Thoracic and head/neck oncology new developments Goh Boon Cher Department of Hematology-Oncology National University Cancer Institute of Singapore Research Clinical Care Education
Scope Lung cancer Screening for lung cancer Adjuvant treatment of NSCLC Molecular subtyping of adenocarcinoma Antiangiogenic therapy for lung cancer Head and neck cancer Human papilloma virus in SCC Novel therapy for HNSCC
Lung cancer and smoking
History of Screening for lung cancer Chest X ray At least 7 studies, 6 randomised All negative for reduction of mortality Lack of no screening control group only less intensive screening Compliance Screening in control group CT scans High resolution Rapid scan in one breath 20% of radiation compared to standard CT thorax
Aug 2002-April 2004 53,454 individuals with at least 30-pack years of smoking Randomised to yearly screens x 3 by LD CT or CXR Less than 20% dose of average diagnostic CT Managed according to physician practice N Engl J Med 2011;365:395
High compliance (95% LDCT; 93% CXR) Higher rates of positive screens in LDCT (24.2% vs 6.9%) 96.4% LDCT and 94.5% CXR were false + 645/100000 person-years in LDCT vs 572/100000 PYin CXR Relative reduction in death rate from lung cancer: 20% (6.8 26.7; p=0.004) Relative reduction in overall mortality: 6.7% (1.2-13.6; p=0.02)
Issues to consider Over-diagnosis leading to excess investigations Study group representation of community Expertise of radiologists representative of community Cost effectiveness
Role of adjuvant chemotherapy Resected NSCLC Research Clinical Care Education
Expected 5 year survival & relapse following surgery for NSCLC Surgical Stage 5 year survival Relapse rate (%) (%) Local Distant IA T1N0M0 67 10 15 IB T2N0M0 57 10 30 IIA T1N1M0 55 IIB T2N1M0 39 12 40 T3N0M0 38 IIIA T3N1M0 T1-3N2M0 25 23 15 60
Post 1995 randomized Adjuvant Trials Study Treatment RT 5YS (%) HR ALPI I-IIIA S MVP 43% 43% NR 0.96 p=0.59 BLT I-III S CDDP based No 60 58 1.02 p=0.9 IALT IB-III S CDDP based 28% 23% 40.4 45.5 0.86 p<0.03 UFT IA-B S UFT No 85 88 0.71 p=0.04 BR10 IB-II S CDDP/VNR No 54 69 0.69 p=0.04 CALGB IB S CBDCA/Pac No 59 57 0.8 p=0.1 ANITA IB-IIIA S CDDP/VNR Yes 43 51 0.89 p=0.013
Analysis of survival benefit of adjuvant chemotherapy by stage Study IB II IIIA Overall HR IALT IB-III 0.95 (0.74-1.23) 0.93 (0.72-1.2) 0.79 (0.66-0.95) 0.86 p<0.03 BR10 IB-II 0.94 0.59 (0.42-0.85) Not tested 0.69 p=0.04 UFT IA-B 0.48 (0.29-0.81) Not tested Not tested 0.71 p=0.04 CALGB IB 0.8 (0.6-1.07) Not tested Not tested 0.8 p=0.1 ANITA IB-IIIA 1.1 (0.76-1.57) 0.71 (0.49-0.94) 0.85 (0.73-0.95) 0.89 p=0.013
Median follow up 5.2 yrs; HR 0.89 (0.82-0.96, p=0.005) Absolute benefit of 5.4% at 5 years Pignon et al J Clin Oncol 2008; 26:3552
NSCLC- Adjuvant Chemotherapy Which patient? Good PS Rapid recovery from surgery No significant co-morbidities Which stage? II-IIIA- definite IB- doubtful Which drug(s)? Cisplatin + vinorelbine most evidenced based UFT- no confirmatory study
Stage IV NSCLC Chemotherapy Targeted therapy
