Post on 07-May-2015
description
transcript
Carcinoma Pulmonar
Cáncer Pulmonar (rodeado de
negatividad)
Estigmatizado por su relación al tabaco “self inflicted “.
Poca cobertura e información de adelantos en los medios de comunicación.
Poco interés por las celebridades.
Pobre apoyo de organizaciones para los pacientes y familiares.
Ideas pesimistas de Médicos, pacientes y familiares sobre resultados de tratamiento.
NSCLC: how oncologists would choose to be treated (1987)
Mackillop WJ, et al. Int J Radiat Oncol Biol Phys 1987;13:929–34
118 Canadian doctorswho treat lung cancer
Yes; 3%
If they had NSCLC, would they choose to be treated with chemotherapy?
For symptomatic metastatic disease
For advanced disease confined to the chest
After surgery for early disease
No
Yes; 9% Yes; 15%
No No
NSCLC: how oncologists would choose to be treated (1994)
105 Japanese doctors who treat lung cancer
Yes; 24%
If they had NSCLC, would they choose to be treated with chemotherapy?
For symptomatic metastatic disease
After surgery for locally advanced
disease
After surgery for early disease
(stage I)
No
Yes; 62% Yes; 33%
NoNo
Motohiro A, et al. Lung Cancer 1994;11(1–2):43–50
Etapa de diagnostico Temprana Localmente avanzada Avanzada
Terapia ‘Standard’ Cirugía RT CT±RT ±CT +CT + BSC
SV 2-años SV 5-años 40% 25-30% 3%
44% con cirugía + CTRT = radioterapiaCT = quimioterapia
Adapted from Jemal A, et al. CA Cancer J Clin 2003;53:5–26
‘Mayor SV’ . . . estabamos cumpliendo los objetivos?
Pac
ien
ts (
%)
50
40
30
20
10
0
INICIO DEL CONOCIMIENTO DE BIOLOGIA MOLECULAR
PRIMARIO
COMPROBACION POR IHQ
thyroid transcription factor 1
(PREDICE NO RESPUESTA DE TK)
CDDP
TK
PEMETREXED
CETUXIMAB
CARCINOMA PULMONAR(ETIOLOGIA)
TABAQUISMO (CIGARRILOS, PIPAS, PUROS). 80% DE LOS CASOS
TABAQUISMO DE SEGUNDA MANO (30%). 3000 MUERTES ANUALES.
RIESGO OCUPACIONAL:
Asbesto
Radon
Hidrocarburos Policiclicos Aromaticos
Metales (arsenico, cromo, niquel)
Tasa de Mortalidad por cancer pulmonar (1930-1998) e influencia del tabaquismo
80
60
40
20
0
1930 1940 1950 1960 1970 1980 1990
tasa por 100,000 poblaciónHombre/mujer
Pulmón y bronquios (hombre)Pulmón y bronquios (mujer)
-1.7
+3.4
Tabaco86% (Hombres)49% (Mujeres)
Sequential changes during lung cancer pathogenesisEarly Intermediate Late
Normal epithelium
Hyperplasia Dysplasia CIS Invasive carcinoma
~80%3p LOH/small telomeric deletions 3p LOH/contiguous
deletions~50%
Microsatellite alterations
~70%9p21 LOH
~80%Telomerase dysregulation
Telomerase upregulation
~60%myc overexpression
~80%8p21-23 LOH
~40%Neoangiogenesis
~40%Loss of Fhit immunostaining
~70%p53 LOH p53 mutations
~80%Aneuploidy
~100%
Methylation
~30%5q21 APC-MCC LOH
~20%K-ras mutation
Hirsch et al 2001LOH, loss of heterozygosity
Factores de Crecimiento Crecimiento Tumoral y Metástasis
Efectos Tumorales– metástasis– proliferación– pérdida de apoptosis– replicación infinita – angiogésis– invasión
Mutaciones en– Familia HER – VEGF– MPM´s– Ras– p53– COX-2
Tumor Primario
Hanahan D, Weinberg RA. Cell. 2000;100:57-70.
