Carcinoma Pulmonar

Viviendo con Cancer pulmonar

PRINCIPALES CAUSAS DE PRINCIPALES CAUSAS DE MORTALIDAD MORTALIDAD

33.5%

% DEL TOTAL DE MUERTES

23.5%

6.7% 4.3% 4.0% 3.7% 2.2% 1.4% 1.2%

he p tic a

1.2%
HI V

1.2%
Ho m ici di o

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E cr Nf, n . O ica b pu stru lm cti on va ar Ne u In mon flu a en e za

C nc er

Ca rd io va sc ul ar

Di ab et e

En f.

Ce re b

US data/Adapted from Cancer Journal for Clinicians, 1994.

Ci rro sis

Su ici di o

CARGA MUNDIAL DE DE CANCER

CASOS

9.1 MILLONES DE NUEVOS CASOS 6.2 MILLONES DE MUERTES 22.4 millones viviendo con Cncer Almzr J. National Cancer Institute. 2004.

RAZONES DEL INCREMENTO EN INCIDENCIA

FACTORES HEREDITARIOS

FACTORES PERSONALES ANCESTROS

TABACO

EXPOSICION AL SOL O VIRUS RADIACION PARASITOS

DIETA

CONSUMO DE ALCOHOL

FACTORES AMBIENTALES

ESTILO DE VIDA

Los Estudios Basados en la Poblacin

Reino Unido: Cncer de pulmn

Regiones de Incidencia Ms Alta

JAPN: Cncer de estmago

CANAD: Leucemia EE.UU.: Cncer de colon BRASIL: Cncer cervical

CHINA: Cncer de hgado

AUSTRALIA: Cncer de la piel

INCIDENCIA CANCER MUJERES tasa por 100,000

INCIDENCIA DE CANCER HOMBRE Tasa por 100,000

Incidencia y Mortalidad mundial de 15 tipos de cancer mas comunes, 2000

Hombres
Pulmn Mama Colon/recto Estmago Higado Prstata Cervix uterino Esfago Vejiga Linfoma No-Hodgkin Cavidad Oral Leucemias Pancreas Ovario Rin
1200 1000 800 600 400 200

Mujeres

Incidencia Mortalidad

200

400

600

800

1000 1200

Miles

Parkin et al 2001

Age-adjusted lung cancer death rates, USA (1930-1998) and the influence of smoking
Rate per 80 100,000 male/female population 60
Lung and bronchus (male) Lung and bronchus (female)

40

20

0 1930 1940 1950 1960 1970 1980 1990

Major presenting symptoms of lung cancer

Patients (%) 100 80 60 40 20 0
Dyspnoea Cough Pain Loss of Haemoptysis appetite

Baseline major presenting symptoms Hollen et al 1999

Types of lung cancer: non-small-cell lung cancer (NSCLC)

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

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

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

Lung cancer diagnosis/staging

Physical examination Bronchoscopy FNA Chest X-ray CT scan Detect signs Precise location of tumour, obtain biopsy Cytology Detect position, size, number of tumours Detect chest wall invasion, mediastinal lymphodenopathy, distant metastases Lymph node staging Detect changes in hormone production, and haematological manifestations of lung cancer Visualise and sample mediastinal lymph nodes NCCN Guidelines 2000

PET scan Laboratory analysis

Mediastinoscopy

FNA, fine-needle aspirate; CT, computed tomography; PET, positron emission tomography

Molecular diagnosis

Goal to identify distinguishing molecular characteristics of tumours in order to develop new diagnostic and therapeutic approaches and predict response Progress new molecular biomarkers and technologies are being identified and evaluated but are not yet routinely used in the clinic

Gandara et al 2001; Mao 2001; Nacht et al 2001; Niklinski et al 2001

Molecular abnormalities in lung cancer

Atypical alveolar hyperplasia Premalignant adenomas Commonly observed genetic changes Inappropriate response to external signals Loss of cell cycle control Loss of apoptosis pathway Loss of contact inhibition Ability to metastasise Angiogenesis Immortality Autocrine growth loops Dysplasia

