Lung cancer

LUNG CANCER

1. Non Small Cell Lung Cancer LUNG CANCER- TREATMENT RECENT ADVANCES & RESULTS Presenter- Dr.Jyotindra singh NIMS,HYDERABAD

2. Introduction Most common malignancy in males around the world. Leading cause of cancer related mortality. Lung cancer recently surpassed heart disease as the leading cause of smoking-related mortality! In India accounts for the commonest cancer in 3 leading cancer registries – Bhopal, Delhi & Mumbai.

3. Incidence & Prevalence

4. Classification & Pathology

5. Pathology

6. Squamous cell carcinoma Incidence of SCC appears to be decreasing relative to adenocarcinoma . Arise centrally –(two third) within the main, lobar, segmental or subsegmental bronchi . Grow slow,metastasize late Extends both intrabronchially & peribrionchially . Because there is exfoliation of the malignant cells from the bronchial surface, squamous cell carcinoma can be detected by cytologic examination at its earliest stage . Peripherally located-undergo central necrosis with resultant cavitation

7. SCC Adeno Ca.

8. Squamous cell carcinoma Better prognosis than adenocarcinoma The more necrosis – the worse the prognosis Well differentiated SCC – more locoregional spread Poorly differentiated SCC – early metastases to distant sites Alveolar filling of peripheral SCC – more favorable prognosis CAVITATTION DUE TO TUMOUR NECROSIS

9. Adenocarcinoma Adenocarcinoma Usually arise in the smaller peripheral airways (as distinct from the cartilage bearing bronchi). Detected earlier by radiology. Most common in non-smokers and women. Rising incidence associated with different pattern of tobacco consumption. More frequently associated with pleural effusions and distant metastases. Premalignant leison is known as atypical alveolar hyperplasia .

10. Adenocarcinoma On routine medical examination, the chest film of a 64-year-old man shows bilateral primary lung tumours in the upper lobes; the lesion on the left side is partly obscured by the clavicle. (b) CT scan clearly defines the irregularly shaped primary lesions (arrows). Synchronous primary lung cancers occur in about 3-5% of patients and can be of different histologic subgroups.

11. PROGNOSTIC FEATURES Scar carcinoma- poor Central fibrosis<5mm- excellent,>15mm – worst Ground glass opacity <3 mm on HRCT –Better prognosis. Incidence of lymph node involvement is less or even absent when greater percentage of ground glass appearance. Central tumours - higher incidence of LN metastasis. BAC (variant)- higher incidence of LN involvement . Neuroendocrine differentiation,WDFA –poor prognosis. ,

12. Risk Factors Smoking Genetic predisposition Genetic trait : Li Fraumeni syndrome (P 53 mutation) Gene polymorphisms: DNA repair genes : XRCC1 COX 2 Interleukin 6 Occupational & Environmental exposure Asbestos exposure: Occupational or residential ( silicate type fibers ) Foundry workers and welders: Ni, Co, Cd Uranium mine workers: Inhaled Radon Air pollution: Diesel exhaust Metal fumes Air sulfate and PAH content Dietary influence Folate & B 12 deficiency Inadequate antioxidant consumption A cigarette is a euphemism for a cleverly crafted product that delivers just the right amount of nicotine to keep its user addicted for life before killing the person.'' World Health Organization director-general Gro Harlem Brundtland

13. Symptoms Symptoms Cough Central growth Hemoptysis Dyspnea / Wheeze Pneumonitis Peripheral growth Pain Cough Dyspnea Lung abscess Regional Spread Hoarseness Dysphagia Diaphragmatic palsy Horner’s Syndrome SVC syndrome Pancoast syndrome

14. Signs Signs directly caused by tumor invasion or compression: Limitation of chest movement Rib tenderness Vocal cord palsy Horner’s syndrome Engorged veins in the chest wall and face Signs due to metastasis Bony tenderness Adrenal insufficiency Organomegaly Paraneoplastic syndromes: Cancer cachexia (MC) Hypercalcemia HPOA & clubbing SIADH Cushing’s Syndrome Carcinoid Syndrome Gynecomastia Cerebellar degeneration Eaton Lambert syndrome Autonomic neuropathy Optic neuritis Pure red cell aplasia DIC Anemia, thrombocytopenia Acanthosis nigricans Hyperkeratosis Hypertrichosis VIP induced diarrhea Hyperamylesmia

