chemotherapy for lung cancer by 001.pptx

Principles of chemotherapeutics and chemotherapy regiments for lung cancer.

1. CHEMOTHERAPY FOR LUNG CANCER GBADAMOSI S.O

2. OUTLINE Introduction Epidemiology Classification Aetiology Pathogenesis Pathologic Types Clinical Features Investigations Treatment Prognosis Complications Prevention Summary

3. Lung cancer is the uncontrolled growth of abnormal cells in one or both lungs These abnormal cells do not carry out the functions of normal cells and do not develop into healthy lung tissue. Chemotherapy is the use of drugs or chemicals to treat cancers. Introduction

4. Introduction Despite advances in surgical techniques and combined therapies, lung cancer remains a disease with a dismal prognosis. Although 1-year survival has improved over the past few decades, overall 5-year survival has remained relatively unchanged at 12% to 16% over the past 30 years.

5. Epidemiology Lung cancer is predominantly a disease of older people. About 2 out of 3 people diagnosed with lung cancer are 65 or older, while less than 2% are younger than 45. The average age at the time of diagnosis is about 70. The male to female lung cancer incidence ratio is approximately 1.5 to 1.

6. 6 Lung cancer ( Aetiology ) Tobacco Smoke Exposure Active Cigarette Cigar Passive Occupational and Environmental Exposures Arsenic, Asbestos, Beryllium, Chromium, Nickel Polycyclic aromatic hydrocarbons Bis(chloromethyl)ether, Cadmium Vinyl chloride

7. 7 Aetiology Genetic Predisposition Gender Ionizing radiation (e.g. radon gas) Diffuse lung fibrosis (e.g. fibrosing alveolitis ) Chronic Obstructive Pulmonary Disease, PTB Dietary Factors

8. Pathogenesis Cancer is a disease involving dynamic changes in the genome. All cancer cells acquire six hallmark capabilities: self-sufficiency in growth signals, insensitivity to antigrowth signals, evading apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis . Events leading to acquisition of these hallmarks can vary widely; although broadly, cancers arise as a result of accumulations of gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes

9. Pathogenesis Oncogenes are abnormal genes that encode proteins. Are known to participate in the regulation of cellular proliferation Non activated oncogenes that are functioning normally are called proto-oncogenes Tumour suppressor genes restrict undue proliferation of cells; and induce the repair of self destruction.

10. Pathogenesis Carcinogens like those found in cigarettes smoke promote mutation or transformation of proto-oncogenes to oncogenes tilting the balance between oncogenesis and tumour suppression in favour of tumour growth. 10-30% lung adenocarcinomas arise via this process from mutations in the ras (H-ras, N-ras, K-ras) proto-oncogen. Other molecular abnormalities found in NSCLC include mutations in the oncogenes c-myc and c-raf and in the tumour suppressor genes - retinoblastoma ( Rb ) and p53 genes

11. Pathogenesis The inactivation of p53 tumour suppressor gene located on the short arm of chromosome 17p creates a situation of uncontrolled cell growth. This is seen in 60-75% of SCLC (common in most epithelial tumours) Chromosomal damage can lead to loss of heterozygosity leading to inactivation of tumor suppressor genes Damage to chromosomes 3p, 5q, 13q, and 17p is commonly found in SCLC

12. Pathogenesis Epidermal growth factor receptor(EGFR) protein regulates cell proliferation, apoptosis and angiogenesis Mutations and amplification involving EGFR - common in NSCLC, allow enhanced tumour cell growth

13. Genetic alterations in lung cancer

14. Molecular mechanisms of pathogenesis of lung cancers

15. List of some genes somatically altered in different histologic subtypes of lung cancer

16. Pathology Malignant lung cancers are divided into 2 main categories: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) Upon diagnosis, 80% of all lung cancers are NSCLC with adenocarcinoma overwhelmingly accounts for 40% of all cases of lung cancer Squamous cell carcinoma, SCLC - found in the central parts of the lung, whereas adenocarcinoma tumours are peripheral in origin 16

