonare a cellule squamose (16%). Come nei maschi, il carcinoma polmonare a piccole cellule θ meno frequente a questi due istotipi (9%). In entrambi i sessi l'etΰ media di incidenza in Italia θ tra i 70 e gli 80 anni. La mortalitΰ nei maschi θ massima tra i 75 e i 79 anni, mentre nelle femmine θ massima tra gli 80 e 84 anni. Deve inoltre essere sottolineato che a partire dalla fine degli anni ottanta fino al 2002 l'incidenza e la mortalitΰ di carcinoma del polmone sono diminuite nel sesso maschile. Nel sesso femminile i dati indicano un aumento dell'incidenza e della mortalitΰ. Tuttavia, per il sesso femminile, la mortalitΰ cresce meno di quanto cresca l'incidenza; il motivo di questo fenomeno θ da ricercare nella maggiore speranza di sopravvivenza offerta dai nuovi schemi di chirurgia associati a radioterapia e chemioterapia adiuvante (vedi terapia).
Eziologia [modifica]
Fumo di sigaretta [modifica]
L'incidenza del cancro ai polmoni θ strettamente correlata al consumo di sigarette, come attesta il grafico comparativo. Fonte:NIH
Il fumo di sigaretta θ considerato il principale agente eziologico per lo sviluppo di carcinoma del polmone.[37] Secondo uno studio elaborato servendosi di proiezioni statistiche, θ responsabile di circa il 90% dei tumori polmonari mortali nei paesi sviluppati.[38] In particolare, sempre secondo uno studio, negli USA il fumo di sigaretta θ responsabile dello sviluppo dell'87% dei casi di neoplasia polmonare (90% negli individui di sesso maschile e 85% nelle donne),[39] con un'incidenza che aumenta considerevolmente se le prime esposizioni avvengono tra i 18 e 25 anni di etΰ.[40] Il fumo di sigaretta contiene circa 60 cancerogeni certi,[41] inclusi i radioisotopi provenienti dal decadimento del radon, il benzopirene e alcune nitrosamine. Inoltre la nicotina presente θ in grado di deprimere la risposta immunitaria, diminuendo la capacitΰ di sorveglianza e di killing delle cellule neoplastiche da parte dei linfociti T e dei linfociti NK.[42] Il rischio percentuale di sviluppo di cancro mortale aumenta con l'aumentare del tempo di esposizione e del numero di sigarette fumate, con graduale diminuzione temporale del rischio in seguito a cessazione totale dell'esposizione.[43] Il fumo di sigaretta non rappresenta solo un fattore di rischio, ma anche un importante elemento in grado di influenzare la prognosi, dimostrato dal fatto che soggetti non fumatori ma con carcinoma del polmone hanno una maggiore percentuale di sopravvivenza a 5 anni rispetto ai fumatori.[44] Inoltre θ stato ampiamente documentato che la cessazione del fumo in seguito alla diagnosi di tumore migliora notevolmente il profilo prognostico.[45]
Del fumo di sigaretta si deve considerare una componente mainstream e una sidestream; la prima, ad alte temperature, θ quella generata da processi di inspirazione attiva. La seconda, a basse temperature, θ il risultato della combustione spontanea tra le dita o nel posacenere. Ultimamente questa distinzione ha assunto un notevole peso epidemiologico, poichι recenti studi[46] hanno dimostrato come la componente sidestream, che rappresenta per larga parte il fumo passivo (85%), sia potenzialmente piω nociva rispetto alla componente mainstream (fumo attivo). Naturalmente all'atto pratico, data la notevole diluizione nell'aria che il fumo passivo subisce prima di essere eventualmente inalato, l'aumento percentuale di rischio di contrarre patologie a cui θ esposto chi lo assume resta notevolmente inferiore rispetto a quello del fumatore attivo. La connessione tra esposizione passiva e aumento del rischio θ stata ulteriormente dimostrata da studi condotti negli USA,[47][48][49][50][51][22] in Europa,[52] in Gran Bretagna[53] e in Australia[54] che hanno documentato un aumento del rischio relativo nei soggetti esposti al fumo passivo (soggetti che vivono o che lavorano con un fumatore attivo).
Radon [modifica]
Media della distribuzione di radon nell'atmosfera terrestre (Bq/m³)
Il radon θ un gas inodore ed incolore, generato dai processi di decadimento del radio, esso stesso prodotto del decadimento dell'uranio, presente diffusamente nella crosta terrestre (granito e minerali usati per la costruzione delle abitazioni). Il radon rappresenta un elemento volatile e radioattivo, in grado di indurre mutazioni a carico del DNA e di rappresentare quindi un rischio concreto di neoplasia; in merito a quest'ultimo punto, ricerche recenti (2006) hanno promosso il radon come secondo fattore di rischio per lo sviluppo di cancro mortale al polmone.[55] I livelli di radon variano in base alla localitΰ e in base alla composizione relativa della crosta terrestre; per esempio in Cornovaglia l'elevata presenza di granito ed altri minerali aumenta a tal punto i livelli di radon da rendere consigliato l'uso di ventilatori ed estrusori per diminuire la concentrazione del gas all'interno degli edifici.[56][57] La United States Environmental Protection Agency (EPA) ha stimato che negli USA almeno in una 1 casa su 15 sono presenti livelli di radon che superano di almeno 4 picocurie per litro (pCi/L, o 148 Bq/m³) i limiti di sicurezza stabiliti.[58] L'Iowa θ lo stato degli USA con la piω elevata concentrazione di radon nell'aria (superiore di 4 pCi/L rispetto al controllo), con un aumento del rischio di sviluppo di cancro mortale del polmone superiore del 50% rispetto alla popolazione non esposta.[59][60] L'esposizione media italiana al radon all'interno degli edifici θ mediamente di 77 Bq/m³; in relazione alla mortalitΰ assoluta per cancro al polmone θ stato stimato che dal 5 al 20% di insorgenza di tumore mortale θ dovuta all'esposizione di radon indoor.[61] In base a questi dati e a successivi esperimenti, una buona ventilazione degli edifici si θ dimostrata essere un provvedimento in grado di diminuire considerevolmente l'esposizione al radon.[62] I decreti legislativi n. 230/1995 e n. 241/2000 impongono inoltre la misurazione dei livelli di radiazione assunta da radon negli individui che lavorano nel sottosuolo.[63]
Amianto [modifica]
Fibre di asbesto (corpo aghiforme circondato da inclusioni rotondeggianti marroni) in aspirato citologico svolto per la diagnosi di tumore polmonare
L'amianto, oltre ad essere implicato nella patogenesi della asbestosi e del mesotelioma pleurico, mostra un ruolo sinergico con il fumo di tabacco per lo sviluppo di carcinoma del polmone.[64] In Gran Bretagna θ stato stimato che il 2-3% dei casi di cancro mortale θ causato dall'amianto.[65] In Italia, la correlazione tra l'esposizione all'amianto e il carcinoma del polmone θ stata documentata per la prima volta del 1995:[66] lo stesso studio ha dimostrato che mentre la sola esposizione all'amianto θ in grado di aumentare il rischio di 5 volte, l'esposizione combinata di amianto e fumo di tabacco θ in grado di aumentare il rischio di 95 volte.
Inquinamento atmosferico [modifica]
Benchι non siano presenti ancora dati definitivi, l'esposizione allo smog e all'inquinamento atmosferico (prodotti della combustione dei derivati del petrolio e prodotti delle lavorazioni che comportano l'uso di metalli particolari come nichel e cromo) θ chiamata in causa nella patogenesi di cancro mortale del polmone.[66]
Virus [modifica]
Ricostruzione tridimensionale del simian virus 40, ritenuto essere coinvolto nella patogenesi di alcune forme tumorali
La capacitΰ oncogena dei virus θ stata ampiamente dimostrata nel modello animale,[67][68] benchι recenti evidenze suggeriscono il ruolo potenziale del papillomavirus,[69] del poliomavirus JC,[70] del simian virus 40 (SV40), del virus BK e del citomegalovirus[71] nella patogenesi del carcinoma del polmone nell'uomo. Questi virus possono alterare il ciclo cellulare e bloccare i processi di apoptosi, promuovendo un anomalo controllo della replicazione cellulare e lo sviluppo successivo di neoplasia.
Predisposizione genetica [modifica]
La presenza di mutazioni ereditarie a carico di p53 (come la sindrome di Li-Fraumeni) e di Rb predispongono al carcinoma del polmone.[72] Un ulteriore gene coinvolto sembra essere il gene che codifica per il citocromo CYP1A1, della famiglia del sistema enzimatico P450,[73] responsabile del metabolismo di alcuni farmaci, di composti aromatici e del benzopirene.[74] Polimorfismi a carico di questo gene comportano un alterato metabolismo dei composti cancerogeni presenti nel fumo di sigaretta, con maggiore suscettibilitΰ al cancro per i soggetti che hanno ereditato la variante enzimatica del CYP1A1.[3]
Malattie polmonari [modifica]
La presenza di enfisema o di bronchite cronica testimonia l'esposizione massiva al fumo di sigaretta;[75] conseguentemente, questi soggetti hanno una probabilitΰ maggiore di sviluppo di cancro mortale del polmone.[37] Una pregressa tubercolosi rappresenta un rischio a sι stante per lo sviluppo di cancro mortale del polmone; tale evento prende il nome di carcinoma su cicatrice,[76] che descrive l'innesco del processo neoplasico nel sito polmonare nel quale θ avvenuto (ed in seguito risolto con cicatrizzazione) il processo tubercolare.
Patogenesi [modifica]
Gli elementi eziologici analizzati portano a mutazioni del DNA che innescano un insieme di modificazioni che hanno come risultato finale un'intensa proliferazione dell'epitelio, con aberrazioni dell'architettura del tessuto polmonare. Con il tempo e con il prolungarsi dell'esposizione, l'insieme di queste modificazioni costituisce il terreno sul quale origina e si muove la neoplasia. Da queste considerazioni si deduce che al disordine neoplastico si associano alterazioni microscopiche, macroscopiche e molecolari, che evolvono in coerenza nel tempo e nello spazio.
Mentre queste ultime verranno discusse nelle sezione Eventi biologico-molecolari, le prime due corrispondono ad alterazioni visibili che sostengono il quadro clinico-patologico. Occorre quindi considerare sempre che simultaneamente al disordine neoplastico visibile, si muove un substrato molecolare sincrono ed evolutivo in grado di condizionare la storia clinica e la prognosi del tumore, conferendo proprietΰ di invasivitΰ, metastatizzazione o resistenza alla chemio-radioterapia.
Alterazioni clinico-patologiche [modifica]
Alterazioni istologiche nel carcinoma del polmone[3]
Tappe anatomo-patogenetiche
Stimolo oncogeno
↓ Stimolo oncogeno
I
I
I
↓
Iperplasia adenomatosa atipica
I
I
I
I
↓
Alterazioni reversibili
Iperplasia epiteliale
↓
Epitelio metaplastico
↓
Alterazioni irreversibili
Displasia
↓
Carcinoma in situ
↓
Carcinoma polmonare a cellule squamose
Adenocarcinoma polmonare
Carcinoma bronchioloalveolare
Come illustra lo schema, un tumore non insorge in un epitelio sano. Occorrono infatti molti anni affinchι che lo stimolo cancerogeno rappresentato dal contatto con uno dei fattori di rischio possa promuovere alterazioni tali da innescare lo sviluppo di tumore. Nell'epitelio bronchiale, l'esposizione ripetitiva al fumo porta ad un'intensa proliferazione (iperplasia) che tuttavia non possiede le alterazioni genetiche tipiche del tumore. Con il tempo ed il perdurare dello stimolo, le cellule che costituiscono il tessuto iperplastico possono andare incontro ad un processo definito metaplasia, un particolare evento caratterizzato dalla trasformazione di un tipo cellulare in un altro. Nel caso del polmone, le cellule che compongono l'epitelio si trasformano da cilindriche a fusate, assumendo un aspetto che nell'insieme viene definito pavimentoso stratificato.[77] Il passo successivo θ rappresentato dalla displasia, una situazione nella quale viene ad essere alterata la normale architettura tissutale. Questo significa che le cellule andranno incontro ad una proliferazione non piω ordinata in base alla fisiologica anatomia del tessuto, ma verranno a svilupparsi, ad esempio, in contesti di pertinenza di altri tessuti. Nel polmone questo θ visibile poichι le cellule pavimentose non si disporranno piω verso il lume del bronco, ma tenderanno ad accumularsi negli strati medi ed inferiori della mucosa, testimoniando che le cellule alterate sono svincolate dalla polarizzazione imposta dall'epitelio stesso. Differentemente dalla metaplasia, che puς essere risolta eliminando lo stimolo nocivo, la displasia θ un processo irreversibile e rappresenta il seme dal quale si genera il carcinoma in situ, definito come una lesione neoplastica che non ha ancora oltrepassato il limite imposto dalla lamina propria. Questi eventi descrivono le tappe patogenetiche che caratterizzano la genesi del carcinoma polmonare a cellule squamose; tuttavia θ stato messo in evidenza[78] che, differentemente da questo tipo, l'adenocarcinoma polmonare e il carcinoma bronchioloalveolare originano da un'alterazione prenoplastica denominata iperplasia adenomatosa atipica, caratterizzata da un'intensa proliferazione di strutture ghiandolari nel contesto del tessuto polmonare.
Eventi biologico-molecolari [modifica]
Per approfondire, vedi la voce Carcinogenesi.
Il terreno attraverso il quale si snoda il disordine neoplastico θ caratterizzato da alterazioni molecolari che possono essere riassunte in sei grandi gruppi patogenetici.[79]
Autosufficienza per la crescita cellulare [modifica]
Una cellula privata di fattori di crescita va rapidamente incontro ad apoptosi. Per questo, acquisire autosufficienza per i fattori di crescita rappresenta un meccanismo fondamentale per innescare e sostenere la carcinogenesi. Diverse alterazioni, su diverse componenti, possono realizzare e promuovere l'autosufficienza: per il carcinoma del polmone assumono particolarmente importanza le vie di segnalazione cellulare che riguardano tre sistemi proteici: EGFR, Ras e Myc.
Segnalazione intracellullare innescata dal legame tra EGFR e il suo agonista. L'iperespressione di EGFR o la sua mutazione attivante θ un importante fattore patogenetico per il carcinoma del polmone
Recettore del fattore di crescita dell'epidermide [modifica]
Per approfondire, vedi la voce Recettore del fattore di crescita dell'epidermide.
Nel tessuto polmonare uno dei recettori per i fattori di crescita θ rappresentato dal recettore del fattore di crescita dell'epidermide o EGFR (anche detto ErbB-1), proteina posta sulla membrana cellulare di molte cellule bronchiali.[80]
Essenzialmente, sono 3 i meccanismi attraverso i quali alterazioni di EGFR possono contribuire allo sviluppo e al mantenimento del carcinoma del polmone.[80]
Iperespressione dei ligandi di EGFR
La continua presenza di molecole in grado di stimolare EGFR, benchι non sia sufficiente ad innescare il processo di carcinogenesi,[81] θ estremamente importante poichι porta ad una condizione perpetua di stimolo proliferativo, promuovendo la proliferazione di cellule precedentemente mutate.
Amplificazione di EGFR
Se il numero di recettori per unitΰ di superficie cellulare aumenta, aumenta di conseguenza la responsivitΰ della cellula ad un dato stimolo esterno.[81] Quindi, una cellula che esprime un maggior numero di recettori θ una cellula con una maggiore capacitΰ proliferativa, condizione che avvantaggia le cellule neoplastiche, che possiedono piω copie del gene di EGFR o un gene costituitavamente espresso.
Mutazioni attivanti di EGFR
Le mutazioni del gene di EGFR possono portare all'indipendenza funzionale del recettore, rendendolo costitutivamente attivo anche in assenza di uno stimolo esterno.[81] Tali mutazioni sono presenti nel 20% dei NSCLC (Carcinoma polmonare non a piccole cellule; vedi, piω oltre, la sezione Classificazione istologica) e nell'80% di NSCLC non responsivi a terapia,[82] con maggiore frequenza nell'adenocarcinoma polmonare,nel sesso femminile e nei soggetti di origine asiatica.[83]
Ricostruzione tridimensionale della struttura della proteina Ras la cui mutazione θ spesso connessa alle forme tumorali resistenti alla chemioterapia
Ras [modifica]
Come precedentemente discusso nella trattazione del ruolo fisiologico di EGFR, la proteina Ras rappresenta un punto di snodo cruciale nella segnalazione di proliferazione e differenziazione cellulare.[84] Mutazioni di Ras, soprattutto dell'isoforma K-Ras, sono presenti soprattutto nell'adenocarcinoma polmonare,[85] benchι, comunque sia, rappresentano un'alterazione tipica (15-20%) di tutte le forme di NSCLC.[86] Mutazioni attivanti di K-Ras si associano molto strettamente all'abitudine al fumo di sigaretta e alla resistenza insorta durante il trattamento chemioterapico.[87]
Myc [modifica]
Myc θ un oncogene che codifica per una proteina che rappresenta il traguardo finale del segnale di proliferazione convogliato da Ras;[88] ciς significa che una mutazione attivante di Myc o una sua iperespressione mima fisiologicamente una mutazione attivante di Ras. Le alterazioni di Myc sono associate a moltissime forme di cancro[89] e nel carcinoma del polmone assumono una valenza particolare le forme cMYC, MYCN e MYCL. Mentre la mutazione di cMyc in circa il 8-20% delle forme di NSCLS, la mutazione delle ultime due forme rappresenta un meccanismo patogenetico fondamentale nello sviluppo di carcinoma polmonare a piccole cellule.[90]
Evasione dalla apoptosi [modifica]
L'apoptosi puς essere definita come morte cellulare programmata che, differentemente dalla necrosi, rappresenta un processo fisiologico e di notevolissima importanza. La regolazione dei processi apoptotici permette il corretto sviluppo di diversi nuovi tessuti a scapito di popolazioni cellulari senescenti o rudimentali. Benchι questi processi siano particolarmente evidenti durante l'embriogenesi, l'apoptosi riveste un ruolo fondamentale anche nell'individuo adulto, soprattutto nell'eliminazione dei linfociti autoreattivi e delle cellule tumorali.[91] Giocoforza, la compromissione di tali meccanismi o l'acquisizione da parte del tumore della capacitΰ di evadere l'apoptosi, rappresenta uno dei momenti cruciali per la progressione della neoplasia.[81]
Ricostruzione tridimensionale della struttura della proteina p53. La perdita di questa proteina θ responsabile della capacitΰ da parte delle cellule neoplastiche di sfuggire dai meccanismi apoptotici
p53
p53 θ una proteina di 53 kilodalton (kDa) che funge da fattore di trascrizione ed θ codificata dal gene TP53.[92][93][94] L'mRNA che traduce per p53 θ trascritto in seguito a danno del genoma, provocato, ad esempio, da radiazioni, agenti chimici e stress ossidativo[95] La proteina p53 cosi tradotta porta alla trascrizione di p21 (arresto del ciclo cellulare),[96] di Gadd45 (riparazione del DNA)[97][98] e di Bax (induttore dell'apoptosi);[99] riassumendo: un danno al DNA promuove la traduzione di p53 che blocca il ciclo cellulare, ripara il DNA e, in caso di insuccesso, innesca l'apoptosi. Per questo, p53 θ stato denominato il guardiano del genoma, in quanto in grado di prevenire l'instaurarsi di danni al DNA e di stabilizzare il genoma.[100]
Mutazioni inattivanti di p53 trasmesse con modalitΰ autosomico recessiva sono le responsabili della sindrome di Li-Fraumeni,[72] che rappresenta una condizione di rischio per lo sviluppo di carcinoma del polmone. Alterazioni di p53 nelle cellule dell'epitelio bronchiale con alterazioni di tipo neoplastico in individui che non hanno ereditato l'allele mutato, sono presenti sia nel carcinoma polmonare a piccole cellule (>90%) che nei NSCLC (>80%).[1]
Bcl-2
Bcl-2 θ una proteina che si lega alla membrana esterna dei mitocondri inibendo l'apoptosi.[81] Questo significa che un aumento dell'espressione di bcl-2 nelle cellule neoplastiche consente la valicazione degli stimoli apoptotici e la sopravvivenza cellulare. Benchι l'iperespressione di bcl-2 rappresenti un punto patogenetico fondamentale nelle varie forme di leucemia e di linfomi, tale alterazione si riscontra frequentemente (>75%) anche nel SCLC.[101] In questo tipo di tumori θ sovente riscontrare un'iperespressione di Bcl-2 e una diminuzione funzionale di p53, elementi che, con meccanismo sinergico, sono in grado di promuovere e sostenere l'aggressivitΰ del microcitoma.
