11Neoadjuvant TherapySmaller phase III trials (60 pts), both stopped earlyStage IIIASurvival advantage with neoadjuvant chemotherapyMed survival 26 mo vs 8 mo; P<0.00164 mo vs 11 mo; P<0.008Rosell et al, NEJM 1994; Roth et al, JNCI 1994
12SWOG 9900 Arm A: Carboplatin/Paclitaxel X3 cycles R ANDOM I Z E Resectable NSCLC,354/600 Planned PatientsSurgeryArm B:Surgery AlonePisters et al, ASCO 2005; abstr 7012
13SWOG 9900, Early Results Chemo + Surgery Surgery P Med PFS 31 mo 20 mo 0.26Overall Survival 47 mo 40 mo 0.47Pisters et al, ASCO 2005; abstr 7012
14Neoadjuvant TherapyFor patients with advanced but potentially resectable disease, possible benefit to survivalPossible increase in surgical resectability rateSome trial interpretation confounded by adjuvant therapy, adjuvant radiationIs benefit equivalent to adjuvant therapy?
15Definitive Therapy for Unresectable Disease: Combined Modality Therapy
16Initial Combination Trial Randomized to Radiation vsChemo RadiationIncreased median survival from9.7 months to 13.8 monthsIncreased 3-Y OS from 11% to 26%Dillman et al, NEJM 1990
17Chemo/RT Combinations Chemo/RT combination shown better than sequential (Cisplatin-based combination)Median survival increased from 13.3 mo to 16.5 mo5-Y OS increased from 8.9% to 15.8%Furuse et al, JCO 1999
18Concurrent vs Sequential Tx Fig 1. Overall survival in patients with NSCLC according to treatment groupFuruse, K. et al. J Clin Oncol; 17:
19SWOG 9019 Stage IIIB only, 50 patients Cisplatin/Etoposide/Concurrent TRTMedian OS 15 months5-Y OS 15%Albain et al, JCO 2002
20Carboplatin-based chemo/RT Median survival 11.4 months with concurrent treatmentMedian survival 14 months with induction followed by concurrent treatmentP=0.154Results consistently inferior to cisplatinVokes et al, PASCO 2004
22SWOG 9504 Med Surv 3-Y OS 4-Y OS 5-Y OS PE/RT Docetaxel S9504 26m 40% 29%PE/RTPES901915m17%Gandara et al, ASCO 2005, abstr 7059
23SWOG 0023 R ANDOM I Z E Gefitinib Cis/Etop Concurrent RT Consolidation DocetaxelPlaceboKelly et al, ASCO 2007; abstr 7513
24Overall Survival From Randomization Median1 YROS2 YROSNEventsin Months100%Gefitinib118712373%46%Placebo125543581%59%80%P = .0160%Overall survival from the time from randomization was 23 months for gefitinib compared to 35 months for placebo. The p value for the test of the null hypothesis is 0.01.40%Median FU time:27 months20%0%1224364860Kelly et al, ASCO 2007; abstr 7513Months After RANDOMIZATION
25SWOG 0023 Closed after DSMB interim analysis Gefitinib Placebo P Median PFS 11m 10m NSDead from Cancer 86% 80%Dead from Toxicity 3% 0%Overall Survival 23m 35mKelly et al, ASCO 2007; abstr 7513
26HOG Phase III; Replicating SWOG 9504 R ANDOM I Z EConsolidationDocetaxelIIIA/B243/259Patients randomizedCis/EtopConcurrent RTObservationHanna et al, ASCO 2007; abstr 7512
28HOG, Phase III Results DSMB interim analysis Closed after 203 pts due to futilityDocetaxel Observation PMedian PFS 12.3m 12.9m 0.94Median Survival 24.3m 26mHospitalizations 28.8% 8.1%Toxic Death 5.5%Hanna et al, ASCO 2007; Mina et al, ASCO 2008
30Chemo or Hospice? Median survival with Best Supportive Care: 5 months Spiro et al, Thorax 2004BMJ Meta-Analysis, 1995Detriment with long-term alkylating agents suggested (AKA: Old Chemo)Cisplatin-Based Trials10% absolute improvement in 1-Y OS, (5% to 15%)Increased median survival 6 weeks
31Chemo or Hospice? Median survival with Best Supportive Care: 5 months Spiro et al, Thorax 2004BMJ Meta-Analysis, 1995Detriment with long-term alkylating agents suggestedCisplatin-Based Trials10% absolute improvement in 1-Y OS, (5% to 15%)Increased median survival 6 weeks