Tobacco carcinogen

Normal epithelium

Lung cancer

Bronchial metaplasia

Carcinoma in situ

NSCLC stages
Lymph nodes Invasion of chest wall Metastasis to distant organs

Main bronchus

Stage 0 Stage IA Stage IIB Stage IIIB Contralateral lymph node Stage IV

5-year survival by TNM status in NSCLC

Stage IA IB IIA IIB IIIA IIIB IV TNM classification T1N0M0 T2N0M0 T1N1M0 T2N1M0 or T3N0M0 T1-3N2M0 orT3N1M0 T4Nany M0 or Tany N3M0 Tany Nany M1 5-year survival (%) 61 38 34 24 13 5 1
Mountain 1997

NSCLC: treatment options overview

Stage I Lobectomy or segment/wedge resection Curative radiotherapy if surgery is 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 II Lobectomy, pneumonectomy, segment/wedge resection as appropriate Curative radiotherapy if surgery contraindicated Adjuvant chemotherapy Adjuvant radiotherapy Stage IV Chemotherapy (platinum based), modest survival benefits New chemotherapy agents External beam radiotherapy (palliative relief) Endobronchial laser or brachytherapy for obstruction

PDQ Guidelines 2000

Advanced NSCLC: new chemotherapy agents

Platinum-based combination therapy gives better response rates than monotherapy and remains the gold standard for first-line therapy for advanced disease Paclitaxel, vinorelbine, docetaxel, gemcitabine In the past 3 decades, median survival in NSCLC patients has only improved by approximately 2 months
Corey Langer 2000; Breathnach et al 2001; Schiller et al 2002

First-line combination chemotherapy: recent randomised trials in advanced NSCLC (1)

Study Regimens Tumour response (%) 19.0 30.0* 12.0 26.5* 32.1* 28 40* 14.0 21.6 21.9 40.6* Median survival (months) 7.4 9.2* 7.7 9.6 10.0 8.8 8.1 8.3** 8.3** 7.2 8.7 1-year survival (%) 28 36 31.6 36.9 39.1 35** 35** 26 32 Le Chevalier et al 1994 Bonomi et al 1996 Vindesine/cisplatin Vinorelbine/cisplatin Etoposide/cisplatin Paclitaxel (135)/cisplatin Paclitaxel (250)/cisplatin/GCSF Mitomycin/ifosfamide/cisplatin Gemcitabine/cisplatin Etoposide/cisplatin Paclitaxel/carboplatin Etoposide/cisplatin Gemcitabine/cisplatin

Crino et al 1998 Belani et al 1998 Cardenal et al 1999

*p<0.05; **combined population; -, not reported

Non-small cell lung cancer chemotherapy: 19752005

Response 1-year rate survival 2-year survival

No chemotherapy 0% Active single agent 15% Active two-drug 25% combination Active three-drug combination 35%

10% 20% 35% 35%

0% 10% 20% 20%

First-line combination chemotherapy: recent randomised trials in advanced NSCLC (2)

Study Regimens Tumour response (%) 28 25 21 22 17 17 Median survival (months) 8 8 7.8 8.1 7.4 8.1 10.9 9.1 10 1-year survival (%) 36 38 31 36 31 34 47 38 42

Vinorelbine (25)/cisplatin (100) Kelly et al 2001 Paclitaxel (225)/carboplatin (AUC 6) Paclitaxel (135)/cisplatin (75) Schiller et al 2002 Gemcitabine (1000)/cisplatin (100) Docetaxel (75)/cisplatin (75) Paclitaxel (225)/carboplatin (AUC 6) Fossella 2001 Docetaxel (75)/cisplatin (75) Docetaxel (75)/carboplatin (AUC 6) Vinorelbine (25)/cisplatin (100)

-, not reported

Fossella 2001; Kelly et al 2001; Schiller et al 2002

Second-line docetaxel for advanced NSCLC

Cumulative 1.0 probability 0.8 0.6 0.4 0.2 0.0 0 Log rank: p=0.01 3 6 9 12 Months 15 18 21 Docetaxel 75 mg/m2 (n=55) Best supportive care (n=49) Docetaxel 75 mg/m2 Median survival 7.5 (months) 1-year survival 37 (%) Best supportive care 4.6 12

