Advances in the Treatment of Lung Cancer Sin Chong Lau Consultant in Medical Oncology

new cases 13% of all new cancers UK Cancer Incidence 2009, Cancer Research UK

new cases 13% of all new cancers UK Cancer Mortality 2010, Cancer Research UK 114 new cases / day

deaths 22% of cancer deaths 6% of all deaths UK Cancer Incidence 2009, Cancer Research UK

deaths 22% of cancer deaths 6% of all deaths UK Cancer Mortality 2010, Cancer Research UK 4 deaths / hour

Survival Men 1 year29.4% 5 years7.8% 10 years4.9% Women 1 year33.0% 5 years9.3% 10 years5.9% England , England & Wales 2007 Survival Rates, Cancer Research UK

Survival Men 1 year29.4% 5 years7.8% 10 years4.9% Women 1 year33.0% 5 years9.3% 10 years5.9% England , England & Wales 2007 Survival Rates, Cancer Research UK 2 nd lowest of the 21 most common cancers 5 year survival rate Breast cancer 85% Colorectal cancer 55%

Progress - 5 Year Survival Rates

5 Year Survival Rates – By Stage Non-Small Cell Lung Cancer IA58-73% IB43-58% IIA36-46% IIB25-36% IIIA19-24% IIIB7-9% IV2-13% Small Cell Lung Cancer Limited18-38% Extensive1%

Have there been any Advances in the Treatment of Lung Cancer?

Lung Cancer Non-Small Cell Lung Cancer 78% Squamous cell carcinoma (32%) Adenocarcinoma (26%) Large cell carcinoma NOS (Not otherwise specified) (35%) Small Cell Lung Cancer 18% Grows more rapidly Very closely linked to cigarette smoking

Lung Cancer Staging Non-Small Cell Lung Cancer Stage I – Small (<5cm) and in only one area Stage II – Larger, may involve lymph nodes Stage III – Larger (>7cm), involves lymph nodes or other parts of the chest or lung Stage IV – Spread to both lungs, other parts of the body or within a pleural effusion Small Cell Lung Cancer Limited – Within one lung field Extensive – Outside one lung field

Lung Cancer Treatment Patient Medical Oncologist Surgeon Clinical Oncologist NONSENSE

Patient Medical Oncologist Surgeon Clinical Oncologist Admin/ Clerical Community Nurse Radio- therapy Unit Chemo- therapy Unit A&E Medical Ward Surgical Ward Radiologist Respiratory Physician Palliative Care Clinical Psychology PathologyGP Lung Cancer CNS

Lung Cancer Treatment Non-Small Cell Lung Cancer Surgery for stage I-II Radiotherapy –Radical for stage I-IIIA –Palliative for stage IIIB-IV Chemotherapy –Adjuvant for stage I-IIIA –Palliative for stage IIIA-IV Small Cell Lung Cancer Surgery (very selected cases) Radiotherapy –Radical for limited stage (combined with chemotherapy) –Palliative or prophylactic for extensive stage Chemotherapy –Radical for limited stage (combined with radiotherapy) –Palliative for extensive stage

Lung Cancer Treatment - Surgery Non-Small Cell Lung Cancer Improvements in pre- operative staging with PET-CT Specialist lung cancer surgeons Video-assisted thoracic surgery (VATS) lobectomy Adjuvant chemotherapy Small Cell Lung Cancer Not routinely practised

PET-CT Tumour – Benign / Malignant Lymph nodes – Sensitive Metastases

Faster recovery Reduced post-operative pain VATS Lobectomy

Lung Cancer Treatment – Adjuvant Chemotherapy Non-Small Cell Lung Cancer Surgically resected Post-operative chemotherapy Treat occult micrometastatic disease to prevent future cancer recurrence Stage Median Overall Survival (months) IA – IB48 – 59 IIA – IIB24 – 30 IIIA -IIIB SEER database validation series of over 31,000 cases

Adjuvant Chemotherapy IALT –4.3% Disease-free survival benefit at 5 years ANITA –Stage II: Overall survival benefit at 5 years improved from 39% to 52% –Stage III: Overall survival benefit at 5 years improved from 26% to 42%