37Why Target VEGF?Actively proliferating tumor cells express more Vascular endothelial growth factor (VEGF) than nonproliferating cells1VEGF may act as an autocrine growth factor1VEGF expression is upregulated in many cancer types, including NSCLC2-4Elevated serum VEGF levels have been associated with poorer outcomes in limited- or early-stage disease2,5-7KEY POINT: Tumor-derived signals result in high levels of VEGF expression, which correlates with poor prognosis and malignant progression.Mandatory SlideADDITIONAL INFORMATIONVascular endothelial growth factor (VEGF) is implicated in tumor biology because it is upregulated by tumor-derived signals1-5 and is overexpressed by many tumor types, including NSCLC.4,6,7 High VEGF levels are also correlated with malignant progression and poorer outcomes in limited-and early-stage disease7-10As observed in tumor malignancy in general, the process of angiogenesis may play a critical role in tumor growth and metastasis of lung cancer.11 A large body of scientific research suggests a strong association between VEGF and increased microvessel density (one of the primary measurements of angiogenesis) in lung cancer. Moreover, VEGF and microvessel density have been shown to correlate with a range of prognostic parameters, including tumor size and metastasis, cancer recurrence, and overall and disease-free survivalREFERENCESShweiki et al. Proc Natl Acad Sci U S A :768–772.Rak et al. Cancer Metastasis Rev. 1995;14:263–277.Kieser et al. Oncogene. 1994;9:963–969.Ravindranath et al. J Androl. 2001;22:432–443.Horiguchi et al. Endocrine. 2004;24:141–146.Lantuejoul et al. J Pathol. 2003;200:336–347.Yuan et al. Int J Cancer Pred Oncol. 2000;89:475–483.Shimanuki et al. Lung. 2005;183:29–42.Hasegawa et al. Intern Med. 2005;44:26–34.Mineo et al. J Clin Pathol. 2004;57:591–597.Hicklin et al. J Clin Oncol. 2005;23:1011–1027.1. Mattern et al. Br J Cancer. 1996;73:931– Yuan A et al. Int J Cancer Pred Oncol. 2000;89:475–483.3. Lantuejoul et al. J Pathol. 2003;200:336– Ravindranath et al. J Androl. 2001; 22:432– Shimanuki et al. Lung. 2005;183:29–42.6. Hasegawa et al. Intern Med. 2005;44:26– Mineo et al. J Clin Pathol. 2004;57:591–597.
38VEGF: A Key Mediator of Angiogenesis Environmental factors(Hypoxia, pH)Growth factorsHormones(EGF, bFGF, PDGF,IGF-1, IL-1, IL-6, estrogen)Genes involved in tumorigenesis(p53, p73, src, ras, vHL, bcr-abl)Increased VEGF levelsBinding and activation of VEGFRPPEndothelial cellactivationPPKEY POINT: A number of environmental, hormonal, and genetic factors can lead to VEGF overexpression.ANGIOGENESISProliferationSurvivalMigrationMandatory SlideADDITIONAL INFORMATIONVEGF plays a key role in the regulation of angiogenesis1Many environmental factors, including hypoxia and low pH, stimulate the expression of VEGF1Hormones (eg, progesterone, estrogen), growth factors (eg, epidermal growth factor [EGF], transforming growth factor-beta [TGF-], basic fibroblast growth factor [bFGF], platelet-derived growth factor [PDGF], insulin-like growth factor [IGF]-1), and cytokines (eg, interleukin [IL]1, IL-6) also stimulate VEGF expression1In addition to exogenous factors, many tumorigenic mutations lead to VEGF upregulation1,2This can include mutations in cellular oncogenes, such as src, ras, and bcr-ablMutations in tumor suppressor genes such as p53, p73, and vHL also lead to upregulation of VEGFVEGF then binds and activates its receptors, stimulating signaling cascades involving phospholipase C, the nonreceptor tyrosine kinase src, phosphatidylinositol-3-kinase, and ras guanosine triphosphatase (GTP-ase) activating protein3Downstream signaling events lead to inhibition of apoptosis, stimulation of mitosis, and cytoskeletal changes associated with motility and vascular permeability3REFERENCES1. Dvorak. J Clin Oncol. 2002;20:4368–4380.2. Ebos et al. Mol Cancer Res. 2002;1:89–95.3. Ferrara et al. Nat Med. 2003;9:669–676.bFGF, basic fibroblastic growth factor; EGF, epidermal growth factor; IGF, insulin-like growth factor; IL, interleukin; PDGF, platelet-derived growth factor; VEGFR, VEGF receptor.1. Dvorak. J Clin Oncol. 2002;20:4368–4380; 2. Ebos et al. Mol Cancer Res. 2002;1:89–95; 3. Ferrara et al. Nat Med. 2003;9:669–676.