15. Investigations Investigations to confirm the disease Sputum cytology (sensitivity 65% - 75%) Transthoracic FNAC (sensitivity 87% - 91%) Bronchoscopic biopsy (70% - 80%) TT-FNAC associated with Pneumothorax (27%) Hemoptysis (5%) Local bleeding (11%) Investigations to assess the stage Imaging Bronchoscopy Mediastinoscopy VATS Investigations to assess fitness for treatment Hemogram Renal and liver function tests Pulmonary function tests

16. Imaging Plain X rays A tumor visible in a chest X ray has usually completed 75% of it’s natural history. Guides local radiotherapy CT scans : Accurate assessment of primary disease. Best for detection of mediastinal and chest wall invasion . Nodal size < 1 cm : 8% chance of occult nodal metastasis Nodal size > 2 cm : 70% chance of occult or overt metastasis Assessment of abdominal disease esp. of adrenal involvement . PET CT has a greater degree of sensitivity for detection of nodal disease that would be missed by size based criteria alone.

17. Mediastinal Nodes EBUS CT PET Sensitivity 92% 76% 80% Specificity 100% 55% 70% Accuracy 98% 61% 73% \ .

18. Bronchoscopy Most valuable invasive investigation as it allows: Confirmation of diagnosis : Biopsy and brushings 80% accurate Low false positive rates 0.8% Transbronchial forceps biopsy positive in 70% Visualization of tumor done in 60% - 75% Staging of the tumor : Extent of bronchial and carinal involvement. Symptom alleviation : Stenting Bleeding control Importance in brachytherapy Response assessment Detection of preinvasive malignancy (screening) : Autoflurosecence bronchoscopy.

19. Staging & Prognosis

20. Staging T1 : 3 cm or less, completely covered by pleura, does not involve main bronchus

21. Staging T2 : > 3cm size. Visceral pleura involved. Main bronchus invasion but > 2cm from carina. Atelectasis / obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.

22. Staging T3 : Chest wall Diaphragm Mediastinal pleura Pericardium Main bronchus <2cm to carina Complete atelectasis / obstructive pneumonitis of entire lung

23. Staging T4 : Carina Vertebrae Great Vessel Esophagus Heart Separate tumour nodule in same lobe MALIGNANT pleural / pericardial effusion

24. Staging N0 : No regional LN metastases N1 : LN mets in ipsilateral peribronchial and/or intrapulmonary (Levels 10, 11, 12, 13, 14) N2 : Ipsilateral mediastinal or subcarinal N3 : Contralateral mediastinal /hilar Ipsilateral or contralateral supraclavicular/ scalene nodes

25. Staging: AJCC 2002 Stage TNM T N M IA T1 N0 M0 IB T2 N0 M0 IIA T1 N1 M0 IIB T2 N1 M0 T3 N0 M0 IIIA T3 N1 M0 T1-T3 N2 M0 IIIB T4 N0-N2 M0 T1-T4 N3 M0 IV T1-T4 N0-N3 M1

26. Chart illustrates the descriptors from the 7th edition of the TNM staging system for lung cancer. 2010;30:1163-1181

27. Staging Controversies Tumor size cutoff of 3 cm . Several authors have demonstrated the prognostic value of size > 5 cm and recommend it be incorporated in T 3 disease . T 3 N M is lumped into stage IIB Prognosis of patients with chest wall disease significantly better than other T 3 category tumors even after complete resection. Even those T 3 patients who have rib destruction have a significantly poorer prognosis as compared to those with soft tissue involvement . Normal lymphatic drainage of the lung doesn't obey the midline! Right sided lymphatics extend to the left border of the trachea across the midline. Survival of patients with level 3 and 7 nodal involvement is markedly poorer.

