Infection VIH et Cancer Bronchique Le cancer bronchique en France 25 000 nouveaux cas par an 5...

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• 1ére cause de mortalité par cancer pour les deux sexes confondus ; première cause chez la femme aux USA !

• % de survie à 5 ans (Mountain 1997)

Stade IAStade IB

Stade IIAStade IIB

Stade IIIA

Stade IIIBStade IV

N0

N1

N2

cTNM6138

3424

13

51

pTNM6757

5539

23

--N3

mN2 : 29cN2 : 7

Survie en fonction du 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.

*sauf inopérable, **toujours T3 pariétal, °sauf certains T4, IIIB pleurale et IRC, °°sauf métastase cérébrale ou surrénale unique

CT-RT° ± modes d’administrationdoses, fractionnement

±CT standardsCT de 2éme ligne/Tarceva®BSC

J Clin Oncol 1997, 15:2996; SOR-FNLCC 2003

CT(ddp)°°

Traitements et stade TNM

+

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 ?

• Increase in cancer-related death in HIV

0 5 10 15 20 %

Coronaropathy

Liver disease

P. carinii pneumonia

Non Hodgkin lymphoma

Atypical mycobacteria

Kaposi sarcoma94

98

Cancer

Louie, JID 2002

Excess of risk of LC in HIVExcess of risk of LC in HIV

• Increase of LC in HIV hospitalized patients

Dufour, Lung 2004

0 5 10 15 20

Lung cancer

Bacterial pneumonia

Other opportunistic infectionP. carinii pneumonia


Kaposi sarcoma 93-96

96-99

30 %


SIR*Post-HAART

SIR*Pre-HAART

Studyn HIV Author

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


• Pre-HAART epidemiological studies

8.93yes1yesR8640Bower

2yes1yesP77,025Herida

no3.8yesR31,616Grulich

no6.5yesR26,181Parker

no4yesR302,834Frish

no2.4yesR60,421Dal Maso

Savès, CID 2003

57

33

HIVNon HIV

% of smokers

risk factors for cardiovascular disease

age 35 to 44 years oldHIV patients, n=274

(APROCO cohort)non HIV-persons, n=1038

(WHO-MONICA project)


• Bias due to difference of smoking habits in HIV ?

• Bias due to difference of smoking habits in HIV ?

Frish, JAMA 2001, Dal Maso, Brit J Cancer 2003; Herida, J Clin Oncol 2003


• Bias due to difference of smoking habits in HIV subgroups ?

• Bias due to difference of smoking habits in HIV subgroups ?

Groups

All

MenWomen

HomosexualIVDUHeterosexual

FrishSIR

4.5

4.37.1

3.76.84.2

Dal MasoSIR

2.4

2.28.7

-9.4-

HeridaSIR

1

1.131.08

0.923.160.99

Parker, Chest 1998

SIR = 6.5

0

10

20

30

40

0

10

20

30

40

100 % of smokersunknown % of smokers

LC observed in HIVLC expected in HIV

• Bias due to difference of smoking habits in HIVexpected number of LC in the general population if 100 %

of the persons were smokers

• Bias due to difference of smoking habits in HIVexpected number of LC in the general population if 100 %

of the persons were smokers


Nu

mb

er

of L

C

Nu

mb

er

of L

C

SIR = 2.5

SIR*Post-HAART

SIR*Pre-HAART

Studyn HIV Author

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


• Pre-HAART epidemiological studies

8.93yes1yesR8640Bower

2yes1yesP77,025Herida

no3.8yesR31,616Grulich

no6.5yesR26,181Parker

no4yesR302,834Frish

no2.4yesR60,421Dal Maso

Louie, JID 2002

• Increase of LC since the use of HAARTbias due to dramatic decrease in AIDS-related mortality

• Increase of LC since the use of HAARTbias due to dramatic decrease in AIDS-related mortality


0 5 10 15 20 %

Coronaropathy

Liver disease

P. carinii pneumonia

Non Hodgkin lymphoma


Kaposi sarcoma 94

98

Cancer

Hérida, J Clin Oncol 2004, Remontet, Resp 2003

• Dramatic increase of LC in HIV-women since the use of HAART

1

3

5

7

SIR

of L

C

Male Female

0

5000

10000

15000

20000

25000

1980 1985 1990 1995 2000

23152+ 41 %

4591+ 182 %

16395

1629

Years

Inci

denc

e

Bias due to smoking epidemic in women ?


Cadranel, Respiration 1999; Bower, AIDS 2004

• Hypothesies for causal factors…increased frequency of smoking in HIV

population, but intensity and duration not differentHIV 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


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

Wistuba, JAMA 1997

Excess of risk, which mechanisms

Normal DysplasiaHyperplasia Metaplasia Carcinoma

Smoking

Increase of genomic instability ?

