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Infection VIH et Cancer Bronchique

Infection VIH et Cancer Bronchique. Le cancer bronchique en France. 25 000 nouveaux cas par an 5 hommes/1 femme; age moyen 60 ans > 80 % cas liés au tabac 85 % CB non à petites cellules 2 malades sur 3 forme étendue/métastatique < 15 % malades guéris

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Infection VIH et Cancer Bronchique

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  1. Infection VIH et Cancer Bronchique

  2. Le cancer bronchique en France • 25 000 nouveaux cas par an • 5 hommes/1 femme; age moyen 60 ans • > 80 % cas liés au tabac • 85 % CB non à petites cellules • 2 malades sur 3 forme étendue/métastatique • < 15 % malades guéris • 1ére cause de mortalité par cancer pour les deux sexes confondus ; première cause chez la femme aux USA !

  3. Survie en fonction du stade TNM • % de survie à 5 ans (Mountain 1997) pTNM 67 57 55 39 23 - - cTNM 61 38 34 24 13 5 1 Stade IA Stade IB Stade IIA Stade IIB Stade IIIA Stade IIIB Stade IV N0 N1 mN2 : 29 cN2 : 7 N2 N3

  4. Traitements et stade TNM • Les standards thérapeutiques actuels Stades IA, IB (N0) Stade IIA, IIB (N1) Stade IIIA (N2) Stade IIIB (N3) Stade IV (M1) Chirurgie* + CT péri-opératoire ± curage médiastinal ± RT** post-op. modes d’administration doses, fractionnement CT-RT° ± CT standards CT de 2éme ligne/Tarceva® BSC CT(ddp)°° ± *sauf inopérable, **toujours T3 pariétal, °sauf certains T4, IIIB pleurale et IRC, °°sauf métastase cérébrale ou surrénale unique J Clin Oncol 1997, 15:2996; SOR-FNLCC 2003

  5. Which questions to be answered ? • Is there an excess of risk ? • Is there a specific clinical presentation ? • Is there a particular histological type ? • Is there a poorer prognosis ? • Is there a particular therapeutic management ?

  6. Kaposi sarcoma 94 Atypical mycobacteria 98 Non Hodgkin lymphoma P. carinii pneumonia Liver disease Coronaropathy Cancer 0 5 10 15 20 % Excess of risk of LC in HIV • Increase in cancer-related death in HIV Louie, JID 2002

  7. 93-96 Kaposi sarcoma 96-99 Atypical mycobacteria Bacterial pneumonia P. carinii pneumonia Other opportunistic infection Lung cancer 30 % 0 5 10 15 20 Excess of risk of LC in HIV • Increase of LC in HIV hospitalized patients Dufour, Lung 2004

  8. Frish 302,834 R yes 4 no Parker 26,181 R yes 6.5 no Grulich 31,616 R yes 3.8 no Dal Maso 60,421 R yes 2.4 no Herida 77,025 P yes 1 yes 2 Bower 8640 R yes 1 yes 8.93 Excess of risk of LC in HIV Author • Pre-HAART epidemiological studies n HIV Study Pre-HAART SIR* Post-HAART SIR* Reviewed in Lavolé, Lung Cancer 2005. *SIR is defined by the number of LC observed in the HIV-population/number of LC expected in the general population matched for age

  9. Excess of risk of LC in HIV • Bias due to difference of smoking habits in HIV ? • risk factors for cardiovascular disease • age 35 to 44 years old • HIV patients, n=274 (APROCO cohort) • non HIV-persons, n=1038 (WHO-MONICA project) % of smokers 57 HIV Non HIV 33 Savès, CID 2003

  10. Excess of risk of LC in HIV • Bias due to difference of smoking habits in HIV subgroups ? Groups All Men Women Homosexual IVDU Heterosexual Frish SIR 4.5 4.3 7.1 3.7 6.8 4.2 Dal Maso SIR 2.4 2.2 8.7 - 9.4 - Herida SIR 1 1.13 1.08 0.92 3.16 0.99 Frish, JAMA 2001, Dal Maso, Brit J Cancer 2003; Herida, J Clin Oncol 2003