Metástasis
Latino America
23 paises
Poblacion total 550 milliones (2004)
– poblacion proyectada para 2050 de 767 milliones
La casa del Tabaco
– Despues del descubrimiento de las americas, Los Europeos adaptaron el habito del tabaco
El consumo del tabaco es la causa mas importante de cancer pulmonar en Latino america
El cancer pulmonar causa el 16% de mortalidad por cancer en hombres y 7% en mujeres
GLOBOCAN 2002
Incidencia y Mortalidad mundial de 15 tipos de cancer mas comunes, 2000
Miles
PulmónMamaColon/rectoGastricoHigadoPróstataCervix uterinoEsófagoVejigaLinfoma No-HodgkinCavidad Oral LeucemiasPancreasOvarioRiñón
Hombres Mujeres
1200 1000 800 600 400 200
Parkin et al 2001
MAYOR MORTALIDAD18 MUERTES /HORA
8
Major presenting symptoms of lung cancer
Baseline major presenting symptoms
0
20
40
60
80
100
HaemoptysisLoss of appetite
PainCoughDyspnoea
Patients(%)
Hollen et al 1999
FIE
BR
ES
INTO
MA
S P
AR
AN
EO
PLA
SIC
OS
TRO
MB
OS
IS
FIE
BR
ES
INTO
MA
S P
AR
AN
EO
PLA
SIC
OS
TRO
MB
OS
IS
Lung Cancer Subtypes
The WHO classification for primary lung cancer recognizes 4 major histology types[1]
Small-cellcarcinoma13.0%
Large-cell carcinoma5.0%
Adenocarcinoma38.3%
19.7%Squamous cell carcinoma
Other*24.0%
Percent distribution by histology among histologically confirmed lung cancer cases, 2001-2004[2]
1. Brambilla E, et al. Eur Respir J. 2001;18:1059-1068.2. SEER Database. Lung and Bronchus Cancer (Invasive), 1975-2004.
*Including adenosquamous carcinoma; carcinomas with
pleomorphic, sarcomatoid or sarcomatous elements;
carcinoid tumor; carcinomas of salivary gland type; and
unclassified carcinoma
Types of lung cancer: small-cell lung cancer (SCLC)
Approximately 20% of all lung cancers
Cellular classification
– small-cell carcinoma
– mixed small-cell/large-cell carcinoma
– combined small-cell carcinoma
Occurs almost exclusively in smokers and is more prevalent in women than men
Lesions most commonly originate in central part of chest
Tendency to disseminate early
Initially chemosensitive, becoming resistant
Squamous-cell carcinoma (~30%)
• Most commonly found in men
• Closely correlated with smoking (dose dependent)
• Tends to spread locally
• More readily detected in sputum
• Highly expressed genes encoding proteins with detoxification/anti-oxidant properties
Types of lung cancer: non-small-cell lung cancer (NSCLC)
Adenocarcinoma (30-50%)
• Most common type of lung cancer in women and non-smokers
• Lesions are usually peripheral
• Worldwide incidence increasing
• Highly expressed genes encoding small-airway-associated and immunologically related proteins
• K-ras mutations frequently reported
• Bronchoalveolar carcinoma is a subtype
Large-cell carcinoma (10-25%)
• Very primitive, undifferentiated cells
• Lesions are usually peripheral
• High tendency to metastasise
Lung cancer diagnosis/stagingPhysical examination Detect signs
Detect position, size, number of tumours
Detect chest wall invasion, mediastinal lymphadenopathy, distant metastases
Lymph node staging. S:82% E:92%. Inf vrs Ca?
Detect changes in hormone production, and haematological manifestations of lung ca.
Access to mediastinal adenopathy
Precise location of tumour, obtain biopsy .90%
Chest X-ray
CT scan
PET scan
Laboratory analysis
Bronchoscopy
Mediastinoscopy
Bone Scan Bone Metastases
FNA Cytology. Peripheral lesions
NCCN Guidelines 2010
EC IIIBT2N2Mo
Adeno Carcinoma PulmonarPET /CT post Tx.