28. Adverse Prognostic Factors Age > 65 Performance status > 2 Advanced stage Presence of mediastinal lymphadenopathy Tumor hypercalcemia Surgical procedure : Limited resection Positive resection margins Biological markers: COX 2 p 53 EGFR erbB2

29. Small cell lung carcinoma 15 – 25 % of all lung cancers Almost exclusively in smokers Distinguished from NSCLC by: Rapid doubling time High growth fraction Early development of wide-spread metastasis Typically arise centrally Most common presentation is a large hilar mass with bulky mediastinal LAN Commonly spread to liver, adrenals, bone and brain. produces paraneoplastic Syndrome. Tumour markers- 3 main groups: Neural, Epithelial, Neuroendocrine .

30. VALG STAGING SYSTEM Very-limited disease : confined to one hemithorax without mediastinal lymph node involvement . Limited disease : confined to one hemithorax including the contralateral lymph nodes (all within radiation field ). Extensive disease : beyond these bounderies. Very-limited disease ~ 5 years Limited disease 1 8-24 months E xtensive disease 10 months SCLC without treatment < 3 months

31. PROGNOSTIC FACTORS The host factors of poor performance status and weight loss Stage (limited versus extensive). In extensive disease, the number of organ sites involved is inversely related to prognosis Metastatic involvement of the central nervous system, the marrow, or the liver is unfavorable compared to other sites In most trials, women fare better than men, although the reasons for this are not known. The presence of paraneoplastic syndromes is generally unfavorable

32. LIMITED STAGE Combination of chemo & radiation combination chemotherapy is the backbone of treatment thoracic radiotherapy significantly improves long term survival Early thoracic radiotherapy gives better results than late radiotherapy. Cisplatin and etoposide are most easily combined within concurrent chemoradiation protocols ( Turrisi et al ) BID radiotherapy gives better local control and better long term survival than QD (5y survival %: 26% Turrisi et al, NEJM 99 ) PCI significantly improves survival by 4-5 % at 5 years when given to complete responders ( Auperin et al )

33. SCLC LD Standard of treatment Cisplatin 80 mg/m 2 d1 Etoposide 120 mg/m 2 d1-3 Q3wk x 4 Thoracic Radiotherapy 45 Gy 1.5 Gy /fraction bid 3 wk Turrisi et al. NEJM 1999

34. EXTENSIVE STAGE DISEASE Primary treatment is chemo Cisplatin or Carboplatin plus Etoposide Median survival approx. 11 months 5 year survival approx 0% Second line therapy> 95 % relapse after first-line treatment Topotecan for chemo sensitive relapse dosease Role of PCI No improvement achieved by Novel agents ( taxanes , topo 1 inhibitors) Biologicals Topotecan (n=71) BSC (n=70) HR (95%CI) P -value MS (weeks) 26 14 0.64 P = 0.0104 6 mo survival 49% 26%

35. Surgery

36. Surgical Aspects in Lung Cancer Management How fit is the patient ? What is the stage, histology, and exact size and location ? Is the patient for Diagnosis Treatment Palliation Diagnostic Bronchoscopy VATS Mediasteinoscopy Mediasteinotomy Treatment Wedge Lobectomy Combined wedge and lobectomy Pneumonectomy Palliation Effusions

37. Surgery : PFT based algorithm Surgery Type Lobectomy /Lesser Pneumonectomy FEV 1 > 1.5 L FEV 1 > 60% DL CO > 60% FEV 1 > 2 L FEV 1 > 60% DL CO > 60% Operate Operate V/Q scan Calculated Post operative FEV 1 & DL CO < 40% > 40% Exercise study V0 2 max < 15 ml/kg/min V0 2 max > 15 ml/kg/min Medically inoperable Average risk

38. NSCLC: Stage at Diagnosis Stage I and II – Surgery as primary treatment Stage III – Multimodality Therapy III A – Neoadjuvant therapy (chemo/radiation) followed by surgery & additional therapy III B – Combination chemotherapy & radiation therapy. Stage IV – Palliative chemotherapy and/or radiation ,best supportive care Stage IV 40% Stage I 10% Stage II 20% Stage IIIA 15% Stage IIIB 15% Ettinger et al. Oncology. 1996;10:81-111.

