advance non-small cell lung cancer final
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Non-Small Cell Lung Cancer: Topic Review & Case Presentation
Tauhid Ahmed Bhuiyan, PharmDPharmacy Practice Resident (R2)King Faisal Specialist Hospital & Research Center (KFSH&RC)Advanced Non-Small Cell Lung Cancer:An Evidenced-Based Review of Targeted Therapies With Case Presentation King Faisal Specialist Hospital and Research Center (KFSHRC) is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. (UAN# 0833-0000-15-039-L01-P, 0833-0000-15-039-L01-T)
ObjectivesTo discuss general overview of lung cancer
To recognize available molecular targets of Non-Small Cell Lung Cancer (NSCLC) and their implications in therapy
To identify diagnostic measures for diagnosing NSCLC
To evaluate available targeted therapies for management of NSCLCI do not have financial relationship and no actual or potential conflict of interest in relation to this activity
TerminologyOnco-gene:A gene that is a mutated (changed) form of a gene involved in normal cell growth
Tumor suppressor gene:A type of gene that makes a protein called a tumor suppressor protein that helps control cell growth. Also called anti-oncogene
Disease free survival: The length of time after primary treatment for a cancer ends that the patient survives without any signs or symptoms of that cancer. Also called DFS, relapse-free survival, and RFS.
Progression free survival: The length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse. Also called PFS.
NCI Dictionaries. National Cancer Institute. Accessed from: http://www.cancer.gov/publications/dictionaries
Lung Cancer Second leading cause of cancer related deaths in both sex
Majority of the new cases occur in the developing countries (55%)
Projection disease burden for 2015, 221, 200 new cases158,040 deaths
Incidence increases with age, 2/3 cases diagnosed in age between 60-79 years
Despite medical advancement, the 5-year survival rate is about 16.8%DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015
Estimated Age-Standardized Rates (World) per 100,000
WHO: International Agency for Research on Cancer. Accessed: June 26, 2015. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx
Epidemiology in Saudi Arabia Based on Saudi Cancer Registry (SCR) [1994-2008]:
Khalid Al-Ahmadi & Ali Al-Zahrani. Int. J. Environ. Res. Public Health 2013. 10:7207-7228
Epidemiology in Saudi Arabia Age specific incidence rate: 25 per 100 000 population
Maghfoor. I et al. Ann Saudi Med 2005; 25(1): 1-12
Classification(Histologically) Lung CancerSmall CellNon-Small CellCombinedTypical CarcinoidAtypical CarcinoidAdenocarcinoma Squamous cell carcinomaLarge Cell carcinoma80-87%37-47%25-32%10-18%DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014
Etiology/PathogenesisAlteration of normal bronchial epithelial cellsMultiple genetic lesions
Activation of proto-oncogene
Inhibition or mutation of tumor suppressor gene
Production of autocrine growth factors contribute to cellular proliferation and malignant transformation
DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014
Risk Factors
Tobacco smoking ( 80% of all lung cancer caused by cigarette smoking)
Family history (first degree relatives with cancer)
Respiratory history (asthma, COPD)
Environmental exposure to carcinogens (e.g. asbestos, benzene, arsenic, etc.)
DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014
Smoking & Lung Cancer RisksFrom UK data, mortality risk of active smoking:Male smoker: 22-fold Female smoker: 12-fold
Passive smoking increases mortality risks for non-smokers by 1.5-foldSpouses of smokers found to have higher risk (~25%) of lung cancer than spouses of non-smokers
Smoking cessation: Measurable difference at 5 years80-90% reduction after 15 yearsCutting the number smoked per day by half of heavy smokers ( 15 cigarettes per day) mortality decreases by 25%Peto R et al. BMJ 2000; 321:323-9Godtfredsen NS. et al. JAMA 2005; 294:1505-10
NSCLCSlow growing than small cell better prognosis
Adenocarcinoma: most common type in non-smokers
Squamous cell carcinoma: common in smokers
Mutations in KRAS, EGFR & EML4-ALK more targeted therapies EGFR: Epidermal Growth Factor ReceptorEML4-ALK: Echinoderm Microtubule-associated protein-Like 4-Anaplastic Lymphoma kinase
KRASMost common mutation: ~25% of all adenocarcinoma
Exclusive to smoker
Mutation has lack of therapeutic efficacy shorter survival
No targeted therapy established so far
Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015https://sangakukan.jp/journal/journal_contents/2013/01/articles/1301-02-1/1301-02-1_earticle.html
EGFRMutation cause receptor deregulation or over expression
Overall frequencies in NSCLC = 10-15%
Most common forms: Deletions in exon 19 and exon 21 [sensitizing EGFR mutation]
Sensitive to small molecule tyrosine kinase inhibitor (TKI) (Erlotinib, Gefitinib)
Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015Brambilla E. et al. Eur Respir J. 2009; 33(6): 14851497 Erlotinib
EML4-ALKEstimates 2-7% of patients with NSCLC and common in young men (median: 52 years)
Due to inversion in chromosome 2 that links EML4 to ALK cancer cell proliferation
Does not occur concurrently with EGFR or KRAS
Sensitive to TKI, Crizotinib
Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015https://sangakukan.jp/journal/journal_contents/2013/01/articles/1301-02-1/1301-02-1_earticle.html
Prevention & Screening Prevention:No known effective method of chemoprevention at this timeNo survival benefit or reproducible results of agents like -carotene, retinoic acid, selenium, -tocopherol, etc.