Evasione dal blocco alla crescita cellulare [modifica]
Nel processo di evoluzione di una neoplasia le cellule acquisiscono gradualmente nuove capacitΰ proliferative svincolandosi dal blocco imposto da alcuni geni denominati per questo oncosoppressori.[81] In generale, meccanismi che portano alla perdita di un solo allele oncosoppressore non sono sufficienti a promuovere lo sviluppo di un tumore; tuttavia, la perdita di entrambi gli alleli (two hits hypothesis) θ strettamente associata a instabilitΰ genetica, ad alterato ciclo cellulare ed, infine, alla proliferazione incontrollata.[102]
La proteina p53 rappresenta un tipico esempio di gene oncosoppressore; un ulteriore classico esempio θ rappresentato dalla Rb, in grado di controllare le diverse tappe del ciclo cellulare.[103] Ogniqualvolta uno di questi geni viene perso o inattivato da mutazione in entrambi gli alleli si parla di loss-of-heterozygosity (LOH).[104] Molti studi,[105] focalizzati soprattutto sul carcinoma polmonare a cellule squamose, hanno messo in evidenza le seguenti loss-of-heterozygosity:
Cromosoma coinvolto Sigla Esempi di
geni presenti
Braccio corto del cromosoma 1
1p PINK1
Braccio corto del cromosoma 3
3p FHIT; RASSF1; VHL
Braccio lungo del cromosoma 3
3q PDCD10
Braccio corto del cromosoma 4
4p FGFR3
Braccio lungo del cromosoma 4
4q Molte chemochine
Braccio lungo del cromosoma 5
5q NSD1
Braccio lungo del cromosoma 8
8q NDRG1
Braccio lungo del cromosoma 9
9q TGFBR1
Braccio corto del cromosoma 10
10p ERCC6
Braccio lungo del cromosoma 10
10q PTEN; ALOX5; CDH23
Braccio lungo del cromosoma 13
13q BRCA2; Rb
Braccio corto del cromosoma 17
17p p53
Braccio lungo del cromosoma 17
17q BRCA1
Braccio lungo del cromosoma 18
18q SMAD4
Braccio corto del cromosoma 19
19p STK11
Omissis
Prevenzione [modifica]
Per definizione, le misure preventive hanno come scopo l'eliminazione dei fattori eziologici e dei fattori di rischio. In questa ottica, la misura preventiva piω efficace per ridurre l'incidenza di carcinoma del polmone θ ridurre al minimo l'esposizione al fumo di sigaretta, sia esso attivo o passivo.[209] In seguito alle evidenze mostrate dagli studi citati in precedenza, risulta essere molto importante prevenire l'esposizione al fumo soprattutto nei soggetti giovani.[40] Negli Stati Uniti d'America, il center for disease control, un ente che si occupa del controllo e della prevenzione delle malattie, ha suggerito di spendere il 15% dei proventi derivanti dalla tassazione dei prodotti del tabacco in programmi di prevenzione.[210]
A partire dal 1998, negli stati occidentali degli USA come la California sono state prese numerose misure per diminuire l'esposizione al fumo passivo nei luoghi pubblici. In seguito, analoghe misure sono state prese in Europa, con l'Irlanda nel 2004, l'Italia e la Norvegia nel 2005, la Scozia nel 2006, l'Inghilterra nel 2007 e la Francia nel 2008. La Nuova Zelanda ha cominciato ad applicare misure contro il fumo nei luoghi pubblici nel 2004. Nello stato del Bhutan, dal 2005, θ in vigore una legge che impone il completo divieto di fumo.[211] In molti paesi, gruppi attivi nella lotta contro il fumo stanno facendo una campagna per simili divieti. Nel 2007, Chandigarh θ diventato la prima cittΰ indiana a diventare "senza fumo". L'India ha introdotto un divieto totale di fumo ai luoghi pubblici il 2 ottobre 2008.
Tuttavia, una politica eccessivamente tesa al proibizionismo nei confronti del fumo di tabacco si θ dimostrata essere positivamente correlata allo sviluppo di attivitΰ criminali di contrabbando, il che ha portato a porre un limite allo sviluppo di decreti legislativi troppo restrittivi.[212]
Nel 2008, uno studio condotto su oltre 77000 soggetti adulti ed anziani ha dimostrato che l'utilizzo protratto di integratori multivitaminici contenenti folati, vitamina C e vitamina E non θ in grado di prevenire l'incidenza di carcinoma del polmone. Inoltre, θ stato osservato che un uso intenso di vitamina E, soprattutto se condotto per lunghi periodi, θ associato ad un aumento del rischio per lo sviluppo di carcinoma del polmone.[213]
L'Organizzazione mondiale della sanitΰ ha richiesto ai governi di eliminare completamente la pubblicitΰ riguardanti il tabacco per prevenire che i giovani inizino a fumare, sostenendo che, nei paesi in cui queste misure sono giΰ state prese, il consumo di tabacco si θ giΰ ridotto del 16%.[214]
Per limitare l'esposizione al radon θ possibile effettuare un controllo della quantitΰ di questo gas nella propria abitazione tramite la sede ARPA piω vicina.
Note [modifica]
1. ^ a b c d e f g h i Harrison, Principi di Medicina Interna, 16a edizione, New York - Milano, McGraw-Hill, 2006. ISBN 88-386-2459-3
2. ^ a b Incidence & Mortality, Lung cancer. Surveillance, Epidemiology and End Results, 2009. URL consultato il 1 luglio 2009.
3. ^ a b c d e f g h i Robbins e Cotran, Le basi patologiche delle malattie - Volume 2, 7a edizione, Torino - Milano, Elsevier Masson, 2008. ISBN 978-88-85675-53-7
4. ^ (LA) Giovanni Battista Morgagni, De sedibus et causis morborum per anatomen indagatis , , 1761.
5. ^ (FR) Gaspard-Laurent Bayle, Recherches sur la phtisie pulmonaire, Paris, 1810.
6. ^ a b Witschi, H (novembre 2001). A short history of lung cancer . Toxicological Sciences 64 (1): 46. DOI:10.1093/toxsci/64.1.4. PMID 11606795.
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8. ^ FW Grannis. History of cigarette smoking and lung cancer. smokinglungs.com. URL consultato il 30-06-2009.
9. ^ Proctor, The Nazi War on Cancer , Princeton University Press, 2000. 173246 ISBN 978-0-691-07051-3
10. ^ Doll, R, Hill AB (novembre 1956). Lung cancer and other causes of death in relation to smoking; a second report on the mortality of British doctors . British Medical Journal 2 (5001): 10711081. DOI:10.1136/bmj.2.5001.1071. PMID 13364389.
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Toxicological Sciences 64, 4-6 (2001)
Copyright © 2001 by the Society of Toxicology
________________________________________PROFILES IN TOXICOLOGY
A Short History of Lung Cancer
Hanspeter Witschi
ITEH and Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616
For correspondence via fax: (530) 752-5300. E-mail: [email protected] .
"Lung cancer continues to be the leading cause of death in both men and women in the US, with over 158,900 deaths in 1999. Worldwide, lung cancer kills over 1 million people a year. Extensive prospective epidemiologic data clearly establish cigarette smoking as the major cause of lung cancer. It is estimated that about 90% of male lung cancer deaths and 7580% of lung cancer deaths in the US are caused by smoking each year" (Hecht, 1999). Clearly, lung cancer is an important and widespread disease that constitutes a major public health problem. This was not always so. Some 150 years ago, it was an extremely rare disease. In 1878, malignant lung tumors represented only 1% of all cancers seen at autopsy in the Institute of Pathology of the University of Dresden in Germany. By 1918, the percentage had risen to almost 10% and by 1927 to more than 14%. In the 1930 edition of the authoritative Springer Handbook of Special Pathology it was duly noted that malignant lung tumors had begun to increase at the turn of the century and perhaps even more so after World War I and that, possibly, they still were on the increase. It was also noted that while most lung tumors occurred in men, there seemed to be a steady increase in women. Duration of the disease, from being recognized until death, was usually from half a year to 2 years and in practically all cases there had been a long history of chronic bronchitis.
What caused such a dramatic increase in an obscure disease? The handbook discusses at some length possible etiologic factors: increased air pollution by gases and dusts, caused by industry; the asphalting of roads; the increase in automobile traffic; exposure to gas in World War I; the influenza pandemic of 1918; and working with benzene or gasoline. However, lung cancer rose at the same rate in countries with fewer automobiles, less industry, fewer paved roads, and in workers not exposed to benzene or gasolineand had not risen in the 19th century after earlier flu pandemics. In 1 or 2 sentences, smoking was briefly mentioned as another possibility, but it was pointed out that as many investigations failed to show an association between smoking and lung cancer as there were positive findings. In summary, there was some suspicion, but by no means certainty that lung cancer would be caused by extraneous agents and no particular importance was given to the smoking of cigarettes. It is interesting to note, however, that in 1929 (presumably too late to be included in the handbook) the German physician, Fritz Lickint published a paper in which he showed that lung cancer patients were particularly likely to be smokers. He then went on a crusade against smoking, and antitobacco activism actually became widespread in Germany.
In a new edition of the handbook in 1969, the views on what causes lung cancerwhich still was on the risehad radically changed. The role of cigarette smoking was discussed in detail over a full 25 pages. Air pollution was mentioned as another possibility; the existence of a city-rural gradient in lung cancer incidence was strongly suggestive. It was now also recognized that chemicals encountered in certain occupations could cause lung cancer: arsenic containing compounds in wine growers, asbestos, and nickel and chromium in mine and smelter workers.
The link between the smoking of cigarettes and lung cancer began to be suspected by clinicians in the 1930s when they noted the increase of this "unusual" disease. Publications began to appear and about 2 decades later the role of smoking as causative agent had been firmly established. A case control study was published in 1940 in Germany and its author flatly stated that "the extraordinary rise in tobacco use was the single most important cause of the rising incidence of lung cancer" (Mόller, 1940). At this time, lung cancer had become the second most frequent cause of cancer death, stomach cancer being the first. In 1943, the German Institute for Tobacco Hazards Research disclosed a study which found that among 109 lung cancer cases only 3 were nonsmokers, a proportion much lower than in the control group. In the 1950s Doll and Hill in England and Cuyler Hammond and Ernest Wynder in the U.S. provided further evidence for a causal association between smoking and lung cancer. Yet, it took a long time until the truth was fully accepted. Smokers, including many physicians, who enjoyed cigarettes could or would not want to imagine or refused to believe that the habit (addiction would be more appropriate) was detrimental to their health. In this context it is interesting to note that 2 personalities who helped like few others to make us aware that chemicals in the environment could cause cancer, strangely failed to grasp the impact of smoking. Wilhelm C. Hueper started out as a physician in industry. By repeatedly and doggedly pointing out possible links between exposure to chemicals in manufacturing processes and the increased incidence of cancer in workers he became unpopular with management, to the extent that on some occasions he was barred from presenting or discussing his findings and conclusions. And yet he maintained that smoking was not a factor in the etiology of lung cancer in humans. Rachel Carson, who in her Silent Spring warned of impending disaster of cancer caused by environmental chemicals never mentions tobacco smoke. Since then, tobacco smoke has become not only the most important carcinogen in our environment, but probably also the only one where we could accomplishand in many places actually already have accomplishedzero exposure.
The smoking of cigarettes had become popular shortly before the turn of the century. Originally, cigarettes were hand rolled and this made them expensive. In 1876, the cigarette manufacturer Allen & Ginter offered a prize for the development of a machine that would speed up the process. When James Albert Bonsack developed a machine that could make 70,000 cigarettes in a 10 h day, Allen & Ginter did not want to use itpartially out of fear that the machine would produce more cigarettes than the market demand justified. James Buchanan Duke had no such qualms; he acquired 2 of the machines and went on to commercial success. In 1889, "Buck" Duke became president of the new American Tobacco Company.
World War I helped to popularize the smoking of cigarettes. Soldiers in the trenches smoked to relieve stress, and so did many civilians, including an increasing number of women at home. General John J. ("Black Jack") Pershing reportedly stated: "You ask me what it is we need to win this war. I answer tobacco as much as bullets." In the following decades, smoking continued to be "enjoyed" by hundreds of thousands until, after the first report of the Surgeon General in 1964, public awareness woke up and smoking became recognized as the hazard it is. The trend in lung cancer incidence slowly decreased and, at least in men, appeared to flatten out.
There was, however, one lung cancer where it had been obvious for a long time that it might be caused by an external agent. As early as 1500, attention was called to this particular condition. In two regions of Germany and Czechoslovakia, Schneeberg and Joachimsthal, there were productive mines, yielding first silver, later nickel, cobalt, bismuth, and arsenic. The word "dollar" actually stems from the word "Thaler;" coins minted from the pure silver of Joachimsthal were called "Joachimsthaler" (i.e., originating from Joachimsthal) or, abbreviated, "Thaler." The miners working these mines developed almost invariably a deadly disease, called "Bergkrankheit" (mountain sickness). Between 1876 and 1938, 60 to 80% of all miners died from the disease which, on average, lasted 25 years. Certain regions of the mines were known as "death pits," where all workers got sick. As a result, lung cancer in miners was recognized as an occupational diseaseand the miners therefore entitled for compensationin 1926 in Germany and in 1932 in Czechoslovakia. While it was thought that chemical constituents of the ore that was produced, most notably arsenic, might be involved in the etiology of these lung cancers, it was early on suspected that "radium emanation" was the main culprit. Measurements published in 1924 in a German physics journal confirmed that the air in the mines contained high concentrations of radon gas, the highest more than 18,000 picocuires per liter.
The manufacture of the atomic bomb and the maintenance of a nuclear arsenal called for large amounts of uranium. In the U.S., uranium was mostly mined on the Colorado plateau. The European experience should have alerted the mining companies to the potential hazards their workers were going to face. However, responsibility for protection was not given to the Atomic Energy Commission, but rather left to the individual states who lacked expertise and equipment to deal with the problem. Although it should have been obvious by then that poorly ventilated uranium mines caused lung cancer, evidence pointing in this direction was suppressed; apathy, bureaucratic conservatism, and government censorship prevented the problem from being tackled. It was said by the mining industry that "ventilating the mines was unnessecary and too expensive." It is estimated that 4000 to 5000 Americans have died or will die from lung cancer caused by working in inadequately ventilated uranium mines. And although the problem has now been recognized for the health disaster it was, compensations are slow to come.
During the last few decades, there has been a shift in forms of lung cancer. In the early studies, the predominant lung cancer form in smokers was squamous cell carcinoma, mostly originating from the epithelium lining the airways. First noticed in 1961, but confirmed mostly during the last two decades there occurred a shift to more peripherally located adenocarcinomas. This is most likely a consequence of changes made in cigarettes. Tar was considered to be the main carcinogenic agent in cigarette smoke, mostly because cigarette smoke condensates ("tar fraction") were the first ingredients isolated from tobacco smoke that could be shown in skin painting studies to produce cancer in animals. It was hoped that production of low tar, low nicotine cigarettes and the addition of filters might decrease cancer risk. It did not, most likely because of changes in smoking pattern. To fulfill the craving for nicotine, smokers of filter cigarettes may inhale smoke more deeply into the lung and retain it longer. With the removal of polycyclic aromatic hydrocarbons in the filter, the preponderant carcinogens in smoke might be tobacco specific nitrosamines and volatile carcinogens in the gas phase. Animal experiments lend plausibility to this; polycyclic aromatic hydrocarbons do cause squamous cell carcinomas in the lungs of animals, whereas nitrosamines are more likely to produce adenocarcinomas.
All evidence linking lung cancer and smoking comes from human experience. Similarly, radon was recognized as a human carcinogen long before some animal data suggested that it was a carcinogen. It is likely that neither agent responsible for lung cancer, the smoking of cigarettes or radon, would have been recognized as a cancer causing agent had it not been for the fact that a previously very rare disease increased in parallel with increased consumption of a widely distributed and highly addictive agent or was associated with a specific occupation. It is an interesting thought that experimental toxicology has little contributed to our understanding of the disease. There are very fewsome might say none at allstudies in which it has been unequivocally demonstrated that tobacco smoke can cause lung cancer in experimental animals.
SUGGESTED READING
Hecht, S. S. (1999). Tobacco smoke, carcinogens and lung cancer. J. Natl. Cancer Inst. 91, 11941210.[Abstract/Free Full Text]
Kluger, R. (1996). Ashes to Ashes. Alfred A. Knopf, New York.
Proctor, R. N. (1995). Cancer Wars: How Politics Shapes What We Know about Cancer. Basic Books, New York.
Proctor, R. N. (1999). The Nazi War on Cancer. Princeton University Press, Princeton, NJ.
Mόller, F. H. (1940). Tabakmissbrauch und Lungencarcinom. Z. Krebsforsch. 49, 5785.
Wynder, E. L. (1994). Prevention and cessation of tobacco use: Obstacles and challenges. J. Smoking-Related Dis. 5,(Suppl. 1), 38.
CiteULike Connotea Del.icio.us What's this?
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J. A Francis, A. K Shea, and J. M Samet
Challenging the epidemiologic evidence on passive smoking: tactics of tobacco industry expert witnesses
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Pathogenesis of Lung Cancer: 100 Year Report
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S. G. Spiro and G. A. Silvestri
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History of Cigarette Smoking and Lung Cance
________________________________________
The most salient fact in the history of lung cancer is that it was very, very rare before the invention of cigarettes.
If one goes into a medical library and pages through old medical texts from the nineteenth century, one finds almost no reference to lung cancer. If one searches through the medical literature up to the year 1900, there are only references to a total of 100 cases of lung cancer. Even as late as 1912, Adler could find only 374 cases. Grosse reviewed 100 years of autopsies in Dresden, Germany, and found that the incidence of lung cancer had gone from 0.3% in 1852 to 5.66% in 1952.
In the nineteenth century, tobacco was smoked by gentlemen only in the form of cigars . Cigarettes, which were basically the sweepings off the floor of the cigar factory, were only smoked by the very poor.
As machines to mass produce cigarettes came into the fore in the 1880s, smoking cigarettes became more common but the number of cigarettes smoked was still, relatively small. During World War I tobacco companies gave away free cigarettes to millions of soldiers, and it was only after the war that large numbers of Americans smoked cigarettes.
Since there is a time lag of approximately 20 to 30 years between the onset of smoking and the development of lung cancer, the damage done was not immediately apparent. Doctors were surprised to see a sudden epidemic of lung cancer cases in the 1930s. They quickly discovered the association between smoking and lung cancer. Large statistical studies in England and the United States in the 1950s (Doll and Hill, Cutler) conclusively proved beyond any shadow of a doubt that cigarette smoking markedly increased the chances of developing lung cancer.
By the 1970s, lung cancer had gone from one of the rarest of cancers to the number one killer cancer in the Western world.
Women did not smoke in the early twentieth century U.S.A.. They were therefore, targeted by an intense marketing campaign in the 1930s, featuring elegant women in evening dresses smoking Lucky Strikes in Cigarette holders. Later they were the target of Virginia Slims. When I was in surgical training at the Mayo Clinic in the early 1970s lung cancer in women was still unusual, but by 1985, lung cancer had became the number one cause of cancer death in women.
The 1990s are the era of discovery, as defectors from the tobacco industry provide an inside view of the treacherous behavior of the tobacco industry and our elected officials. Hopefully, the 1990s will end as the era of tobacco CONTROL.
I have posted an essay on the history of thoracic surgery.
A interesting history of tobacco is located at the Tobacco BBS- Gene Borio A Capsule History of Tobacco
________________________________________
Frederic W. Grannis Jr. M.D
If you have trouble contacting me with the address above, I may also be reached at 76516,[email protected]
www.smokinglungs.com/cighist.htm
Evarts A. Graham and the First Pneumonectomy for
Lung Cancer
Leora Horn and David H. Johnson
From the Division of Hematology and
Oncology, Vanderbilt University School
of Medicine, Vanderbilt-Ingram Cancer
Center, Nashville, TN.
Submitted February 18, 2008; accepted
March 28, 2008.
Authors disclosures of potential conflicts
of interest and author contributions
are found at the end of this
article.
Corresponding author: David H. Johnson,
MD, Vanderbilt-Ingram Cancer
Center, Division of Hematology and
Oncology, 777 Preston Research Building,
2220 Pierce Ave, Nashville, TN
37232-6307; e-mail:
[email protected].
© 2008 by American Society of Clinical
Oncology
0732-183X/08/2619-3268/$20.00
DOI: 10.1200/JCO.2008.16.8260
INTRODUCTION
Smoking . . . a custome lothsome to the eye, hatefull
to the Nose, harmefull to the braine, daungerous to the
Lungs.King James, 16041
Omissis
Although reports of pulmonary malignancies date
to antiquity, lung cancer is largely a disease of modern
man. Before 1900, lung cancers were viewed as
matters of medical curiosity notknownto be in any
degree influenced by medicine and too rare to be of
much practical importance.9 Adler10 compiled the
worlds entire experience of 374 cases in his textbook,
Primary Malignant Growths of the Lung and
Bronchi: A Pathologic and Clinical Study, published
in 1912 (Fig 2). The association between lung cancer
and cigarette smoking was not immediately obvious
to early physicians and scientists. Other posited
causes included effluents from industrial plants, coal
fires, road tars, auto exhaust fumes, gas works, various
pollutants, preceding influenza or tuberculosis,
and even race and sex.11 Sir Richard Doll would later
note that the ubiquity of the [smoking] habit . . .
had dulled the collective sense that tobacco might be
a major threat to health.12
The rarity of lung cancer in the early 1900s is
illustrated by the following vignette. While a student
at Washington University Medical School (St Louis,
MO), the acclaimed surgeon Alton Ochsner claims
that his entire junior class was summoned to witness
a postmortem examination on a lung cancer patient.