39. Surgery : Types Radical operation : Pneumonectomy . Lung Conservation : Lobectomy . Sleeve resection. Wedge resection. Segmentectomy . Mediastinal lymph node dissection: Provides complete nodal staging. Identifies patients who require adjuvant radiotherapy. Improves survival. Improves local control.

40. THORACOTOMY Posterolateral Anterolateral Lateral Mini Muscle sparing

41. SEGMNENTECTOMY WEDGE RESECTION Small peripheral tumour confined to an anatomic segment. Patient has limited pulmonary reserve. Low grade tumour under investigation. Lingulectomy ( encompassing 2 segments)- peripheral NSCLC. LCSG report Ginsberg- limited resection for T1N0 NSCLC- local recurrence 3 fold higher than for lobectomy although ultimate survival not significantly different, Non anatomic and definitive therapy only in poor risk patients. CRITERIA FOR WEDGE RESECTION A tumor < 3cm in diameter Location in outer third of lung Absence of endobronchial extension. Clear margins by frozen section negative mediatinal & hilar node sampling. CALBG ( cancer & leukemia Group B ) - Trial of lobectomy vs sublobar resection. ACOSOG – Trial sublobar resection vs sublobar resection + implanted radiation seeds.

42. Segmentectomy vs wedge rxn Segmentectomy Better deep margin (El Sharif et al Ann Surg Onc 2007) Better nodal evaluation/clearance Wedge resection Adequate for peripheral ( subpleural ), small (1 cm) lesions when margin is wide (diameter of lesion or more) If lesion straddles segmental boundary (i.e. between lingula and upper division)

43. LOBECTOMY BILOBECTOMY Resection of a lung cancer confined to parenchyma of a single lobe. Removal of tumour + peripheral (pleural ) & central lymphatic drainage pathways Leaves sufficient lung volume to fill the pleural void. Ginsberg reported operative mortality – 2% vs 4 % for pneumonectomy . Involves resection of right upper and middle lobe or of the right middle & lower lobe - when a tumour located in anterior segement of RUL Tumour in RML has spread across the minor fissure or approximates an incomplete fissure. When tumour in RML is central-proximity of the origins of superior segmental and middle lobe bronchi Interlobar vascular vascular or nodal involvement.

44. VATS Lobectomy Absolute containdiactions Inability to achieve complete resection –T3 or T4 tumors –N2 or N3 disease Inability to obtain single lung ventilation Large Tumor > 5 cm (too large to remove through utility incision) Relative Conditions that compromise the safety of dissection -- Pre-op chemotherapy / radiation therapy or both -- Presence of hilar lympnadenopathy complicating dissection -- Presence of extensive adhesions Invasion of extra-pulmonary structure

45. 1281 Propensity matched patients (945 VATS, 857 thoracotomy ) Fewer overall complications (35.7% vs. 26.2% p <.0001) Decreased arrhythmias Fewer pulmonary complications Fewer Blood transfusions Shorter Hospital Stay (4 vs. 5 days) Equal operative mortality (1%) Fewer complications Hoksch 1 Less pain Walker 2 Better quality of life Sugiura 3 Better PFTs Nakata 4 Less pneumonia Whitson 5 Earlier recovery Demmy 6 Easier for octogenarians McVay 7

46. SLEEVE LOBECTOMY Resection of lobe along with a circumferential segment of mainstem bronchus. Indicated for endobronchial tumours at the origins of right or upper lobe bronchi. Tumour should be limited to the lung. Pts. With negative mediastinal node has the best survival. Anastomotic complications Granulations Stenosis Bronchovascular fistula

