Docstoc

Advances in Lung Cancer

Document Sample
Advances in Lung Cancer Powered By Docstoc
					Advances in Lung Cancer
Frances Matthews M.D.

• Imaging studies in lung cancer • Expanded role for chemotherapy in Non
Small Cell lung Cancer • Genomics in Lung Cancer • Targeted Therapy • Small Cell Lung Cancer • Screening

Pathology
• Non Small Cell --- 80 %
Adenocarcinoma Squamous cell Large cell

• Small Cell---20 %

Nonsmall cell lung cancer
• Stage I and II • Stage IIIA • Stage IIIB • Stage IV : • Surgery • Chemoradiation +/surgery • Chemoradiation • Chemotherapy

Chemotherapy

PET Scan
• Positron Emission Tomography • 18F- Fluorodeoxyglucose • Molecular imaging • Uptake in malignancy , inflammation,

infection, benign granulomatous disease

Pet Scans
• Pre operatively to evaluate Mediastinum
Sensitivity of 84% Specificity of 89% Negative predictive value 87% Positive predictive value 56%

• Discover metastatic disease
15-20% upstaged

• Evaluate Solitary Lung Nodule

sensitivity 88% • Restaging after chemoradiation

Stage I and II NSCLC
• 30 % of Non- Small cell Lung Cancer
Patients Present with Stage I or II Disease • Primary Treatment is Surgery • 5 year survival IA 67% IB 57% IIA 55% IIB 38%

:

Adjuvant Chemotherapy
• Meta-analysis 1995 of adjuvant
chemotherapy trials from 1965 to 1991 • Trend in favor of chemotherapy, didn’t reach statistical significance ( P = .08 ) • Surgery alone remained standard of care

Recent Adjuvant Trials
• IALT • CALGB 9633 • NCIC CTC JBR.10 • ANITA

International Adjuvant Lung Cancer
• Adjuvant chemotherapy for completely
resected stage I, II , IIIA NSCLC • 1867 patients • Cisplatin based chemo vs. observation • Radiation therapy optional

• Overall survival at 5 years : 44.5% vs.
40.4% ( P < .03 )

• Disease Free survival at 5 years : 39.4%
vs. 34.3% ( P < .003 )

• International Lung Cancer Adjuvant Trial

was the first prospective trial to show a survival advantage for adjuvant chemotherapy • Worldwide 180,000 cases of lung cancer eligible . Adjuvant chemo would save 7000 lives annually.

• NCIC-JRB.10 : 4 cycles cisplatin plus
navelbine -- OS advantage for chemotherapy 14% at 5 years

• ANITA : 4 cycles cisplatin and navelbine—
8.6% at 5 years

Stage IB
• ANITA and JRB-10 failed to demonstrate
survival advantage in Stage IB • CALGB 9633—Taxol/Carbo in stage IB • 384 patients • Improved DFS (P =.027) • Improved 3 year survival (P=.045) • Trend to improvement in 5 year survival but not reaching statistical significance.

NCCN guidelines
• Adjuvant chemotherapy for resected stage
IB to IIIA • IA consider adjuvant chemo if high risk features : poorly differentiated tumor, vascular invasion, wedge resection, close margins.

• Adjuvant Chemo benefit of 4% absolute
improvement in survival translates into treating 25 patients to prevent one additional death at 5 years.

Genomics
• Functional Genomics : Analysis of gene
expression at a genomic scale in which the levels of expression of thousands of genes are examined at the same time.

Genomics in Lung Cancer
• Lung Metagene Model • NEJM August 10, 2006 Nevins, et.al. • Samples from 89 patients with early stage

NSCLC • Identify multiple gene expression profiles that predict recurrence • Metagene : ―Dominant average pattern of expression of the gene cluster across the tumor samples‖

Lung Metagene Model
• Two Validation Groups : ACOSOG Z0030
25 patients and CALGB 9761 91 patients • Overall predictive accuracy for recurrence of 72 and 79 percent

Lung Metagene Model vs. Clinical Profile
• Clinical profile: age, sex, tumor size, stage,
smoking history, histology • ―C Statistic‖ capacity of clinical or genomic information to identify patients according to risk of recurrence • Clinical ―C statistic‖ of .67 improved to .84 in ACOSOG with addition of genomic information • .73 improved to .87 in CALGB group

Stage IA
• 68 with stage IA • Survival 70% at 4 years • Group identified by Metagene model as

―High Risk‖ had survival rate less than 10% • Implications for adjuvant chemotherapy

CALGB 30506 NSCLCA Stage 1
Metagene Analysis High Risk Metagene Analysis Low Risk

• Randomized to adjuvant
chemotherapy or observation

• Observation

Predicting Response to Chemotherapy
• Excision Repair Cross Complementation
Group 1 Protein • 761 tumor specimens from IALT • Benefit from cisplatin chemo associated with absence of ERCC1 • P = .009 • In no chemo group ERCC1 positive tumors had better survival • P = .009