13,14 George Dock, then chief of medicine at
Washington University and a former Osler chief
resident, suggested that the group might not witness
another case in their lifetimes.13,14 Indeed, for
Ochsner, it would be 17 years before he would encounter
another lung cancer. In 1936, however, he
observed nine such cases within a 6-month interval
a veritable epidemic in his opinion.13,14 All of
his patients were heavy smokers who acquired the
habit while serving in the military during the first
World War.13 Three years later, he would publish a
milestone article with Michael DeBakey, the famous
cardiac surgeonwhotrained with Ochsner, in which
they conjectured . . . the increase in smoking
with the universal custom of inhaling is probably
a responsible factor, as the inhaled smoke, constantly
repeated over a long period of time, undoubtedly
is a source of chronic irritation to the
bronchial mucosa.15
Ochsners theory linking cigarette use with the
development of lung cancer was widely disputed,
even ridiculed by some of his peers, including Graham,
ironically. Graham reportedly told his former
trainee, Yes, there is a parallel between the sale of
cigarettes and the incidence of cancer of the lung,
but there is also a parallel between the sale of nylon
stockings and the incidence of lung cancer.13,14
Once, after a lecture to the County Medical Society
in Mobile, AL, a member of the audience rose to
challenge Ochsners radical theory linking cigarettes
to lung cancer. The skeptic stated that he had found
that patients with rectal cancer were more likely to
be smokers and could Dr Ochsner explain that? After
a momentary pause, the ever-decorous Ochsner
reputedly opined that he could not, . . . unless people
in Mobile inhaled much more deeply than those
in New Orleans.16 It was in this era of ambiguity
and even open hostility vis-a`-vis cigarette smoking
as a cause of lung cancer that James Gilmore arrived in St Louis for a
consultation with Graham and his team, as we will describe later.
Of course, what seems patently obvious to us today was not so
clear 70 years ago. Even though others had suspected that cigarettes
were a cause of premature death,11 it wasRaymondPearls 1938 report
in Science that firmly established a linkage.17 A decade later, Graham,
who eventually apologized to Ochsner for his misgivings vis-a`-vis
Ochsners prescient observation,13 would publish a landmark article
with Ernest Wynder linking cigarette smoking with lung cancer.18
Their work, along with that of Richard Doll and Austin Bradford
Hill,19 sparked the formation of large cohort studies that conclusively
established smoking as a causative agent of lung cancer and added
heart disease, stroke, chronic lung disease, other malignancies, and
decreased life expectancy to the list of injurious effects from smoking.
20 Regrettably, however, it would be yet another three decades
before the tobacco industry publicly acknowledged the adverse health
effects of smokingbut only after a long, drawn-out campaign of
misinformation and deception helped along by the [perhaps] unwitting
complicity of physicians.21,22
omissis
http://jco.ascopubs.org/cgi/reprint/26/19/3268.pdf
What causes lung cancer?
The link between tobacco and cancer was established more than 50 years ago.
Smoking causes almost 90% of lung cancer deaths.
http://info.cancerresearchuk.org/prod_cons...000ast-2972.pdf
. -
.
http://chestjournal.chestpubs.org/content/..._suppl/29S.full
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Epidemiology of Lung Cancer*
ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
1. Anthony J. Alberg, PhD, MPH,
2. Jean G. Ford, MD, MPH, and
3. Jonathan M. Samet, MD
+ Author Affiliations
1. *From the Hollings Cancer Center (Dr. Alberg), Medical University of South Carolina, Charleston, SC; and Department of Epidemiology (Drs. Alberg, Ford, and Samet), Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
Next Section
Abstract
Background: The objective of this study was to summarize the published literature concerning the epidemiology of lung cancer.
Methods: A narrative review of published evidence was conducted, identifying and summarizing key reports that describe the occurrence of lung cancer in populations and factors that affect lung cancer risk.
Results: In the United States, lung cancer remains the leading cause of cancer death in both men and women, even though an extensive list of modifiable risk factors has long been identified. The predominant cause of lung cancer is exposure to tobacco smoke, with active smoking causing most cases but passive smoking also contributing to the lung cancer burden.
Conclusions: The reductions in smoking prevalence in men that occurred in the late 1960s through the 1980s will continue to drive lung cancer mortality rates downward in men during the first portion of this century, but rates in women have not yet begun to decrease. Fortunately, exposures to major occupational respiratory carcinogens have largely been controlled, but the population is still exposed to environmental causes of lung cancer, including radon, the second leading cause of lung cancer death.
air pollution
asbestos
cigarette smoking
epidemiology
lung cancer
nutrition
occupation
passive smoking
radiation
tobacco
The vast majority of lung cancer deaths are attributable to cigarette smoking. Any action that prevents cigarette smoking initiation or promotes cessation among dependent smokers is a step to preventing lung cancer. This includes tobacco control activities to affect policy, such as cigarette taxes and smoke-free workplace legislation, as well as individual-level interventions to prevent the onset or continuation of smoking.
Epidemiologic evidence is the foundation for primary and secondary disease prevention. Epidemiologic approaches are used to track the occurrence of disease, to characterize natural history, and to identify determinants of disease. The benefits of intervention programs, whether based in risk factor interventions or screening, are also assessed using epidemiologic approaches. For lung cancer, routine mortality statistics confirmed the clinical impression that the disease became more frequent across the first half of the 20th century. Case-control and cohort studies, the epidemiologic study designs thatare used to evaluate exposure/disease associations, causally linked smoking to lung cancer in investigations reported from the 1950s onward.123 As we have continued to follow lung cancer incidence and mortality rates, we have readily shown that their rise and decline parallel past trends of cigarette smoking.4 The epidemiologic evidence and the complementary biological understanding of respiratory carcinogenesis have unassailably supported the conclusion that smoking causes lung cancer. Epidemiologic findings are also relevant to patient care, because skilled clinicians weigh alternative diagnoses depending on risk factor profiles of patients.
At the end of the 20th century, lung cancer had become one of the leading causes of preventable death.5 It was a rare disease at the start of that century, but exposures to new etiologic agents and an increasing life span combined to make lung cancer a scourge of the 20th century. Although tobacco had been widely used throughout the world for centuries, the present pandemic of lung cancer followed the introduction of manufactured cigarettes with addictive properties, which resulted in a new pattern of sustained exposure of the lung to inhaled carcinogens.6 German scientists in Nazi Germany conducted some of the earliest research on the links between smoking and lung cancer.7 By the early 1950s, epidemiologic studies in Britain and the United States using the case-control method had shown that cigarettes were strongly associated with the risk for lung cancer8910; this association was corroborated by the pioneering cohort studies of British physicians, US veterans, and volunteers recruited by the American Cancer Society.1112 By 1964, the evidence was sufficient to support a conclusion by the US Surgeon General that cigarette smoking caused lung cancer.11 The Royal College of Physicians had reached the same conclusion 2 years before.12 Passive smoking, the involuntary inhalation of tobacco smoke by nonsmokers, has also been found to cause lung cancer.1314
Although its predominant cause is now widely known (tobacco smoking), there are other causes as well, some acting in concert with smoking to synergistically increase risk. The suspicion that radon was a cause of lung cancer in underground miners, raised early in the 20th century, led to what was probably the first occupational respiratory carcinogen to be identified15; radon in indoor environments is now considered as the second-leading cause of lung cancer in the United States.16 The list of human occupational causes of lung cancer also includes arsenic, asbestos, chromates, chloromethyl ethers, nickel, polycyclic aromatic hydrocarbons, radon progeny, and other agents.17 Outdoor air pollution, which includes combustion-generated carcinogens, is also considered to contribute to the lung cancer burden in urban dwellers. Indoor air contains several respiratory carcinogens, including radon, asbestos, and cigarette smoke. In some developing countries, exposure to fumes from cooking stoves and fires is associated with lung cancer risk. Beginning in the 1970s, associations of diet with lung cancer risk have been vigorously investigated with the anticipation that dietary micronutrients that modify the high lung cancer risk in smokers might be found. The biological basis for prevention of cancer through supplementation of micronutrients is addressed in another article in this supplement.
Even though the epidemiology of lung cancer has been extensively investigated for > 50 years, there are still active areas of research, some quite relevant to prevention. Investigation of lung cancer and diet continues, using both observational and experimental approaches, and concern remains over the risk of indoor and outdoor pollutants, including, for example, radon and diesel emissions. There has also been a need for research to track the risks of smoking over time, because the cigarette has evolved in its design characteristics, and yields of tar and nicotine, as assessed by standard protocol using a machine, have declined since the 1950s. The histologic characteristics of lung cancer in a number of developed countries, including the United States, have also changed in the past few decades such that the frequency of adenocarcinoma has risen and that of squamous cell carcinoma has declined.4 There is also emerging evidence on genetic determinants of lung cancer risk. A current research approach, termed molecular epidemiology, melds the population and laboratory tools that are used to address susceptibility to environmental carcinogens. Whereas the evidence from the traditional epidemiologic approaches conclusively established the carcinogenicity of tobacco smoke, molecular epidemiology should characterize the sequence of molecular and cellular changes as a nonmalignant cell becomes malignant and genetic factors that possibly determine susceptibility to tobacco smoke. Biomarkers of exposure, dosage, susceptibility, and genetic damage may allow epidemiologic investigations to uncover specific pathways of human lung carcinogenesis and provide useful intermediate markers for prevention studies.
Previous SectionNext Section
Materials and Methods
A narrative review of published evidence on the epidemiology of lung cancer was conducted. Key reports that described the occurrence of lung cancer in populations and factors that affect lung cancer risk were identified. This was accomplished using a combination of approaches that included cataloguing reports from the authors files and augmented with MEDLINE searches. The MEDLINE searches included a term for lung cancer along with additional terms for various exposures that have been studied in relation to lung cancer (eg, cigarette, smoking, asbestos, radiation). In the updating of recent literature, emphasis was placed on systematic reviews when these were available.
Our objective was to provide a summary of the epidemiologic evidence on lung cancer, with an emphasis on issues that are relevant to prevention. This literature is now extraordinarily large; therefore, we did not attempt to conduct a comprehensive review and systematic synthesis. Such syntheses have been periodically carried out by expert review groups, including the committees assembled to prepare the US Surgeon Generals reports on smoking and health and other federal documents and expert committees of other governments and organizations, including the UK Royal College of Physicians and Scientific Committee on Tobacco and the World Health Organizations International Agency for Research on Cancer (IARC). Several relevant reports have been published, including the 2004 IARC monographs on active and involuntary smoking18 and the 2004 report of the Surgeon General.19
The topics covered were agreed on by consensus of the writing committee with initial input from the ACCP Guidelines Panel. As prior versions of this article underwent several rounds of external review, additional topics were added as recommended by the external reviewers, the ACCP Lung Cancer Guidelines Panel, the Thoracic Oncology Network, the Health and Science Policy Committee, and the Board of Regents of the American College of Chest Physicians. On the basis of the agreement of all parties, we did not attempt to grade the evidence or generate formal guidelines.
Previous SectionNext Section
Results
Patterns of Occurrence
Survival:
The 5-year relative survival rate for lung cancer for the period of 1995 to 2001 was 15.7%, reflecting a steady but slow improvement from 12.5% from 1974 to 1976.20 The 5-year relative survival rate varies markedly depending on the stage at diagnosis, from 49 to 16 to 2% for local, regional, and distant stage disease, respectively.20 Stage at diagnosis accounts for the most marked variation in prognosis, but patient characteristics associated with poorer survival also include being older, male, and African American.20
Temporal Trends:
Because of the high case-fatality rate of lung cancer, incidence and mortality rates are nearly equivalent; consequently, routinely collected vital statistics provide a long record of the occurrence of lung cancer. We are amid an epidemic of lung cancer that dates to the first half of the last century.
Sex:
Lung cancer was rare until the disease began a sharp rise around 1930 that culminated by mid-century with lung cancer becoming the leading cause of cancer death among men.21 The epidemic among women followed that among men, with a sharp rise in rates from the 1960s to the present, propelling lung cancer to become the most frequent cause of female cancer mortality.21 As the leading cause of cancer death among women, lung cancer is a major womens health issue. As a result of historical cigarette smoking patterns, the epidemic of lung cancer started later in women than men, but in contrast to the situation in men, lung cancer incidence rates in women have not yet begun to decrease consistently.20 Far more men than women still die from lung cancer each year, but the gender gap in lung cancer mortality is steadily narrowing and will eventually close.2223 This trend is due to historical smoking patterns, with smoking prevalence having peaked approximately 2 decades earlier among men than women.2223
Examination of time trends of age-specific lung cancer mortality rates in the United States further highlights the differing epidemic patterns in men compared with women. The sex- and race-specific mortality rates are now almost all decreasing.22 The rates of lung cancer in the younger age groups have been declining during the past several decades in men and during the past decade in women.22 As the younger birth cohorts age, their reduced risk for lung cancer foreshadows substantial reductions in the overall occurrence of lung cancer, but the reductions will be greater for men than for women. These patterns all are consistent with population patterns of smoking prevalence over time.22
Tobacco smoking accounts for such a large proportion of lung cancer that there have been few data on the occurrence of lung cancer among nonsmokers. Evidence from the American Cancer Society Cancer Prevention Study (CPS) I and II cohorts indicates that there has not been a strong temporal trend in lung cancer death rates among male nonsmokers, but there has been an upward trend among female nonsmokers, mostly confined to elderly women.23 The data from these cohorts also indicate that among nonsmokers, lung cancer death rates are greater in men than in women and greater in African-American than white women.
Race and Ethnicity:
The patterns of occurrence of lung cancer by race and ethnicity make lung cancer a relevant disease for those concerned with the health of minorities. Of particular note is that whereas lung cancer incidence rates are similar among African-American and white women, lung cancer occurrence is approximately 45% higher among African-American men than among white men.20 This racial disparity may be partially due to greater susceptibility of African-American smokers to smoking-induced lung carcinogenesis.24 The higher mortality rates of lung cancer in African-American compared with white individuals reflect not only their higher incidence rate but also the poorer survival from lung cancer among African-American compared with white individuals. The 5-year relative survival rate was 13% lower in African-American compared with white individuals during the period 1995 to 2001.20 This racial gap persisted within each stage at diagnosis category and for men and women.20
Lung cancer mortality rates among Hispanic, Native American, and Asians/Pacific Islander individuals are significantly lower than rates among African-American and non-Hispanic white individuals.25 Nevertheless, lung cancer poses a considerable public health burden among these groups.
Socioeconomic Status:
Lung cancer is more likely to occur in the poor and less educated, a pattern that is observed in many countries worldwide. For example, in Canada, the risk for lung cancer in both sexes was inversely associated with income, education, and social class, even after adjustment for cigarette smoking.26 In China, those who were classified as low income had a sixfold increased risk of lung cancer compared with those in the high-income category.27 In the Netherlands, the risk for lung cancer was inversely associated with attained education, an association that was not attributable to occupational exposures.28 Lower socioeconomic status has also been observed to be associated with later stage at diagnosis.29
Socioeconomic status is associated with a constellation of interacting determinants of lung cancer risk, such as smoking, diet, and exposures to inhaled carcinogens in the workplace and general environment. Lower socioeconomic status is associated with an unfavorable profile for all of these factors. Advancing our understanding of the complex linkages between components of socioeconomic status and lung cancer risk is essential to effectively addressing this social class disparity and reducing lung cancer rates in the poorer segments of society.
Geographic Patterns:
Lung cancer is the most commonly diagnosed cancer worldwide,30 but its geographic distribution shows marked regional variation: age-standardized incidence rates range > 60-fold among men and 30-fold among women (Fig 1,, 2 ).31 Because of differences in cancer registration between countries, caution is needed in interpreting these data. However, this marked variation in rates cannot be explained on the basis of diagnostic practices and data quality alone. Lung cancer tends to be most common in developed countries, particularly in North America and Europe, and less common in developing countries, particularly in Africa and South America.31 The low rates of lung cancer in Africa are comparable to US rates in 1930, when rates of lung cancer were < 5 per 100,000 for both sexes.32 In contrast, African-American individuals in the United States, an epicenter, now experience lung cancer incidence rates that are among the highest in the world. As the lung cancer epidemic begins to subside in the developed countries, it is on the rise in the developing world.30
Within countries, lung cancer incidence among men invariably exceeds that in women, by well more than 100% in most nations. The international rankings of lung cancer incidence of men and women from the same countries tend to differ only slightly, so the highest rates of lung cancer occur in the same regions of the world for both sexes.
Substantial geographic variation in lung cancer mortality rates has also been observed within countries. For example, during the period 1997 to 2001, the age-adjusted lung cancer mortality rates varied more than threefold between the state with the highest rate (Kentucky, 78 per 100,000) and the state with lowest rate (Utah, 25 per 100,000).20 Trends in its regional distribution can provide clues about determinants of lung cancer. In the past, rates tended to be highest in urban areas, which led to conjecture that air pollution might be a cause of the lung cancer epidemic.33 Later on, several hypotheses3435 were prompted by patterns observed in a systematic review of US lung cancer mortality rates for the period 1950 to 1969,36 particularly the rates among men. For example, high rates in coastal areas were postulated to reflect employment in shipyards with attendant asbestos exposure. This hypothesis was then tested in a series of population-based case-control studies that showed that employment in the shipbuilding industry was indeed associated with an excess risk for lung cancer.37 Another shift then took place in the distribution of lung cancer within the United States, with lung cancer mortality rates among white men becoming highest in the South and lower in the Northeast.38 This temporal fluidity in the geographic variation underscores the need for regularly monitoring lung cancer mortality patterns.
Etiology of Lung Cancer
Although the causes of lung cancer are almost exclusively environmental, there is likely substantial individual variation in susceptibility to respiratory carcinogens. The risk for the disease can be conceptualized as reflecting the joint consequences of the interrelationship between the following: (1) exposure to etiologic (or protective) agents, and (2) individual susceptibility to these agents. The environment in its broadest sense may influence the risk for disease through direct exposures or indirectly by affecting the likelihood of exposure to exogenous agents. Given the multifactorial etiology of lung cancer, synergistic interactions among risk factors may have substantial consequences for lung cancer risk. These interactions have typically been considered on an agent-by-agent basis, such as the synergistic effect of cigarette smoking on the lung cancer risk from asbestos exposure.39 Our emerging understanding of cancer genetics indicates the additional relevance of gene/environment interactions.
Given the many risk factors that have been identified for lung cancer, a practical question is the relative contribution of these factors to the overall burden of lung cancer. The population attributable risk approach takes into account the magnitude of the relative risk (RR) associated with an exposure along with the likelihood of exposure in the general population. These attributable risk estimates include joint contributions of risk factors that sometimes have synergistic relationships. For example, the attributable risk estimate for cigarette smoking includes the lung cancer risk attributed to the independent effects of cigarette smoking and further includes the risk for lung cancer from smoking as a result of its synergistic interactions with factors such as asbestos and radon. For this reason, the total percentage can be > 100%. Lung cancer has a well-characterized set of important risk factors and established synergistic interactions between risk factors, and these reasons contribute to the attributable risks summing to considerably more than 100%. As reviewed next, population attributable risk estimates for lung cancer indicate that in the United States, active smoking is responsible for 90% of lung cancer; occupational exposures to carcinogens for approximately 9 to 15%; radon for 10% of lung cancer,16 and outdoor air pollution for perhaps 1 to 2%.40 The contribution of nutritional factors cannot yet be precisely determined; consequently, estimates of the role of dietary factors range widely.41
Environmental and Occupational Agents
Smoking:
A single etiologic agent (cigarette smoking) is by far the leading cause of lung cancer, accounting for approximately 90% of lung cancer cases in the United States and other countries where cigarette smoking is common.42 Compared with never-smokers, smokers who have smoked without quitting successfully have an approximate 20-fold increase in lung cancer risk. Few exposures to environmental agents convey such risks for any disease. In general, trends of lung cancer occurrence closely reflect patterns of smoking, but rates of occurrence lag smoking rates by approximately 20 years. Analyses using statistical modeling techniques show a tight association between national mortality rates and smoking.43 The unequivocal role of cigarette smoking in causing lung cancer is one of the most thoroughly documented causal relationships in biomedical research.644
The burden of lung cancer that is attributable to smoking has been extensively documented. Using an attributable risk approach, the annual number of deaths caused in the United States by smoking-related lung cancer during the period from 1995 to 1999 was 122,800.19 Peto et al42 used a different attributable risk method to quantify the burden of smoking-related deaths from lung cancer in the major developed countries. For 1990, the US total was 127,000, the highest in the world, with country-specific estimates ranging down to 150 for Tajikistan. The total for the developed countries was 457,371.42 A staggering future burden of lung cancer has been forecast for China, where the numbers are predicted to reach several millions by mid-century.4546
Cigar smoking is also an established cause of lung cancer.47 The lung cancer risks associated with cigar smoking are substantial but less than the risks observed for cigarette smoking as a result of differences in smoking frequency and depth of inhalation. The same pattern holds true for pipe smoking.48 With respect to smoking of nontobacco products, the potential role of smoking marijuana on lung cancer risk has been of interest. Despite the plausibility of marijuana as a risk factor for lung cancer, the evidence to date has not documented an association after adjusting for tobacco smoking.49
The risk for lung cancer among cigarette smokers increases with the duration of smoking and the number of cigarettes smoked per day.50 This observation has been made repeatedly in cohort and case-control studies. Risk models have been derived to estimate quantitatively how lung cancer risk varies with number of cigarettes smoked, duration of smoking, and age. Such models are useful for estimating the future burden of lung cancer under various scenarios of tobacco control. In one widely cited analysis, Doll and Peto50 proposed a quantitative model for lung cancer risk on the basis of data from the cohort study of British physicians. This model predicted a stronger effect of duration of smoking than of amount smoked per day. Thus, a tripling of the number of cigarettes smoked per day was estimated to triple the risk, whereas a tripling of duration of smoking was estimated to increase the risk 100-fold.51 These quantitative dimensions of the dosage-response relationship between smoking and lung cancer have implications concerning the now widespread smoking among youths. Those who start at younger ages have a greater likelihood of becoming a heavier smoker and remaining a smoker.52 The exponential effect of duration of smoking on lung cancer risk markedly increases the lifetime risk for those who become regular smokers in childhood and places them at increased risk at younger ages. Prevention approaches that delay the age of onset of smoking in a population could have substantial impact on the incidence of lung cancer by shortening the duration of smoking. In considering the likelihood of lung cancer in a particular patient, clinicians should give more weight to the duration of smoking and less to actual age.
