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Ca. Pulmon .2012

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Dr. Luis M. Zetina T
Cancer Consultants GT

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Ca. Pulmon .2012

  1. 1. Carcinoma Pulmonar
  2. 2. 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.
  3. 3. 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 For advanced disease For symptomatic early disease confined to the chest metastatic disease No No NoYes; 3% Yes; 9% Yes; 15% Mackillop WJ, et al. Int J Radiat Oncol Biol Phys 1987;13:929–34
  4. 4. 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 After surgery for For symptomaticearly disease (stage locally advanced metastatic disease I) disease No No NoYes; 24% Yes; 62% Yes; 33% Motohiro A, et al. Lung Cancer 1994;11(1–2):43–50
  5. 5. ‘Mayor SV’ . . . estabamos cumpliendo los objetivos? 50 40 Pacients (%) 30 20 10 0Etapa de diagnostico Temprana Localmente avanzada AvanzadaTerapia ‘Standard’ Cirugía RT CT ±RT ±CT +CT + BSCSV 2-añosSV 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
  6. 6. INICIO DEL CONOCIMIENTO DE BIOLOGIA MOLECULAR
  7. 7. thyroid transcription factor 1 PRIMARIOCOMPROBACION POR IHQ
  8. 8. (PREDICE NORESPUESTA DE TK)
  9. 9. CDDPPEMETREXED TKCETUXIMAB
  10. 10. 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)
  11. 11. Tasa de Mortalidad por cancer pulmonar (1930-1998) e influencia del tabaquismo 80 Pulmón y bronquios (hombre) Pulmón y bronquios (mujer) 60 -1.7tasa por Tabaco100,000 86% (Hombres) 40 49% (Mujeres)poblaciónHombre/mujer +3.4 20 0 1930 1940 1950 1960 1970 1980 1990
  12. 12. Sequential changes during lung cancer pathogenesis Early Intermediate Late Normal Hyperplasia Invasive Dysplasia CIS epithelium carcinoma3p LOH/small telomeric deletions 3p LOH/contiguous ~80%Microsatellite alterations deletions ~50% 9p21 LOH ~70% Telomerase Telomerase upregulation ~80% dysregulation myc overexpression ~60% 8p21-23 LOH ~80% Neoangiogenesis ~40% Loss of Fhit immunostaining ~40% p53 LOH p53 mutations ~70% Aneuploidy ~80% Methylation ~100 5q21 APC-MCC LOH % ~30% K-ras mutation ~20%LOH, loss of heterozygosity Hirsch et al 2001
  13. 13. Factores de CrecimientoCrecimiento Tumoral y Metástasis Metástasis Mutaciones en – Familia HER Efectos Tumorales – VEGF – metástasis – MPM´s – proliferación – Ras – pérdida de apoptosis – p53 – replicación infinita – COX-2 – angiogésis – invasión Tumor Primario Hanahan D, Weinberg RA. Cell. 2000;100:57-70.
  14. 14. HER1/EGFR Inhibidores: Modo de Actividad Antitumoral Anticuerpo Monoclonal TK inhibidor ↓ Proliferacion ↑ Apoptosis ↓ Invasion ↑ Sensibilidad a radioterapia ↓ Metastasis ↓ Adhesion ↓ AngiogenesisEtessami A, Bourhis J. Drugs Fut. 2000;25:895-899.Moyer J, Barbacci EG, Iwata KK, et al. Cancer Res. 1997;57:4838-4848.Harari PM, Huang SM. Semin Radiat Oncol. 2002;12(Suppl 2):21-26.