47. Pneumonectomy The indications are central tumors that involve the main bronchus Large parenchymal cancers that violate the fissures or invade the interlobar vessels , or hilar lymph node involvement. Pneumonectomy in the latter situation should be reserved for cases in which higher stations are benign and a complete resection is possible. The operative mortality for pneumonectomy is about twice that of lobectomy . Patients with N2 disease or centrally locally invasive tumours are treated by induction therapy- due to extent of their disease they need pneumonectomy Extended Pneumonectomy Intrapericardial pneumonectomy Supra aortic pneumonectomy Carinal pneumonectomy

48. CHEST WALL INFILTRATION Tumors invading the chest wall are often resectable . The involved ribs should be transected several centimeters beyond the margin of gross involvement. In most cases, one rib and intercostal tissue above and below the tumor should also be included in the resection. For posterior defects, support by the remaining chest wall muscles and scapula is usually sufficient. Anterior and lateral defects more often require reconstruction. For isolated chest wall invasion with N0 or N1 positive nodes, there is no known role for neoadjuvant therapy. There is controversy regarding the necessity of chest wall resection when invasion is confined to the parietal pleura.

49. DIAPHRAGM When invasion occurs, that portion of the diaphragm should be resected with a wide margin of normal tissue without regard to the extent of the defect. If the defect is small and can be closed primarily without tension- Prosthetic material/muscle flap When a large area of diaphragm has been resected or when the phrenic nerve has been resected - diaphragmatic reconstruction. When the defect is peripheral, it may be possible to reinsert the remaining cut edge at a higher level on the chest wall

50. PERICARDIUM Total resection of the pericardium on the left can be performed without reconstruction. Partial defects should be closed to prevent herniation and strangulation of the left ventricle. On the right side, all pericardial defects, regardless of size, require repair . Large defects can be closed with the pericardial fat pad, a pleural flap, or nonautologous material such as bovine pericardium or polytetrafluoroethylene (PTFE). A small opening be left in the repair or that the prosthetic material be fenestrated to prevent cardiac tamponade .

51. VERTEBRA Vertebral body invasion is considered T4 disease and thus unresectable . DeMeester and colleagues described a technique of partial vertebral resection for tumors fixed to the paravertebral fascia. They use a through the transverse process, costotransverse foramen, and superficial vertebral body . En bloc pulmonary resection and complete vertebrectomy with reconstruction by a combined anterior and posterior approach. Used when - tumor extent is completely delineated, node-negative, totally resectable , and, after careful evaluation with MRI, does not involve the spinal canal.

52. Pancoast tumor “ Pancoast Tumor” is a neoplasm located at the apical pleuropulmonary groove adjacent to the subclavian vessels. Symptoms arise as a result of neoplastic involvement of the brachial plexus, nerve roots, sympathetic chain, ribs, and chest wall. Ptosis of the left eyelid, miosis of the pupil and decreased sweating of the left face, arm and upper chest (Horner's syndrome ) chest film- large tumour of the right upper lobe that has destroyed the adjacent rib. CT scan reveals rib and soft tissue involvement as well as destruction of an adjacent vertebral body. Biopsy showed a squamous cell carcinoma. Many centres are now reporting more adenocarcinomas than squamous cell type.

53. Preliminary Supraclavicular Exploration Dissection of: Supraclavicular nodes S.C. artery Brachial plexus Scalene muscles Phrenic nerve Adverse prognostic factors: Horner’s syndrome N 2 , N 3 disease Incomplete resection 9% 5yr survival Posterolateral (Shaw - Paulson) Anterior cervicothoracic ( Dartevelle ) Hemi-clamshell (Burt) Anteroposterior “hook” ( Niwa ) VATS - Posterior

54. Lymph node dissection Lobe specific mediastinal nodal dissection in NSCLC: Right Side : Upper lobe (1,2,3,4,7) Middle lobe (1,2,3,4,7) Lower lobe (1,2,3,4,7,8,9) Left Side : Upper lobe (4,5,6,7) Lower lobe (4,5,67,8,9)

55. Technique of Mediastinal Lymph Node Dissection Right Paratracheal – clear all tissue from SVC to trachea and from upper lobe bronchus to the subclavian artery Left Aorto -Pulmonary Window –clear all tissue from phrenic nerve to the descending aorta and from the left upper lobe bronchus to the subclavian artery Subcarinal - clear out all tissue bordered by the right and left bronchi and pericardium Video Assisted Mediastinoscopic Lymphadenectomy (VAMLA)