Cigarette smokers can benefit at any age by quitting smoking. The likelihood of lung cancer developing decreases among those who quit smoking as compared with those who continue to smoke.52 As the period of abstinence from smoking cigarettes increases, the risk for lung cancer decreases.53 However, even for periods of abstinence of > 40 years, the risk for lung cancer among former smokers remains elevated compared with never-smokers.5354 The benefits derived from smoking cessation also depend on the duration of smoking; for a given period of abstinence, the decrease in risk increases as the duration of smoking decreases.53 In general, studies55 have shown comparable reductions in risk after cessation regardless of sex, type of tobacco smoked, and histologic type of lung cancer.
The benefits of physician (and other clinician) intervention for smoking cessation are well established.56 The results of research in this area have been translated into an evidence-based clinical practice guideline for treating tobacco dependence on the basis of the 5 As: ask whether a patient smokes, assess willingness to quit, advise to quit, assist with quitting, and arrange follow-up.56
The composition of cigarettes has evolved considerably since the 1950s. The marketplace has shifted from mainly unfiltered cigarettes to predominantly filtered cigarettes. The filters in use in the United States are predominantly cellulose acetate, whereas charcoal filters are used extensively in Japan and some other countries.57 In the mid-1960s, ventilation holes were added to the filter, which dilute the smoke with air drawn through them. However, smokers can readily block the holes with their fingers, which are left unblocked by the machines that are used to test cigarettes. There have also been substantial changes in the design of the cigarette and in the tobacco used. Reconstituted tobacco has been used increasingly since the 1960s, there have been changes to the cigarette paper and additives used, and most cigarettes are more ammoniated in the United States.57
A concomitant shift toward lowered levels of tar and nicotine, as measured by a smoking machine, has occurred.58 Cigarette tar refers to the condensable residue of cigarette smoke (ie, the total particulate matter of cigarette smoke deposited on the filter of the machine, less the moisture and nicotine). Tar is a complex mixture that includes many chemicals that are cancer initiators and/or promoters.58 Tar and nicotine yields are measured with a smoking machine according to a standardized protocol established by the Federal Trade Commission (FTC) that specifies such details and puff volume, the frequency of puffing, and the length to which the cigarette is to be smoked.59
Studies59 using biomarkers of exposure to and dosage of tobacco smoke components show little relationship of levels of these markers with tar or nicotine yield as measured by the FTC protocol. These studies have been conducted in both the population context and during smoking in the laboratory setting. For example, Coultas et al60 collected saliva for analysis for cotinine level and end-tidal breath samples for measurement of carbon monoxide level in a population sample of New Mexico Hispanic individuals who were included in a respiratory health survey. After taking account of numbers of cigarettes smoked, biomarker levels were not associated with the yields of tar and nicotine of the current brand smoked. Djordjevic et al61 evaluated smoking pattern and biomarkers in the laboratory setting, contrasting smokers of medium-yield and low-yield cigarettes. The smokers had greater puff volumes and frequencies than are specified in the FTC protocol and had substantially greater intakes of tar and nicotine than implied by the brand listings. The lack of association of tar and nicotine yields with biomarker levels partially reflects compensatory changes in smoking patterns for those who switch from higher to lower yield products. The compensation includes blocking of the ventilation holes, more frequent and deeper puffs, and an increase in the number of cigarettes smoked.62
The gradual reduction in machine-measured tar yield would be expected to have reduced smokers exposures to carcinogens if the FTC test protocol were predictive of carcinogen dosages delivered to the lung.58 However, questions remain as to whether the FTC test method is informative with regard to lung cancer risk or risks for smoking-caused diseases more generally.6263 Epidemiologic studies have been conducted to assess whether the seemingly substantial changes in tar and nicotine yield, as measured by the FTC protocol, have resulted in parallel changes in the risk of smoking. Epidemiologic studies have been the key source of information because they can provide direct evidence on the risks of smoking cigarettes, as they are actually smoked during use, including any compensatory behavior.
For lung cancer and for other diseases, three lines of epidemiologic data have been available on changes in products. The first comes from case-control studies that compared the smoking history profiles of people with lung cancer with those of control subjects. The second comes from cohort studies that tracked the risk for lung cancer over time, as the products smoked changed. The third comes from assessment of the temporal changes in age-specific patterns of lung cancer mortality rates in comparison with changes in cigarette characteristics.
The initial evidence came primarily from case-control studies that compared risks in people who had used filter-tipped cigarettes with people who had smoked nonfiltered cigarettes exclusively.6465 This evidence suggests that filtered cigarettes and cigarettes with lower tar yields slightly reduce the risk for lung cancer associated with cigarette smoking compared with nonfiltered cigarettes or with higher tar yields.666768 This comparison could be made among smokers in the 1960s because there was still a substantial proportion who had not used filtered cigarettes at all. For example, in one of the first studies, Bross and Gibson64 compared lung cancer risk of smokers of filtered and nonfiltered cigarettes among patients who were seen at Roswell Park Memorial Cancer Institute in Buffalo; individuals were classified as filter cigarette smokers when they had used these products for at least 10 years.
The relevant cohort studies are the American Cancer Society CPS I and CPS II studies and the British Physicians Cohort. In a 1976 publication, Hammond et al69 compared mortality risks from lung cancer and other diseases by tar yield of products smoked by CPS I participants. The follow-up interval spanned from 1960 to 1972. Smokers were placed into three categories of products smoked: low yield (< 17.6 mg per cigarette), high yield (25.8 to 35.7 mg per cigarette), and medium yield (intermediate). The standardized mortality rate for lung cancer in low- and medium-yield smokers was approximately 80% of the rate in high-yield smokers. A further analysis of tar yield using the same data set confirmed that risk for lung cancer death increased with tar yield.70
Further insights have been gained by comparing the risks in the two CPS studies of the American Cancer Society; this comparison addresses whether risks have changed, comparing smokers with disease developing from 1960 to 1972 with a similar group of smokers with disease developing during the initial follow-up of CPS II, from 1980 to 1986.7172 If the risk for lung cancer associated with smoking is decreasing over time, then the expectation would be that risks for smokers would be less in CPS II than in CPS I. In fact, the opposite was observed, with increasing lung cancer mortality in male and female smokers in CPS II compared with CPS I.73
In an analysis with a similar pattern of findings, Doll et al74 compared the risks for death from lung cancer and other causes during the first and second 20 years of the 40-year follow-up of the British physician cohort. Lung cancer mortality increased among smokers in the second 20 years (from 1971 to 1991), even though products smoked during this period would have had a substantially lower tar and nicotine yield than those smoked during the first 20 years (from 1951 to 1971). For the first 20 years, the annual lung cancer mortality rate among current smokers was 264 per 100,000, and for the second 20 years, it was 314 per 100,000. In 2004, Doll et al75 reported the findings at 50 years of follow-up; compared with lifelong nonsmokers, the risk for lung cancer was increased fourfold among former smokers and > 14-fold among current smokers. Among current smokers, the RRs increased from 7.7 to 13.7 to 24.5 among smokers of 1 to 14, 15 to 24, and > 25 cigarettes per day, respectively.
The third line of observational evidence comes from descriptive analyses of age-specific trends of lung cancer mortality.186276 Successive birth cohorts have had differing patterns of exposure to cigarettes of different characteristics and yields. For example, the cohort of individuals who were born between 1930 and 1940 and started to smoke in the 1950s was one of the first to have the opportunity to smoke primarily filter-tipped cigarettes. Subsequent birth cohorts would have had access to the increasingly lower yield products, whereas earlier cohorts had access initially only to nonfiltered cigarettes. Patterns of temporal change in age-specific rates of lung cancer mortality in younger men have been examined to assess whether there has been a decline greater than expected from changing prevalence, duration, and amount of smoking, thereby indicating a possible effect of cigarette yield.
Data on lung cancer mortality in younger men in the United Kingdom have been interpreted as indicating a possible reduction in lung cancer risk associated with changes in cigarettes.6276 A sharp decline in lung cancer mortality has occurred across the past few decades in UK men < 50 years of age. The decline seems greater than anticipated from trends in prevalence and other aspects of smoking: age starting and number of cigarettes smoked. A similarly steep decline has not taken place in the United States. Given the ecologic nature of the data under consideration, uncertainty remains with regard to their interpretation, and alternative explanations have been proposed, including less intense smoking at younger ages in more recent birth cohorts.62
This discussion highlights the complexity of isolating the precise effect on lung cancer risk of the continually changing cigarette. The data available to evaluate these effects have limitations, particularly in capturing the experience of successive birth cohorts in either case-control or cohort studies that were appropriately designed. The UK mortality data suggest a greater effect of changes in cigarettes than is found in the case-control and cohort studies. As recommended by the Institute of Medicine,77 surveillance is needed to track the health consequences of the changing cigarette.
Several expert panels have reviewed the findings. The Institute of Medicine77 conducted a comprehensive review on various harm reduction strategies for reducing the disease burden caused by smoking, including lower yield cigarettes. There are also new products in various phases of development that are intended to deliver nicotine without direct combustion of tobacco. The Institute of Medicine report concluded that smoking lower-yield products had not been shown to benefit the health of smokers. This topic was addressed in the 2004 report of the US Surgeon General,19 with the conclusion that although characteristics of cigarettes have changed during the last 50 years and yields of tar and nicotine have declined substantially, as assessed by the Federal Trade Commissions test protocol, the risk of lung cancer in smokers has not declined.
Results of some case-control and screening studies have suggested a potentially higher risk for smoking-associated lung cancer in women compared with men,787980 but methodologic issues cloud the interpretation of these studies, particularly a lack of focus on the most informative comparisons.81 Furthermore, the evidence from prospective cohort studies fails to support the notion of a sex differential in susceptibility to lung cancer from smoking.82 The equal rates of lung cancer mortality in younger US men and women corresponding to a time of equal smoking prevalence also provides evidence against an important sex difference in susceptibility to smoking-induced lung cancer.22 The evidence against this hypothesis outweighs the evidence in favor of the hypothesis on the basis that the results of studies that have compared the RR estimates for men and women for a specific degree of smoking history demonstrate very similar associations.82
The development of menthol cigarettes was targeted specifically at African-Americans and women.8384 African-Americans are more likely than white individuals (69 vs 29%) to smoke menthol cigarettes,85 and the menthol smoke delivery levels of common cigarette brands have increased significantly since the 1980s.8687 This has led to the hypothesis that menthol cigarettes explain the greater susceptibility to lung cancer from cigarette smoking in black vs white individuals24 and thus the disparity in lung cancer risk between US black and white individuals, especially among men.
Menthol cigarettes may cause a greater increase in lung cancer risk than nonmenthol cigarettes, either by increasing systemic exposure to toxicants from tobacco smoke or by affecting the metabolism of nicotine and/or tobacco smoke carcinogens. Initially, this hypothesis gained currency because of the potential for increased nicotine uptake through the effects of menthol in the respiratory tract. These include an increase in the smoothness of tobacco smoke, which promotes deeper inhalation; stimulation of cold receptors, which results in airway cooling effects that mask the irritation caused by cigarette smoke, promoting deeper inhalation and altered inhalation frequency; further masking of irritation through anesthetic effects8688; and increased permeability and diffusibility of smoke constituents.87
There is limited information on the molecular mechanisms by which mentholation might increase the health risk of smoking. Seventy to 80% of nicotine is metabolized to cotinine, and cytochrome P450 2A6 is responsible for 90% of this conversion.89 The P450 2A6 gene has multiple functional polymorphisms that vary by race. The observation that menthol competitively inhibits cotinine metabolism by the monkey analog of a human UDP-glucuronyltransferase90 suggested that inhibition of either CYP2A6 or UDP-glucuronyltransferase by menthol might alter nicotine and cotinine metabolism. African-American and white menthol smokers have similar baseline cotinine levels.91 Human studies89919293 have suggested that smoking mentholated cigarettes inhibits nicotine metabolism, so smokers experience higher dosages of nicotine for a given level of smoking. Menthol inhibits the microsomal oxidation of nicotine to cotinine,92 suggesting that smoking mentholated cigarettes may lead to inhibition of nicotine metabolism. In a randomized, crossover study of seven African-American and seven white individuals, Benowitz et al93 found that the systemic intake of nicotine was not affected by mentholation, but smoking mentholated cigarettes inhibited the metabolism of nicotine. By slowing the metabolism of nicotine and thereby reducing the need for nicotine from smoking, menthol may reduce the number of cigarettes smoked per day. A menthol effect might explain why African-American individuals smoke fewer cigarettes per day than white individuals. It may also explain, in part, the variation by race and gender in the correlation between cotinine level and cigarettes smoked per day among smokers of menthol cigarettes,94 possibly reflecting the effect of menthol on nicotine inactivation by P450 2A6.89
However, the epidemiologic data suggest that, overall, smokers of mentholated cigarettes do not have an increased risk for lung cancer compared with smokers of nonmentholated cigarettes. This evidence is based primarily on hospital-based case-control studies,95969798 but also includes a population-based case-control study99 and a cohort study within a health maintenance organization.100 Furthermore, menthol cigarettes have not been associated with any specific histologic subtypes of lung cancer.101
Evidence that menthol cigarettes might carry greater risks were observed in one case-control study97 in which black, male, heavy smokers of mentholated cigarettes (> 37.5 pack-years, or ≥ 21 cigarettes per day) had a higher risk than white men with similar smoking histories. In the cohort study,100 the RR for lung cancer among men but not women was slightly elevated in menthol smokers compared with nonmenthol smokers, with a graded increase in lung cancer risk with increasing duration of menthol cigarette use.
The evidence does not indicate that menthol cigarettes are an important contributor to the high rates of lung cancer in African-American individuals. A more definitive answer to this question will emerge if future studies address several methodologic challenges, including misclassification of menthol cigarette exposure as a result of brand ambiguity; potential for selection bias in hospital-based case-control studies, as a result of lower prevalence of menthol cigarette use among African-American patients at university hospitals used for such studies than in the general population; and lack of information about compensatory mechanisms.102
Passive smokers inhale a complex mixture of smoke now widely referred to as secondhand smoke or as environmental tobacco smoke (ETS). Passive smoking was first considered as a possible risk factor for lung cancer in 1981, when two studies that described increased lung cancer risk among never-smoking women who were married to smokers were published. Hirayama103 reported the findings from a cohort study in Japan that showed that among nonsmoking women, those with a husband who smoked cigarettes were at higher risk for lung cancer than those whose husband was a nonsmoker. A case-control study in Athens reported by Trichopolous et al104 shortly thereafter replicated this finding. Additional evidence rapidly accrued, such that by 1986 two important summary reports were published. The National Research Council reviewed the epidemiologic evidence and concluded that nonsmoking spouses who were married to cigarette smokers were approximately 30% more likely to have lung cancer develop than nonsmoking spouses married to nonsmokers and that this relationship was biologically plausible.105 Almost one fourth of lung cancer cases among never-smokers were estimated to be attributed to exposure to passive smoking.105 The 1986 Surgeon General report also judged passive smoking to be a cause of lung cancer,13 an inference corroborated by the 1992 review of the evidence and risk assessment by the US Environmental Protection Agency, which classified ETS as a known human (class A) carcinogen.14 Estimates indicate that passive smoking accounts for approximately 3,000 lung cancer deaths per year in the United States.14 Since these conclusions were reached, several major studies106107 have been conducted to characterize further the association of passive smoking with lung cancer, while taking into account some of the limitations of earlier studies, particularly small sample sizes, exposure misclassification, and omission of some potential confounding factors.
Passive smoking is more weakly associated with lung cancer than is active smoking, as expected given the generally lower dosages of carcinogens that are passively received by the lung of the nonsmoker compared with the dosages received by the active smoker. Because of broad societal implications, the conclusion that this association is causal has generated controversy, some driven by the effort of the tobacco industry to maintain continued questioning of the evidence.108109 Questions have been raised about the method of the epidemiologic studies, including confounding and misclassification of exposure to environmental tobacco smoking. Review groups1314106110 have nonetheless concluded that the association between ETS and lung cancer cannot be attributed to methodologic limitations of epidemiologic data.
Studies have been directed at the specific venues where nonsmokers are exposed to tobacco smoke, including the home, workplaces, and public places. Much of the literature has focused on the increased risk associated with being married to a smoker, an exposure variable that can be readily ascertained. Metaanalyses have been conducted periodically to summarize the evidence from the epidemiologic studies. A 2002 metaanalysis by Boffetta111 found a 25% increased risk associated with marriage to a smoker; this excess risk seemed to be due to exposure to passive smoking because it could not be explained by confounding or misclassification. This finding was consistent with the 29% estimated increased risk among women whose husband smoked in the metaanalysis of Taylor et al,112 who observed that the association was consistent across study designs and in Western and non-Western nations. Workplace exposure to secondhand smoke was associated with a 17% increase in lung cancer risk in the metaanalysis of Boffetta.111
The studies of passive smoking provide further evidence documenting the dosage/response relationship between cigarette smoke and lung cancer. The dosages extend to far lower levels than those of active smoking and increased risk is observed, suggesting that there is no threshold for tobacco carcinogenesis.13
Lung cancer occurs in multiple histologic types as classified by conventional light microscopy. The four major types include squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and small cell undifferentiated carcinoma; together, these four types of lung cancer account for > 90% of lung cancer cases in the United States.113 Notable shifts have taken place in the incidence rates of lung cancer by histologic type.114 After steadily increasing occurrence during the period from 1973 to 1987, adenocarcinoma supplanted squamous cell carcinoma as the most frequent form of lung cancer.114 Adenocarcinoma increased markedly in all race and sex subgroups.114
Despite extensive research, the mechanisms that lead to these different types of lung cancer remain uncertain. Hypotheses have focused on the cells of origin of lung cancers and on pathways of differentiation of malignant cells.113 An area of active interest is characterizing the likelihood that dysplastic lesions that are detected by fluorescence bronchoscopy will progress to invasive cancer115 and relating the distribution of these lesions vis a vis the distribution of invasive lung cancer tumors on the basis of epidemiologic findings. CT scans are generally being used to identify peripheral lesions (usually adenocarcinoma), whereas fluorescence bronchoscopy is being used for the detection of central airway lesions, predominantly preinvasive squamous cell carcinoma. Smoking has been shown to cause each of the major histologic types, although the dose/response relationship with number of cigarettes smoked varies across the types, being steepest for small cell undifferentiated carcinoma.115116 There are a few suggestive links of histologic type with occupational agents: small cell lung cancer has been reported to be in excess in workers who are exposed to chloromethyl ethers and in underground miners who are exposed to radon progeny.113
In the initial decades of the smoking-caused epidemic of lung cancer, squamous cell carcinoma was the most frequent type of lung cancer observed in the population, and small cell carcinoma was the next most frequent. In the late 1970s, the first evidence of a shift toward a predominance of adenocarcinoma was noted,113117118 and now adenocarcinoma of the lung is the most common histologic type.112 The decline in lung cancer rates has been more rapid for squamous cell and small cell carcinomas than for adenocarcinoma, which is just beginning to show a lower incidence rate.114 In women, the Surveillance, Epidemiology, and End Results4 data from 1973 to 1996 indicated that the incidence rates of squamous cell, small cell, and large cell carcinomas at least reached a plateau, whereas the rate for adenocarcinoma were still rising.
Although changing patterns of diagnosis and classification of lung cancers could have led to these changes over time, most observers have set aside an artifactual change.113117118 Beginning in the 1970s, new techniques for the diagnosis of lung cancer became available, including the fiberoptic bronchoscope and thin-needle aspiration119; improved stains for mucin, the hallmark of adenocarcinoma, were also introduced. Using data from the Connecticut Tumor Registry, Thun et al119 showed that the rise in adenocarcinoma antedated these diagnostic innovations.
Hypotheses concerning the shift in histopathology have focused on the potential role of changes in the characteristics of cigarettes and consequent changes in the dosages of carcinogens inhaled.120 Puff volume has likely increased in the past few decades with the possibility that patterns of deposition in the lung have changed, tending toward enhanced deposition of tobacco smoke in the peripheral airways and alveoli.120 Nitrate levels in tobacco smoke have also increased, which enhances the combustion of tobacco smoke. Although more complete combustion decreases the concentrations of polycyclic aromatic hydrocarbons, the increased production of nitrogen oxides contributes to increased formation of tobacco-specific nitrosamines. An increase in dosage of the potent tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone has been postulated as one factor leading to the increase in adenocarcinoma.120121 Nitrosamine 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone induces lung carcinomas, predominantly adenomas and adenocarcinomas, in mice, regardless of route of administration.121122
Few studies can provide data to test these hypotheses because of the need for longitudinal observation of lung cancer risk in relation to the characteristics of the cigarettes smoked over time. Thun et al119 compared risks for lung cancers of the various histologic types among participants in the American Cancer Society CPS I and CPS II. They found markedly rising risks associated with smoking for adenocarcinoma of the lung in both men and women during the approximate 20 years separating the two studies. Thun et al119 concluded, The increase in lung adenocarcinoma since the 1950s is more consistent with changes in smoking behavior and cigarette design than with diagnostic advances. In a study123 that compared tumor location in lung cancer patients, lower-tar cigarettes were associated with a higher likelihood of peripheral than central tumors.