  15. 15. GLOBOCAN 2002Latino 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
  16. 16. Incidencia y Mortalidad mundial de 15 tipos de cancer mas comunes, 2000 Hombres MujeresPulmónMamaColon/rectoGastrico MAYOR MORTALIDADHigadoPróstata 18 MUERTES /HORACervix uterinoEsófagoVejigaLinfoma No-HodgkinCavidad OralLeucemiasPancreasOvarioRiñón 1200 1000 800 600 400 200 Miles Parkin et al 2001
  17. 17. 8
  18. 18. 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
  19. 19. FIE SIN BRETR TOM OM AS BO P SIS ARA NE OP LA SIC O S
  20. 20. Lung Cancer Subtypes The WHO classification for primary lung cancer recognizes 4 major histology types[1] *Including adenosquamous carcinoma; carcinomas with pleomorphic, sarcomatoid or Other* sarcomatous elements; 24.0% carcinoid tumor; carcinomas of Adenocarcinoma salivary gland type; and 38.3% unclassified carcinoma Large-cell carcinoma Small-cell 5.0% carcinoma 19.7% 13.0% Squamous cell carcinoma 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.
  21. 21. 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
  22. 22. Types of lung cancer: non-small-cell lung cancer (NSCLC) Squamous-cell carcinoma (~30%) Adenocarcinoma (30-50%) • Most commonly found in men • Most common type of lung cancer in women and non-smokers • Closely correlated with smoking (dose • Lesions are usually peripheral dependent) • Worldwide incidence increasing • Tends to spread locally • Highly expressed genes encoding small- • More readily detected in sputum airway-associated and immunologically related proteins • Highly expressed genes encoding proteins with detoxification/ • K-ras mutations frequently reported anti-oxidant properties • Bronchoalveolar carcinoma is a subtype Large-cell carcinoma (10-25%) • Very primitive, undifferentiated cells • Lesions are usually peripheral • High tendency to metastasise
  23. 23. Lung cancer diagnosis/stagingPhysical examination Detect signsBronchoscopy Precise location of tumour, obtain biopsy .90%FNA Cytology. Peripheral lesionsChest X-ray Detect position, size, number of tumoursCT scan Detect chest wall invasion, mediastinal lymphadenopathy, distant metastasesPET scan Lymph node staging. S:82% E:92%. Inf vrs Ca?Laboratory analysis Detect changes in hormone production, and haematological manifestations of lung ca.Mediastinoscopy Access to mediastinal adenopathyBone Scan Bone Metastases NCCN Guidelines 2010
  24. 24. Adeno CarcinomaPulmonarPET /CT post Tx. EC IIIB T2 N2 Mo
  25. 25. Carcinoma Escamoso TAC 11-1-2011Pulmonar. 72 años.Dx. Oct. 2009 IMAGEN PET METABOLISMO FUSION NECROSIS
  26. 26. Survival by Pathologic Stage: IASLC New Classification Deaths/N MST 5-Yr, % IA 1168/3666 119 73 IB 1450/3100 81 58 IIA 1485/2579 49 46 100 IIB 1502/2252 31 36 IIIA 2896/3792 22 24 80 IIIB 263/297 13 9 IV 224/266 17 13 Patients (%) 60 40 20 0 0 2 4 6 8 10 Survival YrsGoldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNMstage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thoracic Oncol.2007;2:706-714.
  27. 27. NSCLC: treatment options overview Stage I Stage II• Lobectomy or segment/wedge resection • Lobectomy, pneumonectomy,• Curative radiotherapy if surgery is segment/wedge resection as contraindicated appropriate• Adjuvant RT ?? • Curative radiotherapy if surgery• Adjuvant QT ?? contraindicated • Adjuvant chemotherapy • Adjuvant radiotherapy Stage IIIA Stage IV• Surgery alone • Chemotherapy (platinum based),• Chemotherapy + modest survival benefits radiotherapy/neoadjuvant therapy • New chemotherapy agents• Post-operative radiotherapy • External beam radiotherapy (palliative• Radiotherapy alone relief) Stage IIIB • Endobronchial laser or brachytherapy• Chemotherapy alone for obstruction• Chemotherapy + radiotherapy• Radiotherapy alone PDQ Guidelines 2000
  28. 28. 1000000 new lung cancers yearly 80% NSCLC 33% resectable NSCLC 75% candidates to adjuvant Chemo180.000 patients candidates to adjuvant Chemo 4.5% increase in survival 7000 deaths could be avoided