17. Lung cancer presents clinically at an advanced stage with over 70% of patients having inoperable disease at diagnosis About 5-10% of newly diagnosed lung cancers present with asymptomatic lesions on CXR or chest CT 90% of patients are symptomatic at diagnosis and many report having new symptoms up to a year prior to presentation. Clinical Features

18. Clinical Features Lung cancers manifest with symptoms produced by : Local tumour effect Locoregional spread Metastatic spread Paraneoplastic syndromes 06/08/2010 18

19. Clinical Features Local primary tumour effect: Cough (up to 75% of cases) Bronchial mucosa ulceration Interruption of bronchial peristalsis Post obstructive pneumonia Dyspnoea (up to 60% of cases) Central airway obstruction leading to atelectasis and persistent infections Pleural effusions Pulmonary embolism; SVCO Lymphangitis carcinomatosis 19

20. Local tumour effects: Chest pain (20-50%) Invasion of chest wall structures Haemoptysis (5-25%) Usually low volume blood streaking of sputum However can be massive in erosion of bronchial or pulmonary vessels Wheezing American Thoracic Society, European Respiratory Society. Pretreatment evaluation of non-small-cell lung cancer. Am J Respir Crit Care Med. 1997;156:320–332. Clinical Features

21. Features due to loco-regional spread Superior vena cava syndrome (obstruction of SVC) Stridor ( upper airway obstruction ) Hoarseness ( left vocal cord paralysis due to recurrent laryngeal nerve impingement ) Chylothorax (thoracic duct) Palpitations (pericardial effusion) Dysphagia ( enlargement of the subcarinal lymph nodes can cause dysphagia by compressing the middle third of the oesophagus ) 21

22. Pancoast tumour: Arise posteriorly in the apex of the upper lobe NSCLC is the commonest cause Infiltration of C8, T1 and T2 nerve roots cause gnawing pain over the shoulder, medial border of the scapula, progressing down the medial aspect of the arm to the little and ring fingers Hand muscle atrophy Horner syndrome Bone destruction

23. Features suggesting need to evaluate for metastatic disease Spiro SG, Gould MK, Colice GL. Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic syndromes. Chest . 2007;132(3 Suppl ):149S–160S

24. Paraneoplastic manifestations

25. 25 Investigations Imaging Modalities Plain chest radiograph Chest CT scan Chest MRI PET Scan Establishing Tissue Diagnosis Flexible fibreoptic bronchoscopy Percutaneous needle biopsy Sputum cytology Pleural fluid cytology Pleural biopsy Mediastinoscopy VATS

26. Investigations Others Tumour markers ( carcinoembryonic antigen(CEA), neuron specific enolase (NSE), retinol binding protein, cytokeratin 19 fragments) FBC, EUCR, Serum Uric acid, LFT Brain CT/MRI; Abdominal CT; Spinal Xray /MRI

27. Plain Chest radiograph Chest radiographs may show the following: Pulmonary nodule, mass, or infiltrate. Mediastinal widening Atelectasis Hilar enlargement Pleural effusion

28. Chest CT Improved modality over CXR CT is most useful in delineating the key features of the primary tumour (size, presence of satellite nodules, associated atelectasis and infection, and invasion of adjacent structures); these features are essential in establishing the clinical T stage. It also demonstrates regional lymph nodes and delineates pleural involvement

29. Chest MRI Chest MRI scanning is often the test of choice for focused examination for extent of chest wall invasion, diaphragmatic involvement, superior sulcus tumours, brachial plexus invasion, or invasion of the spine .

30. PET Scan PET scanning using radiolabelled fluoro-18–2-deoxyglucose (FDG) has proven to be an excellent modality for evaluating solitary pulmonary nodules The average sensitivity and specificity of FDG-PET scanning for detecting a malignancy is reported to be 0.97 and 0.78, respectively.

31. Bronchoscopy When a lung cancer is suggested, bronchoscopy provides a means for direct visualization of the tumour. It allows determination of the extent of airway obstruction, and allows collection of diagnostic material under direct visualization with direct biopsy of the visualized tumour, bronchial brushings and washing, and trans bronchial biopsies.

32. Biopsy Transthoracic needle biopsy, guided by CT or fluoroscopy, is preferred for tumours located in the periphery of the lungs because peripheral tumours may not be accessible through a bronchoscope.