Diet:
Research on diet and lung cancer has now been conducted for nearly 3 decades. The possible role of diet in modifying the risk for lung cancer has been the focus of intensive investigation, driven initially by the rationale that specific micronutrients might have anticarcinogenic activity. The most thoroughly investigated dietary factors are also those that seem to have the greatest implications for prevention: fruits, vegetables, and specific antioxidant micronutrients that are commonly found in fruits and vegetables. Much of the research on diet and lung cancer has been motivated by the hypothesis that diets that are high in antioxidant nutrients may reduce oxidative DNA damage and thereby protect against cancer.124
The results of case-control and prospective cohort studies have tended to show that individuals with high dietary intake of fruits or vegetables have a lower risk for lung cancer than those with low fruit or vegetable intake.125 Evidence from cohort studies126127128129130 published since 2000 has tended to reinforce this notion. In the European Prospective Investigation Into Cancer and Nutrition Study,131 a strong protective association was observed with fruit but not vegetable consumption. A stronger protective association was observed for fruit than vegetable consumption in a pooled analysis of seven cohort studies.132
To better understand the basis of this protective association, fruits and vegetables have been grouped into classes and also examined individually in relation to lung cancer risk. For example, tomatoes133134135 and cruciferous vegetables129135 have been associated with a reduced risk for lung cancer in a number of studies, at least for the highest vs lowest categories of consumption. These food-based analyses can help to clarify whether protection against lung cancer is conferred by the complex mixture contained in fruits and vegetables or by the presence of specific biochemical constituents in particular fruits and vegetables.
Fruits and vegetables are the major dietary source of antioxidant micronutrients. Two different strategies are used to evaluate the relationship of micronutrients to lung cancer risk in observational epidemiologic studies: (1) using data summarized from food-frequency questionnaires to estimate micronutrient intake, and (2) drawing blood samples from study participants and assaying the concentrations of micronutrients in circulation. The former approach provides a better average measure of micronutrient exposure, whereas the latter approach has the advantage of measuring micronutrient concentrations closer to the cellular level, where the postulated biological effect occurs. The differences in measurement approaches may lead to different results in certain situations. A metaanalysis136 of selenium and lung cancer found that selenium intake as measured by questionnaire showed no association (RR, 1.0; 95% confidence limit [CL], 0.8, 1.3), whereas associations in the protective direction were observed for selenium concentrations measured in toenails (RR, 0.5; 95% CL, 0.2, 0.9) or serum (RR, 0.8; 95% CL, 0.6, 1.1).
Studies of both dietary intake137138139140 and prediagnostic blood concentrations141142 suggested a protective association between carotenoids and lung cancer. The evidence for vitamin C is scant but suggestive of a protective association, whereas the data on vitamin A has yielded null findings.143 Reports from cohort studies have tended to reinforce the previous findings of protective associations with intake of a variety of carotenoids128135144 or an antioxidant index.140 However, a pooled analysis139 of seven cohort studies did not find strong protective associations with any carotenoids other than β-cryptoxanthin.
More recently, studies have examined phytochemicals such as flavonoids and isothiocyanates in relation to lung cancer risk. Phytochemicals are low-molecular-weight molecules produced by plants. Of the many classes of phytochemicals, those studied in relation to lung cancer include phytoestrogens, flavonoids, and glucosinoids. The tumor-promoting effects of steroid hormones can be blocked by phytoestrogens. Soya beans are a primary source of a specific class of phytoestrogens known as isoflavonoids. Flavonoids exhibit potent antioxidant activity. Flavonoid intake has been at least weakly associated with lung cancer in some of the preliminary studies145146 of this topic. Isothiocyanates are metabolites of the class of phytochemicals known as glucosinolates. Isothiocyanates could exert anticancer effects by blocking carcinogens via induction of phase 2 detoxification enzymes, such as glutathione S-transferase. Cruciferous vegetables contain high concentrations of glucosinolates; therefore, consumption leads to higher endogenous isothiocyanate concentrations. As with cruciferous vegetables,147 lung cancer risk is consistently lower with higher intakes or urinary levels of isothiocyanates.148149150 When isothiocyanates have been studied in combination with a common polymorphism in the GSTM1 gene, the decreased risk for lung cancer associated with isothiocyanates has been especially pronounced in people with the GSTM1 null genotype.148149150 This provides an example of a potential gene/diet interaction that may be relevant to lung carcinogenesis.
Studies of fruits, vegetables, and micronutrients have been the centerpiece of studies of diet and lung cancer, but a wide range of dietary and anthropometric factors have been investigated. For example, the results of a metaanalysis151 showed that alcohol drinking in the highest consumption categories was associated with increased risk for lung cancer. Anthropometric measures have also been studied, indicating a tendency for people with lower body mass index (BMI) to have increased lung cancer risk relative to heavier people.152153 However, effects of both alcohol drinking and low BMI may be difficult to separate from the concomitant effects of smoking. When considering the possible relationships between lung cancer and factors such as alcohol drinking and lower BMI, cigarette smoking cannot be dismissed as a possible explanation.
The overwhelming contribution of cigarette smoking as a cause of lung cancer poses a challenge to detecting the role that other lifestyle factors, such as diet, may play in the cause of lung cancer. Cigarette smoking is now so closely associated with less healthful lifestyles in the United States and some other countries, such as less healthful diets,154 that it is often difficult to disentangle the dietary factor(s) of interest from the effects of smoking. Cigarette smoke can directly affect circulating concentrations of dietary factors; for example, smokers tend to have lower circulating concentrations of antioxidant micronutrients even after accounting for differences in dietary intake.154 In addition, associations between dietary factors and lung cancer risk are likely to be far weaker than the association with active smoking, and diet is measured with much greater error in general than is smoking. Even for a dietary factor, such as vegetable consumption, which is fairly consistently associated with a lower risk for lung cancer, the highest exposure category is typically associated with at most a halving in the risk for lung cancer. Therefore, in interpreting the evidence, residual confounding cannot be readily set aside as an explanation for the observed associations between dietary factors and lung cancer.155
Chemoprevention Trials:
The experimental rationale for trials of beta carotene and retinoids is offered in another article in this Supplement (Lung Cancer Chemoprevention by Gray et al). Experimental data indicated a potential for prevention with these agents; observational data were supportive of the hypothesis that beta-carotene and retinoids might have chemopreventive activity.124 However, a protective association between beta-carotene and lung cancer was not found in three randomized, double-blind, placebo-controlled chemoprevention trials156157158 of beta-carotene reported during the 1990s. In fact, beta-carotene supplementation was associated with an increased risk for lung cancer among the high-risk populations of heavy smokers in the α-Tocopherol β-Carotene Cancer Prevention Study,156 and smokers and asbestos-exposed workers in the Carotene and Retinol Efficacy Trial.158
In summary, observational evidence suggests that smokers who eat more vegetables are at lower risk for lung cancer than those who consume fewer vegetables. The evidence is not as consistent for fruit consumption. The specific constituents of vegetables that confer protection are not known. The results of the chemoprevention trials clearly suggest a more complex role for micronutrients than previously proposed.
Physical Activity:
Several studies159160161 have reported that more physically active individuals have a lower risk for lung cancer than those who are more sedentary, even after adjustment for cigarette smoking. As with the assessment of any lifestyle factor other than smoking with lung cancer risk, potential residual confounding by cigarette smoking needs to be considered as an alternative explanation.
Occupational Exposures:
Investigations of occupational groups, often heavily exposed over a long time to workplace agents, have provided substantial understanding of the carcinogenicity of a number of chemicals and physical agents. Among cancers that are associated with occupational exposures, cancer of the lung is the most common.162 Estimates derived from case-control studies163164165166167168169 of the proportion of lung cancer that is contributed to by occupational exposures, via independent or shared causal pathways, have ranged widely, but most point estimates or ranges have included values from 9 to 15%. Although disagreement persists concerning specific estimates,170 the message is clear: in industrialized nations, the contribution of occupational exposures to the lung cancer burden is small compared with that of cigarette smoking, but large compared with contributions of most other exposure classes. Cigarette smoking potentiates the effect of some known occupational lung carcinogens.40
Lung cancer has been observed to be associated with many workplace exposures. Workers who are exposed to tar and soot (which contains benzo[a]pyrene), such as coke oven workers,171172 in concentrations that exceed those present in urban air173 are at increased risk for lung cancer. Occupational exposures to a number of metals, including arsenic, chromium, and nickel, are also causes of lung cancer.174 For many of the worker groups exposed to these agents, there were substantial increments in risk. However, in developed countries, these hazards have largely been controlled.
For some other workplace agents, the evidence has been less clear. The results of numerous case-control and cohort studies are compatible with a weak association between exposure to diesel exhaust and the development of lung cancer.175 Although inadequate control of cigarette smoking limits the inferences that can be drawn from many of these studies, exposure to diesel exhaust remains a likely explanation for these findings.175 This association remains a public health concern because the public is exposed to diesel exhaust in urban areas, and in some European countries diesel vehicles are increasingly used.41
The question of whether silica dust is a risk factor for lung cancer has been controversial.176177178 A twofold increase in lung cancer risk was estimated from a metaanalysis179 of the relationship between silicosis and lung cancer mortality. Effects of smoking were not well controlled in most of the studies.179 The evidence on silica exposure, absent consideration of the presence of silicosis, is less clear.180181 In 1997, the IARC did classify crystalline silica as a human carcinogen182; however, some still continue to question its carcinogenicity181 and the role of silica exposure vs that of fibrosis in people with silicosis.180
Asbestos:
Asbestos, a well-established occupational carcinogen, refers to several forms of fibrous, naturally occurring silicate minerals.183 The epidemiologic evidence dates to the 1950s, although clinical case series had previously led to the hypothesis that asbestos causes lung cancer.184185 In a retrospective cohort study published in 1955, Doll186 observed that asbestos textile workers at a factory in the United Kingdom had a 10-fold elevation in lung cancer risk and that the risk was most heavily concentrated during the time frame before regulations were implemented to limit asbestos dust in factories. A sevenfold excess of lung cancer was subsequently observed among insulation workers in the United States.187188 The risk for lung cancer has been noted to increase with increased exposure to asbestos189 and to be associated with the principal commercial forms of asbestos.190 Whether asbestos acts directly as a carcinogen or through indirect mechanisms, such as causing chronic inflammation that eventually leads to cancer development, remains uncertain.191192
Asbestos and cigarette smoking both are independent causes of lung cancer, but in combination they act synergistically to increase the risk for lung cancer in a manner that is compatible with a multiplicative effect.193 Cigarette smoking may increase the lung cancer risk associated with asbestos exposure by enhancing retention of asbestos fibers.194
Radiation:
Epidemiologic studies of populations that were exposed to high doses of radiation showed that lung cancer is one of the cancers associated with exposure to ionizing radiation.195 However, the risks for low-dose radiation, more relevant to contemporary workers and the general population, have proved difficult to characterize.195 Assessing the cancer risk that is associated with low-dose radiation among humans is methodologically difficult because the signal-to-noise ratio is highly unfavorable.196 Nevertheless, large cohort studies,16197198 particularly the study of Japanese atomic bomb survivors, have provided understanding of the risks of low-dose ionizing radiation.
The following two types of radiation, classified by rate of energy transfer to the tissue, are relevant to lung cancer: low linear energy transfer (LET) radiation (eg, x-rays, gamma rays) and high-LET radiation (eg, neutrons, radon). High-LET radiation produces ionization of relatively higher density in tissues than low-LET radiation, so in equivalent doses, more biological damage is produced by high-LET than low-LET radiation.199 For both types of radiation, the majority of the epidemiologic evidence comes from cohorts that were exposed at levels substantially greater than those experienced by the general population. Risk assessment methods are then used to estimate risks to the population.
Radon is an inert gas that is produced naturally from radium in the decay series of uranium. Two of the decay products of radon emit α particles that, by virtue of their high energy and mass, can cause damage to the DNA of cells of the respiratory epithelium. Epidemiologic studies200201 of underground miners of uranium and other ores have established exposure to radon daughters as a cause of lung cancer. In the miners who were exposed to radon in past centuries, very high lung cancer risks were observed; these fell for more recent workers, but the epidemiologic studies16 still show clear evidence of existing cancer risk. Cigarette smoking and radon decay products synergistically influence lung cancer risk in a manner that is supraadditive but submultiplicative.16201
Radon is of broader societal interest because it is a ubiquitous indoor air pollutant that enters buildings in soil gas. On average, indoor exposures to radon for the general population are much less than those received by occupational groups such as uranium miners. For example, even the lowest historical radon concentration in a uranium mine is roughly 50 to 100 times higher than in the average home.201 Exposure to radon in indoor air is also assumed to cause lung cancer, but the magnitude of the risk is uncertain because of the assumptions underlying the extrapolation of findings from uranium miners to the generally lower exposures indoors. These assumptions relate to dose, dose rate, and dosimetry and also reflect the lack of information on risks of exposures of women and children. Strengthening biological evidence supports the assumption that a single hit to a cell by an α particle causes permanent cellular change, an assumption that leads to a nonthreshold dose/response relationship.
The assumptions made by the Environmental Protection Agency and the Biological Effects of Ionizing Radiation IV and VI Committees of the National Research Council led to estimates that approximately 15,000 to 20,000 lung cancer deaths per year in the United States are caused by radon.202 Case-control studies203204 concerning indoor exposure to radon as a risk factor for lung cancer, undertaken to assess risks directly, have produced findings that are generally consistent with downward extrapolation of risk models based on the underground miners. This coherence lends support to using extrapolation of the miner data to estimate the risk of indoor radon.
Epidemiologic data relating low-LET radiation to lung cancer stem from three principal populations: the atomic bomb survivors in Japan,205 patients with diseases such as ankylosing spondylitis206 or tuberculosis207208 who received multiple radiation treatments, and occupational groups in professions that expose workers to radiation.209 The single, high-dose exposure of the atomic bomb survivors was associated with significant lung cancer risk.205 Regardless of their age when the atomic bombs were dropped, the excess of lung cancer did not occur until the survivors reached older ages, when cancer usually occurs,205 and a consideration of radiation and smoking together suggests an additional relationship.198
The risks associated with exposure to lower doses of low-LET radiation have been estimated in two ways. Statistical models have been used to extrapolate from the atomic bomb survivors data to lower doses. Patients who had tuberculosis and received radiation therapy have also been studied; they were intermittently exposed to radiation. Such intermittent, low-dose exposures may be most pertinent for the general population because this exposure pattern is the most common in technologically advanced societies. Studies of patients with tuberculosis suggest that if any risk for lung cancer is associated with this exposure pattern, then it is small,207208 suggesting that the assumptions on which the higher risk estimates that were obtained from the data of atomic bomb survivors may in actual fact not hold.208
Low-LET radiation therefore seems to be associated with higher lung cancer risk when exposure occurs at a higher dose rate.208 These results contrast with those for high-LET radiation, suggesting that the two types of radiation have different dose-rate relationships.208
Air Pollution:
During a typical day, the average adult inhales approximately 10,000 L of air.210 Consequently, even the carcinogens that are present in the air at low concentrations are of concern as a risk factor for lung cancer. Extrapolation of the risks associated with occupational exposures to the lower concentration of carcinogens in polluted ambient air leads to the conclusion that a small proportion of lung cancer cases could be due to air pollution.162211
Carcinogens that are generated by combustion of fossil fuels include polycyclic aromatic hydrocarbons and metals such as arsenic, nickel, and chromium.174 In considering respiratory carcinogenesis, the constituents of air pollution will vary by locale and over time depending on the pollution sources.212 Consequently, epidemiologic investigations of air pollution and lung cancer have been limited by the difficulty of estimating exposure. Nevertheless, descriptive evidence is consistent with a role for air pollution in causing lung cancer. Urbanization and lung cancer mortality are linked.213214215 This association could arise from differences in the distributions of other lung cancer risk factors, such as smoking and occupational exposures, by degree of urbanization. Adjustment for these factors may considerably attenuate the effect of urban location,216217 but an urban effect persists in a number of studies.40
Air pollution has been assessed as a risk factor for lung cancer in both case-control and cohort studies. Whereas early evidence from case-control and cohort studies was found wanting, more recently the evidence supports a causal role for air pollution.218
Two prospective cohort studies219220 that partially addressed weaknesses of earlier studies add evidence that suggests air pollution is weakly associated with the risk for lung cancer. By prospectively studying air pollution levels in relation to risk for lung cancer and by controlling for possible confounders such as age, smoking, and socioeconomic status at the individual level, these studies surmount some shortcomings noted of much previous research.221 In a study of six US cities,219 the adjusted risk for lung cancer mortality in the city with the highest concentration of fine particles was 1.4 times (95% confidence interval [CI], 0.8 to 2.4) higher than in the least polluted city. Using data from the American Cancer Society CPS II, Pope et al220 observed that compared with the least polluted areas, residence in areas with high sulfate concentrations was associated with an increased risk for lung cancer (adjusted RR, 1.4; 95% CI, 1.1 to 1.7) after adjustment for occupational exposures and the factors mentioned previously. However, unlike in the Six-Cities Study,222 fine-particulate concentration was not associated with lung cancer risk. In a subsequent update, follow-up was extended to 1998. In that report, the risk for lung cancer was observed to increase 14% for each 10-μg/m3 increase in concentration of fine particles.
By contrast, in the American Cancer Society CPS I cohort, air pollution was not associated with lung cancer risk; in that study, men were stratified according to exposures in the workplace, but exposure assessment for air pollution was based on proxy, less specific measures of air pollution.221 Some case-control studies223224225 have reported indexes of air pollution to be modestly associated with elevated risks for lung cancer, but others226 have reported no association.
Another research approach to evaluate the risk of air pollution has been to investigate populations that reside around point sources of pollution, such as factories and smelters. Proximity of residence to the pollution source can be used as a proxy for exposure. Many industries have been studied using this approach. Areas surrounding nonferrous smelters, which emit arsenic, have been of particular interest. An ecologic study reported by Blot and Fraumeni35 in 1975 suggested that excess lung cancer occurred in US counties with copper, lead, or zinc smelting and refining industries. The results of several subsequent case-control studies227228229 lend support to this hypothesis by showing that the risk for lung cancer increased the nearer that people lived to nonferrous smelters, after accounting for personal cigarette smoking and employment at the smelter. Other case-control studies230231 did not replicate this finding but were also limited by their failure to account for smoking and employment at the smelter.
Doll and Peto,162 in their 1981 review of the causes of cancer, estimated that perhaps 1 to 2% of lung cancer was related to air pollution. Even in light of more recent findings, this seems to remain a reasonable estimate.232 The body of evidence linking air pollution to lung cancer is solidifying,218 but the public health impact of this exposure is small relative to cigarette smoking, at least in developed country settings where research has been conducted. This is to be expected, given that respiratory doses of carcinogens from active smoking are significantly greater than those received from the inhalation of atmospheric contaminants.
An individuals total exposure to air pollution depends on indoor as well as outdoor exposures. Indoor air quality has large potential health implications because people may spend substantial amounts of time indoors. Indoor air pollution may stem from incoming outdoor air or originate indoors from tobacco smoking, building materials, soil gases, household products, and combustion from heating and cooking.233 A trade-off exists between energy efficiency and indoor air quality because ventilation allows heated/cooled air to escape but improves indoor air quality.234
As discussed, in more developed countries, two of the most important indoor pollutants that most strongly increase lung cancer risk in never-smokers are passive smoking13 and radon.202 Asbestos exposure may pose a risk to building occupants, but concentrations are generally very low.183 Of major concern in the developing world is the indoor air contamination resulting from the use of unprocessed solid fuels, notably coal, for cooking and space heating.235 Mumford et al236 inferred that smoky coal was likely to be a major determinant of the geographic distribution of lung cancer in Xuan Wei, China, a finding corroborated by an animal model.237 Evidence supporting a causal association was strengthened by the results of a retrospective cohort study that showed that switching from use of unvented fire pits to stoves with chimneys almost halved the risk for lung cancer.238
Host Factors:
Genetic susceptibility to lung cancer has long been postulated. Environmental agents, even cigarette smoking, cause lung cancer in only a minority of exposed people, leading to the hypothesis that susceptibility is inherently determined. Epidemiologic studies244 showing that a family history of lung cancer predicts increased risk further support a genetic basis for lung cancer susceptibility. This long-postulated hypothesis is now being actively addressed using the approach of molecular epidemiology. Full coverage of this topic is beyond the scope of this report; aspects of genetic susceptibility for lung cancer have been reviewed.239240241242243
Familial aggregation of lung cancer has been primarily demonstrated in both case-control and cohort studies.244 In these studies, a family history of lung cancer tended to be associated with increased risk for lung cancer; most of the studies controlled for smoking, which is known to aggregate in families. In a large study in Louisiana, segregation analysis suggested that lung cancer inheritance was consistent with a Mendelian codominant autosomal gene determining early onset of disease.245 Conversely, the largest study of lung cancer in twins reported to date did not provide evidence indicating a genetic basis for susceptibility.246 Follow-up of 15,924 male twin pairs in the United States did not show greater concordance in monozygotic compared with dizygotic twins, and death rates from lung cancer were similar by zygosity group in surviving twins whose sibling died of lung cancer. The results of a linkage analysis based on 52 extended pedigrees indicated that a locus on chromosome 6q2325 was associated with a major susceptibility to lung cancer.247
In a genetic epidemiology study of lung cancer in nonsmokers in Detroit, Schwartz et al248 explored familial risk for lung cancer and found an association between risk and a history of lung cancer in a first-degree relative (odds ratio, 1.4; 95% CI, 0.8 to 2.5). The association was much stronger in those aged 40 to 59 years at diagnosis compared with older people. This pattern of risk with age suggests that genetic factors may be more important at younger ages. This general finding was confirmed by a subsequent, complex segregation analysis of the same data.249
Research Findings on the Genetic Basis of Lung Cancer:
With application of the new and powerful tools of modern molecular and cell biology, research findings are now characterizing the changes in cells that are caused by exposure to tobacco smoke and providing a framework for understanding the genetic and epigenetic basis of lung cancer risk. Figure 3 , proposed by Hecht,121 offers a general schema for the process of carcinogenesis by tobacco smoking. Viewed in the framework set by this type of model, research findings mirror the predictions of the multistage model in many respects and are enhancing understanding of the mechanisms by which smoking causes cancers of the lung and other organs. A rapidly expanding literature addresses dosimetry and metabolism of tobacco carcinogens at the cellular and molecular levels, genetic determinants of susceptibility, and patterns of genetic changes in the tissues of smokers and in the cancers that the tissues develop.121241 Much of the research conducted to date has been based in case-control studies that compared the genotypes of lung cancer cases with those of control subjects. Studies have also been conducted using cohort designs with affected and nonaffected people sampled from the cohort and biological samples analyzed for the markers of interest.