Carcinoma Escamoso Pulmonar. 72 años.Dx. Oct. 2009
11-1-2011
NECROSIS
IMA
GE
NIMA
GE
NM
ETA
BO
LIS
MO
FU
SIO
NFU
SIO
N
TAC
PET
Survival by Pathologic Stage: IASLC New Classification
Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thoracic Oncol. 2007;2:706-714.
0 2 4 8 100
20
100
Pat
ien
ts (
%)
6
40
60
80
Survival Yrs
IAIBIIAIIBIIIAIIIBIV
1168/36661450/31001485/25791502/22522896/3792
263/297224/266
119814931221317
73584636249
13
5-Yr, %MSTDeaths/N
NSCLC: treatment options overview
PDQ Guidelines 2000
Stage I• Lobectomy or segment/wedge
resection• Curative radiotherapy if surgery is
contraindicated• Adjuvant RT ??• Adjuvant QT ??
Stage II• Lobectomy, pneumonectomy,
segment/wedge resection as appropriate
• Curative radiotherapy if surgery contraindicated
• Adjuvant chemotherapy• Adjuvant radiotherapy
Stage IIIA• Surgery alone• Chemotherapy +
radiotherapy/neoadjuvant therapy• Post-operative radiotherapy• Radiotherapy alone
Stage IIIB• Chemotherapy alone• Chemotherapy + radiotherapy• Radiotherapy alone
Stage IV• Chemotherapy (platinum based),
modest survival benefits• New chemotherapy agents• External beam radiotherapy
(palliative relief)• Endobronchial laser or
brachytherapy for obstruction
1000000 new lung cancers yearly
80% NSCLC
33% resectable NSCLC
75% candidates to adjuvant Chemo
180.000 patients candidates to adjuvant Chemo
7000 deaths could be avoided
4.5% increase in survival
The treatment algorithm for NSCLC
NSCLCEarly(stage I/II/IIIa)
Advanced (stage IIIb/IV)
First-line
Second-/ third-line
Suitable for chemotherapy?
Yes No (PS4, frail elderly)
PT-baseddoublet
BSCSingleagent
No YesElderly/ PS2–3?
Relapse
Surgery + chemotherapy
Radiotherapy (if unfit for surgery)
PS = performance status; PT = platinum; BSC = best supportive care
Chemotherapy– docetaxel– pemetrexed
Tarceva
Locally advanced
Chemotherapy(PT doublet)
+ concomitantradiotherapy
Carcinoma Pulmonar(Historia y desarrollo)
Meta-analisis confirman beneficio de SVida con QT en
NSCLC avanzado
NSCLC Collaborative Group. BMJ 1995;311:899–909
BSC + CDDP (6-8m)
BSC (2-4m)
Resultados Tx. Con protocolos basados cisplatin (11 ensayos)
1930 1940 1950 1960 1970 1980 1990 2000 2010
100
80
60
40
20
0
So
bre
vid
a (%
)
0 6 12 18 24Tiempo desde randomizacion (meses)
1990s
Carcinoma Pulmonar
Historia . E1594 (n=1155)
QT 1era linea NSCLC avanzado llego
“PLATEAU”
Urgente necesidad de Nuevos opciones de
tratamiento
1990s
Schiller JH, et al. N Engl J Med 2002;346:92–8
1.0
0.8
0.6
0.4
0.2
0
0 5 10 15 20 25 30
Meses
Cisplatino/paclitaxel (R)Cisplatino/gemcitabineCisplatino/docetaxelCarboplatino/paclitaxel (R)
dis
trib
uti
on
fu
nct
ion
SV
ida
1930 1940 1950 1960 1970 1980 1990 2000 2010
Sv ½ 7.9mTR: 19%
Carcinoma PulmonarHistoria Terapeutica
AprobadoUS
1930 1940 1950 1960 1970 1980 1990 2000 2010
Avastin + QT significativamente prolonga
sobrevida comparado con QT sola en 1 era. Linea NSCLC
avanzado
Primer estudio fase III que aumenta SVida media mas alla
de 1 año
2005
Sandler A, et al. J Clin Oncol 2005;23 (Suppl. 16):2s (Abs. LBA4)
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36 42