Targeted Therapy
• Monoclonal Antibodies against VEGF :
Bevacizumab

• Tyrosine Kinase Inhibitors of VEGF
Production • Erlotinib Gefitinib

Angiogenesis
• New Blood Vessel Formation • Physiologic in embryonic development,

wound healing, ovulation • Multiple endogenous stimulators and inhibitors of angiogenesis • Vascular Endothelial Growth Factor prominent role in stimulating angiogenesis

Angiogenesis in Malignancy
• Pathologic • Essential for tumor growth more than a

few millimeters in size • Essential for tumor metastases • VEGF prominent role • Targeting VEGF proved useful in treating malignancy

Vascular Endothelial Growth Factor
• Glycoprotein, several isoforms • Mitogen for endothelial cells • Role in physiologic and pathologic

angiogenesis • 77% of NSCLCA tissues express VEGF • VEGF expression correlates with poor prognosis in NSCLCA

• Antibodies Against VEGF • Inhibitors of production of VEGF • VEGF trap

Bevacizumab
• Monoclonal Antibody • Humanized • Binds to and clears VEGF-A • Approved for metastatic colon cancer in
2004 • Activity in a variety of solid tumors

Bevacizumab in NSCLC
• Phase II study carboplatin/taxol +/-

bevacizumab • 99 patients, advanced or recurrent NSCLC • 3 arms: 15/kg bevacizumab plus carbo/taxol 7.5/kg bevacizumab plus carbo/taxol Carbo/taxol alone • Control arm had option of bevacizumab 15mg/kg every three weeks on disease progression

• Carbo/taxol + Bevacizumab

15mg/kg vs. control • Response rate 31.5 % vs. 18.8% • TTP: 7.4 vs. 4.2 months (P = .023) • Survival: 17.7 vs. 14.9 months (P = .63)

E4599
• Phase II/III in advanced untreated NSCLC
(non-squamous) • Taxol/Carbo +/- Bevacizumab • Median survival 10.2 vs. 12.5 months (P=.0075) • First trial to show survival advantage of a targeted biologic therapy in combination with chemotherapy in NSCLCA

Toxicities of Bevacizumab
• • • • •
Mucocutaneous bleeding Hypertension Increase arterial thrombotic events Nephrotic syndrome Hemoptysis –Life threatening in 6 patients (of 99). Fatal in 4 of 6. • Risk factors: Central tumors close to major blood vessels, Squamous cell cancers, Tumor necrosis • Wound dehiscence

• Bevacizumab not indicated if:

Squamous Cell Cancers Brain Metastases Hemoptysis Uncontrolled Hypertension Bleeding or Thrombotic disorders Poor performance status

Ongoing Trials
• Bevacizumab in combination with Erlotinib • Bevacizumab in combination with other
chemotherapy drugs • Bevacizumab as a component of adjuvant or neoadjuvant therapy • Bevacizumab in squamous cell malignancies and in brain metastases

Tyrosine Kinase Inhibitors
• Erlotinib • Gefitinib • ZD6474 • Sunitinib • Sorafenib

Epidermal Growth Factor Receptor
• EGFR has an essential role in tumor
progression • Tyrosine Kinase inhibitors block intracellular phosphorylation of EGFR • Epidermal Growth Factor Receptor signaling impaired • Inhibits production of VEGF

Gefitinib
• Small Molecule Tyrosine Kinase inhibitor • Iressa Survival Evaluation in advanced lung

cancer • Gefitinib vs. placebo • Conditional approval in 2003 on the basis of 10% response rate in clinical study • Use restricted to responders after ISEL study showed no survival advantage.

Erlotinib
• NCI CTC BR.21 • 731 Patients • NSCLCA with disease progression after • • • •

chemotherapy Erlotinib 150mg./day PO vs. Placebo Median survival 6.7 vs. 4.7 months (p<.001) One year survival 29.7% vs. 20.5% Quality of life improvement

Erlotinib
• FDA indication for locally advanced or
metastatic NSCLC after failure of one or more chemotherapy regimens

Predictive Markers for Response
• Never Smokers • Asian • Women • Adenocarcinoma • Bronchoalveolar histology

Biomarkers
• EGFR overexpression • EGFR gene amplification • EGFR Mutations

EGFR Mutations
• 12 to 13% of non squamous lung cancers • Exon 19 • Exon 21 • More common in never smokers , women,
Asians

Ideal Trial of Gefitinib
• Phase II of gefitinib • EGFR mutations correlated with clinical
features of response • Responses in 46% with EGFR mutation • 29% with gene amplification • 9% with neither