The understanding of the epigenetic changes that may be involved in the causal pathway to lung cancer is advancing rapidly. For example, there is increasing evidence that methylation of cytosine in the DNA, leading to hypermethylation of promoter regions, is frequent in most types of cancers, including lung cancer.250 Promoter regions of many human genes have loci rich in CpG dinucleotides, regions referred as CpG islands.250251 Hypermethylation of the CpG islands can be detected by polymerase chain reaction methods. Cells with abnormal methylation of genes have been detected in sputum before the diagnosis of lung cancer, suggesting that hypermethylation could be a useful marker for early detection.252253
In a general formulation of determinants of cancer risk, the risk depends on carcinogen exposure and the factors that determine host susceptibility, including genetic predisposition.254 For tobacco smoking and lung and other cancers, the elements of this paradigm all are topics of inquiry, using the combination of laboratory- and population-based studies indicated in the diagram. Biomarkers are central to the molecular epidemiology approach; the term refers to making measurements of indicators of exposure and dose, susceptibility, and response in biological materials, including tissue samples, blood, urine, and saliva.255 As research evolves within this paradigm, a more complete biological understanding of the specific events underlying the multistage model, originally proposed on a conceptual basis, can be anticipated.
This framework indicates multiple points where genetically determined host characteristics might be important: carcinogen metabolism and activation, and DNA repair capacity, for example. Reviews have been published,240256257258 and the evidence has expanded and deepened our understanding of how smoking injures cells and causes cancer and indicates potential approaches to identification of high-risk individuals and molecular screening.
The metabolism of toxic agents, including carcinogens, generally proceeds through two phases.259 In phase 1, unreactive nonpolar compounds are converted, usually by oxidative reactions, to highly reactive intermediates. These intermediates are then able to form complexes with conjugating molecules in phase 2 conjugation reactions, which are usually less reactive and more easily excreted. However, the intermediate metabolite may react with other cellular components, such as DNA, before conjugation occurs. This binding to DNA may be the first step in the initiation of the carcinogenic process.259
Many carcinogenic compounds in tobacco smoke (eg, polycyclic aromatic hydrocarbons) undergo metabolic activation by phase 1 enzymes of the cytochrome p450 system to form reactive intermediates that bind to DNA and cause genetic injury. Several of these enzymes have been investigated with regard to lung cancer risk, including CYP1A1. For CYP1A1, the current evidence suggests that two specific polymorphisms, the MspI polymorphism260 and a polymorphism in exon 7,261 are associated with increased risks for lung cancer.
Glutathione S-transferase is a phase 2 enzyme that detoxifies reactive metabolites of polycyclic aromatic hydrocarbons. There are at least four genetically distinct classes of the glutathione S-transferases: μ, α, π, and θ. The risk estimates from a metaanalysis262 indicate that individuals with the GSTM1 null genotype have higher risk for lung cancer than those with the GSTM1 present genotype, but a pooled analysis262 of data from 21 case-control studies did not indicate that this susceptibility was stronger among cigarette smokers than among nonsmokers. The importance of interactions between genes is highlighted by the joint assessment of the CYP1A1 Ile462Val and GSTM1 null polymorphisms in nonsmokers, which indicated that the combination of the two variant genotypes was associated with a greater than fourfold increased likelihood for lung cancer compared with the combination of the two nonvariant genotypes.263
There are other candidates for determinants of susceptibility to lung cancer in smokers, including oncogenes and suppressor genes and DNA repair capacity.239 One gene of particular interest for lung cancer is p53, a tumor suppressor gene.254258 This gene has been described as at the crossroads for multiple cellular response pathways that are considered relevant to carcinogenesis.258 The gene is frequently mutated in lung cancers, > 90% of small cell cancers and > 50% of non-small cell cancers. The spectrum of mutations in smokers seems to be different from that in nonsmokers.254258 In fact, Denissenko et al264 showed binding of an activated metabolite of benzo[a]pyrene to the same p53 codons where mutations are commonly observed in lung cancers in smokers. However, epidemiologic studies265 of common polymorphisms in the p53 gene have not shown strong associations with lung cancer risk.
Substantial research has been directed at DNA repair and susceptibility to lung cancer and other tumors.257266 People with specific rare, recessive traits (eg, xeroderma pigmentosa) have long been known to be at increased risk for cancer. DNA repair capacity has now been examined as a specific risk factor for lung cancer, with the underlying hypothesis that lesser capacity would lead to greater lung cancer risk from the multiple DNA-damaging components of tobacco smoke. Although much research remains to be done to clarify the association between variation in DNA repair capacity and lung cancer risk, the evidence suggests that this is a promising lead.241 There are a variety of phenotypic assays for susceptibility to DNA damage. Individuals with a less proficient DNA repair capacity phenotype as measured by a nonspecific mutagen sensitivity assay have been shown to have an increased risk for lung cancer in some studies.267268 Studies of DNA repair genes have been conducted, including studies of XPA, XPD, radiograph repair complementation groups 1 and 3 (XRCC1 and XRCC3), excision repair cross complementation group 1 (ERCC1), and hoGG1. One of the most extensively studied DNA repair genes is the nucleotide excision repair gene ERCC2/XPD (eg, references269270). The evidence to date has not yet revealed a consistent pattern of associations for the Asp312Asn or Lys751Gln polymorphisms of the ERCC2/XPD gene.271 The findings of a review of polymorphisms in three genes in the base excision repair pathway (OGG1, APE1/APEX1, and XRCC1) showed that for the OGG1 Ser326Cys polymorphism, individuals with the Cys/Cys genotype had an elevated risk for lung cancer (summary odds, 1.24; 95% CL, 1.01, 1.53).272
Presence of Acquired Lung Disease:
In addition to hereditary factors, increased susceptibility to lung cancer may result from underlying lung disease. Such acquired lung diseases assume two major forms: (1) those that obstruct airflow, such as COPD; and 2) fibrotic disorders that restrict lung capacity, such as pneumoconiosis.273 Associations between lung cancer and both types of acquired lung disease have been noted, but as mentioned below this topic is complex and many issues await resolution, even after debate for > 60 years.274
A substantial body of evidence suggests that COPD or impaired lung function is associated with the occurrence of lung cancer.275 Cigarette smoking is the principal cause of both COPD276 and lung cancer, being so strongly causally associated with both of these illnesses that presuming that statistical adjustment procedures remove the effect of cigarette smoking may not be well founded. Therefore, clarifying the relevance of COPD to the development of lung cancer awaits further proof that this association is not accounted for by cigarette smoking. One potential mechanism that is hypothesized to link COPD with lung cancer is α1-antitrypsin deficiency, and evidence to support this notion includes the observation that the prevalence of α1AD carriers was higher in patients with lung cancer than in the general population and higher in patients who had lung cancer and had never smoked.249 Alternatively, the presence of COPD may indicate that the affected individual has received a greater dose of tobacco carcinogens than the typical unaffected individual. Regardless of mechanism, the presence of COPD is a clinically useful risk indicator.
Several studies277278279280 found inverse associations between asthma and lung cancer. However, a metaanalysis281 that rigorously controlled for smoking revealed a positive association between asthma and the risk for lung cancer, especially nonadenocarcinoma lung cancer. Subsequently, asthma was found to be associated with lung cancer mortality in the Second National Health and Nutrition Examination Survey Mortality Study (from 1976 to 1992).282 Several potential mechanisms have been proposed to explain this association: (1) mucociliary dysfunction leading to accumulation of toxicants, such as lung carcinogens, in the airway; (2) free radical damage to DNA, as a result of imbalance between oxidants and antioxidants; and (3) chronic inflammation, leading to chronic mitogenesis, and increased likelihood of conversion of endogenous DNA damage into mutations.281 Appropriately designed studies are needed to establish whether and how asthma might increase the risk for lung cancer.
Clarifying the possible relationship between pneumoconioses and lung cancer poses particularly vexing challenges. Even for asbestos exposure, which is clearly established as a potent cause of lung cancer,190 whether lung cancer results from asbestos per se or from asbestosis remains controversial.191 Asbestos is likely to cause lung cancer via multiple mechanistic pathways.283284 For other mineral fibers, the situation is murkier. For example, determining whether silica exposure or silicosis mediates the increased lung cancer risk in silica-exposed individuals has proved difficult.285286 The presence of silicosis is associated with an increased risk for lung cancer.179 Understanding the basis of this association will entail isolating the independent effects of silica exposure and lung fibrosis while taking into account exposure to smoking and other lung carcinogens.177192
Such differences in the pattern of associations between pneumoconioses and lung cancer emphasize that fibrosis is not a homogeneous exposure but one that depends on the properties of the specific mineral fiber or other environmental agent. Properties of the agent, such as its size, shape, and durability, and the effects of other exposures such as cigarette smoking are important considerations in assessing the potential harmfulness of an agent.283
In addition to pneumoconioses, two other forms of interstitial lung disease (ILD) have been most consistently linked to lung cancer: idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). The potential relationship between these conditions and lung cancer is controversial, because ILD has alternatively been hypothesized to do the following: (1) cause lung cancer, (2) be caused by lung cancer, and (3) share common pathogenetic mechanisms with lung cancer.287 Until recently, epidemiologic studies of ILD were hindered by the variable criteria used to diagnose this rare condition. However, recent improvements to an international classification system have facilitated investigation of the potential association between ILD and lung cancer.
The variability in the diagnostic criteria for IPF until 1998 probably contributed to the wide-ranging associations (from increased risk to protection) that have been observed between IPF and lung cancer.287 The results of autopsy studies have shown high rates of lung cancer in patients with IPF.287 However, IPF, specifically, usual interstitial fibrosis, is a histopathologic marker of inflammatory response to a variety of toxic exposures that are common in lung cancer, including connective tissue disease, chemotherapy, radiotherapy, and surgery. In the absence of clinical data, autopsy findings are prone to overestimate the role of IPF as a risk factor for lung cancer. However, estimates based on registry data may have limited validity as a result of possible misclassification of smoking status and the lack of histologic confirmation. Misclassification of IPF in such studies likely attenuates the association between IPF and lung cancer.192 Similarly, in studies that rely on death certificates, underreporting may lead to the lower reported lung cancer prevalence among individuals who had a diagnosis of IPF, compared with the general public.
ILD may also occur in the context of SSc, a rheumatologic disorder with a myriad of local and/or systemic manifestations. ILD, which occurs in most cases of SSc, is the major cause of morbidity and mortality as a result of SSc. Lung cancer is the most frequently reported malignancy in SSc, usually occurring in patients with SSc and concurrent ILD.
Compared with the general population, lung cancer occurs more frequently among those with SSc, especially those with ILD, even after adjustment for cigarette smoking.287 A mechanism proposed to explain this association is genetic damage induced by inflammation and fibrosis and the subsequent repeated cellular injury and repair.287 Another hypothesis for the increased lung cancer risk seen in patients with SSc relates to enhanced lung cancer susceptibility resulting from the frequent use of immunosuppressive drugs.287 Alternatively, the potential role of repeated chest imaging resulting in overdiagnosis bias cannot be ruled out as an explanation for the observed associations between SSc and lung cancer.287
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Conclusions
The path to preventing lung cancer is charted by the identification of numerous exposures that are causally associated with lung cancer. If steps can be taken to reduce or eliminate the exposure to these agents, then this would be expected to reduce the risk for lung cancer. Preventive strategies can be pursued in the public policy arena or in public health interventions directed at individual behavior. Cigarette smoking provides a useful example to illustrate the multiple levels that can form the basis of preventive strategies. In the legislative/regulatory arena, examples of tobacco control strategies include legislation that limits cigarette advertising, that reduces childrens access to cigarettes, and that prohibits smoking in the workplace. Litigation against cigarette manufacturers has also proved to be a productive component of tobacco control strategies, as exemplified by the settlement between states and the tobacco industry. Behavioral interventions to prevent children and adolescents from starting to smoke cigarettes and behavioral/pharmacologic interventions to promote smoking cessation are individual-level approaches that, if successful, could be expected to reduce the occurrence of lung cancer.
In developing lung cancer prevention strategies, certain patient groups warrant particular attention. Steps need to be taken toward the goal of reducing the very high lung cancer incidence rates in African-American men.288 Lung cancer is a major womens health issue. As a result of historical cigarette smoking patterns, the epidemic of lung cancer started later in women than in men; but in contrast to the situation in men, lung cancer incidence rates in women have not yet begun to decrease consistently.25 Although lung cancer remains a critical public health problem, the decrease in the overall lung cancer burden that is occurring in the United States, as in much of the developed world, reflects the successes of preventive strategies. A critical global priority is to prevent the uptake of cigarette smoking in developing countries where smoking prevalence is still low in order to prevent the increase in morbidity and mortality from lung cancer that is certain to follow an increase in smoking prevalence.
A consideration of the epidemiology of lung cancer consistently reinforces one major theme: the pandemic of lung cancer is a consequence of the tragic and widespread addiction to cigarettes throughout the world. Curtailing the pandemic of lung cancer will require preventing youths from starting to smoke cigarettes and effectively promoting smoking cessation among addicted smokers. There are other causes that also need control, but fortunately there have been successes in reducing exposures to occupational carcinogens in countries of the developed world.
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Figure 1.
Age-adjusted lung cancer incidence rates in women worldwide in 2002. Source: IARC, GLOBOCAN 2002 (www-dep.iarc.fr).
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Figure 2.
Age-adjusted lung cancer incidence rates in men worldwide in 2002. Source: IARC, GLOBOCAN 2002 (www-dep.iarc.fr).
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Figure 3.
Scheme linking nicotine addiction and lung cancer via tobacco smoke carcinogens and their induction of multiple mutations in critical genes. Adapted from Hecht.121 PAH = polycyclic aromatic hydrocarbon.
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Acknowledgments
We thank Elisa Mundis and Charlotte Gerczak for assistance in the preparation of this article.
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Footnotes
Abbreviations: BMI = body mass index; CI = confidence interval; CL = confidence limit; CPS = Cancer Prevention Study; ETS = environmental tobacco smoke; FTC = Federal Trade Commission; IARC = International Agency for Research on Cancer; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; LET = linear energy transfer; RR = relative risk; SSc = systemic sclerosis
The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
o Accepted June 5, 2007.
o Received May 30, 2007.
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Mortality in women and men in relation to smoking
Omissis
Summary
In this paper, pooled data from three prospective population studies in
Copenhagen are used to compare total and cause-specific mortality in relation
to smoking habits. A sample population, comprising more than 30 000 individuals
whose date and cause of death was recorded, was monitored between
1964 and 1994. Information was collected from individuals via a self-administered
questionnaire on smoking behaviour in never-smokers, ex-smokers,
those smoking fewer than 15 cigarettes a day, and those smoking more than
15 cigarettes a day. Data were also collected for those using other forms of
tobacco, and on inhalation.
Positive associations were confirmed for both men and women for smoking
and lung cancer (together with other causes of death). The authors noted
that while relative risks associated with smoking were higher for women in
relation to respiratory and vascular disease, there were no differences
between women and men in the relative risk of smoking-related cancers. The
authors cautiously concluded that although women may be more sensitive
than men in terms of some causes of death, lung cancer in not among them.
omissis
What Are the Known Key Factors
That Increase the Individual Risk
for Lung Cancer?
Smoking is the major risk factor, accounting
for about 90% of lung cancer incidence.
There are additional exogenous
and endogenous factors contributing to
the individual risk, such as the following:
Low consumption of fruit and vegetables
Genetic predisposition
Exposure to non-tobacco procarcinogens,
carcinogens, and tumor promoters
Previous lung disease such as chronic
obstructive pulmonary disease (COPD)
Previous tobacco-related cancer
Passive smoking
Omissis
Dr. Biesalski is Professor and Head, Department of
Biological Chemistry and Nutrition, University of
Hohenheim, Stuttgart, Germany.
Dr. Bueno de Mesquita is at the National Institute of
Public Health and the Environment, Bilthoven, The
Netherlands.
Dr. Chesson is at the Rowett Research Institute,
Aberdeen, Scotland.
Dr. Chytil is Professor, Department of Biochemistry,
Vanderbilt University, Nashville, TN.
Dr. Grimble is Professor, Institute of Human
Nutrition, Southampton, England.
Dr. Hermus is Professor, Strategy and Program
Department, Netherlands Organization for Applied
Scientific Research (TNO), Delft, The Netherlands.
Dr. Kφhrle is Professor, Department of Internal
Medicine, University of Wόrzburg, Wόrzburg,
Germany.
Dr. Lotan is Professor and Associate Vice President
for Cancer Prevention, Department of Tumor Biology,
M.D. Anderson Cancer Center, Houston, TX.
Dr. Norpoth is Professor Emeritus of Toxicology,
Institute of Hygiene and Occupational Medicine,
University of Essen, Essen, Germany.
Dr. Pastorino is at the Royal Brompton Hospital,
London, England.
Dr. Thurnham is in the Human Nutrition Research
Group, Department of Biology and Biomedical
Sciences, University of Ulster, Coleraine, Northern
Ireland.
Adapted with permission from European Journal of
Cancer Prevention, 1997;6:316-322.
This article is also available online at
www.ca-journal.org.
http://caonline.amcancersoc.org/cgi/reprint/48/3/167.pdf
Nature Reviews Cancer 3, 733-744 (October 2003) | doi:10.1038/nrc1190
There is a Correction (1 January 2004) associated with this article.
Tobacco carcinogens, their biomarkers and tobacco-induced cancer
Stephen S. Hecht1 About the author
Top of page
Abstract
The devastating link between tobacco products and human cancers results from a powerful alliance of two factors nicotine and carcinogens. Without either one of these, tobacco would be just another commodity, instead of being the single greatest cause of death due to preventable cancer. Nicotine is addictive and toxic, but it is not carcinogenic. This addiction, however, causes people to use tobacco products continually, and these products contain many carcinogens. What are the mechanisms by which this deadly combination leads to 30% of cancer-related deaths in developed countries, and how can carcinogen biomarkers help to reveal these mechanisms?
www.nature.com/nrc/journal/v3/n10/abs/nrc1190.html
Emerging tobacco hazards in China: 1. Retrospective
proportional mortality study of one million deaths
BoQi Liu, Richard Peto, ZhengMing Chen, Jillian Boreham, YaPing Wu, JunYao Li,
T Colin Campbell, JunShi Chen
Abstract
Objective To assess the hazards at an early phase of
the growing epidemic of deaths from tobacco in
China.
Design Smoking habits before 1980 (obtained from
family or other informants) of 0.7 million adults who
had died of neoplastic, respiratory, or vascular causes
were compared with those of a reference group of 0.2
million who had died of other causes.
Setting 24 urban and 74 rural areas of China.
Subjects One million people who had died during
19868 and whose families could be interviewed.
Main outcome measures Tobacco attributable
mortality in middle or old age from neoplastic,
respiratory, or vascular disease.
Results Among male smokers aged 3569 there was a
51% (SE 2) excess of neoplastic deaths, a 31% (2)
excess of respiratory deaths, and a 15% (2) excess of
vascular deaths. All three excesses were significant
(P < 0.0001). Among male smokers aged >70 there
was a 39% (3) excess of neoplastic deaths, a 54% (2)
excess of respiratory deaths, and a 6% (2) excess of
vascular deaths. Fewer women smoked, but those who
did had tobacco attributable risks of lung cancer and
respiratory disease about the same as men. For both
sexes, the lung cancer rates at ages 3569 were about
three times as great in smokers as in nonsmokers, but
because the rates among nonsmokers in different
parts of China varied widely the absolute excesses of
lung cancer in smokers also varied. Of all deaths
attributed to tobacco, 45% were due to chronic
obstructive pulmonary disease and 15% to lung
cancer; oesophageal cancer, stomach cancer, liver
cancer, tuberculosis, stroke, and ischaemic heart
disease each caused 58%. Tobacco caused about 0.6
million Chinese deaths in 1990 (0.5 million men).