Time (months)
Pro
bab
ilit
y
10.3 12.3
Carboplatin/paclitaxel + Avastin
Carboplatin/paclitaxel
Sandler A, et al. N Engl J Med 2006;355:2542–50
History of Therapy in Advanced NSCLC: FDA Approval Dates
First lineSecond lineThird lineMaintenanceNot approved
1970 1980 1990 2000
MedianOS (mos)
12+
~ 6~ 2-4
BSC Single-agent platinum Doublets
Bevacizumab + PC
Carboplatin*1989
ErlotinibPemetrexed2004
Docetaxel1999
PaclitaxelGemcitabine 1998
Vinorelbine1994
Docetaxel2002
Bevacizumab2006
Gefitinib2003
Standard therapies
*Label does not include NSCLC-specific indication Pemetrexed
2008/2009
Histology-directed therapy
~ 8-10
Cisplatin*1978
1. FDA Web site. 2. NCCN. Clinical practice guidelines in oncology. v.3.2011. 3. Schrump, et al. Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.
‘Better life’ . . . are we meeting the objective?
Significant toxicity
– myelosuppression
– neuropathy
Limited improvement in QoL
i.v. administration
Need for premedication
Benefits
DisadvantagesTumour control
Improved survival
Chemotherapy
Interlinking Factors to Guide Personalized Therapy in NSCLC
Clinical Factors Histologic Factors
Molecular Factors
Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:148-150.
Histology Will Be Suboptimal for Selecting Chemotherapy (or Targeted
Therapy) Histologic subtyping groups tumors based on microscopic
pattern recognition by a pathologist (using 1800s’ technology)
At best, histology = “crude molecular selection”
Molecular ProfilingMolecular ProfilingVan LeeuwenHoek
“ It is much more important to know what kind of patient has a disease,
than to know what kind of disease a patient has”
Caleb Parry. 18th Century physician, Bath.
“We used to think our fate was in our stars. Now we know, in large measure, our fate is
in our genes”J.D Watson. Time Magazine 20 March 1989
Why Perform Molecular Testing?
Outcomes of Molecular Testing
For predictive and prognostic value
Predictive: Who is likely to do better with a particular therapy?
Prognostic: Who is likely to do better or worse, independent of therapy?
To improve clinical outcomes
Give best treatments first (eg, consider timing of EGFR TKI)
Provide access to agent (eg, crizotinib for ALK-positive NSCLC)
Identify subsets who might benefit from targeted therapy (eg, cetuximab)
To facilitate clinical research
May improve patient outcomes Better understanding of molecular oncology
Diagnosis Tumor is resected and measured
Stage IA+B: Observation
Stage II-IIIA: Adjuvant therapy
Early-Stage NSCLC Treatment Protocol
Who to treat?27% of stage IA and 42% of stage IB patients recur and die
– Q: How to identify individuals at higher risk?41% of patients with stage II NSCLC are cured with surgery alone and do not need adjuvant treatment
– Q: How to identify patients that can be cured by surgery alone?– Q: How can patient selection among those given adjuvant
therapy improve HR and cure rate?
Importance of Molecular Staging
Potential Oncogenic Drivers in NSCLC
ALK (~ 5%)
Adenocarcinoma
Bang Y, et al. ASCO 2010. Abstract 3. Reprinted with permission.