  11. SIR = 2.5 Excess of risk of LC in HIV • Bias due to difference of smoking habits in HIV • expected number of LC in the general population if 100 % of the persons were smokers 40 40 SIR = 6.5 30 30 LC observed in HIV Number of LC Number of LC 20 20 LC expected in HIV 10 10 0 0 unknown % of smokers 100 % of smokers Parker, Chest 1998

  12. Excess of risk of LC in HIV Author • Pre-HAART epidemiological studies n HIV Study Pre-HAART SIR* Post-HAART SIR* Frish 302,834 R yes 4 no Parker 26,181 R yes 6.5 no Grulich 31,616 R yes 3.8 no Dal Maso 60,421 R yes 2.4 no Herida 77,025 P yes 1 yes 2 Bower 8640 R yes 1 yes 8.93 Reviewed in Lavolé, Lung Cancer 2005. *SIR is defined by the number of LC observed in the HIV-population/number of LC expected in the general population matched for age

  13. Excess of risk of LC in HIV • Increase of LC since the use of HAART • bias due to dramatic decrease in AIDS-related mortality Kaposi sarcoma 94 Atypical mycobacteria 98 Non Hodgkin lymphoma P. carinii pneumonia Liver disease Coronaropathy Cancer 0 5 10 15 20 % Louie, JID 2002

  14. 25000 16395 23152 + 41 % 20000 7 15000 5 Incidence 4591 + 182 % SIR of LC 10000 3 1629 5000 1 0 1980 1985 1990 1995 2000 Years Male Female Excess of risk of LC in HIV • Dramatic increase of LC in HIV-women since the use of HAART Bias due to smoking epidemic in women ? Hérida, J Clin Oncol 2004, Remontet, Resp 2003

  15. Excess of risk of LC in HIV • Hypothesies for causal factors… • increased frequency of smoking in HIV population, but intensity and duration not different • HIV status seems probable, but the mechanisms remain unknown : • degree of immune deficiency • duration of immune deficiency • oncogenic role of HIV per se • other oncogenic virus • role of HAART Cadranel, Respiration 1999; Bower, AIDS 2004

  16. Normal Hyperplasia Metaplasia Dysplasia Carcinoma Excess of risk, which mechanisms Smoking + HIV + ID + HAART… 3p LOH, microsatellite alterations 9p21 LOH telomerase upregulation, MYC over expression 8p21-23 LOH neoangiogenesis, loss of FHIT, P53 mutations, aneuploidy, methylation 5q21 APC-MCC LOH, K-ras 12 mutation Increase of genomic instability ? Wistuba, JAMA 1997

  17. Alshafie Sridhar Vyzula Tirelli 11 19 16 36 49.7 48 44.5 38 82 100 94 89 90 84 100 94 - - - - - 60 py 30 py 40 cig/dy Clinical presentation of LC in HIV Lavolé Spano • Epidemiological characteristics n 44 44 age 42 42 % male 93 93 % smoker 100 100 . duration 28 28 . quantity 30 py 30 py Br J Sur 1984; Chest 1992; Lung Cancer 1996; Cancer 2000; Lung Cancer 2003; Med Oncol 2004

  18. Clinical presentation of LC in HIV Alshafie Sridhar Vyzula Tirelli Lavolé Spano • Epidemiological characteristics n 11 19 16 36 44 44 age 49.7 48 44.5 38 42 42 % male 82 100 94 89 93 93 % smoker 90 84 100 94 100 100 . duration - - - - 28 28 - . quantity 60 py 30 py 40 cig/dy 30 py 30 py Br J Sur 1984; Chest 1992; Lung Cancer 1996; Cancer 2000; Lung Cancer 2003; Med Oncol 2004