This will rise to 0.8 million in 2000 (0.4 million at ages
3569) or to more if the tobacco attributed fractions
increase.
Conclusions At current age specific death rates in
smokers and nonsmokers one in four smokers would
be killed by tobacco, but as the epidemic grows this
proportion will roughly double. If current smoking
uptake rates persist in China (where about two thirds
of men but few women become smokers) tobacco will
kill about 100 million of the 0.3 billion males now
omissis
www.bmj.com/cgi/reprint/317/7170/1411.pdf
Lung Cancer in India
D. Behera and T. Balamugesh
Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research,
Chandigarh, India
ABSTRACT
Background. Lung cancer is one of the commonest malignant neoplasms all over the world. It
accounts for more cancer deaths than any other cancer. It is increasingly being recognized in
India.
Methods. We did a systematic review of the published studies on epidemiology, diagnosis and
treatment of lung cancer in India. Literature from other countries was also reviewed.
Results. With increasing prevalence of smoking, lung cancer has reached epidemic proportions
in India. It has surpassed the earlier commonest form of cancer, that of oropharynx, and now
is the commonest malignancy in males in many hospitals. In addition to smoking, occupational
exposure to carcinogens, indoor air pollution and dietary factors have recently been implicated
in the causation of lung cancer. Squamous cell carcinoma is still the commonest histological
type in India in contrast to the Western countries, although adenocarcinoma is becoming more
common. Molecular genetics of lung cancer has opened up new vistas of research in
carcinogenesis. Various modalities for early detection through screening are being investigated.
Majority of the patients have locally advanced or disseminated disease at presentation and are
not candidates for surgery. Chemotherapy applied as an adjunct with radiation improves
survival and the quality of life. New anticancer drugs, which have emerged during the last
decade, have shown an improved efficacy- toxicity ratio.
Conclusions. In view of our large population, the burden of lung cancer will be quite enormous
in India. Drastic measures aimed at discouraging people from smoking must be taken to reduce
the morbidity and mortality due to lung cancer.
Omissis
SMOKING AND LUNG CANCER
IN INDIA
Smoking is the most important contributory
factor in the causation of lung cancer52.
Nota 52:
52. Hammond EC, Horn D. Smoking and death
rates: Report on 44 months of follow-up of 187,
783 men. II. Death rates by cause. JAMA 1958;
166 : 1294-04.
In patients with lung cancer a history of active
tobacco smoking is present in 87% of males and
in 85% of females. History of passive tobacco
exposure is found in only three per cent.
The relative risk of developing lung cancer is
2.64 for bidi smokers and 2.23 for cigarette
smokers with 2.45 as the overall relative risk35.
Bidi is more carcinogenic as has been shown in
studies by Jussawalla and Jain49 and Pakhale
et al51. Hooka smoking has also been associated
with lung cancer as reported by Nafae et al31.
In a recent study by Gupta et al45, 80% of men
and 33% of women among the patients were
ever-smokers as compared to 60% of men and
20% of women among controls. The odds ratio
(OR) for ever-smoking was 5.0 (95% CI=3.11-
8.04) among men and 2.47 (95% CI=0.79-7.75)
among women. Smoking of bidi and hooka as
well as cigarettes had similar ORs for
cumulative consumption. The risk increased
with both the duration and quantity of all
smoking products45.
Nota 45
45. Gupta D, Boffetta P, Gaborieau V, Jindal SK.
Risk factors of lung cancer in Chandigarh,
India. Indian J Med Res 2001; 113 : 142-50.
PASSIVE SMOKING AND LUNG
CANCER
Environmental tobacco smoke is a known
lung carcinogen. A meta-analysis of 41 studies
showed that environmental tobacco exposure
carries a relative risk of development of lung
cancer of 1.48 (1.13-1.92) in males and 1.2 (1.12-
1.29) in females53. Risk increases with increase in
exposure. Exposure at work place results in a
relative risk of 1.16. In a study on non-smoking
lung cancer patients, environmental tobacco
exposure during childhood carried an OR of 3.9
(95% CI-1.9-8.2). There was an increasing risk
with increase in number of smokers in the
household and the duration of exposure.
Women had a higher OR of 5.1. Work place, and
vehicular pollutant exposure have shown a
weak association. Another study by Rapiti
et al54 has shown that environmental tobacco
smoke exposure during childhood is strongly
associated with the risk of later development of
lung cancer (OR 3.9, 95% CI=1.9-8.2).
Omissis
www.vpci.org.in/upload/Journals/pic130.pdf
Declining Incidence Rate of Lung Adenocarcinoma in the United States*
1. Fan Chen, DrPH,
2. William F. Bina, MD, MPH, and
3. Philip Cole, MD, DrPH
+ Author Affiliations
1. *From the Department of Community Medicine (Drs. Chen and Bina), School of Medicine, Mercer University, Macon, GA; and School of Public Health (Dr. Cole), University of Alabama at Birmingham, Birmingham, AL.
Next Section
Abstract
Background: Adenocarcinoma of the lung (ADL) increased worldwide during the last half century. We now report that a continuous decline of ADL began in the United States in 1999.
Method: Incidence rates of ADL and squamous cell carcinoma of the lung (SQL) from The Surveillance Epidemiology and End Results Program were reviewed for the 31-year period beginning in 1973. The low-tar cigarette (tar ≤ 15 mg) consumption/per capita by year was estimated based on cigarette consumption/capita data and the market share of low-tar cigarette of the same year in the United States.
Results: From 1973 to 1998, the age-adjusted incidence rate of ADL increased 83% in men, and > 200% in women. From 1999 through 2003, the rate declined 14% in men and 8% in women. An analysis of age-specific incidence rates of ADL according to birth cohort demonstrates that rates declined progressively among persons born after 1934 for both genders. The increase in low-tar cigarette consumption did not precede the increase in ADL incidence rates, and the decline of ADL incidence after 1998 occurred without a preceding decline of low-tar cigarette consumption.
Conclusion: Since 1999, the ADL incidence has declined. The temporal trend of ADL incidence may suggest that air pollution could be the possible determining cause for the trend. Increasing use of low-tar cigarettes in the United States and the decline in environmental tobacco smoke may be contributors but are less likely to be the driving force.
adenocarcinoma
air pollution
incidence rate
low-tar cigarette
lung cancer
Incidence rates of squamous cell carcinoma of the lung (SQL) have declined over the past 24 years. The decline in SQL is attributable to the decline in smoking that started during the 1960s. In contrast, numerous studies1234567 report that adenocarcinoma of the lung (ADL) has been increasing over the past several decades. The age-adjusted incidence of ADL in Connecticut increased nearly 17-fold in women (from 0.9 to 15.2 cases per 100 000 person-years) and nearly tenfold in men (from 2.4 to 23.2 cases per 100 000 person-years) from 1950 through 1991.8 Devesa et al9 reported that, through 1997, ADL incidence rose in virtually all areas of the world, with the increases among men exceeding 50% in many parts of Europe. It has been hypothesized that the trend of increase in ADL is mainly due to the dissemination of low-tar filter cigarettes.101112 It has been pointed out that low-yield, filter-tipped cigarettes, introduced since the 1950s, are inhaled more deeply than smoke from earlier unfiltered cigarettes. Inhalation transports tobacco-specific carcinogens more distally toward the bronchoalveolar junction where adenocarcinomas often arise. Second, blended reconstituted tobacco, introduced in the 1950s, releases higher concentrations of nitrosamines from tobacco stems. Nitrosamines from tobacco are known to induce lung adenocarcinomas in rodents when injected systemically.8 Air pollution is another concern when trying to understand the trend of lung cancer. Vineis and colleagues13 reported a significantly higher odds ratio (1.30) of lung cancer for those exposed to nitrogen dioxide (NO2) at levels ≥ 30 μg/m3 compared to those who were exposed to NO2 at levels < 30 μg/m3. In this article, we report that the 50 years increasing trend has stopped, and a declining incidence rates of ADL after 1998 appears in the United States.
Previous SectionNext Section
Materials and Methods
Lung cancer incidence rates from the Surveillance Epidemiology and End Results (SEER) Program were reviewed for the available 31-year period from 1973 to 2003. The SEER database provides information on persons with cancer in diverse geographic areas, which constitute approximately 10% of the US population. The nine standard SEER regions include the states of Connecticut, Hawaii, Iowa, New Mexico, and Utah, as well as the metropolitan areas of Atlanta, GA, Detroit, MI, San Francisco/Oakland, CA, and Seattle/Puget Sound, WA. We describe time trends in the age-adjusted incidence rates of ADL (International Classification of Diseases for Oncology codes 8140, 8211, 82308231, 82508260, 8323, 84808490, 85508560, 85708572) and SQL (International Classification of Diseases for Oncology codes 80508076). Birth cohort-specific rates for both genders are also presented.
To assess whether the patterns of ADL incidence are associated with the use of low-tar cigarettes (tar ≤ 15 mg per cigarette) in the United States, we describe per capita total cigarette consumption as well as per capita low-tar cigarette consumption by years. This consumption was based on the market share of low-tar cigarettes and total cigarette sales in each year. These data were obtained from the Federal Trade Commission.14
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Results
Figure 1 shows that the incidence rates of ADL for men and women are parallel to one another. Since 1973, the rates of ADL increased and then leveled off from 1993 to 1998, followed by a declining trend since 1999 for both genders. This fact of similarity may suggest the major cause has similar impact on both men and women despite the different smoking behavior between the two genders. In contrast, the age-adjusted incidence rate of SQL peaked in 1982 for men but peaked in 1991 for women. The SQL incidence in 2003 compared to their peak declined 52% for men and 18% for women. These facts may reflect the difference in smoking behavior for men and women. The incidence rate of ADL in men surpassed that of SQL in 1992. The age-adjusted incidence rate of ADL in women is approximately twofold higher than that of SQL for all years. For the period 1998 to 2003, the incidence rate of ADL declined 14% for men and 8% for women.
Figure 2 describes the age-specific incidence rates of ADL for men according to birth cohort. It shows that, compared to the birth cohort 1890, incidence rates for all subsequent cohorts increased progressively with peak rates for the 1930 to 1934 birth cohort. The incidence rates for all subsequent cohorts declined at nearly all ages. A very similar pattern is demonstrated in Figure 3 for female subjects. For women, the highest age-specific incidence rates also were seen for the 1930 to 1934 birth cohort.
Figure 4 shows the temporal patterns of lung cancer incidence rate by histologic types and the temporal trend of cigarette consumption in the United States. Peak cigarette consumption occurred approximately 15 years earlier than the peak in SQL incidence rates, reflecting the induction period. The peak in ADL occurred > 30 years later than the peak of cigarette consumption, suggesting that causes other than cigarettes may play a major role in the sharp increase in ADL incidence, or the induction time for ADL is much longer than 30 years. While the sharp increase of low-tar cigarette consumption began in 1973, the sharp increase in ADL incidence rate had by then existed for approximately 20 years. From 1973 to 1981, the consumption of low-tar cigarettes increased 584% and the incidence rate of ADL increased 55%. Low-tar cigarette consumption leveled off from 1981 to 2000. However, the age-adjusted incidence rate of ADL declined consistently after 1998. In 1973, the ADL and SQL cases counted for 17.3% and 31.0% of all lung cancer cases, respectively; but in 2000, ADL and SQL accounted for 29.8% and 22.8% of the lung cancer cases.
Previous SectionNext Section
Discussion
The increase of ADL incidence rates, especially in women, was first observed in 1950 and confirmed in 1956.15 The incidence rate of ADL among men surpassed that of SQL in 1992. These increases may be due in part to diagnostic advances that make it easier to perform biopsies on tumors in small, distal airways where these tumors often arise. However, the increase in ADL started in the 1950s, > 2 decades prior to the major diagnostic advances that occurred in 1980s. Moreover, the male to female ratio was 2.5 in 1973, and decreased to 1.3 by 2002. There is no reason to believe that diagnostic advances were greater for women than for men; therefore, the rapid increase is likely to be a real increase rather than artifact. Of course, diagnostic advances cannot explain the considerable decrease after 1998.
The similarity of the ADL incidence curves of men and women, over time, is much greater than the similarity of SQL incidence curves of men and women. The turning points of ADL incidence, ending increase and beginning decline, occurred in 1999 for both genders. This suggests that the major cause of ADL is a more general phenomenon and has impacts on men and women in the same way, such as air pollution. Different behaviors between genders, such as smoking, are less likely to be the major cause, because it cannot explain why the peaks of ADL in both genders are on the same year. In contrast, smoking is the major cause of SQL. The incidence rates of SQL peaked in 1982 for men but peaked in 1991 for women, which could be explained by different smoking behaviors between men and women. The substantial decline in SQL started in 1982 for men, approximately 18 years later than the substantial decline of cigarette consumption. This indicates that the induction period for SQL is approximately 18 years. If the induction period for ADL is similar to that for SQL, we can assume that the possible determining factor for ADL started to increase around 1940 or even earlier, and then it started to decrease in 1980. It is not clear what is the possible determining factor, ie, the major cause of ADL, that can fully explain the temporal trend of 50 years increase and the recent 5 years declining. The possible speculated factors include air pollution caused by industrialization and urbanization. The remarkable increase in automobile density as an indicator of industrialization and air pollution started in 1945 in the United States.16 The substantial decline of national air pollutant emissions started in 1980.17 This coincidence with a reasonable induction period for both increase and decline suggests the necessity for further studies in the air pollution hypothesis. Vineis et al13 conducted a nested case-control study in 10 European countries and found a 30% statistically significant increase in the risk of lung cancer developing for those who were exposed to NO2 levels ≥ 30 μg/m3 compared to those who were exposed to NO2 levels < 30 μg/m3. Nyberg et al18 reported a result of a population-based case-control study covering the lung cancer cases in Stockholm County, from 1950 to 1990. They found that those with the highest exposure to NO2 had an estimated 44% statistically significant increase in risk for lung cancer compared to those who had the lowest levels, adjusting for age, year, smoking habits, radon exposure, and occupational exposures known to be associated with lung cancer. These studies suggest a need for further studies to test whether air pollution is the major cause of ADL.
Another possible cause that is the effect of increased consumption of low-tar cigarettes since 1970s. Although the low-tar cigarette (tar ≤ 15 mg) was developed in 1955, Figure 4 demonstrated that its sales did not rise sharply until 1972. This result is similar to the results reported by Giovino et al.19 However, the increase in ADL predated this by approximately 20 years. The rapid increase of ADL incidence rate was evident by the 1950s or 1960s.20 Between 1981 and 1998, both low-tar cigarette sales and ADL incidence fluctuated at high levels, but a remarkable decline in ADL started in 1999 and continued thereafter. This decline is not preceded by a decline in consumption of low-tar cigarette. The lack of temporal association between ADL and the low-tar cigarette consumption in either rise or decline argues against the hypothesis that the use of low-tar cigarettes is the major cause of the increase in ADL incidence rate, although it is one of the causes of the ADL.
Another possible explanation for the ADL trend may be environmental tobacco smoke (ETS). In recent years, more strict regulations have been enacted that reduced ETS exposure. These changes may partially explain the recent down trend of ADL incidence. However, based on the nationwide Current Population Survey,21 only 4 states reported smoke-free public areas in 1992, but 32 states in 1995. If the policies restricting ETS were enacted in most states during 1990s, it is then less likely to be the cause of down trend of ADL that started in 1999, because the years between the policies and the down trends are too short for the expected induction period. Moreover, the total lung cancer cases attributed to ETS is approximately 3,000/yr in the United States, which accounts for < 2% of the 172,570 new lung cancer cases a year.22 If the decline in the number of people who were exposed to ETS is 10%/yr, we would expect < 0.2% changes in number of lung cancer cases. This number is therefore too small to explain the remarkable change in ADL incidence. In fact, for the period 1998 to 2003, the incidence rate of ADL declined 14% for men and 8% for women. Such large reductions could not be explained by a decline in the number of people who were exposed to ETS.
The recent 5-year decline in the age-adjusted incidence rate of ADL, especially in men, is further explained by birth cohort patterns. Both genders show the same pattern, with persons born after 1930 having progressive declines in age-specific incidence rate of ADL. This suggests that incidence rates in both genders will continue to decrease in coming years. It is not clear why the highest age-specific incidence rate for all ages occurred in 1930 to 1934 birth cohorts, and after that the age-specific incidence rates start to decline.
Limitation
This study is a descriptive study. The estimation of consumption of low-tar cigarettes is based on the average level in the whole United States. In fact, the consumption of low-tar cigarettes may vary by areas (rural vs metropolitan), race/ethnicity, gender, age, and education. The increase of consumption of low-tar cigarettes after 1973 may play some role in the increase of ADL incidence in some areas or some populations, but is not sensitive enough to be detected by this study, in which the average level of the United States was used.
In summary, this study described the fact that ADL incidence has declined since 1999. The driving force for its long period increase, and subsequent decline in recent years is not clear. The possible causes may include air pollution, low-tar cigarette consumption, and ETS.
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Figure 1.
Incidence rates according to histologic type and gender. Rates are age adjusted to the 2000 standard population.
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Figure 2.
Incidence rates of ADL among men according to birth cohort.
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Figure 3.
Incidence rates of ADL among women according to birth cohort,
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Figure 4.
Incidence rates of lung cancer among men by histologic type and cigarette consumption.
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Footnotes
Abbreviations: ADL = adenocarcinoma of the lung; ETS = environmental tobacco smoke; NO2 = nitrogen dioxide; SEER = Surveillance, Epidemiology, and End Results; SQL = squamous cell carcinoma of the lung
The authors have no conflicts of interest to disclose.
o Accepted November 22, 2006.
o Received July 6, 2006.
Previous Section
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http://chestjournal.chestpubs.org/content/131/4/1000.full
The Increasing Incidence of Lung
Adenocarcinoma: Reality or Artefact?
A Review of the Epidemiology of
Lung Adenocarcinoma
ANNE CHARLOUX,* ELISABETH QUOIX,** NORMAN WOLKOVE,* DAVID SMALL,* GABRIELLE PAULI**
AND HARVEY KREISMAN*
Charloux A (Pavillon Laennec, Hτpitaux Universitaires de Strasbourg, 1 place de lhτpital, BP 426, 67091 Strasbourg
Cedex, France), Quoix E, Wolkove N, Small D, Pauli G and Kreisman H. The increasing incidence of lung adenocarcinoma:
Reality or artefact? A review of the epidemiology of lung adenocarcinoma. International Journal of Epidemiology
1997; 26: 1423.
Lung adenocarcinoma is the most common cell type in females (smokers or non-smokers) and in non-smoking males. Its
incidence has been increasing in younger cohorts of males and females until very recent years. Changes in classification
and in pathological techniques account for some of this increase. In females and non-smoker males, the increase could
be partly due to a detection bias in former studies. Nevertheless, successive cohorts over time seem more likely to
develop adenocarcinoma and less likely to develop squamous cell carcinoma. These differences between birth cohorts
suggest that the increasing incidence of adenocarcinoma is not only due to changes in pathological diagnosis.
Geographical differences are also observed: in Europe, the squamous cell type still predominates and an increase in
incidence of adenocarcinoma has only been reported in the Netherlands. In Asia, in the 1960s and 1970s, the proportion
of adenocarcinoma was higher than in North America or Europe and seems to be increasing. To what extent these
differences are due to differences in establishing diagnosis remains unknown.
Despite these biases in temporal and geographical trends detailed in this review, there has probably been a true
increase in incidence of adenocarcinoma. An explanation for this should be sought in studies on detailed smoking history
and passive smoking exposure, occupational exposure, diet and cooking, pollution and other environmental factors.
omissis
Adenocarcinoma and Tobacco Consumption
The increase in incidence of adenocarcinoma could be
partly explained by an increase in tobacco smoking.
Several authors have found a dose-response relationship
between adenocarcinoma and cigarette smoking,
however this was weaker than that between squamous
cell carcinoma and smoking.2730 This risk increased
with both number of cigarettes per day and duration of
smoking.27,28 Reduction of tobacco consumption in the
1960s in males has been followed by a recent decrease
in incidence of squamous cell carcinoma, but not by a
decrease in incidence of adenocarcinoma. Some factors
could partly explain these differences in temporal
trends between subtypes. Relative risk for adenocarcinoma
has been found to decrease more slowly
after smoking cessation than that for squamous cell carcinoma.
27,31 Variations in composition of cigarette
tobacco with time could have played an important role.
These variations could have favoured the development
of adenocarcinomas at the expense of squamous cell
carcinomas. This could explain too why differences in
incidence patterns between squamous cell carcinoma
and adenocarcinoma are less pronounced in women,
who started smoking 1020 years later than men. For
example, introduction of filter cigarettes in the 1950s
has been incriminated in the increase in incidence of
adenocarcinoma which occurred 20 years later, in the
1970s.25 Filters remove larger particles in cigarette
smoke, thus reducing deposition of those particles in
central airways where squamous cell carcinoma
develop preferentially. This could lead to a reduction
in incidence of the squamous cell type, but not of the
adenocarcinoma subtype which primarily occurs in
peripheral areas of the lung.32 Moreover, smokers,
especially women, who switched from non-filter to filter
cigarettes increased the number of cigarettes smoked
per day, which increases the risk of lung cancer.33
Smokers of filter cigarettes take larger puffs and inhale
more deeply than smokers of plain cigarettes. Consequently,
an increased deposition of smoking particles in
the small airways could result in an increased risk of
adenocarcinoma.34 In France, smokers decreased their
consumption of plain cigarettes and black tobacco
much later than in the USA. These particularities may
explain why no increase in the incidence of adenocarcinoma
has yet been described.34 Impact of tar and
nicotine level, additives and their variations with time
on lung cancer differentiation deserve to be analysed.
