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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• 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
Atypical mycobacteria
Kaposi sarcoma 93-96
96-99
30 %
Excess of risk of LC in HIVExcess of risk of LC in HIV
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
Excess of risk of LC in HIVExcess of risk of LC in HIV
• 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)
Excess of risk of LC in HIVExcess of risk of LC in HIV
• 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
Excess of risk of LC in HIVExcess of risk of LC in HIV
• 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
Excess of risk of LC in HIVExcess of risk of LC in HIV
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
Excess of risk of LC in HIVExcess of risk of LC in HIV
• 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
Excess of risk of LC in HIVExcess of risk of LC in HIV
0 5 10 15 20 %
Coronaropathy
Liver disease
P. carinii pneumonia
Non Hodgkin lymphoma
Atypical mycobacteria
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 ?
Excess of risk of LC in HIVExcess of risk of LC in HIV
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
Excess of risk of LC in HIVExcess of risk of LC in HIV
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
. 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
. 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
Clinical presentation of LC in HIV
Br J Sur 1984; Chest 1992; Lung Cancer 1996; Cancer 2000; Lung Cancer 2003; Med Oncol 2004
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
Clinical presentation of LC in HIV
• Extensive disease at presentation
Clinical presentation of LC in HIV
• Clinical TNM staging at presentation
Clinical presentation of LC in HIV
Br J Sur 1984; Chest 1992; Lung Cancer 1996; Cancer 2000; Lung Cancer 2003; Med Oncol 2004
0
20
40
60
80
100
Stage I
Stage II
Stage III
Stage IV
Alshafie Sridhar Vyzula Tirelli Lavolé
% o
f to
tal
Spano
• % of stage IIIB-IV similar as controls
0
20
40
60
80
100
Alshafie Sridhar Vyzula Tirelli Lavolé
Non HIV
HIV
% o
f sta
dg
e II
I-IV
Clinical presentation of LC in HIV
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
Clinical presentation of LC in HIV
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
Prognostic factors on survival
• Difference in TNM staging at presentation
0
20
40
60
80
100
Alshafie Sridhar Vyzula Tirelli Lavolé
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
• Difference in PS at presentation
Prognostic factors on survival
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
Prognostic factors on survival
• 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 ?
Br J Sur 1984; Chest 1992; Lung Cancer 1996; Cancer 2000; Lung Cancer 2003
0
25
50
75
100
Alshafie Tirelli Lavolé
OthersHIVLung cancer
Prognostic factors on survival
• 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
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
• 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