Shepherd et al 2000

NSCLC stage IIIA: role of neoadjuvant chemotherapy

Surgical resection alone fails to cure the majority of patients with NSCLC Neoadjuvant chemotherapy still experimental 3 randomised trials showed improvement in survival with neoadjuvant cisplatin-based chemotherapy (Bunn et al 2000) An additional Phase III trial of gemcitabine/cisplatin has demonstrated response in >70% of patients, with tumour downstaging of nodes in 53% (van Zandwijk 2000) Neoadjuvant docetaxel was associated with a trend towards longer median survival in a large Phase III trial (Mattson 2001)

NSCLC stage IIIA/IIIB: chemotherapy and radiotherapy

Study No. patients 320 611 Treatment regimens Response Median rate (%) survival (months) 66.0 84.0 13.3 16.5 14.6 17.0 15.6 15 20 Furuse et al 1999, Phase III Curran et al 2000, Phase III I) CT with sequential Rx II) CT with concurrent Rx I) Cis/vinb followed by sequential Rx on Day 50 II) Cis/vinb with concurrent Rx from Day 1 III) Cis/VP-16 with concurrent Rx twice-daily from Day 1 I) Cis/etop/Rx cis/etop II) Cis/etop/Rx docetaxel

Gandara et al 2000, Phase II

71

CT, chemotherapy (cisplatin/vindesine/mitomycin); Rx, radiotherapy; cis, cisplatin; vinb, vinblastine; etop, etoposide; -, not reported

Lung cancer: future developments

Current treatment remains unsatisfactory Earlier diagnosis New molecular-based classification Improved treatment
novel targeted biological agents, immunological approaches, gene therapy less toxic combinations

Prevention

Earlier diagnosis
Obstructive lung disease (chronic bronchitis and emphysema) Genetic risk factors Sputum cytology Molecular tumour markers Low-dose spiral computed tomography Positron emission tomography Laser-induced fluorescence endoscope (LIFE) bronchoscopy
Edell 1997; Hirsch 2001

Sequential changes during lung cancer pathogenesis

Early Normal epithelium Hyperplasia Intermediate Dysplasia CIS Late Invasive carcinoma ~80% ~50% Telomerase upregulation ~70% ~80% ~60% ~80% ~40% ~40% ~70% ~80% ~100% ~30% ~20%

3p LOH/small telomeric deletions Microsatellite alterations 9p21 LOH Telomerase dysregulation myc overexpression

3p LOH/contiguous deletions

8p21-23 LOH Neoangiogenesis Loss of Fhit immunostaining p53 LOH Aneuploidy Methylation
5q21 APC-MCC LOH K-ras mutation
LOH, loss of heterozygosity

p53 mutations

Hirsch et al 2001

Prognostic and predictive factors

p53 status Other cell cycle components including p27, p15, p16, pRb, cyclin and CDK K-ras mutations HER2/neu and epidermal growth factor receptor (EGFR) Beta tubulin Expression of matrix metalloproteinase and inhibitors DNA topoisomerase II and II Single nucleotide polymorphism in myeloperoxidase gene reduces risk of lung cancer Heparin-binding growth factor pleiotrophin

Strategies for signalling inhibition

Immune effector cell Anti-ligand mAbs Bispecific Abs Ligand/toxin scFv/toxin conjugate conjugates Ligandgenistein conjugates

Anti-receptor mAbs Inhibitors of other signalling molecules Intracellular scFvs

Nucleus Tyrosine kinase inhibitors (TKIs) Antisense

Novel biological approaches (1)

Inhibitors of the EGFR family small molecule TKIs of EGFR, eg gefitinib, erlotinib monoclonal antibodies to EGFR, eg cetuximab monoclonal antibodies to HER2, eg trastuzumab Farnesyl transferase inhibitors Inducers of apoptosis, eg cyclooxygenase-2 (COX-2) inhibitors, inhibitors of protein kinase C, gene therapy, bcl-2 antisense oligonucleotide