  19. Clinical presentation of LC in HIV Alshafie Sridhar Vyzula Tirelli Lavolé Spano • Epidemiological characteristics n 11 19 16 36 44 44 age 49.7 48 44.5 38 42 42 % male 82 100 94 89 93 93 % smoker 90 84 100 94 100 100 . duration - - - - 28 28 - . quantity 60 py 30 py 40 cig/dy 30 py 30 py Br J Sur 1984; Chest 1992; Lung Cancer 1996; Cancer 2000; Lung Cancer 2003; Med Oncol 2004

  20. 100 80 SCC Other 60 % of total LC 40 SC 20 ADC 0 Alshafie Sridhar Vyzula Tirelli Lavolé Spano Clinical presentation of LC in HIV • Histological type Br J Sur 1984; Chest 1992; Lung Cancer 1996; Cancer 2000; Lung Cancer 2003; Med Oncol 2004

  21. Clinical presentation of LC in HIV • No ADC predominance compared to controls 50 Non HIV % of adenocarcinoma 25 HIV 0 Alshafie Vyzula Tirelli Lavolé Br J Sur 1984; Chest 1992; Cancer 2000; Lung Cancer 2003

  22. Clinical presentation of LC in HIV • Extensive disease at presentation

  23. 100 80 Stage I 60 Stage II % of total 40 Stage III Stage IV 20 0 Spano Alshafie Sridhar Vyzula Tirelli Lavolé Clinical presentation of LC in HIV • Clinical TNM staging at presentation Br J Sur 1984; Chest 1992; Lung Cancer 1996; Cancer 2000; Lung Cancer 2003; Med Oncol 2004

  24. Clinical presentation of LC in HIV • % of stage IIIB-IV similar as controls 100 80 60 Non HIV % of stadge III-IV HIV 40 20 0 Alshafie Sridhar Vyzula Tirelli Lavolé Br J Sur 1984; Chest 1992; Lung Cancer 1996; Cancer 2000; Lung Cancer 2003

  25. Clinical presentation of LC in HIV • Almost all heavy smokers • Male predominance (but also male predominance in HIV population of industrialized countries) • Similar to LC in the general population matched for age • Characteristics of LC in HIV-patients are those observed in young people • adenocarcinoma predominance • extensive disease at diagnosis

  26. Survival of LC in HIV • Clinical studies on survival Powles VIH/non VIH 4/4 mo. ns 11/22% - Vyzula VIH/non VIH 8/12.5 mo. p=0.003 10/50% 0/18% Tirelli VIH/non VIH 5/10 mo. p=0.0001 10/48% 0/25% Lavolé VIH/non VIH 9/13 mo. p=0.01 33/55% 13/34% Alshafie VIH/non VIH 4/7 mo. p=0.003 0/20% 0/8% Sridhar VIH/non VIH 3/10 mo. p=0.002 0/32% 0/0% Median 1-yr survey 2-yr survey Br J Sur 1984; Chest 1992; Lung Cancer 1996; Cancer 2000; Lung Cancer 2003; Br J Cancer 2003

  27. Classical factors… Other factors ? ? Prognostic factors on survival TNM: RR=2.2 IC95% [1.3-3.9] PS: RR=11 IC95% [3.6-34] HIV: RR=1.7 IC95% [1-2.9] Lavolé, in press 2004

  28. Non HIV Prognostic factors on survival • Difference in TNM staging at presentation 100 80 60 % of stadge III-IV HIV 40 20 0 Alshafie Sridhar Vyzula Tirelli Lavolé Br J Sur 1984; Chest 1992; Lung Cancer 1996; Cancer 2000; Lung Cancer 2003

  29. Prognostic factors on survival • Difference in PS at presentation p < 0,01 100 75 PS < 2 % of patients 50 PS 2-4 25 0 HIV Non HIV Maybe at cause ? Lavolé, in press 2004