33. Molecular testing Molecular testing forms an important part of the full pathologic evaluation of patients with metastatic non–small cell lung cancer (NSCLC). This includes testing for epidermal growth factor receptor ( EGFR ) mutation and anaplastic lymphoma kinase ( ALK ) mutation. Such testing is indicated because they are very effective and less toxic targeted treatments are available for patients with EGFR and ALK mutation

34. 34 Lung Cancer (Treatment) Depends on: Histological cell type The tumour size, location and extent of the tumour (stage) The general health of the patient (scales of performance status).e.g. WHO/ Zubrod /ECOG scale; Karnofsky scale

35. 35 Staging for NSCLC Tumour (T) Tx : Malignant cells in bronchial secretions, no other evidence of tumour on imaging or bronchoscopy T0: No evidence of primary tumour Tis: Carcinoma in situ T 1 : <3cm and not involving main bronchus/pleura T 2 : >3cm,or involving main bronchus and pleura T 3 : any size, invading chest wall, diaphragm, mediastinal pleura, pericardium or 2cm to carina. T>7cm diameter with nodules in same lobe T 4 : invading mediastinum, heart, great vessels, trachea, oesophagus , vertebral body, carina, malignant effusion. Nodes (N) N : no regional node metastases N 1 : ipsilateral hilar node metastases N 2 : ipsilateral mediastinal or subcarinal node metastases N 3: contralateral medastinal or hilar nodes Metastases (M) M : no distant metastasis M 1 : distant metastases

36. 36 Staging for NSCLC -Staging groups based on TNM system and 5 year survival Stage TNM Operability 5-yrs %. I T 1-2 N M Op 50-70 II T 1-2 N 1 M Op 35-45 III a T 3 N 1 M Op 25 T 1-3 N 2 M Op III b T 1-4 N 3 M non -op 10 T 4 N 0-2 M non -op IV T1-4,N0-3,M 1 non -op <5

37. Stage 1 : Cancer is located only in lungs and has not spread to any lymph nodes. Stage 2: Cancer in the lung and nearby lymph nodes. Stage 3: Cancer in the lung and mediastinal nodes. 3A – nodes on same side of the chest; 3B – nodes on opposite side of the chest. Stage 4: Advanced stage. Cancer has spread to both lungs and other organs.

38. SCLC Staging The TNM and staging systems (I-IV) are appropriate for SCLC. Many physicians, however, use the old Veteran’s Administration staging system because there is less variation in survival for the stages described by the TNM system when applied to SCLC. Both treatment options and prognosis can be adequately communicated by the use of a two-stage system. In the two-stage system developed by the Veteran’s Administration Lung Cancer study group, small cell lung cancer is staged as “limited disease” or “extensive disease.” Limited disease for SCLC (30% of patients) typically is defined as no detectable disease outside of the hemithorax , with or without ipsilateral , mediastinal, hilar , or supraclavicular lymph nodes. Extensive disease (70% of patients) is any disease occurring beyond the sites listed for limited disease.

39. Performance Status Scales

40. Treatment Surgery, chemotherapy, and radiation are the main treatment options for NSCLC. Chemotherapy +/- radiotherapy is usually used for SCLC Because most lung cancers cannot be cured with currently available therapeutic modalities, the appropriate application of skilled palliative care is an important part of the treatment.

41. Treatment Chemotherapy Approximately 80% of all patients with lung cancer are considered for chemotherapy at some point during the course of their illness. Multiple randomized, controlled trials and large meta-analyses all confirm the superiority of combination chemotherapy regimens up front for advanced NSCLC. The American Society for Clinical Oncology (ASCO) guidelines recommend that first-line treatment for NSCLC include a platinum combination. In younger patients, with a good performance status or in the adjuvant setting, cisplatin is preferred, but in older patients or those with significant comorbidities, carboplatin may be substituted.

42. Treatment - Chemotherapy For patients with adequate performance score, the standard first-line chemotherapy recommendations currently consist of a platinum doublet, with several reasonable non-platinum combinations as an alternative. Numerous randomized studies have been conducted that compare the benefits of single-agent versus doublet regimens. A meta- analysis that reviewed 65 of these trials found a significant benefit in response and median survival with a cytotoxic doublet. There was no survival benefit with the addition of a third cytotoxic agent.