Early lung cancer screening studies failed to demonstrate a survival advantage
Screening:In 2010, National Lung Cancer Screening Trial (NLST) [RCT, N= 53,000]:Comparison: CXR vs. Low dose CT (LDCT)Results: 20% relative risk reduction of death from lung cancer using LDCT
Current recommendation (agreement between all the guideline bodies): Annual screening with LDCT for selected (55-80 years) high risk current (30 PPY) or former (quit within 15 years) smokers DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015
Clinical PresentationsIn general, location and extent of the tumor determine the presenting signs and symptoms
Common initial signs and symptoms:Cough with or without hemoptysis, dyspnea, and chest pain or discomfort
Systemic symptoms of malignancy:Anorexia, weight loss, and fatigue
Extra-pulmonary signs and symptoms:Neurologic deficits, bone pain or pathological fracture, abnormal liver function, etc.
Paraneoplastic syndromesMay involve any systems, e.g. endocirne, neuromuscular or muscoskeletal, cardiovascular, GI, or renal
DiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014A group of symptoms that may develop when substances released by some cancer cells disrupt the normal function of surrounding cells and tissue
Diagnosis
Diagnosis Thorough history and physical examination Detecting signs and symptoms of primary tumor, regional spread of the tumor, distant metastases, and paraneoplastic syndrome
Laboratory tests: CBC, serum electrolytes, LFTs, renal and bone profile
Tissue sampling: Sputum cytology, bronchoscopy, transthoracic needle biopsy, thoracentesis (depends on location of tumor)Molecular studies and biomarker analysis: Cobas EGFR Mutation Test Fluorescence in situ hybridization (FISH) test: Alk mutation
Other diagnostic tests:Chest radiograph, endobronchial ultrasound, CT scans, and PET scansDiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015
PET: A positron emission tomography (PET)scanis a type of imaging test. It uses a radioactive substance called a tracer to look for disease in the body. APET scanshows how organs and tissues are working19
TNM Staging Estimate prognosis and guidance of therapy Staging system established by American Joint Committee on Cancer (AJCC)
TNMSize of the tumorExtent of Nodal Involvement Presence of metastatic sitesDiPiro J. Lung Cancer. In: Pharmacotherapy: A Pathophysiological Approach, 2014
Quick Reference Guide
Lababede O. et al. CHEST 1999; 115:233235
Management
Goals of Therapy Limited Stage (I & II)Complete remission
Advanced Stage (III & IV)Prolong progression free survivalImprove quality of life Minimizing side effects due to the treatment
Treatment Approaches Resectable (Stage I, II, IIIA)
Surgery: treatment of choice
Radiation therapy: when medically inoperable
Chemotherapy: adjuvant Cisplatin-based regimen in resected Stage II and IIIAVinorelbine/cisplatin (VC) most data on survival benefit Non-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015
Treatment Approaches (Unresectable/Advanced Stages) Reports by Non-Small Cell Lung Cancer Collaboration Group on 52 pivotal studies of patients with advance stage showed that:Chemotherapy surgery/radiotherapy improves median survival by 2-4 months 1-year absolute survival rate improved by 10%
Treatment depends on patient-specific factors such as age, performance status, and co-morbid conditionsNon-Small Cell Lung Cancer, NCCN Guidelines Version 7. 2015
Eastern Cooperative Oncology Group (ECOG) Performance Score
Status 0-2: consistent predictor of better response and improved survival following chemotherapy Status 2 + comorbidities: require less intensive therapy Status 3: do not respond to chemotherapy http://www.cancernews.com/data/Article/273.asp
Targeted Therapies Newer type of cancer treatment that uses drugs or other substances to more precisely identify and attack cancer cells, while doing little damage to normal cellsAmerican Cancer Society
FDA approved specific targeted therapies Erlotinib: EGFR positive mutation Crizotinib: EML4-ALK positive mutation Bevacizumab*: if neither positive
*In combination with chemotherapy: carboplatin + paclitaxel
Erlotinib (Tarceva)Small molecule TKI used as:First-line: patient with EGFR mutationSecond line: locally advanced/metastatic NSCLC after progression on at least one prior chemotherapy
Dose: 150 mg by mouth daily until disease progression or unacceptable toxicity
Drug-drug interaction: strong CYP3A4 (inducers/inhibitors); proton pump inhibitors
Side effects: Dermatologic: skin rash (49% to 85%; grade 3: 5% to 13%; grade 4:
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