  29. 29. The treatment algorithm for NSCLC Early Advanced (stage I/II/IIIa) NSCLC (stage IIIb/IV) Surgery + Suitable for chemotherapy? chemotherapy Yes No First-line (PS4, frail Radiotherapy Elderly/ elderly) (if unfit for No Yes PS2–3? surgery) PT-based Single BSC doublet agent Locally advanced Relapse Chemotherapy (PT doublet) Chemotherapy Tarceva + concomitant Second-/ – docetaxel radiotherapy third-line – pemetrexedPS = performance status; PT = platinum; BSC = best supportive care
  30. 30. Carcinoma Pulmonar (Historia y desarrollo) 100 BSC + CDDP (6-8m) 80 BSC (2-4m) 1990s Sobrevida (%) 60 Meta-analisis 40 confirman beneficio de 20 SVida con QT en 0 NSCLC avanzado 0 6 12 18 24 Tiempo desde randomizacion (meses) Resultados Tx. Con protocolos basados cisplatin (11 ensayos)1930 1940 1950 1960 1970 1980 1990 2000 2010 NSCLC Collaborative Group. BMJ 1995;311:899–909
  31. 31. Carcinoma Pulmonar Historia . E1594 (n=1155) 1.0 Cisplatino/paclitaxel (R) 1990s distribution function SVida Cisplatino/gemcitabine 0.8 Cisplatino/docetaxel QT 1era linea NSCLC Carboplatino/paclitaxel (R) 0.6 avanzado llego 0.4 “PLATEAU”5 10 15 20 25 30 0.2 Sv ½ 7.9m Urgente necesidad de TR: 19% 0 Nuevos opciones de tratamiento Meses 1930 1940 1950 1960 1970 1980 1990 2000 2010 Schiller JH, et al. N Engl J Med 2002;346:92–8
  32. 32. Carcinoma Pulmonar Historia Terapeutica 1.0 Carboplatin/paclitaxel + Avastin Carboplatin/paclitaxel 2005 0.8Probability 0.6 Avastin + QT significativamente prolonga sobrevida comparado 0.4 con QT sola en 1 era. Linea 0.2 NSCLC avanzado 10.3 12.3 0 Primer estudio fase III que 0 6 12 18 24 30 36 42 Time (months) aumenta SVida media mas alla de 1 añoSandler A, et al. J Clin Oncol 2005;23 (Suppl. 16):2s (Abs. LBA4) Aprobado US 1930 1940 1950 1960 1970 1980 1990 2000 2010 Sandler A, et al. N Engl J Med 2006;355:2542–50
  33. 33. History of Therapy in Advanced NSCLC: FDA Approval Dates Docetaxel Gefitinib 2002 2003 Standard therapies First line Docetaxel Erlotinib Second line Pemetrexed 1999 Third line 2004 Maintenance Paclitaxel Bevacizumab Not approved Gemcitabine 2006 1998 *Label does not include Pemetrexed NSCLC-specific indication Vinorelbine 2008/2009 1994 Carboplatin* 12+ 1989 Median Cisplatin* OS (mos) 1978 ~ 8-10 ~6 ~ 2-4 1970 1980 1990 2000 Bevacizumab + PC BSC Single-agent platinum Doublets Histology-directed therapy1. 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.
  34. 34. ‘Better life’ . . . are we meeting the objective? Benefits Che moth e r apy Tumour controlImproved survival Disadvantages Significant toxicity – myelosuppression – neuropathy Limited improvement in QoL i.v. administration Need for premedication
  35. 35. Interlinking Factors to Guide Personalized Therapy in NSCLC Clinical Factors Histologic Factors Molecular FactorsAdapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:148-150.
  36. 36. 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” Van LeeuwenHoek Molecular Profiling
  37. 37. “ 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
  38. 38. Why Perform Molecular Testing?Outcomes of Molecular Testing  Predictive: Who is likely to do better with a particularFor predictive and therapy?prognostic value  Prognostic: Who is likely to do better or worse, independent of therapy?  Give best treatments first (eg, consider timing of EGFR TKI)To improve clinical  Provide access to agent (eg, crizotinib for ALK-positiveoutcomes NSCLC)  Identify subsets who might benefit from targeted therapy (eg, cetuximab)To facilitate clinical  May improve patient outcomesresearch  Better understanding of molecular oncology
  39. 39. Importance of Molecular Staging Early-Stage NSCLC Treatment Protocol Stage IA+B: Observation Stage II-IIIA: Adjuvant therapy Diagnosis Tumor is resected and measuredWho 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 anddo 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?