43. Combinations

44. Dose of medications

45. Side effects of chemotherapeutic agents Cisplatin – Highly emetogenic , nephrotoxicity, ototoxicity, myelosuppression , anaphylaxis, alopecia Carboplatin – nausea/vomiting, myelosuppression , alopecia, asthenia Docetaxel – Anaphylactic reaction, Alopecia, Myelosuppression Paclitaxel – Myelosuppression , Arthralgia/Myalgia, Anaphylactic reactions Vinorelbine – Neuropathy, Neutropenia, Anaemia Pemetrexed – Nausea, Fatigue, Myelosuppression , Anorexia

46. Treatment - Chemotherapy Premedication Intravenous fluid Steroids – Dexamethasone Antiemetics – Ondansetron Antihistamine Xanthine oxidase inhibitors - Allopurinol

47. Treatment Newer medications : Targeted therapy EGFR inhibitors for NSCLC– Gefitinib , Erlotinib , Afatinib ALK receptor inhibitors for NSCLC- Crizotinib ( Xalkori ), Ceritinib

48. Targeted therapy Multiple randomized clinical trials have demonstrated that patients with activating mutations within EGFR have significant improvement in disease response with decreased toxicity when treated with erlotinib , compared to traditional chemotherapy, as first-line therapy. Due to these findings, it is advocated that all patients with newly diagnosed advanced adenocarcinoma of the lung have their cancer tested for EGFR-activating mutations and treated with erlotinib if a mutation is identified. The most common toxicities seen with EGFR inhibitors are acneform -type rash, diarrhoea, and a small risk of interstitial lung disease . Maemondo M, Inoue A, Kobayashi K, et al.; North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med . 2010;362(25):2380–2388.

49. Treatment: Targeted therapy A reported nonrandomized clinical trial of crizotinib , a TKI that targets the ALK kinase domain, demonstrated encouraging rates of disease control (90%) in patients with advanced lung cancer with EML4–ALK translocations. In October 2011, the FDA gave crizotinib approval for treatment of NSCLC with ALK–EML4 translocations. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol . 2012;13(10):1011–1019.

50. Treatment - Immunotherapy Newer medications : Immunotherapy Immune check point inhibitors: Nivolumab ( Opdivo ) for squamous cell carcinomas; Pembrolizumab ( Keytruda ) for metastatic NSCLC. Works by interfering with molecular breaks known as PD-1 that normally prevents the immune system from attacking tumours.

51. The monoclonal antibody, Bevacizumab , which targets the VEGF, is approved for first-line treatment of NSCLC when combined with cytotoxic chemotherapy. A large randomized phase III study published in 2006 demonstrated an improvement in OS, 12.3 versus 10.3 months for those patients who received bevacizumab in addition to carboplatin and paclitaxel for advanced NSCLC Due to the high risk of life-threatening haemoptysis seen in early clinical trials, patients with squamous cell lung cancer or a history of haemoptysis were excluded from this study. Crino L, Dansin E, Garrido P, et al. Safety and efficacy of firstline bevacizumab -based therapy in advanced non-squamous non-small-cell lung cancer ( SAiL , MO19390): a phase 4 study. Lancet Oncol . 2010;11(8):733–740 . Treatment: Immunotherapy

52. Side Effects of newer medications: EGFR inhibitors – Skin rash, Diarrhoea, Itching, Nausea/Vomiting. ALK receptor inhibitors – Recurrent upper respiratory tract infections, Anorexia, Insomnia, Dizziness, Diarrhoea. Immune checkpoint inhibitors – Rash, Pruritus, Body swelling, Myalgia, Dizziness, Fever. Antiangiogenesis – Haemoptysis, Hypertension, Proteinuria

53. Summary Lung cancer is a significant cause of morbidity and mortality – commonest cause of cancer death worldwide. Cigarette smoking remains a significant risk factor Treatment modalities include surgery, chemotherapy and radiotherapy based on the histologic type, stage of the disease and performance status of the patient.

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