Infection VIH et Cancer Bronchique

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
• gt 80 cas liés au tabac
• 85 CB non à petites cellules
• 2 malades sur 3 forme étendue/métastatique
• lt 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 dadministration 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, 152996 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
Excess of risk of LC in HIV

• Increase in cancer-related death in HIV

Louie, JID 2002
7
Excess of risk of LC in HIV

• Increase of LC in HIV hospitalized patients

Dufour, Lung 2004
8
Excess of risk of LC in HIV

• Pre-HAART epidemiological studies

SIR
Post-HAART
SIR
Pre-HAART
Study
n 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
9
Excess of risk of LC in HIV

• Bias due to difference of smoking habits in HIV ?

of smokers
57

• risk factors for cardiovascular disease
• age 35 to 44 years old
• HIV patients, n274
• (APROCO cohort)
• non HIV-persons, n1038 (WHO-MONICA project)

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 Heterosex
ual
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
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
100 of smokers
unknown of smokers
Parker, Chest 1998
12
Excess of risk of LC in HIV

• Pre-HAART epidemiological studies

SIR
Post-HAART
SIR
Pre-HAART
Study
n HIV
Author
no
4
yes
R
302,834
Frish
no
6.5
yes
R
26,181
Parker
no
3.8
yes
R
31,616
Grulich
no
2.4
yes
R
60,421
Dal Maso
2
yes
1
yes
P
77,025
Herida
8.93
yes
1
yes
R
8640
Bower
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
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
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
Clinical presentation of LC in HIV

• Epidemiological characteristics

Lavolé
Spano
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

• Epidemiological characteristics

Lavolé
Tirelli
Vyzula
Sridhar
Alshafie
Spano
n
44
36
16
19
11
44
age
38
44.5
48
49.7
42
42
male
93
89
94
100
82
93
smoker
100
94
100
84
90
100
. duration
28
-
-
-
-
28
-
. quantity
30 py
40 cig/dy
30 py
60 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

• Epidemiological characteristics

Lavolé
Tirelli
Vyzula
Sridhar
Alshafie
Spano
n
44
36
16
19
11
44
age
38
44.5
48
49.7
42
42
male
93
89
94
100
82
93
smoker
100
94
100
84
90
100
. duration
28
-
-
-
-
28
-
. quantity
30 py
40 cig/dy
30 py
60 py
30 py
Br J Sur 1984 Chest 1992 Lung Cancer 1996
Cancer 2000 Lung Cancer 2003 Med Oncol 2004
20
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
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. p0.003 10/50 0/
18
Tirelli VIH/non VIH 5/10 mo. p0.0001
10/48 0/25
Lavolé VIH/non VIH 9/13 mo. p0.01 33/55 13/34

Alshafie VIH/non VIH 4/7 mo. p0.003 0/20 0/8
Sridhar VIH/non VIH 3/10 mo. p0.002 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
Prognostic factors on survival
TNM RR2.2 IC95 1.3-3.9 PS RR11 IC95
3.6-34 HIV RR1.7 IC95 1-2.9
Lavolé, in press 2004
28
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 lt 0,01
100
75
PS lt 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 , plt0.04)
• 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
  , p0.009)
• disease control is less frequent (25 vs 50 ,
  plt0.01) and grade III hematological toxicities
  more comon (75 vs 25 , p0.02)

Lavolé, Lung Cancer 2005
34
Therapeutic management

• Interactions between CT and HAART

Antiproteases RT, SQ, IND
NRTI ddc, ddi, d4T
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
Kaposis 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 lt 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