  40. 40. Potential Oncogenic Drivers in NSCLC KRAS Adenocarcinoma EGFR BRAF HER2 Other PIK3CA ALK c-MET Other ALK (~ 5%)Bang Y, et al. ASCO 2010. Abstract 3. Reprinted with permission.
  41. 41. Lung Cancer Molecular Consortium Analysis in Lung Adenocarcinomas No Mutation Detected KRAS 22% AKT1 NRAS EGFR MEK1 EML4-AKL 17% MET AMP 7% HER2 PIK3CA 2% BRAF 2% Double Mutants 3% Mutations found in 54% (280/516) of tumors completely tested (95% CI: 50% to 59%)Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01
  42. 42. Interpatient Heterogeneity in the Molecular Characteristics of NSCLC Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)65-yr-old male smoker, squamous KRAS Mt In 2012:  Most oncologists would agree that these patients have very different malignancies  Most oncologists would agree that these patients should receive different therapy
  43. 43. Interpatient Heterogeneity in the Molecular Characteristics of NSCLC Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)65-yr-old male 39-yr-old smoker, female squamous never-smoker, adenoca KRAS Mt EGFR Mt In 2012:  Most oncologists would agree that these patients have very different malignancies  Most oncologists would agree that these patients should receive different therapy
  44. 44. Interpatient Heterogeneity in the Molecular Characteristics of NSCLC Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)65-yr-old male 39-yr-old smoker, female squamous never-smoker, adenoca KRAS Mt EGFR Mt54-yr-old malenever-smoker, adenoca ALK fusion  Most oncologists would agree that these patients have very different malignancies  Most oncologists would agree that these patients should receive different therapy
  45. 45. 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 EGFR Mutations Detected mutations in tumors 36% – 52% of never smokers – 15% of former smokers – 6% of current smokers 60% Never (n = 302) 4% Current (n = 20) Former (n = 181)D’Angelo SP, et al. J Clin Oncol. 2011;29:2066-2070.
  46. 46. HER1/EGFR Inhibidores: Modo de Actividad Antitumoral Anticuerpo Monoclonal TK inhibidor ↓ Proliferacion ↑ Apoptosis ↓ Invasion ↑ Sensibilidad a radioterapia ↓ Metastasis ↓ Adhesion ↓ AngiogenesisEtessami A, Bourhis J. Drugs Fut. 2000;25:895-899.Moyer J, Barbacci EG, Iwata KK, et al. Cancer Res. 1997;57:4838-4848.Harari PM, Huang SM. Semin Radiat Oncol. 2002;12(Suppl 2):21-26.
  47. 47. Angiogenesis Tumoral Tumor 1. Secrecion de 4. Aparecen Factores nueva vasculatura angiogenicos tumoral2. Destruccion Proteolitica De matriz 3. Proliferacion extracellular y migracion endotelial Brote capilar
  48. 48. Agentes Blanco para vias VEGF Anticuerpos Anti-VEGF VEGF Soluble (bevacizumab) VEGFRs (VEGF-Trap) Anticuerpos VEGFR (IMC-1121b) P P P P P P P P VEGFR-1 VEGFR-2 Endotelio Inh. pequeña-molecula VEGFR – Vatalanib (PTK787) – Sunitinib (SU11248) – Sorafenib (BAY 43-9006)Podar and Anderson. Blood. 2005;105:1383. – ZD6474
  49. 49. Agentes Biologicos dirijidos a blancos moleculares específicos involucrados en la formación y desarrollo del tumorCetuximab Avastin Receptor VEGF (control de angiogénesis) VEGF r PTK/ZK (TKI) HER1/EGFR TarcevaTKIs Control cel crecimiento y multiplicacion HER1/EGFR = epidermal growth factor receptor; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor
  50. 50. Prospective Trials of EGFR TKIs vs Chemotherapy in EGFR-Mutated Patients Trial Treatment N RR, % Median PFS, Mos Median OS, Mos TKI Chemo TKI Chemo TKI Chemo NEJ002[1] Gefitinib vs carboplatin/ 230 74 31 10.8 5.4 30.5 23.6 paclitaxel WJTOG3405[2] Gefitinib vs Not cisplatin/ 172 62 32 9.2 6.3 30.9 reached docetaxel OPTIMAL[3] Erlotinib vs Not carboplatin/ 165 83 36 13.1 4.6 NR reported gemcitabine EURTAC[4] Erlotinib vs Not platinum-based 174 58 15 9.7 5.2 NR reported doublet1. 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.