  30. Prognostic factors on survival • Impact of HIV-status • severity of immune deficiency, not demonstrated • duration of immune deficiency, not evaluated • role of HAART, not evaluated • surmortality due to HIV-related mortality ? • impact of LC treatment ? Br J Sur 1984; Chest 1992; Lung Cancer 1996; Cancer 2000; Lung Cancer 2003

  31. Prognostic factors on survival • Surmortality due to HIV-related mortality… 100 HAART 75 Others % of total mortality 50 HIV Lung cancer 25 0 Alshafie Tirelli Lavolé Very unprobable ? Chest 1992; Br J Sur 1984; Lung Cancer 2003

  32. Therapeutic management • Surgical management • absence of large series • similar indications that for the general population, but surgery is less frequently performed in HIV-patients because of poorer PS (64 % vs 100 %, p<0.04) • absence of post-operative surmortality • Radiation management • few case-reports • increase frequency of radiation esophagitis ? Massera, Lung Cancer 2000; Lavolé, in press; Cooper, JAMA 1984; Costleigh, AmJGastro 1995; Vallis, Lancet 91

  33. Therapeutic management • Medical management • absence of prospective studies evaluating efficiency or toxicity of chemotherapy for LC in HIV-patients • indications and drugs similar as for the general population, but CT is less frequently performed in HIV-patients because of poorer PS (71 % vs 100 %, p=0.009) • disease control is less frequent (25 % vs 50 %, p<0.01) and grade III hematological toxicities more comon (75 % vs 25 %, p=0.02) Lavolé, Lung Cancer 2005

  34. Therapeutic management • Interactions between CT and HAART NRTI ddc, ddi, d4T Antiproteases RT, SQ, IND NRTI AZT anemia neutropenia CYP450 neuropathy Anthracyclines Alcaloïdes Taxanes Cyclophosphamide Etoposide Carboplatine Taxanes Cisplatine Vinorelbine Washington, J AIDS Hum Retrovirol 1998; Flexner NEJM 1998; Scagliotti JCO 2002

  35. HIV-related Lung Cancer • How to improve these results ? • to better inform the HIV-population and to encourage smoking cessation • to propose a chest X ray in very large clinical situations and maybe to include HIV-populations in CT-scan screening studies • to open a national database on HIV-related LC • to perform prospective clinical studies evaluating effectiveness and toxicity of chemotherapy in HIV-patients

  36. HIV-related Lung Cancer… a Growing Concern… Jacques Cadranel and Armelle Lavolé Service de Pneumologie et Réanimation Respiratoire UPRES EA3493 Hôpital Tenon, Paris - Université Paris VI

  37. Lung tumors in HIV Kaposi’s sarcoma . RR = 177 . Role of HHV8 Lymphoma . RR = 44-77 . Role of EBV Lung carcinoma . RR = ? . Oncogenic virus ? Cadranel, Respiration 1999

  38. Pre-test : question #1 • Which of the following statements are true concerning the epidemiology of lung cancer in the HIV-population ? • A. LC is more frequent in the HIV-population • B. Increase of LC is more obvious in HIV-women than men • C. LC in the HIV-population is as frequent as in the non HIV-population matched for age • D. LC in HIV-population is as frequent as in non HIV-population matched for smoking habits • E. LC has increased in the HIV-population since the use of HAART

  39. Pre-test : question #2 • Which of the following statements are true concerning the clinical presentation of lung cancer in HIV-patients ? • A. Adenocarcinoma is the most frequent histology • B. One third of patients are non smokers • C. Most patients are PS < 2 • D. Disease is most frequently diagnosed at stage I-IIIA • E. Immunodeficiency is usually severe

  40. Pre-test : question #3 • Which of the following statements are true concerning the prognosis and treatment of lung cancer in HIV-patients ? • A. Prognosis is poorer than in non HIV-patients • B. Poorer prognosis is related to more extensive disease • C. Poorer prognosis is related to the use of less optimal treatment compared with non HIV-patients • D. Chemotherapy is less effective in HIV-patients • E. Post-operative mortality is increased in HIV-patients

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