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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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Infection vih et cancer bronchique l.jpg

Infection VIH et Cancer Bronchique


Le cancer bronchique en france l.jpg

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 !


Survie en fonction du stade tnm l.jpg

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


Traitements et stade tnm l.jpg

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


Which questions to be answered l.jpg

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 ?


Excess of risk of lc in hiv l.jpg

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


Excess of risk of lc in hiv7 l.jpg

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


Excess of risk of lc in hiv8 l.jpg

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


Excess of risk of lc in hiv9 l.jpg

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


Excess of risk of lc in hiv10 l.jpg

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


Excess of risk of lc in hiv11 l.jpg

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


Excess of risk of lc in hiv12 l.jpg

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


Excess of risk of lc in hiv13 l.jpg

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


Excess of risk of lc in hiv14 l.jpg

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


Excess of risk of lc in hiv15 l.jpg

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


Excess of risk which mechanisms l.jpg

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


Clinical presentation of lc in hiv l.jpg

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


Clinical presentation of lc in hiv18 l.jpg

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


Clinical presentation of lc in hiv19 l.jpg

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


Clinical presentation of lc in hiv20 l.jpg

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


Clinical presentation of lc in hiv21 l.jpg

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


Clinical presentation of lc in hiv22 l.jpg

Clinical presentation of LC in HIV

  • Extensive disease at presentation


Clinical presentation of lc in hiv23 l.jpg

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


Clinical presentation of lc in hiv24 l.jpg

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


Clinical presentation of lc in hiv25 l.jpg

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


Survival of lc in hiv l.jpg

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


Prognostic factors on survival l.jpg

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


Prognostic factors on survival28 l.jpg

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


Prognostic factors on survival29 l.jpg

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


Prognostic factors on survival30 l.jpg

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


Prognostic factors on survival31 l.jpg

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


Therapeutic management l.jpg

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


Therapeutic management33 l.jpg

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


Therapeutic management34 l.jpg

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


Hiv related lung cancer l.jpg

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


Hiv related lung cancer a growing concern l.jpg

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


Lung tumors in hiv l.jpg

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


Pre test question 1 l.jpg

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


Pre test question 2 l.jpg

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


Pre test question 3 l.jpg

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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