  51. 51. IPASS: PFS in EGFR Mutation–Positive and –Negative Patients EGFR Mutation Positive EGFR Mutation Negative Gefitinib (n = 132) Gefitinib (n = 91) 1.0 Carboplatin/paclitaxel (n = 129) 1.0 Carboplatin/paclitaxel (n = 85) HR: 0.48 (95% CI: 0.36-0.64; HR: 2.85 (95% CI: 2.05-3.98; 0.8 P < .0001) 0.8 P < .0001)Probability of PFS Probability of PFS Gefitinib events , n (%) 97 (73.5) Gefitinib events, n (%) 88 (96.7) 0.6 C/P events, n (%) 111 (86.0) 0.6 C/P events, n (%) 70 (82.4) 0.4 0.4 0.2 0.2 0 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Mos Mos Treatment by subgroup interaction test, P < .0001  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.
  52. 52. Respuesta a erlotinibJunio 2005 Agosto 2005
  53. 53. FLEX: Response and OS by IHC ScoreFLEX: Response Rate by EGFR Expression Levels Predictive Value of High EGFR for (IHC Score) Survival Benefit With CT + Cetuximab Low EGFR Expression High EGFR Expression (< 200), n = 776 (69%) (≥200), n = 345 (31%) Low EGFR High EGFR HR: 0.99 HR: 0.73 (95% CI: 0.84-1.16) 100 (95% CI: 0.58-0.93) 44.4 80 OS (%) 60 29.6 32.6 28.1 40 20 0 Mos 0 6 12 18 24 30 Mos P = .36 P = .002 Interaction P = .044 Treatment interaction test P = .040 CT + cetuximab O’Byrne et al. JPO 20120, CT + cetuximab CT 12 (suppl), S558 (LBOAI) CTPirker R, et al. Lancet. 2009;373:1525-1531. Pirker R, et al. WCLC 2011. Abstract O-01.06.
  54. 54. Thymidylate Synthase Expression in Lung Cancer ma lung ou s rc ino al all am oc a N o rm S m ll Sq u en Ce Ad TS  SCLC: highest TS  Squamous: high TSBhattacharjee A, et al. Proc Natl Acad Sci U S A.  Adeno: low TS2001;98:13790-13795.
  55. 55. EML4-ALK Translocations in NSCLC 1 HELP 496 981EML4 Basic WD EML4-ALK frequency: ~ 4% (64/1709)EML4-ALK 1 496 1059 Primarily in adenocarcinomavariant 1 More common in younger patients More common in never-smokers 1 1058 1620 (~ 20%)ALK Kinase TMSoda M, et al. Nature. 2007;448:561-566.
  56. 56. 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 study1. Tan W, et al. ASCO 2010. Abstract 2596.
  57. 57. Tumor Responses to Crizotinib for Patients With ALK-Positive NSCLC  Kwak and colleagues evaluated safety and efficacy of crizotinib in ALK- positive NSCLC patients (N = 82) 60 PD SD PR CR 40 Percent Change From 20 0 Baseline -20 -40 -30% -60 -80 -100 10 20 30 40 50 60 70 79 Patient No.Kwak EL, et al. N Engl J Med. 2010;363:1693-1703. Copyright © 2010 Massachusetts Medical Society.All rights reserved.