What s the benefit of chemotherapy? Platinum-based chemotherapy compared with BSC: superior median survival and 1- and 2-year survival Better symptom control and quality of life BSC Rapp 10% 20% Cullen 18% 28% BLT 19% 28% Meta-analysis 16% 26% chemo (1YS)
Progress in advanced stage NSCLC
How was this possible? Research Clinical Care Education
Opening the black box - molecular basis of lung cancer Significantly mutated pathways in lung adenocarcinomas. Hanahan & Weinberg. Cell. 2000, Ding Nature 2008
Targeted therapies EGFR inhibitors Gefitinib (Iressa) Erlotinib (Tarceva) Cetuximab (Erbitux) VEGF inhibitors Bevacizumab (Avastin)
Patients with activating mutations in tumour EGFR have excellent response to EGFR TKIs Exon 18 G719 Inframe deletions exon19 Inframe insertions exon 20 Subs L858 or L861 in exon21
Clinical Attributes that predict EGFR mutations in NSCLC P<0.001 for all EGFR activating mutations in NSCL adenocarcinoma 10-15% Caucasians 30-40% Asians Shigematsu et al. Int J Cancer 2006;118:257
No chemotherapy options left 70 year old man, stage IV NSCLC diagnosed July 2008 Received several types of chemotherapy. No chemotherapy options left Treated with gefitinib 2008 Still alive
Initial treatment with EGFR TKI 66 year old man Lung cancer diagnosed May 2010 Stage 4, oxygen dependent Treated with erlotinib.
EGFR TKI monotherapy vs chemotherapy in advanced stage NSCLC with EGFR mutations
Angiogenesis Tumor growth Dependent on angiogenesis and on vascular endothelial growth factor (VEGF) VEGF is overexpressed in NSCLC & is associated with poor prognosis
1 st line chemotherapy + bevacizumab 60 year old man Lung cancer diagnosed Feb 2008 Stage 4 Treated chemotherapy + Bev Still alive Sandler NEJM 2006
Bevacizumab with combination chemotherapy ECOG study 878 pts with stage IIIb and IV NSCLC Carboplatin + paclitaxel +/- bevacizumab SCC excluded OS 12.3 months vs 10.3 months Hazard ratio 0.79 (p=0.003) PFS 6.2 mths vs 4.5 mths; HR 0.66 (p<0.001) RR 35% vs 15% (p<0.001) Bleeding events 4.4% vs 0.7% (p<0.001) Sandler et al N Engl J Med 2006;355(24)2542
Targeted therapy- making further progress Traditional classification of lung cancer 4% 15% 12% NSCLC histologies: Adenocarcinoma Squamous cell carcinoma Large cell carcinoma 24% 45%
Classification of lung adenocarcinoma 2010: - multiple molecular subsets AZD6244 GDC-0941 PLX 4032 Lapatinib Gefitinib erlotinib sunitinib crizotinib ARQ 197
Head and neck cancer Human papilloma virus in SCC HN Combined modality treatment for head and neck cancers Incorporation of novel agents in head and neck cancers
HPV 16 commonest OS PFS Response rate:82%vs 55% J Natl Cancer Inst 2008;100(1):261
ERBITUX: Mechanisms of action EGFR-targeted monoclonal antibody therapy has demonstrated additive or synergistic antitumor activity in a variety of animal models in vitro and in vivo when administered in combination with chemotherapy and/or radiation therapy Courtesy of José Baselga (modified)
1 st -line SCCHN: EXTREME trial
Overall survival (%) Erbitux in 1 st -line SCCHN EXTREME: Significant OS benefit 100 90 80 CT (n=220) CT + Erbitux (n=222) 70 60 50 40 7.4 months 10.1 months HR=0.80 [95% CI: 0.64 0.99] p=0.04 + 2.7 months 30 20 10 0 0 3 6 9 12 15 18 21 24 Months Vermorken et al. NEJM 2008