+ HIV + ID + HAART…

. quantity

. duration

% smoker

% male

age

n

42

30 py

28

100

93

44

Lavolé

40 cig/dy

-

94

89

38

36

Tirelli

30 py

-

100

94

44.5

16

Vyzula

60 py

-

84

100

48

19

Sridhar

-

-

90

82

49.7

11

Alshafie

Br J Sur 1984; Chest 1992; Lung Cancer 1996; Cancer 2000; Lung Cancer 2003; Med Oncol 2004

Clinical presentation of LC in HIV

• Epidemiological characteristics

42

30 py

28

100

93

44

Spano

• Histological type



0

20

40

60

80

100

SCC

Other

LC

SC

ADC

Alshafie Sridhar Vyzula Tirelli Lavolé

% o

f to

tal

Spano

• No ADC predominance compared to controls

Br J Sur 1984; Chest 1992; Cancer 2000; Lung Cancer 2003

0

25

50

Non HIV

HIV

Alshafie Vyzula Tirelli Lavolé

% o

f ad

eno

carc

ino

ma


• Extensive disease at presentation


• Clinical TNM staging at presentation



0

20

40

60

80

100

Stage I

Stage II

Stage III

Stage IV


% o

f to

tal

Spano

• % of stage IIIB-IV similar as controls

0

20

40

60

80

100


Non HIV

HIV

% o

f sta

dg

e II

I-IV


Br J Sur 1984; Chest 1992; Lung Cancer 1996; Cancer 2000; Lung Cancer 2003

• 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 peopleadenocarcinoma predominanceextensive disease at diagnosis


AlshafieVIH/non VIH

4/7 mo.p=0.003

0/20%

0/8%

SridharVIH/non VIH

3/10 mo.p=0.002

0/32%

0/0%

VyzulaVIH/non VIH

8/12.5 mo.p=0.003

10/50%

0/18%

TirelliVIH/non VIH

5/10 mo.p=0.0001

10/48%

0/25%

LavoléVIH/non VIH

9/13 mo.p=0.01

33/55%

13/34%

Median

1-yr survey

2-yr survey

Survival of LC in HIV

• Clinical studies on survival

Br J Sur 1984; Chest 1992; Lung Cancer 1996; Cancer 2000; Lung Cancer 2003; Br J Cancer 2003

PowlesVIH/non VIH

4/4 mo.ns

11/22%

-

Classical factors… Other factors ?

?

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 survival


• Difference in TNM staging at presentation

0

20

40

60

80

100


Non HIV

HIV

% o

f sta

dg

e II

I-IV


• Difference in PS at presentation


0

25

50

75

100

PS < 2

PS 2-4

p < 0,01

Non HIV HIV

% o

f pa

tien

ts

Maybe at cause ?Lavolé, in press 2004


• Impact of HIV-statusseverity of immune deficiency, not

demonstratedduration of immune deficiency, not evaluatedrole of HAART, not evaluatedsurmortality due to HIV-related mortality ?impact of LC treatment ?


0

25

50

75

100

Alshafie Tirelli Lavolé

OthersHIVLung cancer


• Surmortality due to HIV-related mortality…

Chest 1992; Br J Sur 1984; Lung Cancer 2003

% o

f to

tal m

ort

ality

HA

AR

T

Very unprobable ?

Massera, Lung Cancer 2000; Lavolé, in press; Cooper, JAMA 1984; Costleigh, AmJGastro 1995; Vallis, Lancet 91

Therapeutic management• Surgical management

absence of large seriessimilar 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 managementfew case-reportsincrease frequency of radiation esophagitis ?

Therapeutic management• Medical management

absence of prospective studies evaluating efficiency or toxicity of chemotherapy for LC in HIV-patientsindications 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

CYP450

AntiproteasesRT, SQ, IND

AnthracyclinesAlcaloïdesTaxanes

CyclophosphamideEtoposide

CarboplatineTaxanes

NRTIddc, ddi, d4T

neuropathy

CisplatineVinorelbine

NRTIAZT

anemianeutropenia

Washington, J AIDS Hum Retrovirol 1998; Flexner NEJM 1998; Scagliotti JCO 2002

• Interactions between CT and HAART

Therapeutic management

HIV-related Lung Cancer• How to improve these results ?

to better inform the HIV-population and to encourage smoking cessationto propose a chest X ray in very large clinical situations and maybe to include HIV-populations in CT-scan screening studiesto 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…

Jacques Cadranel and Armelle Lavolé

Service de Pneumologie et Réanimation RespiratoireUPRES EA3493

Hôpital Tenon, Paris - Université Paris VI

Cadranel, Respiration 1999

Kaposi’s sarcoma. RR = 177. Role of HHV8

Lymphoma. RR = 44-77. Role of EBV

Lung carcinoma. RR = ?. Oncogenic virus ?

Lung tumors in HIVLung tumors in HIV

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


• 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


• 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

Infection VIH et Cancer Bronchique Le cancer bronchique en France 25 000 nouveaux cas par an 5...

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Transcript of Infection VIH et Cancer Bronchique Le cancer bronchique en France 25 000 nouveaux cas par an 5...