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

Advances in the Treatment of Lung Cancer

Sin Chong Lau

Consultant in Medical Oncology

41 428 new cases13% of all new cancers

UK Cancer Incidence 2009, Cancer Research UK

41 428 new cases13% of all new cancers

UK Cancer Mortality 2010, Cancer Research UK

114 new cases / day

34 859 deaths22% of cancer deaths

6% of all deaths

UK Cancer Incidence 2009, Cancer Research UK

34 859 deaths22% of cancer deaths

6% of all deaths

UK Cancer Mortality 2010, Cancer Research UK

4 deaths / hour

Survival

• Men• 1 year 29.4%• 5 years 7.8%• 10 years 4.9%

• Women• 1 year 33.0%• 5 years 9.3%• 10 years 5.9%

England 2005-09, England & Wales 2007 Survival Rates, Cancer Research UK

Survival

• Men• 1 year 29.4%• 5 years 7.8%• 10 years 4.9%

• Women• 1 year 33.0%• 5 years 9.3%• 10 years 5.9%

England 2005-09, England & Wales 2007 Survival Rates, Cancer Research UK

2nd lowest of the 21 most common cancers

5 year survival rateBreast cancer 85%Colorectal cancer 55%

Progress - 5 Year Survival Rates

0102030405060708090

100

1971-75

1976-80

1981-85

1986-90

1991-95

1996-00

2001-05

2006-09

Progress - 5 Year Survival Rates

0102030405060708090

100

1971-75

1976-80

1981-85

1986-90

1991-95

1996-00

2001-05

2006-09

5 Year Survival Rates – By Stage

• Non-Small Cell Lung Cancer

• IA 58-73%• IB 43-58%• IIA 36-46%• IIB 25-36%• IIIA 19-24%• IIIB 7-9%• IV 2-13%

• Small Cell Lung Cancer

• Limited18-38%• Extensive 1%

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

ClinicalOncologist

Surgeon

MedicalOncologist

Patient

NONSENSE

LungCancerCNS

GP

Pathology

ClinicalPsychology

PalliativeCare

RespiratoryPhysician

Radiologist

SurgicalWard

MedicalWard

A&E

Chemo-therapyUnit

Radio-therapyUnit

CommunityNurse

Admin/Clerical

ClinicalOncologist

Surgeon

MedicalOncologist

Patient

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

StageMedian Overall Survival (months)

IA – IB 48 – 59

IIA – IIB 24 – 30

IIIA -IIIB 9 - 14

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%

www.adjuvantonline.com

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 100 57-70 (2000)

Imatinib

Demetri N Engl J Med 347 472-80 (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

• …..• 2009 – 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

Gene Frequency in NSCLC

EGFR 10-35%

KRAS 15-25%

FGFR1 20%

PTEN 4-8%

ALK 3-7%

HER2 2-4%

MET 2-4%

DDR2 ~4%

BRAF 1-3%

PIK3CA 1-3%

AKT1 1%

MEK1 1%

NRAS 1%

RET 1%

ROS1 1%

Shaw N Engl J Med 365 158-67 (2011)

Crizotinib

ALK inhibitor

After 12 weeks of treatment

Other Targets&DrugTherapies

Gene Frequency in NSCLC Drug

EGFR 10-35% Gefitinib, Erlotinib

KRAS 15-25%

FGFR1 20%

PTEN 4-8%

ALK 3-7% Crizotinib

HER2 2-4% Afatinib

MET 2-4% Crizotinib

DDR2 ~4% Dasatininb

BRAF 1-3% Vemurafenib

PIK3CA 1-3%

AKT1 1%

MEK1 1%

NRAS 1%

RET 1% Sorafenib?

ROS1 1% Crizotinib

Smoking

• 87% (men) & 84% (women) of lung cancers attributable to smoking

• 19.4% of all new cancer cases attributable to smoking

Smoking Cessation

Cumulative risk (%) of death from lung cancer by age 75

0

5

10

15

20

45 50 55 60 65 70 75

Current smoker

Stopped smoking at 60

Stopped smoking at 50

Stopped smoking at 40

Stopped smoking at 30

Lifelong non-smoker

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