56. Complete Resection Free resection margins proved microscopically At least a lobe specific mediastinal nodal dissection with complete hilar and intrapulmonary nodal dissection. At least 6 nodes should have been removed with 3 from mediastinal nodes. No extracapsular extension in the nodes. Highest mediastinal node removed should be microscopically free. Ramon et al Lung Cancer (2005) 49 , 25—33

57. Criteria for inoperability Tumor based criteria : Cytologically positive effusions. Vertebral body invasion. Invasion or in casement of great vessels. Extensive involvement of Carina or trachea. Recurrent laryngeal nerve paralysis. Extensive mediastinal lymph node metastasis. Extensive N 2 or any N 3 disease.

58. Patterns of failure In stage I tumors : Local recurrence rate = 7% Distant failure rate = 20% Second primary cancer = 34% Martini et al, J Thor Cardiov Surg 1995; 109: 95 – 110 . In stage II / III tumors : Intrathoracic failure rate: 31% 5 yr survival in clinical N2 negative nodes: 27 % 5 yr survival in clinical N2 positive nodes : 8 % Tumors measuring 1-2 cm have a mediastinal nodal metastasis rate of 17% as compared to those measuring 2 to 3 cm, when the rate is 37 % Patients who fail after surgery, present with extrathoracic disease 70% of the time , local recurrence in 20% and local and distant metastasis in 10 %. 2 nd primary lung cancers are known to occur at a rate of 1% per year in survivors.

59. Role of Radiotherapy Plays an important role in the management of approx 85% of patients with non small cell lung cancers. RT can be applied in the following settings: With curative intent With Palliative intent RT is the most common treatment modality in majority of patients in India as : Majority of the patients present with hilar or mediastinal disease. Disease bulk prevents the use of surgical techniques . Associated comorbidities and poor lung function make patients not suitable for surgery. Advanced age and poor socioeconomic status make RT an attractive treatment option.

60. RT: Advanced Disease Aim : To achieve local control due to high probability of death due to progression of systemic disease. Indications : T 3 disease N 1 or small N 2 disease No evidence of distant metastasis Weight loss < 12% of body weight < 50% of normal working time spend in bed. Aim : To achieve relief of symptoms only when disease is too advanced for local control Indications : T 4 disease Extensive N 2 or N 3 disease Distant metastasis Weight loss > 12% of body weight > 50% of normal working time spend in bed.

61. Advanced techniques Recent innovations 3 DCRT IMRT IGRT Respiratory gating : Tumors in lung may move by as much as 5-10 mm during normal quiet breathing. The PTV may be effectively doubled if this is taken into account Two techniques of respiratory gating are: Breathhold techniques : Active : Using valves and spirometers Passive : Voluntary breath holding Synchronized gating technique : Uses free breathing with synchronized beam delivery.

62. IMRT

63. Role of Postoperative Radiotherapy Indications : Advanced disease: Margin positive ( < 0.5 cm ) Microscopic or macroscopic residual disease Hilar or mediastinal node positivity Mediastinal or chest wall invasion. Dose : 30 – 40 Gy in 10-20 # over 2 weeks . Why is data regarding PORT inadequate? Unlike surgical series none of the studies have taken into account the extent and site of nodal involvement which have been found to be important prognostic variables. Many studies reported used inadequate doses .

64. Brachytherapy As far back as 1922, Yankauer placed capsules of radium through a rigid bronchoscope into the region of bronchogenic carcinoma. Brochoscopic afterloading flexible applicator based technique first reported by Mendiondo et al. Role : As a palliative measure Indications : Patients with clinically significant endobronchial component who are not suitable for other forms of therapy. Life expectancy > 3 months. Ability to tolerate a bronchoscopy. Absence of bleeding diathesis.