KRAS
EGFR
BRAF
HER2
PIK3CA
ALK
c-MET
Other
Other
Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01
Lung Cancer Molecular Consortium Analysis in Lung Adenocarcinomas
Mutations found in 54% (280/516) of tumors completely tested (95% CI: 50% to 59%)
No Mutation Detected KRAS
22%
EGFR17%EML4-AKL
7%
DoubleMutants 3%
BRAF 2%PIK3CA 2%HER2MET AMPMEK1NRASAKT1
Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)
65-yr-old malesmoker,
squamous
KRAS Mt
Interpatient Heterogeneity in the Molecular Characteristics of NSCLC
In 2012: Most oncologists would agree that these patients have very different malignancies
Most oncologists would agree that these patients should receive different therapy
Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)
39-yr-old female
never-smoker,adenoca
EGFR Mt
Interpatient Heterogeneity in the Molecular Characteristics of NSCLC
In 2012: Most oncologists would agree that these patients have very different malignancies
Most oncologists would agree that these patients should receive different therapy
65-yr-old malesmoker,
squamous
KRAS Mt
ALK fusion
54-yr-old malenever-smoker,
adenoca
Interpatient Heterogeneity in the Molecular Characteristics of NSCLC
Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)
Most oncologists would agree that these patients have very different malignancies
Most oncologists would agree that these patients should receive different therapy
39-yr-old female
never-smoker,adenoca
EGFR Mt
65-yr-old malesmoker,
squamous
KRAS Mt
Prevalence of EGFR Mutations by Smoking Status
EGFR mutation status (exons 19 and 21) determined in 2142 adenocarcinoma samples from Memorial Sloan- Kettering Cancer Center
Incidence of EGFR mutations in tumors– 52% of never smokers– 15% of former smokers– 6% of current smokers
D’Angelo SP, et al. J Clin Oncol. 2011;29:2066-2070.
EGFR Mutations Detected
Never (n = 302)
Current (n = 20)
Former (n = 181)
36%
4%
60%
Angiogenesis Tumoral
Tumor
4. Aparecen nueva vasculatura
tumoral
1. Secrecion deFactores
angiogenicos
3. Proliferacion y migracion endotelial
2. Destruccion ProteoliticaDe matriz
extracellular
Brote capilar
Agentes Blanco paravias VEGF
VEGFR-2VEGFR-1P
PPPP
PPP
Endotelio Inh. pequeña-molecula VEGFR – Vatalanib (PTK787)– Sunitinib (SU11248)– Sorafenib (BAY 43-9006)– ZD6474
Anticuerpos VEGFR
(IMC-1121b)
VEGFAnticuerposAnti-VEGF (bevacizumab)
Soluble VEGFRs
(VEGF-Trap)
Podar and Anderson. Blood. 2005;105:1383.
Agentes Biologicos dirijidos a blancos moleculares específicos involucrados en la formación y
desarrollo del tumor
HER1/EGFR = epidermal growth factor receptor; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor
CetuximabCetuximab
TarcevaTarceva
TKIs Control celcrecimiento ymultiplicacion
rr
HER1/EGFR
Receptor VEGF(control de
angiogénesis)
Avastin
VEGF
PTK/ZK(TKI)
Trial Treatment N RR, % Median PFS, Mos Median OS, Mos
TKI Chemo TKI Chemo TKI Chemo
NEJ002[1] Gefitinib vs carboplatin/paclitaxel
230 74 31 10.8 5.4 30.5 23.6
WJTOG3405[2] Gefitinib vs cisplatin/docetaxel
172 62 32 9.2 6.3 30.9 Not reached
OPTIMAL[3] Erlotinib vs carboplatin/gemcitabine
165 83 36 13.1 4.6 NR Not reported
EURTAC[4] Erlotinib vs platinum-based
doublet174 58 15 9.7 5.2 NR Not
reported
Prospective Trials of EGFR TKIs vs Chemotherapy in EGFR-Mutated Patients
1. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388. 2. Mitsudomi T, et al. Lancet Oncol. 2010;11:121-128. 3. Zhou C, et al. Lancet Oncol. 2011;12:735-742. 4. Rosell R, et al. ASCO 2011. Abstract 7503.