39Summary of Anti-VEGF Proposed Mechanisms of Action Based on Preclinical Models 1May regress existing microvasculature1,2KEY POINT: Based on preclinical models, anti-VEGF agents are thought to have a triple MOA that includes regression of existing microvasculature, normalization of surviving vasculature, and inhibition of vessel regrowth and neovascularization.2May normalize surviving mature vasculature3-5Mandatory SlideADDITIONAL INFORMATIONThis is a graphic representation and summary of the triple mechanism of action (MOA) of anti-VEGF agents, along with the consequences of their actionsMay regress existing microvasculature1,2Direct and rapid changes include a significant reduction in microvascular density, as seen in preclinical models1-3May normalize surviving mature vasculature3-5Reversal of structural and functional abnormalities may improve the vasculature’s capacity for drug delivery, as seen in preclinical models3-5May inhibit vessel regrowth and neovascularization2,3,6Genentech is pursuing research to expand the understanding of the MOA of bevacizumab and other monoclonal antibodies that bind to VEGFREFERENCESLee et al. Cancer Res. 2000;60:5565–5570.Inai et al. Am J Pathol. 2004;165:35–52.Gerber et al. Cancer Res. 2005;65:671–680.Jain. Science. 2005;307:58–62.Tong et al. Cancer Res. 2004;64:3731–3736.Hicklin et al. J Clin Oncol. 2005;23:1011–1027.3May inhibit vessel regrowth and neovascularization2,3,61. Lee et al. Cancer Res. 2000;60:5565–5570; 2. Inai et al. Am J Pathol. 2004;165:35–52; 3. Gerber et al. Cancer Res. 2005;65:671–680; 4. Jain Science. 2005;307:58–62; 5. Tong et al. Cancer Res. 2004;64:3731–3736; 6. Hicklin et al. J Clin Oncol. 2005;23:1011–1027.
40Avastin® (bevacizumab) Recombinant humanized monoclonal IgG1 antibodyRecognizes all isoforms of VEGF-A and blocks VEGF functionHalf-life is approximately 20 days (range, 11 to 50 days)KEY POINT: Bevacizumab is a recombinant humanized monoclonal immunoglobulin (IgG) antibody that binds all isoforms of VEGF-A.Mandatory SlideADDITIONAL INFORMATIONBevacizumab is a recombinant humanized mAb of the lgG1 isotype1Bevacizumab binds all isoforms of VEGF(-A)2At least 4 different VEGF isoforms, with different molecular weights (121, 165, 189, and 206 kDa) and heparin-binding properties, are created by alternative splicing of the VEGF(-A) gene.The estimated half-life of bevacizumab is 20 days (range, 11 to 50 days)1Blockade of VEGF with bevacizumab inhibited VEGF-induced proliferation of endothelial cells in vitro and tumor growth in vivo3REFERENCES1. Avastin® (bevacizumab) prescribing information. South San Francisco, Calif: Genentech; 2006.2. Ferrara et al. Nat Med. 2003; 9:669–676.3. Presta et al. Cancer Res. 1997;57:4593–4599.Avastin® (bevacizumab) prescribing information. South San Francisco, Calif: Genentech; 2006.