Mode of action of EGFR inhibitors

EGF/TGF Extracellular Membrane Intracellular EGFR-TKI R R Antibody

Proliferation

Signalling

Growth factors Chemotherapy/ radiotherapy sensitivity

DNA

K K

EGFR-TKI Cell survival (anti-apoptosis)

Angiogenesis

Metastasis R, epidermal growth factor receptor

Clinical development of anti-EGFR agents in NSCLC

Gefitinib

Phase II studies of once-daily, oral gefitinib in NSCLC (Kris et al 2002; Fukuoka et al 2003)

antitumour activity, symptom relief, favourable safety profile

Phase III first-line combination studies in stage III/IV NSCLC (Giaccone et al 2002; Johnson et al 2002)

no added benefit over combination chemotherapy alone

Erlotinib

Phase II study in EGFR-positive, previously treated stage IIIB/IV NSCLC (PerezSoler et al 2001)

antitumour activity, favourable safety profile

Phase III first-line combination and third-line monotherapy studies ongoing in NSCLC Phase I study of cetuximab alone and in combination with cisplatin in patients with EGFR-positive advanced tumours Phase II cetuximab combination studies ongoing in EGFR-positive NSCLC

Cetuximab

Tumour angiogenesis
Tumour 1. Secretion of angiogenic factors 2. Proteolytic destruction of 3. Endothelial extracellular matrix cell proliferation and migration 4. Appearance of new tumour vasculature

Sprouting capillary

Novel biological approaches (2)

Anti-angiogenic agents monoclonal antibodies, eg bevacizumab (rhuMab-VEGF) VEGF receptor TKIs, eg ZD6474, PTK787 matrix metalloproteinase inhibitors thalidomide Vascular targeting agents, eg combretastatin A4 phosphate, ZD6126

NSCLC stage IIIB and IV:

Phase III trials in progress, July 2003 (1)
Sponsor NCI, NCCTG NCIC-Clinical Trials Group Cell Pathways NCI, NCCTG, NCIC-Clinical Trials Group, SWOG Ligand Pharmaceuticals NCI, SWOG Sanofi-Synthelabo Reference regimen Placebo Placebo Docetaxel/placebo Cisplatin/etoposide/ radiotherapy/ docetaxel/placebo Vinorelbine/cisplatin Paclitaxel/carboplatin Cisplatin/vinorelbine Investigational regimen Carboxyamidotriazole Erlotinib Docetaxel/exisulind Cisplatin/etoposide/ radiotherapy/ docetaxel/gefitinib Vinorelbine/cisplatin/bexarotene Paclitaxel/carboplatin/tirapazamine Cisplatin/vinorelbine/tirapazamine

NCI, National Cancer Institute; NCCTG, North Central Cancer Treatment Group; SWOG, Southwest Oncology Group

NSCLC stage IIIB and IV:

Phase III trials in progress, July 2003 (2)
Sponsor Genentech ISIS Pharmaceuticals NCI, ECOG Abgenix, Immunex Roche, Genentech, OSI Pharmaceuticals Roche, Genentech, OSI Pharmaceuticals Roche, Genentech, OSI Pharmaceuticals Reference regimen Paclitaxel/carboplatin Paclitaxel/carboplatin Paclitaxel/carboplatin/ radiotherapy Paclitaxel/carboplatin Gemcitabine/cisplatin/ placebo Paclitaxel/carboplatin/ placebo Placebo Investigational regimen Paclitaxel/carboplatin/erlotinib Paclitaxel/carboplatin/ISIS 3521 Paclitaxel/carboplatin/radiotherapy/ thalidomide Paclitaxel/carboplatin/ABX-EGF Gemcitabine/cisplatin/erlotinib Paclitaxel/carboplatin/erlotinib Erlotinib

NCI, National Cancer Institute; SWOG, Southwest Oncology Group; ECOG, Eastern Cooperative Oncology Group

NSCLC stage IIIB and IV:

Phase II/III trials in progress, July 2003
Sponsor NCI, ECOG NCIC-Clinical Trials Group NCI, Memorial Sloan-Kettering Cancer Center Reference regimen Paclitaxel/carboplatin Paclitaxel/carboplatin/ placebo Docetaxel Investigational regimen Paclitaxel/carboplatin/bevacizumab Paclitaxel/carboplatin/BMS-275291 Oblimersen/docetaxel

NCI, National Cancer Institute; ECOG, Eastern Cooperative Oncology Group; SWOG, Southwest Oncology Group;

SCLC:
Phase III trials in progress, July 2003
Sponsor Reference regimen Investigational regimen Disease stage Limited

First-line combined Adjuvant BCG and EORTC Lung modality treatment monoclonal antibody Cancer (at least 2-drug BEC2 Cooperative chemotherapy and chest Group radiotherapy) Vrije Universiteit Medisch Centrum Carboplatin/paclitaxel Cyclophosphamide/ doxorubicin/ etoposide

Extensive

EORTC, European Organization for Research and Treatment of Cancer; BCG, Bacillus Calmette Guerin

Summary

Despite improved detection and advances in treatment modalities, only limited progress has been made in the outcome for patients with lung cancer Targeted molecular therapeutic agents offer new hope for the future Through molecular characterisation of a patients tumour, it may become possible to offer more rational, less toxic treatment

Incidencia de Cancer

From Jemal, A. et al. CA Cancer J Clin 2005;55:10-30. Copyright 2005 American Cancer Society

Lung cancer is the most common cancer worldwide, yet

lung cancer is surrounded by negativity:

Stigmatised by its association with tobacco seen as self inflicted Low media profile - underreported Little celebrity interest People do not hear about progress in lung cancer detection and treatment Some clinician and general public hopelessness about lung cancer and treatment outcomes Insufficient funding for lung cancer research/treatments Scarcity of support services for lung cancer patients Disparate access to care and treatment

NSCLC: how oncologists would choose to be treated (1987)

118 Canadian doctors who treat lung cancer
If they had NSCLC, would they choose to be treated with chemotherapy?

After surgery for early disease No

For advanced disease confined to the chest No

For symptomatic metastatic disease No

Yes; 3%

Yes; 9%

Yes; 15%

Mackillop WJ, et al. Int J Radiat Oncol Biol Phys 1987;13:92934

NSCLC: how oncologists would choose to be treated (1994) 105 Japanese doctors
who treat lung cancer If they had NSCLC, would they choose to be treated with chemotherapy?

After surgery for early disease (stage I) No

After surgery for locally advanced disease No

For symptomatic metastatic disease

No

Yes; 24%

Yes; 62%

Yes; 33%
Motohiro A, et al. Lung Cancer 1994;11(12):4350

Patient power in lung cancer is difficult

Few lung cancer patients live long enough to advocate on their own behalf Almost all lung cancer organizations worldwide were started by non-patients Few lung cancer specific organizations in existence Cancer charities focus their efforts on antitobacco campaigns, not on promoting the rights of lung cancer patients

What can patient advocates do to improve lung cancer outcomes? Raise the profile of the disease

raise lung cancer awareness amplify the patient voice create more positive images of the disease and treatment

Help improve early detection rates

raise awareness of signs and symptoms

Help improve treatment and care

provide information and support educate public and professionals

Support lung cancer research

secure funding raise awareness and recruitment for clinical trials

The general response to lung cancer

Smokers and non-smokers often feel they are held responsible for their disease

family or friends not in touch since diagnosis friends and acquaintances cross the road to avoid contact it is assumed patients lung cancer was caused by smoking even when the patient denied ever smoking many anti-smoking campaigns underline smoking and its association with lung cancer

The patient perspective of lung cancer

Disbelief Uncertainty

What did he say now? (jargon) the long wait for diagnosis Is everything possible being done? contradictory statements by physicians second opinions

An impression from 1200 questions posed via an interative forum on the Longkanker Informatiecentrum website

The patient perspective of lung cancer (contd)

Fear

poor prognosis few treatment options

Unrealistic hope of recovery Guilt Dealing with the response of family and friends

The patient perspective on experimental drugs

Last hope

Well try anything! Well

Unrealistic expectations

New drugs are much better than older drugs

Unrealistic media coverage Accessibility

Are they not giving this to me because its expensive?