EGFR Mutation Positive EGFR Mutation Negative
Treatment by subgroup interaction test, P < .0001
HR: 0.48 (95% CI: 0.36-0.64; P < .0001)
Gefitinib events , n (%) 97 (73.5)C/P events, n (%) 111 (86.0)
Gefitinib (n = 132)Carboplatin/paclitaxel (n = 129)
HR: 2.85 (95% CI: 2.05-3.98; P < .0001)
Gefitinib events, n (%) 88 (96.7)C/P events, n (%) 70 (82.4)
0 4 8 12 16 20 240
0.2
0.4
0.6
0.8
1.0
Pro
ba
bil
ity
of
PF
S
0 4 8 12 16 20 240
0.2
0.4
0.6
0.8
1.0
Pro
ba
bil
ity
of
PF
S
Gefitinib (n = 91)Carboplatin/paclitaxel (n = 85)
Mos Mos
Clinical characteristics are insufficient for selection of first-line EGFR TKI therapy
Front-line EGFR TKI should be restricted to EGFR mutation–positive patientsMok TS, et al. N Engl J Med. 2009;361:947-957.
IPASS: PFS in EGFR Mutation–Positive and –Negative Patients
Junio 2005 Agosto 2005
Respuesta a erlotinib
Pirker R, et al. Lancet. 2009;373:1525-1531. Pirker R, et al. WCLC 2011. Abstract O-01.06.
FLEX: Response and OS by IHC Score
6Mos
0
2040
OS
(%
)
60
P = .36
CT + cetuximabCT
Treatment interaction test P = .040
P = .002
O’Byrne et al. JPO 20120,12 (suppl), S558 (LBOAI)
Interaction P = .044
CT + cetuximabCT
FLEX: Response Rate by EGFR Expression Levels(IHC Score)
Low EGFR Expression (< 200), n = 776 (69%)
High EGFR Expression (≥200), n = 345 (31%)
28.1
44.4
0 12 18 24 30
80100
Low EGFR High EGFR
HR: 0.99 (95% CI: 0.84-1.16)
HR: 0.73 (95% CI: 0.58-0.93)
Predictive Value of High EGFR for Survival Benefit With CT + Cetuximab
Mos
29.6 32.6
Squamous
Small
CellAdenocarcinoma
Normal lu
ng
TS
SCLC: highest TS Squamous: high TS Adeno: low TSBhattacharjee A, et al. Proc Natl Acad Sci U S A.
2001;98:13790-13795.
Thymidylate Synthase Expression in Lung Cancer
EML4-ALK frequency:~ 4% (64/1709)
Primarily in adenocarcinoma More common in younger patients More common in never-smokers
(~ 20%)
EML4-ALK frequency:~ 4% (64/1709)
Primarily in adenocarcinoma More common in younger patients More common in never-smokers
(~ 20%)
Soda M, et al. Nature. 2007;448:561-566.
EML4-ALK Translocations in NSCLC
EML4
EML4-ALK variant 1
ALK1 1058 1620
10591
1 496 981HELP
TM
Kinase
WDBasic
496
Crizotinib in Patients With Advanced ALK-Positive NSCLC
Crizotinib (PF-02341066)– Dual selective inhibitor of ALK and c-MET
• ATP-competitive inhibitor• Orally available small molecule
– Potent inhibition of cell growth and induction of apoptosis in NSCLC cell lines
– Demonstrated safety in dose-escalation study
1. Tan W, et al. ASCO 2010. Abstract 2596.
Tumor Responses to Crizotinib for Patients With ALK-Positive NSCLC
Kwak EL, et al. N Engl J Med. 2010;363:1693-1703. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
Per
cen
t C
han
ge
Fro
m
Bas
elin
e
Patient No.
60
40
20
-40
-10010 20 40 50 60 70 7930
0
-20
-60
-80
-30%
PD SD PR CR
Kwak and colleagues evaluated safety and efficacy of crizotinib in ALK-positive NSCLC patients (N = 82)
Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
Algorithm for Therapy of Advanced-Stage NSCLC: 2009
*Docetaxel, paclitaxel, vinorelbine.