Erlotinib in EGFR Mutation Positive NSCLCA
• • • • • • • • •
Phase II, advanced stage, no prior chemo 1047 screened 43 with exon 19 or 21 EGFR mutations Erlotinib 150 mg/day 70% never smokers Exon 19: 20% CR , 75% PR Exon 21: 5.5% CR, 61% PR TTP 13.3 months 1 Year OS 82%

First-Line Erlotinib
• Phase II study, 50 patients • Women, nonsmoking, adenocarcinoma • Advanced stage disease • No previous chemotherapy • 1 and 2 year overall survival 68% and
38%

Erlotinib toxicities
• Rash • Dry Skin • Conjunctivitis/Keratitis • Diarrhea

Multi – Targeted Therapy
• Neoplasia is an extremely complex process • Blocking a single pathway or target has
shown limited efficacy • Trials of multi - targeted approach

Erlotinib + Chemotherapy
• No improvement in response, time to
progression or survival with addition of erlotinib to standard chemotherapy in phase III trials

Investigational Tyrosine Kinase Inhibitors in Lung Cancer
• ZD 6474 (vandetanib) inhibits EGFR and
VEGFR-2 receptor tyrosine kinase inhibitor • Phase II studies of advanced NSCLC after platinum based chemo • Improved PFS compared to gefitinib • ZD6474 + docetaxel improved PFS compared to docetaxel alone

Sunitinib/Sorafenib
• • • • • •
Multi-targeted tyrosine kinase inhibitors Oral Agents Phase II trials in pre-treated NSCLC RR 9.5% with sunitinib Stable disease of 43 % and 59% Toxicity greater with sunitinib (38% discontinued)

Fig 5. Key signaling pathways involved in tumor growth and progression. bFGF, basic fibroblast growth factor; VEGF, vascular endothelial growth factor; TGF{alpha}, transforming growth factor alpha

Herbst, R. S. et al. J Clin Oncol; 23:3243-3256 2005

Copyright © American Society of Clinical Oncology

Bevacizumab plus Erlotinib
• Phase III study

Small Cell Lung Cancer
• 15% of lung cancers • Faster growing • Metastasize early • Sensitive to chemotherapy and radiation • Relapse is common • Lower cure rate than NSCLCA

Small Cell Lung Cancer
Limited Stage • Confined to the chest within a single radiation portal • 33% • Combined chemoradiation • Prophylactic brain radiation • 3 year survival 15 – 20% Extensive Stage • Not confined to a single radiation portal • 67% • Chemotherapy • Palliative radiation • Median survival 8 to 10 months

• 286 patients with extensive stage small

cell lung cancer • Response to chemotherapy • Randomized to prophylactic cranial radiation or observation • Symptomatic brain metastases in 16.8% vs. 41.3% in favor of radiated group • One year survival 27.1% vs. 13.3%

Cancer Screening
• Disease with substantial morbidity and
mortality • High prevalence in detectable preclinical state • Possibility of improved treatment with early detection • Availability of low cost screening test with low inconvenience, high sensitivity and specificity

Lung Cancer Screening
• Chest xray and sputum cytology useful in

finding early stage lung cancer but in randomized trials not effective in reducing lung cancer mortality.

Early Lung Cancer Action Project
• 1990’s • High risk persons age 60 or older • Cat Scan detection rate for solitary non calcified

nodules 23% vs. 7% by chest xray • Malignant disease in 2.7% by cat scan and 0.7% by chest xray • Chest CT improved ability to detect early lung cancer

International Early lung Cancer Action Program
• • • • • • • •
NEJM October 26, 2006 31,567 screened with low dose cat scan 484 diagnosed with lung cancer 412 were stage I 88% 10 year survival If surgery was within a month—92% 10 year survival 8 participants who did not have surgery dies in 5 years Conclusion : Cat scan can detect curable lung cancer

Cost Effective?
• Cost of cat scan $200 • Incidence of finding cancer 1.3% on

baseline catscan and 0.3% on annual screening

• Does lung cancer screening with cat scan
reduce mortality from lung cancer?

National Lung Cancer Screening Trial
• 50,000 enrolled • Ages 55-74 • 30 pack year smoking • Low dose spiral CT vs. Digital CXR • Baseline, 2 annual studies • Designed to detect 20% difference in lung
cancer mortality • Data collection until 2009

Smoking Cessation
• 85% of lung cancer related to smoking • Risk increases 20-30% by living with a
smoker • Nicotine replacement • Bupropion • Counseling • Varenicline

Summary
• Expanded Role for Adjuvant
Chemotherapy in resected lung cancer • Targeted therapy Monoclonal antibodies (bevacizumab) Tyrosine kinase inhibitors (erlotinib) • Genomics role in prognosis • Predicting response to treatment • Screening for early stage disease


				
DOCUMENT INFO
Shared By:
Categories:
Stats:
views:336
posted:4/19/2008
language:English
pages:68