41Randomized Phase II/III Arm A:Carboplatin/Paclitaxel+PlaceboR ANDOM I Z EAdvanced Non-Squamous NSCLC,855 PatientsBev untilprogressionArm B:Carboplatin/Paclitaxel+BevacizumabSandler et al, NEJM 2006
42Exclusion Squamous cell carcinoma Central tumors Brain mets (Actively screened for prior to enrollment)HemoptysisAnticoagulation (Except ASA 81mg)Sandler et al, NEJM 2006
43Phase III: Overall Survival 1.012 mo 24 mo MedianPC 44.4% 15.4% mo0.8BV/PC 51.0% 22.0% moMedian 12.3 moHR: 0.80, P = .0130.6Proportion survivingMedian 10.3 mo0.40.2KEY POINT: Overall survival was significantly prolonged by the addition of bevacizumab to paclitaxel and carboplatin.0.0Mandatory SlideADDITIONAL INFORMATIONA significantly higher percentage of patients in the bevacizumab group were alive at 12 months (51% vs 44.4%) and 24 months (22% vs 15.4%)The median overall survival was 12.3 months vs 10.3 months for the bevacizumab plus PC group vs PC aloneThe hazard ratio was 0.80, with a 20% relative reduction in the risk of death; P = .013REFERENCESAvastin® (bevacizumab) prescribing information. South San Francisco, Calif: Genentech; 2006.612182430364248Patients at riskPC44431819010436951BV/PC434340216127542583MonthsAvastin® (bevacizumab) prescribing information. South San Francisco, Calif: Genentech; 2006.
45PCB ConclusionsSignificant gains in survival for patients treated with bevacizumabCarboplatin/Paclitaxel/Bevacizumab has become new treatment standard for many cooperative groups(For this patient population)Sandler et al, NEJM 2006
47The HER Family of Receptors EGFTGFAmphiregulinBetacellulinHB-EGFEpiregulinNRG2NRG3HeregulinsBetacellulinHeregulinsLigand-bindingdomainTransmembraneHER1 is also known as EGFR, or erb-b1, and is a member of a family of membrane receptor tyrosine kinases known as the HER family, which also includes HER2, HER3, and HER4.These receptors have different ligand-binding affinities, as shown in this slide.Epidermal growth factor (EGF) and transforming growth factor alpha (TGF) are the 2 most important ligands of HER1.The neuregulins (NRGs) are important ligands for HER3 and HER4.In normal cells, HER2 is intrinsically devoid of any ligand-binding activity. It is an important signaling partner of HER1 and HER3, and functions as a coreceptor.Ligand binding leads to receptor interaction, and the resulting stearic change activates the intrinsic kinase activity of these HER family receptor tyrosine kinases.The activated kinase phosphorylates itself and its partner on conserved tyrosine residues and initiates a signal transduction cascade, that eventually activates key regulators like mitogen-activated protein kinase (MAPK) and PI3K.All HER family proteins, with the exception of HER3, have intrinsic kinase activity.Since 1984, it has been recognized that HER1 can be overexpressed in lung cancer.HER2 appears to be less frequently expressed in NSCLC; expression levels of HER1 and HER2 are independent.Considerably less information is available on the expression of HER3 and HER4 in lung cancer. Patterns of coexpression of HER3 and HER4 are not well defined.TyrosinekinasedomainHER1erb-b1 EGFRHER2erb-b2 neuHER3erb-b3HER4erb-b4Roskoski. Biochem Biophys Res Commun. 2004;319:1.Rowinsky. Annu Rev Med. 2004;55:433.Franklin WA, Veve R, Hirsch FR, et al. Epidermal growth factor receptor family in lung cancer and premalignancy. Semin Oncol. 2002;29(suppl4):3-14.Roskoski R Jr. The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem Biophys Res Commun. 2004;319:1-11.Rowinsky EK. The erbB family: targets for therapeutic development against cancer and therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors. Annu Rev Med. 2004;55:
48Potential Consequences of EGFR Dysregulation SignalingcascadesEGFRPI3KMAPKNucleusGene activation Cell cycle progressionMG1SG2MycFosJunPInvasionAngiogenesisMetastasisProliferationCell surface receptors bind ligands that activate the receptor and regulate cell functions.EGFR can bind EGF as well as several other ligands (eg, TGF).The binding of ligand results in 2 receptors joining together in a process known as dimerization.Upon dimerization, the intracellular tyrosine kinase domains of the receptor may transphosphorylate the dimer partner, initiating a signaling cascade. Subsequent transduction of the signal to the nucleus leads to regulation of genetic functions, such as gene activation/suppression and cell cycle regulation.In malignancies, such as NSCLC, overexpression or dysregulation of EGFR may increase the signaling response and result inCell cycle progression leading to cellular proliferation.Decreased apoptotic response leading to increased cellular survival even in the presence of abnormal cell functions resulting from toxic stimuli such as radiation or chemical damage.Production of cell factors that promote angiogenesis and further cellular proliferation.Increased invasiveness and metastasis.SurvivalApoptosisMAPK = mitogen-activated protein kinase.Roskoski. Biochem Biophys Res Commun. 2004;319:1.Rowinsky. Annu Rev Med. 2004;55:433.Roskoski R Jr. The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem Biophys Res Commun. 2004;319:1-11.Rowinsky EK. The erbB family: targets for therapeutic development against cancer and therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors. Annu Rev Med. 2004;55:
49Epidermal Growth Factor Receptor EGFR expression upregulated in a number of cancersMost NSCLC found to express EGFRInhibition of EGFR can induce apoptosis and reduce tumor proliferation
50EGFR-Targeted Approaches TOXINThere are a number of ways to target EGFR dysregulation.Antibodies against EGFR can act as receptor antagonists and prevent ligand binding, eg, cetuximab.Antibodies may prevent receptor dimerization, eg, trastuzumab (HER2).Antibodies against ligand also block binding, and this approach may be useful when 1 ligand binds to several receptors.Using a small molecule that specifically targets and either reversibly or irreversibly inhibits the tyrosine kinase activity is an approach that may block signaling by all active EGFR forms, including those receptors with mutated or deleted extracellular domains.Erlotinib and gefitinib are 2 ATP-competitive inhibitors of the EGFR tyrosine kinase.Mutations in the tyrosine kinase domain that lead to increased growth factor signaling correlate with increased clinical responsiveness to these TKIs. These mutations may result in increased sensitivity to erlotinib and gefitinib.Further prospective studies are required to better understand the prognostic and predictive value of EGFR tyrosine kinase domain mutations.Conjugates of a ligand and a cytotoxic agent (eg, TP-38 and DAB389EGF) or an antibody and a cytotoxic agent (eg, scFv-14e1-ETA fusion toxin) are another approach that may have the advantage of killing the cell after internalization, in addition to inhibiting tyrosine kinase activity.Anti-EGFRblockingantibodiesAntiligandblockingantibodiesTyrosinekinaseinhibitorsLigand-toxinconjugatesHER dimerizationinhibitorsAdapted from Noonberg and Benz. Drugs. 2000;59:753.Noonberg SB, Benz CC. Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily: role as anticancer agents. Drugs. 2000;59:Erbitux® [package insert]. Branchburg, NJ, and Princeton, NJ: ImClone Systems and Bristol-Myers Squibb Company; 2004.Sampson JH, Akabani G, Archer G, et al. Clinical outcome and distribution measure of a recombinant chimeric protein composed of transforming growth factor alpha and a mutated Pseudomonas exotoxin (TP-38) via convection-enhanced microinfusion on a phase I study for malignant brain tumor. Proc Am Soc Clin Oncol. 2003;22:99. Abstract 397.Frankel AE, Liu TF, Thorburn AM, Tatter SB, Willingham MC. Recombinant toxin DAB389EGF produces regressions of human glioma xenografts in nude mice. Proc Am Soc Clin Oncol. 2004;23:220. Abstract 3101.Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist. 2002;7(suppl 4):2-8.
51Cisplatin/Vinorelbine/Cetuximab Randomized Phase III trialCis/VinorelbineWith or without CetuximabCetuximab till disease progressionPirker et al, PASCO 2008
52Cetuximab Toxicity with Chemo RashFebrile neutropeniaNo difference in treatment-related mortalityPirker et al, PASCO 2008
54ConclusionsCetuximab added to first line chemotherapy with CV demonstrated superior survival over CV alone in patients with EGFR detectable advanced NSCLCWould other platin-based combinations have a more acceptable toxicity profile?