65. Intraoperative Brachytherapy Mostly used for Stage IIIA disease close or positive margins Improved local control

66. Cedars Brachytherapy 3 radiation catheters Minimally invasive surgery Radiation beads are placed down the catheters Then the beads are removed Very targeted – lung motion is not an issue Catheters for radiation beads

67. Chemotherapy & Targeted therapy

68. Chemotherapy Based upon the premise that 70% - 80% patients will have micrometastasis during presentation. Situations where CCT can be used: Neoadjuvant CCT as an induction regimen Adjuvant chemotherapy with or without radiation* Palliative chemotherapy in systemic disease. No advantage of consolidation chemotherapy has been established.

69. CCT regimens Standard chemotherapy regimens: CAP regimen (q 3 weekly x 6 cycles) Cyclophosphamide Adriamycin Cisplatin CVP regimen 3 drug regimens have better response rates but survival benefit is absent. In a study by Schiller et al using 4 different platinum based CCT regimens* failed to reveal any benefit of a particular combination.

70. First-line Therapy: 2013 Column A Cisplatin Carboplatin Column B Vinorelbine Gemcitabine Paclitaxel Docetaxel Pemetrexed Nab-paclitaxel Irinotecan Column C Bevacizumab Cetuximab ? Option 1: choose 1 from column A and 1 from column B Option 2: choose 2 from column B Option 3: option 1 + column C (for certain patients) Option 4: choose 1 from column D (for selected patients ) Column D Erlotinib Crizotinib National Comprehensive Cancer Network clinical practice guidelines in oncology: Non-small-cell lung cancer (v2.2013). www.nccn.org y Advanced Non-Small-Cell Lung Cancer : 2013 GUIDELINES

71. Contenders for Second Line and Beyond Non-small cell lung cancer pemetrexed gefitinib Small cell lung cancer topotecan

72. Targeted therapy EGFR Inhibitors Gefitinib ( Iressa ) Erlotinib ( Tarceva ) EGFR Monoclonal antibodies Cetuximab ( Erbitux ) VEGF Monoclonal antibodies Bevacizumab ( Avastin ) Many ongoing trials but what has emerged from already concluded ones is: Iressa does not prolong survival & no benefit from adding to chemo also (IDEAL phase II trials, INTACT & ISEL phase III trials) Erbitux may not show any benefit in combination with chemo Avastin may show improved response in combination with chemo but there is increased Grade III hemoptysis in squamous cell carcinomas (10%). Median time to progression increased by a mere 3 months .

73. DNA Membrane Extracellular Intracellular R K R K EGFR-TKI EGFR-TKI Signalling Proliferation Cell survival (anti-apoptosis) Growth factors Chemotherapy/ radiotherapy sensitivity Angiogenesis Metastasis û û û R, epidermal growth factor receptor EGF/TGF α Gefitinib : Mechanism of Action

74. • Relatively new treatment concept • Established in early 1990s at Karolinska Institute, Stockholm, Sweden • Few fractions/high doses/steep gradients • Goal is tumor ablation indicated – Medical inoperability • Improved therapeutic ratio over fractionated RT courses Stereotactic Radiation for Lung Cancer (SBRT)

75. Stereotactic Body Radiotherapy VS Standard radiotheraypy 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

76. Results- Tumor Response After RFA RFA is the use of high-frequency electrical current to heat a specific volume of tissue to temperatures high enough to cause destruction of undesired malignant cells. • Lifting of the deflated lower lobe off of the diaphragm and sometimes with takedown of the inferior pulmonary ligament in cases where the tumor is located in the lower lobe, is beneficial during ablation to protect the diaphram . 1 3 months post-RFA

77. CALGB 14053 Randomized trial of “ sublobar resection ” vs. Lobectomy Clinical stage IA(T1a) with PFTs adequate for lobectomy Lobectomy VATS or Thoracotomy Sublobar Resection Wedge resection or segmentectomy VATS or Thoracotomy

78. Lung Cancer Surgery: future Wu C-Y, et. al. Ann. Thorac. Surg. 2013 Feb;95(2):405–11. Gonzalez-Rivas D, et al. Multimedia Manual of Cardiothoracic Surgery. 2012 Mar