NNK, a tobacco specific N nitrosamine, preferentially
causes adenocarcinoma in rodents. This carcinogen,
which increased in cigarette smoke between 1978 and
1992 by about 45%, could be one factor responsible for
the increase in incidence of adenocarcinoma.34
http://ije.oxfordjournals.org/cgi/reprint/26/1/14.pdf
Second hand smoke, age of exposure and lung cancer risk
Kofi Asomaning, MB ChB MS,1 David P. Miller, ScD,1 Geoffrey Liu, MD,1 John C. Wain, MD,2 Thomas J. Lynch, MD,3 Li Su, BS,1 and David C. Christiani, MD1,4
1 Department of Environmental Heath, [Environmental and Occupational Medicine and Epidemiology Program] (D.P.M., K.A., G.L., L.S., D.C.C.), Harvard School of Public Health, Boston MA 02115
2 Thoracic Surgery Unit, Department of Surgery (J.C.W.), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston MA 02114
3Oncology Unit (T.J.L), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston MA 02114
4Pulmonary and Critical Care Unit (D.C.C.), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston MA 02114
Address correspondence to Dr. David C. Christiani, Harvard School of Public Health, 665 Huntington Avenue Bldg 1 Room 1402, Boston, MA 02115. Tel. 617-432-3323, Fax. 617-432-3441, Email: [email protected]
Kofi Asomaning and David Miller contributed equally to this work.
The publisher's final edited version of this article is available at Lung Cancer.
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o AbstractIntroductionMaterials and MethodsResultsDiscussionReferencesAbstract
Background
Exposure to second hand smoke (SHS) has been identified as a risk factor for lung cancer for three decades. It is also known that the lung continues to grow from birth to adulthood, when lung growth stops. We hypothesize that after adjusting for active cigarette smoking, if SHS exposure took place during the period of growth i.e. in the earlier part of life (0 to 25 years of age) the risk of lung cancer is greater compared to an exposure occurring after age 25.
Method
Second hand smoke exposure was self-reported for three different activities (leisure, work and at home) for this study population of 1669 cases and 1263 controls. We created variables that captured location of exposure and timing of first exposure with respect to a study participant's age (0 - 25, >25 years of age). Multiple logistic regressions were used to study the association between SHS exposure and lung cancer, adjusting for age, gender and active smoking variables.
Result
For study participants that were exposed to SHS at both activities (work and leisure) and compared to one or no activity, the adjusted odds ratio (AOR) for lung cancer was 1.30(1.08-1.57) when exposure occurred between birth and age 25 and 0.66(0.21-1.57) if exposure occurred after age 25 years. Respective results for nonsmokers were: 1.29 (0.82-2.02) and 0.87 (0.22-3.38), and current and ex smokers combined 1.28 (1.04-1.58) and 0.66 (0.15-2.85).
Conclusion
All individuals exposed to SHS have a higher risk of risk of lung cancer. Furthermore, this study suggests that subjects first exposed before age 25 have a higher lung cancer risk compared to those for whom first exposure occurred after age 25 years.
Keywords: Second hand smoke, age of exposure, lung cancer risk
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o AbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction
Lung cancer is the leading cause of cancer death for both men and women in the United States. Past studies have demonstrated the association between active cigarette smoking (mainstream smoke, MSS) or second hand smoke (SHS) exposure and the risk of adult non-small cell lung cancer (NSCLC). However, less is known about the effect of the age of exposure, particularly to SHS, on the risk of NSCLC (1-3). Most studies (4-18) have focused on paternal and maternal smoking during pregnancy and the effect on childhood illnesses and cancers in general or more recently the risk of lung cancer for non-smoking women exposed to tobacco smoke during childhood (19-28). Very few studies (19, 22, 29, 30) have focused on the effect of the period of exposure relevant for lung cancer development while also assessing the significance of lifetime exposure by location.
The lung continues to grow from birth to adulthood (31) and most lung growth is over by age 18 (32-34), but lung volume continues to expand to 25, suggesting additional growth may occur (35-39). Exposure of target organs to carcinogens during periods of rapid cell division or childhood is known to increase the risk of cancer and elevated exposure to carcinogens has been associated with higher levels of both DNA-adducts and somatic aberrations in cancer cells and may lead to genetic abnormalities that result in the development into cancer (40, 41).
SHS consists of emissions from cigarettes, pipes and cigars, as well as exhaled materials from MSS, which contains several chemicals including over 50 known carcinogens (40, 42, 43). The concentrations of benzol(a)pyrene, toluene, dimethylnitrosamines in SHS is much higher than in MSS, and the smaller particles in SHS are more likely to be deposited in the lung. SHS may induce DNA adducts, sister chromosome exchange (44), oxidative DNA damage (45, 46), and increased number of p53 mutations in lung cancer (47, 48), suggesting a similar etiologic mechanism for cases exposed to SHS and to MSS.
SHS exposure may occur at home (including childhood exposure from parents/other family members and exposure from spouse/family members in adulthood), at work (occupational exposure), and at leisure (exposure at public places other than work). Due to public health education and as a result of legislation in several developed countries, exposure to second hand smoke is declining at work and public places but direct marketing to younger populations by tobacco companies has contributed to continued high exposure among youths (49-52). The intensity or frequency of exposure in work places has been noted to be generally higher than that of at home or leisure places (53), and results from a previous study has suggested that SHS exposure at work places may have a stronger effect on NSCLC risk than exposure at home or at leisure places (54).
We hypothesize that after adjusting for active cigarette smoking, if the SHS exposure took place during the critical period of growth i.e. in the earlier part of life (0 to 25 years of age) the risk of lung cancer is greater compared to an exposure occurring after age 25.
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o AbstractIntroductionMaterials and MethodsResultsDiscussionReferencesMaterials and Methods
Study Population
This study was reviewed and approved by the Institutional Review Boards of the Massachusetts General Hospital and the Harvard School of Public Health. The study population of 1669 cases and 1263 controls is derived from a large case control study evaluating the molecular epidemiology of lung cancer, which began in 1992 at the Massachusetts General Hospital (MGH). Eligible cases included any person over the age of 18 years, with a diagnosis of primary lung cancer. An MGH lung pathologist confirmed all cases. The controls were the friends or spouses of cancer patients or the friends or spouses of other surgery patients in the same hospital. Potential controls that carried a previous diagnosis of any cancer (other than non-melanoma skin cancer) were excluded from participation. Controls were recruited among friends and non-blood related family members of the cases (usually spouses) (41%). If friends of lung cancer patients were not available, controls were recruited from friends and family of patients either receiving thoracic surgery, chemotherapy or radiation treatment for a condition other than lung cancer (59%).
Data collection
Interviewer-administered questionnaires (a modified version of the detailed American Thoracic Society health questionnaire) collected information on demographics, occupational exposures, and detailed smoking histories from each subject. Some participants chose to complete the questionnaire at home, and return it by mail in a self-addressed stamped envelope. Participants were contacted by telephone when there was missing data. Age, gender, race, weight, education, medical history, smoking history, family history of cancer, work history, exposure to various substances, participation in many activities, and food preparation and consumption data were collected. Smoking status was defined as non-smoker (smoked less than one cigarette per day for less than a year), ex-smoker (quit smoking at least one month prior to diagnosis) and current smoker (at time of diagnosis). Pack-years were calculated to estimate the cumulative exposure to smoking by multiplying the number of packs smoked per day by the number of years smoked. Second hand smoke exposure was self-reported for three different activities (leisure, work and at home) and determined from information obtained in the health questionnaire. Exposure for each location was categorized as an indicator variable equal to 1 if the participant reported exposure to SHS and equal to 0 otherwise. We created a similar indicator variable that captured timing of first exposure with respect to a study participant's age (0 - 25, >25 years of age).
Population characteristics were tabulated, and significant differences in the distribution of the principal covariates were tested using the chi square, Fisher exact, and student t tests, where appropriate. Multiple logistic regressions was used to assess the association between second hand smoke and lung cancer risk, adjusting for age, gender, indicator variables for smoking status (non-smoker, ex-smoker and current smoker) and a continuous variable for cumulative smoking exposure (pack-years).
Statistical Analysis
Demographic and clinical information were compared across smoking and SHS locations for both cases and controls. Multiple logistic regression was used to assess the association between SHS and lung cancer risk, adjusting for age (continuous variable), gender, indicator variables for smoking status (non-smoker, ex-smoker and current smoker), a continuous variable for cumulative smoking exposure (pack-years) and an indicator variable for alcohol intake (yes, no). Where indicated, the odds ratio (OR) and 95 % confidence intervals (CI) for the risk of lung cancer was calculated from these models. All statistical testing was done at the two-sided 0.05 level, and SAS software version 9.1 (SAS Institute, Cary, NC) was used.
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o AbstractIntroductionMaterials and MethodsResultsDiscussionReferencesResults
Patient characteristics
There were a total of 1669 cases and 1263 controls. The distribution of demographic and clinical characteristics by smoking status is summarized in Table1. Overall median age (standard deviation) was 62 (12) years, males were 49%; 604 (21%) non smokers, 1464 (50%) ex smokers, 864 (29%) current smokers; median packyears (standard deviation) for ex and current smokers 39 (37). Patients with early stage (stages I an II) numbered 803 (50%), with adenocarcinoma 698 (42%), squamous 339 (21%), others 615 (37%).
Table I
Table 2 shows the distribution of SHS exposure by location and age at exposure. No exposure to SHS at work or leisure 212 (7%), one activity 727 (25%), or both 1993 (68%). Persons with exposure to SHS between birth and age 25 numbered 403 (14%), and after age 25, 2529 (86%). Exposure at home was excluded from further analysis since there was little variability by outcome status (most subjects reported exposure from birth).
Table II
Distribution of SHS variables for all subjects
Adjusted odds ratios of SHS at work and leisure are shown in table 3. For study participants who were exposed to SHS at both activities and compared to one or no activity, the adjusted odds ratio (AOR) for lung cancer was 1.30(1.08-1.57) when exposure occurred between birth and age 25 and 0.66(0.21-1.57) if exposure occurred after age 25 years. Respective results for nonsmokers were: 1.29 (0.82-2.02) and 0.87 (0.22-3.38), and for current and ex smokers combined: 1.28 (1.04-1.58) and 0.66 (0.15-2.85).
Table III
Adjusted Odds Ratio (95%CI) of SHS duration at Work and Leisure places and lung cancer risk*
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o AbstractIntroductionMaterials and MethodsResultsDiscussionReferencesDiscussion
Previous studies of biochemical markers of exposure and toxicological studies, confirm that there is a causal association between the risk of NSLC and exposure to SHS(2). Similar conclusions have been reached by past summary scientific reports (43, 55). We suggest further that subjects first exposed before age 25 have a higher lung cancer risk compared to those for whom first exposure occurred after age 25 years. Consistent results are seen in our study for different smoking categories, i.e. current, past and non smokers. Our results go to further support the hypothesis that SHS has a similar harmful effect as for cases exposed to MSS.
Growing evidence (19, 22, 29, 30) suggests that exposure to SHS in childhood increases the risk of lung cancer in adulthood. With the decline of adult smoking in public and work places in the United States and Europe but still very prevalent in other regions around the world, SHS exposure and associated risks are still a major source of uncontrolled exposure in younger individuals, especially in children without the ability to negotiate a smoke free environment at home, work or leisure. Most lung cancers occur in smokers but still a significant proportion (approximately 10%) develops in lifetime nonsmokers (56) and approximately 3,000 lung cancer deaths occur each year among adult nonsmokers in the United States as a result of exposure to SHS (57). No risk-free level of exposure to SHS exists(43) and exposure to SHS has also been linked with slowed lung growth in children (58). In a study that investigated the effects of SHS exposure in childhood and the subsequent risk of lung cancer among female primary lung cancer cases and their hospital based controls (matched on age, residential area and lifetime smoking status), Wang and colleagues (30) showed that passive smoking from household exposure to tobacco smoke significantly increased the risk of lung cancer for both smoking and non smoking pairs when exposed under the age of 15 years (p<0.05). In a similar study in Taiwan, Lee et al (22) found that environmental tobacco smoke exposure occurring in childhood increased the effect of high doses of exposure in adult life in the development of lung cancer. In women exposed to greater than 20 smoker-years, compared to never exposed, the risk of lung cancer was 1.8 (1.2-2.9). When the exposure was greater than 40 years the risk was 2.2 (1.4-3.7). In addition, when smoker-years was treated as a continuous variable, the increased risk associated with a one unit increase larger for childhood exposure compared to adulthood (1.35 vs.1.27). In a population-based case-control study of lung cancer among lifetime nonsmoking women and with measured lifetime residential and workplace environmental tobacco smoke, the odds ratio for women with passive exposure as a child and as an adult was 1.63 (0.8-3.5) and for those exposed only as an adult 1.20 (0.5-3.0). Although no increase was observed with childhood exposure only, there were just 2 cases in that category.
SHS exposure and associated risks are increasingly becoming a major source of uncontrolled exposure in younger individuals, especially in children without the ability to negotiate a smoke free environment at home, work or leisure. A worldwide study among students aged 13-15 years (58), showed that nearly half of never smokers were exposed to SHS at home (46.8%), and a similar percentage were exposed in places other than the home (47.8%). Never smokers exposed to SHS at home were 1.4-2.1 times more likely to be susceptible to initiating smoking than those not exposed. Students exposed to SHS in places other than the home were 1.3-1.8 times more likely to be susceptible to initiating smoking than those not exposed, especially for SHS exposure at home.
The strengths of this study include large sample size, relatively homogeneous population, and almost complete demographic and smoking information. However, we acknowledge several limitations to our study. As expected of a case control study, recall bias may have affected our results. Smoking and SHS exposure history were collected by questionnaire and patients' recall and are not validated biochemically. However, given the nature of controls (friends and non blood related family) the impetus to recall would be similar (non differential) across case status, with controls possibly as affected by diagnosis of friend or family member. Nondifferential misclassification biases to the null making the odds ratio a conservative estimate of the actual magnitude of association
We also observed similar and consistent results in different smoking categories. To ensure that control selection was representative we compared the smoking habits of our controls to the smoking habits of the general Massachusetts population and found no significance differences. It is most likely that these controls would have been referred to MGH for treatment, if they were to become cases as they were either their spouses or friends. Residual confounding may be another limitation that exists for the results in our study. We observed a slightly stronger effect of SHS exposure among smokers as compared to non smokers, which may be explained partly by residual confounding. However, the associations were consistent in different subgroups of smoking status (past, current and non smokers), and we adjusted for pack-years of smoking and years since cessation (for past smokers) in all of the analysis. Residual confounding may bias the magnitude of the association but it is unlikely to change the direction of the association. In our analysis we did not adjust for the duration or the amount of SHS exposure.
To conclude, results from this epidemiological study support the evidence that individuals first exposed to SHS before age 25 have a higher lung cancer risk compared to those for whom first exposure occurred after age 25 years. These results need to be confirmed by other independent studies and further studies are needed to more accurately assess the SHS exposure and fully investigate the SHS-age of exposure interaction and to what extent this is influenced by the duration or the amount of SHS exposure.
Acknowledgments
The authors gratefully acknowledge the assistance of Linda Lineback, Barbara Bean, Andrea Shafer, Jessica Shin, Jeanne Jackson and Andrea Solomon for patient recruitment and data collection; Lucy Ann Principe, Salvatore V. Mucci, and Richard Rivera-Massa for data entry.
Grant Support NIH Grants: CA74386 and ES00002, Flight Attendant Medical Research Institute
Footnotes
Conflict of Interest Statement None declared.
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www.ncbi.nlm.nih.gov/pmc/articles/PMC2515267/
OMISSIS
One such disease is lung cancer, the most common
cause of cancer death in both men and women. The risk of dying from lung cancer is
22 times hither among male smohers and 12 times higher among female smokers
compared with people u ho have never smoked.The risk of lung cancer declines steadil)
in people who quit smoking; after IO years of abstinence, the risk of lung cancer is about
3) to 50 percent of the risk for continuing smokers,. Smoking cessation also reduces
the risk of cancers of the larynx. oral cavity. esophagus. pancreas. and urinary bladder.
Coronary heart disease (CHD) is the leading cause of death in the United States.
Smokers have about twice the risk of dying from CHD compared with lifetime
nonsmokers. This excess risk is reduced by about half among ex-smokers after only 1
year of smoking abstinence and declines gradually thereafter. After 15 years ot
abstinence the risk of CHD is similar to that of persons who have never smoked.
Compared with lifetime nonsmokers. smokers have about twice the risk ofdying from
stroke, the third leading cause of death in the United States. After quitting smoking.
the risk of stroke returns to the level of people who have never smoked: in some studies
this reduction in risk has occurred within 5 years. but in others as long as IS years of
abstinence were required.
Cigarette smoking is the ma.jor cause of chronic obstructive pulmonary disease
(COPD). the fifth leading cause of death in the United States. Smoking increases the
risk of COPD by accelerating the ape-related decline in lung function. With sustained
abstinence from smoking. the rate of decline in lung function among former smokers
returns to that of never smokers. thus reducing the risk of developing COPD.
Influenza and pneumonia represent the sixth leading cause of death in the United
States. Cigarette smohing increases the risk of respiratory infections such as intluenla.
pneumonia. and bronchitis. and smoking cessation reduces the rish.
Cigarette smohing is a major cause of peripheral artery occlusive disease. This
condition causes substantial mortality and morbidity: complications may include intermittent
claudication. tissue ischemiu and gangrene. and ultimately. loss of limb.
Smoking cessation substantially reduces the risk of peripheral arter) occlusive disease
compared with continued smoking.
The mortalit> rate from abdominal aortic aneurysm is two to fi\,e times higher in
current smokers than in never smohers. Former smohers ha\e half the excess rish of
dying from this condition relative to current smohcrs.
About 20 million Americans currently ha\,e. or ha\c had. an ulcer of the stomach 01
duodenum. Smohers have an increased rish of developin g gastric or duodenal ulcers.
and this increased rish is reduced h> quitting smohing.
OMISSIS
http://profiles.nlm.nih.gov/NN/B/B/C/T/_/nnbbct.pdf
OMISSIS
1.34 Smoking causes increased risk of cancers in several sites, pre-eminently the lung, but also several others such as the oral cavity, pharynx, larynx, oesophagus, pancreas and bladder. The association between smoking and certain cancers of the head and neck is discussed in Part Six.
OMISSIS
www.archive.official-documents.co.u...part-1.htm#1.31
Cancro
Il rischio di morire di cancro ai polmoni θ 22 volte maggiore negli uomini che fumano sigarette e 12 volte nelle donne fumatrici, rispetto ai non fumatori.
Il fumo della sigaretta incrementa il rischio di molti tipi di cancro inclusi i cancri: delle labbra, del cavo orale, della faringe, della laringe, dell'esofago, del pancreas, della cervice uterina, delle vie urinarie e dei reni.
Prima causa di morte nei soggetti maschi, il cancro ai polmoni θ sempre piω frequente nelle donne. Il tabagismo θ il fattore di rischio principale: il 90% dei casi θ attribuito al fumo di sigaretta! I primi sintomi della malattia si presentano solo ad uno stadio giΰ avanzato (tosse, difficoltΰ respiratorie, espettorazioni con sangue); le cure variano in base al tipo di malattia (chirurgiche, radioterapiche, chemioterapiche) e le possibilitΰ di guarigione sono limitate.
Il fumo θ il responsabile di 9 casi di tumore ai polmoni su 10!
Confronto tra i polmoni di un fumatore (a sinistra) e di un non fumatore (a destra)
Nella figura a fianco, la superficie del polmone θ di colore grigio-scuro a causa delle particelle di catrame inalate per un lungo periodo da un fumatore. I noduli bianchi sono il carcinoma tipico del polmone, chiamato a piccole cellule. Questi tumori sono tra i piω veloci a diffondersi.
Una persona che fuma un pacchetto di sigarette al giorno ne consumerΰ in vita sua 500.000! Sapendo che una sigaretta rilascia circa 1/100 di grammo di particelle, alla fine saranno piω di 5 kg di sostanze tossiche rilasciate nei polmoni!
Il fumo caldo del tabacco altera progressivamente il rivestimento mucoso dei bronchi e paralizza le piccole ciglia protettive. Continuando a fumare, le piccole ciglia polmonari - che rivestono le cellule dei bronchi e che servono a respingere il pulviscolo, i microbi e le secrezioni - si alterano fino a scomparire. L'evacuazione delle secrezioni e di tutte le particelle e pulviscolo contenuti nell'aria che si respira diventa impossibile. La tosse diventa il solo modo per eliminare parzialmente muco e particelle. Infine, allo stadio finale, il progredire dell'infiammazione trasforma profondamente il rivestimento mucoso dei bronchi e provoca una "metaplasia della mucosa", che farΰ da terreno al cancro: le cellule invece di rimanere su un solo strato si sovrapporranno. La metaplasia ci impiega oltre un anno a scomparire dopo che si θ smesso di fumare completamente.
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