55ConclusionsCetuximab added to first line chemotherapy with CV demonstrated superior survival over CV alone in patients with EGFR detectable advanced NSCLCWould other platin-based combinations have a more acceptable toxicity profile?Further refining patient selection may increase the current modest survival benefitEGFR FISHKRAS mutation
57Second-Line TherapyChemotherapy with newer agents (docetaxel) given second-line:Improved survival from 4.6 months (Best supportive care)To 5.9 months1-Y survival from 11% to 19%Shepherd et al, JCO 2000
58Docetaxel Survival Curve Improvement in overall QOL, pain, appetite, and fatigue with Docetaxel compared with BSCShepherd et al, JCO 2000
59Pemetrexed Median Survival: 8.3 months 1-Y Survival: 29.7% Arm A: R ANDOM I Z ERecurrent NSCLC,571 PatientsMedian Survival:7.9 months1-Y Survival:29.7%Arm B:DocetaxelHanna et al, JCO 2004
60Pemetrexed Median Survival: 8.3 months 1-Y Survival: 29.7% Arm A: R ANDOM I Z ERecurrent NSCLC,571 PatientsMedian Survival:7.9 months1-Y Survival:29.7%Arm B:DocetaxelHanna et al, JCO 2004
62Proposed Mechanism of Action of EGFR-Targeted TKIs Inhibit EGFR kinase activityPPPhosphorylationPPI3KPMAPKMandatory SlideWhile their mechanism of action has not been fully characterized, it is postulated that EGFR TKIs inhibit EGFR tyrosine kinase activity by preferentially occupying the ATP binding site within the intracellular TKD.Bind at a higher affinity than the ATP substratePrevent receptor phosphorylation and signal activationThe prevention of signal transduction within the tumor cell may have several potential antitumor effectsDecreases activation of antiapoptotic genes, thereby increasing the rate of apoptosisDecreases activation of genes promoting cell cycle progressionReduces angiogenic signalsThe potential net effects are tumor growth inhibition and tumor shrinkage.While HER1 TKIs downregulate MAPK and PI3K activity, they do not directly inhibit these kinases per se. They are thought to elicit their biologic activity by inactivating the tyrosine kinase activity of EGFR, which results in the inhibition of downstream cascades such as MAPK and PI3K.NosignalingBCL2BAXMG1G2STumor cell survivalApoptosisG1 arrestTumor cell proliferationArteaga. Semin Oncol. 2003;30(suppl 7):3.Arteaga. Semin Oncol. 2003;30(suppl 7):3.
63Erlotinib single agent trial Arm A:ErlotinibR ANDOM I Z EAdvanced NSCLC,731 Patients1-2 Prior Chemo RegimensArm B:PlaceboShepherd et al, PASCO 2004
64Erlotinib single agent trial Arm A:ErlotinibR ANDOM I Z EOverall SurvivalErlotinib 6.7 moPlacebo 4.7 moP<0.001Advanced NSCLC,731 Patients1-2 Prior Chemo RegimensArm B:PlaceboShepherd et al, PASCO 2004
65Erlotinib Single Agent Survival Shepherd et al, PASCO 2004
66Erlotinib in Combination StudyPatientsMedian SurvivalMedian TTPTALENT1 (Gem/Cis with Erlotinib or placebo)1172301 days v 309 days167 days v 179 daysTRIBUTE2 (Carbo/Tax with Erlotinib or placebo)105910.8m v 10.6m5.1m v 4.9m1. Gatzmeier et al, PASCO Herbst et al, PASCO 2004
67Chemotherapy for Metastatic Disease First, second, third-line therapy:Improves survivalImproves quality of life
68What next? Histology-derived treatment selection Treatment/Prognosis driven by molecular profilesOngoing efforts to understand interactions between targeted agents and chemo
70Small Cell Lung Cancer 10-15% new lung cancers are SCLC Decreasing proportion over time~32,000 cases yearly
71SCLC--Staging Limited stage Extensive stage Involving the ipsilateral hemithorax within a single radiation portMay encompass contralateral hilar nodes“Not metastatic”, no malignant effusionExtensive stagePresence of obvious metastasesMalignant effusion
72Survival Limited Stage Median survival 3 months without treatment Median survival months with treatment~25% 5-year survival**Turrisi et al, NEJM, 1999
73Survival Limited Stage Extensive Stage Median survival 3 months without treatmentMedian survival months with treatment~25% 5-year survival*Extensive StageMedian survival 6 weeks without treatment**Median survival with treatment 8-11 months***<5% 2-year survival*Turrisi et al, NEJM, 1999; **Green et al, Am J Med 1969; ***Aisner et al, JCO 1996
74Conclusions, SCLCSCLC is a highly aggressive and rapidly fatal diseaseSignificant gains in life expectancy and QOL have been made with chemotherapy and radiationDespite previous gains, plateaus in survival have been reached, and further gains with conventional therapy will be modest at best
75Lung Cancer: So are we crazy? Despite pessimism, advances HAVE been made in survival and QOL in treatment of lung cancerFurther advances will require rationally-designed agents and careful monitoring for efficacy