Lack of understanding about role of therapy

Difficulties in communicating with the palliative patient: a physician perspective Communicating on patient level

Decision to start treatment or not Decision to stop treatment Bringing bad news Answering prognosis questions Needing more time than is available

communicating with the palliative patient: a physician perspective (contd) Multidisciplinary inconsistencies in messages
Too high treatment expectations from patients Adapting to emotional responses in different patients Finding a balance between hope and reality Family wants are different to patient needs

Communicating for success

Content

what information do you give? how do you give it? ( e.g. how to make it easy) how can internet support you in conveying your message?

Relationship

what is the effect of the patient personality on you and vice- versa? (e.g. do you have a relationship of equality with your patient?)

Organisation

how is communication organised in your department? (e.g., what is the supportive role of oncology nurses?)

How can we help the lung cancer patient together?

If you get frustrated that you cant offer your patients the most optimal treatment: work with us Ensure clinicians are informed: help us to address attitudes of some cliniciansIf we cancer and its treatment to lung work together

we patients and carers: partner with us Create informedcan improve the lives to provide good internet and written information of lung cancer
Empower all members of the patient network: collaborate patients worldwide efforts to reinforce the important roles of each stakeholder in the patient treatment network

The lung cancer epidemic in Europe*

*Data for 1995

Bray F, et al. Eur J Cancer 2002;38:99166

NSCLC: significant unmet medical need

Early (stage I;II;IIIa): 30% Locally advanced (stage IIIa;IIIb): 30% Metastatic (stage IV): 40% Limited efficacy of standard regimens Issues with tolerability and acceptability of chemotherapy agents

Advanced NSCLC: what should our treatment goals be for patients?

Longer life
increased

overall survival (OS)

Better life
improved

response rate (RR) time to progression (TTP) improvement

prolonged

symptomatic reduced

toxicity quality of life (QoL)

improved

Longer life . . . are we meeting the objective? 50

Patients (%)
40 30 20 10 0 Stage at diagnosis Standard therapy Early stage Surgery RT CT Locally advanced RT +CT 2530% Distant CT + supportive care 3%

2-year survival rate 5-year survival rate 40% 44% with surgery + CT
RT = radiotherapy CT = chemotherapy

Adapted from Jemal A, et al. CA Cancer J Clin 2003;53:526

Better life . . . are we meeting Benefits the objective?

Che mo ther a
Tumour control Improved survival

py
Disadvantages

Significant toxicity
myelosuppression neuropathy

Limited improvement in QoL i.v. administration Need for premedication

The treatment algorithm for NSCLC

Early (stage I/II/IIIa)
Surgery + chemotherapy Radiotherapy (if unfit for surgery)

NSCLC

Advanced (stage IIIb/IV)

Suitable for chemotherapy? Yes Elderly/ PS23? Yes Single agent Relapse Chemotherapy docetaxel pemetrexed Tarceva No (PS4, frail elderly)

First-line
No

Locally advanced
Chemotherapy (PT doublet) + concomitant radiotherapy

PT-based doublet

BSC

Second-/ third-line

PS = performance status; PT = platinum; BSC = best supportive care

The treatment algorithm for NSCLC (contd)

NSCLC
Advanced (stage IIIb/IV)
Suitable for chemotherapy? Yes Elderly/ PS23? Yes Single agent No (PS4, frail elderly)

First-line
No

PT-based doublet

BSC

First-line chemotherapy for NSCLC

Survival distribution function
1.0 0.8 0.6 0.4 0.2 0 0 30

Overall survival (all randomised cases) Cisplatin/paclitaxel Cisplatin/gemcitabine Cisplatin/docetaxel Carboplatin/paclitaxel

1.0 0.8 0.6 0.4 0.2

Progression-free survival (eligible cases)

10

15 Months

20

25

10

Median survival with chemotherapy is <1 year

15 20 Months

25

30

No clear differences between various combinations of agents

Schiller JH, et al. N Engl J Med 2002;346:928

DRAMATICA RESPUESTA A ERLOTINIB