  58. 58. Algorithm for Therapy of Advanced- Stage NSCLC: 2009 Proposed Treatment Algorithm EGFR mutation positive Molecular Good PS Clinical (PS) POOR PS Erlotinib Nonsquamous Histologic Squamous Single-agent chemotherapy Bevacizumab Bevacizumab First Clinical eligible ineligible line Platinum/pemetrexed (or other*) ± Platinum/pemetrexed Platinum/gemcitabine bevacizumab (or other*) (or other*) Maintenance End of first-line chemotherapy Bevacizumab or erlotinib or Pemetrexed or Based on previous Erlotinib pemetrexed erlotinib therapy Progression Chemotherapy by Based on Based on Based on previous therapy Second algorithm previous therapy previous therapy line *Docetaxel, paclitaxel, vinorelbine.Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
  59. 59. Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy 2012 Advanced-Stage NSCLC & PS 0-1 EGFR mutation ELM4-ALK EFGR mutation and ALK EFGR mutation and ALK positive positive negative and nonsquamous negative and squamous histology histology Bevacizumab Bevacizumab appropriate inappropriate Erlotinib or Consider crizotinib Consider Consider Consider gefitinib first or second line carboplatin/paclitaxel + cisplatin or carboplatin cisplatin or first line bevacizumab combined with carboplatin or pemetrexed, docetaxel combined with cisplatin/pemetrexed or gemcitabine or docetaxel or ± bevacizumab paclitaxel gemcitabine or or paclitaxel cisplatin/vinorelbine or ± cetuximab cisplatin/vinorelbine ± cetuximabUpdated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
  60. 60. Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy 2012 Advanced-Stage NSCLC & PS 0-1 EGFR mutation ELM4-ALK EFGR mutation and ALK EFGR mutation and ALK positive positive negative and nonsquamous negative and squamous histology histology Bevacizumab Bevacizumab Molecular appropriateHistology: Clinical inappropriate Erlotinib or Consider crizotinib Consider Consider Consider gefitinib first or second line carboplatin/paclitaxel + cisplatin or carboplatin cisplatin or first line bevacizumab combined with carboplatin or pemetrexed, docetaxel combined with cisplatin/pemetrexed or gemcitabine or docetaxel or ± bevacizumab paclitaxel gemcitabine or or paclitaxel cisplatin/vinorelbine or ± cetuximab cisplatin/vinorelbine ± cetuximabUpdated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
  61. 61. Major Themes in Therapy of Advanced NSCLC 2012: Interrelationships Among Histology,Maintenance Therapy, and Predictive Biomarkers Histology Maintenance Therapy Predictive Biomarkers Looking Forward to 2015: Moving From Empiric to Individualized From “One Size Fits All” to “Tailored” and “Individualized” Therapy
  62. 62. Transition From Empiric to Tailored and Individualized Cancer Therapy Empiric therapy Tailored and individualized therapyGandara DR, et al. Clin Lung Cancer. 2009;10:148-150.
  63. 63. Terapia Anti-VEGF normaliza microvasculature tumoral Jain RK. Nat Med 2001;7:987–9 AVASTIN Vasculature Anormal Normalizacion de vasculatura tumoralVasculatura normal despues de  Vasos aumentan Terapia anti-angiogenic therapy permeabilidad tortuosidad  Normalidad de tamaño, forma y permeabilidad de vasos  Difusion de medicamentos  Reduccion de presion comprometida intratumoral.  Mejoria de oxigenacion  Potential mejoria en difusion de medicamentos
  64. 64. Terapia Anti-VEGF inhibe neo-vascularizacion Neovascularizacion despues de implantacion de celulas tumorales Control Antes de 1 dia despues 6 dias despues 9 dias despues implantation implantacion implantacion implantacion Celulas LLC Anti-VEGF therapy* Antes de 1 dia despues de 6 dias despues de 9 dias despues de implantacion celulas implantation implantacion implantation LLC* Anti-VEGF agent: SU11248(VEGFR TKI) Osusky KL, et al. AngiogenesisLLC = Lewis lung carcinoma 2004;7:225–33

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