Lung Cancer Treatment - Radiotherapy Non-Small Cell Lung Cancer Concurrent chemoradiotherapy Stereotactic body radiotherapy Small Cell Lung Cancer Prophylactic cranial irradiation Concurrent chemoradiotherapy

Concurrent Chemoradiotherapy Stage III non-small cell lung cancer –Improves median overall survival by 3-4 months (to 17 months) –Improves 5 year survival rate from 9 to 16% Limited stage small cell lung cancer –Improves 5 year survival rate from 18 to 24% But more side-effects –Myelosuppression, oesophagitis, pneumonitis RTOG 9410, JCOG 9104

Prophylactic cranial irradiation Treatment of the brain with radiotherapy to prevent recurrent cancer Limited stage –Halves (54% reduction) the risk of subsequent brain metastases –Improves 3 year survival rate from 15 to 21% Extensive stage –Risk of subsequent brain metastases at 1 year reduced from 40 to 15% –Improves 1 year survival rate from 13 to 27% Acute toxicities of fatigue, hair loss, headaches and nausea Possible long-term risk of neurotoxicity

Stereotactic Body Radiotherapy Standard radiotherapy – 6 weeks 5 year survival rates 10 – 30% SBRT – 1 to 5 days Local control rates 90% 3 year survival rates 56 – 60% RTOG 0236

Lung Cancer Treatment - Chemotherapy Small Cell Lung Cancer Cisplatin/Carboplatin & Etoposide Response rates 60-90% Median duration of response 6-8 months OakleyOriginals

Lung Cancer Treatment - Chemotherapy Non-small Cell Lung Cancer Doublet: –Cisplatin / Carboplatin –Etoposide / Vinorelbine / Paclitaxel / Docetaxel / Gemcitabine / Pemetrexed Improves 1 year survival from 20 to 29% Improves quality of life

Have there been any meaningful Advances in the Treatment of Lung Cancer?

Targeted Therapies Hanahan & Weinberg. Cell (2000)

Imatinib Demetri N Engl J Med (2002)

Gefitinib 2002 – Dramatic responses (Female, East Asian, never smokers with adenocarcinoma) 2004 – EGFR activating mutations predict for response 2005 – ISEL trial – no benefit on unselected patients – license withdrawn … – IPASS trial

IPASS EGFR mutation positive patients –Response rate with Gefitinib 71.2% –Response rate with CbPac 47.3% –Progression free survival HR 0.48 (0.36 – 0.64) –Median overall survival >18 months (all patients) Driver mutations or ‘Oncogene addiction’

Other Targets GeneFrequency in NSCLC EGFR10-35% KRAS15-25% FGFR120% PTEN4-8% ALK3-7% HER22-4% MET2-4% DDR2~4% BRAF1-3% PIK3CA1-3% AKT11% MEK11% NRAS1% RET1% ROS11%

Shaw N Engl J Med (2011) Crizotinib ALK inhibitor After 12 weeks of treatment

Other Targets & Drug Therapies GeneFrequency in NSCLCDrug EGFR10-35%Gefitinib, Erlotinib KRAS15-25% FGFR120% PTEN4-8% ALK3-7%Crizotinib HER22-4%Afatinib MET2-4%Crizotinib DDR2~4%Dasatininb BRAF1-3%Vemurafenib PIK3CA1-3% AKT11% MEK11% NRAS1% RET1%Sorafenib? ROS11%Crizotinib

Smoking 87% (men) & 84% (women) of lung cancers attributable to smoking 19.4% of all new cancer cases attributable to smoking

Smoking Cessation Parkin Br J Cancer 105 S6-13 (2011)

Summary Despite advances in the treatment of lung cancer with modern surgical and radiotherapy techniques and novel targeted therapies: Lung cancer survival rates are abysmal especially when compared with breast and bowel cancer

Summary Smoking cessation will prevent future cancers and smoking rates are falling Personalised therapy for lung cancer is coming

Summary Four more people will have died from lung cancer in the past hour

Thank you for listening