79. Conclusions Minimally Invasive Lobectomy is the new standard for early stage lung cancer surgery Equivalent oncologic results Decreased morbidity Faster recovery Improved completion of adjuvant therapy Thoracoscopic (VATS) Lobectomy is well established The roles of sublobar resection and Robotic surgery require further investigation

80. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor 81 Wayne McLaren as the Marlboro man (1976) Dying from Lung Cancer (1992)

81. Death is a natural event

82. THANK YOU

83. Standard of Care For Peripheral Nodules 1940’s Pneumonectomy 1960’s Lobectomy 1990’s ? Segmentectomy /Wedge (and adjuvant local/systemic Rx) Surgical Resection of the Lung

84. Randomized Trial of Lobectomy Versus Limited Resection for T1 N0 Non-Small Cell Lung Cancer (125 Lobectomy , 122 Limited Resection) RJ Ginsberg, LV Rubinstein and Lung Cancer Study Group Ann Thorac Surg 1995;60:615-23

85. Lobectomy vs Limited Resection Time to death (from any cause) by treatment logrank p=0.088 (one-tailed) Ginsberg and Rubinstein Ann Thorac Surg

86. Wedge Resection Versus Lobectomy for Stage I (T1 N0 M0) Non-Small Lung Cancer Landreneau, et.al., J Thorac Cardiovasc Surg 1997;113:691-700

87. Wedge vs Lobectomy for Stage I NSCLC p=0.889 Landreneau, et.al., J Thorac Cardiovasc Surg 1997;113:691-700

88. Wedge vs Lobectomy for Stage I NSCLC Open WR VATS WR Vs. Lobe P< Op Mortality (%) Vs. 3.3 0.20* Postop Stay (days) 7.7 6.5 Vs. 10.1 0.0002* Local Recur (%) 17 15 Vs. 5 0.08* Local/Systemic Recurrence (%) 24 23 vs. 17 0.43* *- all WR (n=95) vs. Lobe (n=124) Statistical Methods: Life Table Analyses Obtained by Log Rank and Wilcoxson Tests Landreneau, et.al., J Thorac Cardiovasc Surg 1997;113:691-700

89. Comparison Between Sublobar Resection and 125Iodine Brachytherapy After Sublobar Resection in High-Risk Patients with Stage I Non–Small-Cell Lung Cancer                R.  Santos, A. Colonias , D. Parda , M. Trombetta , RH Maley , R. Macherey , S. Bartley, T. Santucci , RJ Keenan, RJ Landreneau   Surgery 2003, Oct;134(4): 691-7

90. Sublobar Resection (n=102) Sublobar Resection With Brachy (n=96) Local Recurrence 19 (18.6%) 1 (1%) p=.0001 Hospital Mortality 0 (0%) 3 (3%) p=ns Hospital Stay 7 days 8 days p=ns Survival % 1, 2, 3 and 4 year 93, 73, 68, 60% 96, 82, 70, 67% p=ns Systemic Recurrence 29 (28.4) 22 (23%) p=ns Pre-op FEV 1% predicted 65% 53% p=ns Results The FEV 1 did not change postoperatively in the sublobar resection with brachytherapy group in the interval of follow-up

91. Lobectomy vs Sublobar Resection “Effect of Tumor Size on Prognosis in Patients with Non-Small Cell Lung Cancer: The Role of Segmentectomy as a Type of Lesser Resection” Okada M, Nishio W, Sakamoto T, Uchino K, Yuki T, Nakagawa A, Tsubota N. “J Thorac Cardiovasc Surg. 2005 Jan;129(1):87-93” An evaluation of surgical resection in 1272 NSCLC patients

92. TUMOR SIZE Segmental Resection Lobectomy Wedge Resection 20 mm or less 96.7 92.4 85.7 20-30 mm 84.6 87.4 39.4 More than 30 mm 62.9 81.3 Lobectomy vs Sublobar Resection 5 Year Cancer Specific Survival “Stage I” “ Okada, M , et al J Thorac Cardiovasc Surg. 2005 Jan;129(1):87-93”