Molecular Clinical (PS)
Progression
Clinical
Histologic
Second
line
First line
Ma
inte
na
nc
e
Bevacizumab or erlotinib or pemetrexed
Pemetrexed or erlotinib Erlotinib Based on
previous therapy
Chemotherapy by algorithm
Based on previous therapy
Based on previous therapy
Based on previous therapy
End of first-line chemotherapy
Platinum/pemetrexed (or other*) ± bevacizumab
Platinum/pemetrexed (or other*)
Platinum/gemcitabine (or other*)
Bevacizumab eligible
Bevacizumab ineligible
Single-agent chemotherapy
SquamousNonsquamousErlotinib
EGFR mutation positive Good PS POOR PS
Proposed Treatment Algorithm
Advanced-Stage NSCLC & PS 0-1
EFGR mutation and ALK negative and nonsquamous
histology
EFGR mutation and ALK negative and squamous
histology
Bevacizumab appropriate
Bevacizumab inappropriate
EGFR mutation positive
Erlotinib or gefitinibfirst line
Consider crizotinib
first or second line
ELM4-ALK positive
Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy
2012
Consider carboplatin/paclitaxel
+ bevacizumab or
cisplatin/pemetrexed± bevacizumab
Considercisplatin or carboplatin
combined with docetaxel or
gemcitabine or paclitaxel
orcisplatin/
vinorelbine ± cetuximab
Considercisplatin or carboplatin
combined with pemetrexed, docetaxel or
gemcitabine or paclitaxel
orcisplatin/vinorelbine
± cetuximab
Molecular
Advanced-Stage NSCLC & PS 0-1
EFGR mutation and ALK negative and nonsquamous
histology
EFGR mutation and ALK negative and squamous
histology
Bevacizumab appropriate
Bevacizumab inappropriate
EGFR mutation positive
Erlotinib or gefitinibfirst line
Consider crizotinib
first or second line
ELM4-ALK positive
Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy
2012
Consider carboplatin/paclitaxel
+ bevacizumab or
cisplatin/pemetrexed± bevacizumab
Considercisplatin or carboplatin
combined with docetaxel or
gemcitabine or paclitaxel
orcisplatin/
vinorelbine ± cetuximab
Considercisplatin or carboplatin
combined with pemetrexed, docetaxel or
gemcitabine or paclitaxel
orcisplatin/vinorelbine
± cetuximab
Histology: Clinical
Predictive Biomarkers
Histology Maintenance Therapy
Looking Forward to 2015:Moving From Empiric to Individualized
From “One Size Fits All” to “Tailored” and “Individualized” Therapy
Major Themes in Therapy of Advanced NSCLC 2012: Interrelationships Among Histology,
Maintenance Therapy, and Predictive Biomarkers
Tailored and individualized therapy
Empiric therapy
Gandara DR, et al. Clin Lung Cancer. 2009;10:148-150.
Transition From Empiric to Tailored and Transition From Empiric to Tailored and Individualized Cancer TherapyIndividualized Cancer Therapy
Terapia Anti-VEGF normaliza microvasculature tumoral
Normalizacion de vasculatura tumoral despues de
Terapia anti-angiogenic therapy
Vasculature AnormalVasculatura normal
Jain RK. Nat Med 2001;7:987–9
Vasos aumentan permeabilidad tortuosidad
Difusion de medicamentos comprometida
Normalidad de tamaño, forma y permeabilidad de vasos
Reduccion de presion intratumoral.
Mejoria de oxigenacion
Potential mejoria en difusion de medicamentos
AVASTIN
Terapia Anti-VEGF inhibe neo-vascularizacion
Osusky KL, et al. Angiogenesis 2004;7:225–33
*Anti-VEGF agent: SU11248(VEGFR TKI)LLC = Lewis lung carcinoma
Neovascularizacion despues de implantacion de celulas tumorales
Antes de implantacion celulas
LLC
1 dia despues de implantation
6 dias despues de implantacion
9 dias despues de implantation
Anti-VEGF therapy*
Antes de implantationCelulas LLC
1 dia despues implantacion
6 dias despues implantacion
9 dias despues implantacion
Control