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Lung cancer

This document discusses lung cancer treatment and recent advances. It begins with an introduction on lung cancer being the most common malignancy worldwide and a leading cause of cancer death. It then covers topics like incidence and prevalence rates, classification and pathology of lung cancer types (non-small cell vs. small cell), staging systems, risk factors, investigations, imaging, surgery, chemotherapy regimens for different stages, and prognosis factors. Key points emphasized are the rising rates of adenocarcinoma, importance of imaging and staging for determining treatment options, and multimodality therapy for locally advanced stages.

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LUNG CANCER- TREATMENT RECENT ADVANCES & RESULTS Presenter- Dr.Jyotindra singh NIMS,HYDERABAD Non Small Cell Lung Cancer
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.
Incidence & Prevalence Incidence per 100,000 3.8 India 12.1 26.6 China 67.5 13.3 Japan 44.6 12.9 22 120 100 22 80 51.2 60 33.5 40 55.7 Males Females Male Female 2002 2000 1998 1996 1994 1992 1990 0 1988 80 1986 60 1984 40 1982 20 1980 0 20 1978 USA 1976 UK 1974 Sweden
Classification & Pathology
Pathology Primary Lung Cancer Small Cell type (20% – 30%) Non Small cell type (70% - 80%) Bronchial surface epithelial type Squamous cell (30 - 50%) Goblet cell type Adenocarcinoma (20 - 40%) Clara cell type Large Cell (10 – 15%) Type II alveolar cell type Adenosquamous Bronchial gland type Carcinomas with sarcomatous elements Neuroendocrine Others
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
Adeno Ca. SCC
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
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.
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.
PROGNOSTIC FEATURES • Scar carcinoma- poor • Central fibrosis<5mmexcellent,>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. • • RET MET Central tumours- higher incidence of LN metastasis. ROS1 EGFR KRAS No known genotype BAC (variant)- higher incidence of LN involvement . ALK • Neuroendocrine differentiation,WDFA –poor prognosis. BRAF HER2 PIK3CA ,
Risk Factors • Smoking • Genetic predisposition – Genetic trait : Li Fraumeni syndrome (P53 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 & B12 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
Symptoms Cough Central growth Hemoptysis Dyspnea / Wheeze Pneumonitis Symptoms Pain Cough Peripheral growth Dyspnea Hoarseness Lung abscess Dysphagia Diaphragmatic palsy Regional Spread Horner’s Syndrome SVC syndrome Pancoast syndrome
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 SIADH Cushing’s Syndrome Carcinoid Syndrome Gynecomastia Cerebellar degeneration Eaton Lambert syndrome Autonomic neuropathy Optic neuritis Pure red cell aplasia DIC Anemia, thrombocytopenia • Paraneoplastic syndromes: Acanthosis nigricans – Cancer cachexia (MC) – Hypercalcemia – HPOA & clubbing Hyperkeratosis Hypertrichosis VIP induced diarrhea Hyperamylesmia
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
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.
Mediastinal Nodes EBUS CT PET Sensitivity 92% 76% 80% Specificity 100% 55% 70% Accuracy 98% 61% 73% .
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.
Staging & Prognosis
Staging • T1: – 3 cm or less, completely covered by pleura, does not involve main bronchus
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.
Staging • T3: – – – – – Chest wall Diaphragm Mediastinal pleura Pericardium Main bronchus <2cm to carina – Complete atelectasis / obstructive pneumonitis of entire lung
Staging • T4: – – – – – – Carina Vertebrae Great Vessel Esophagus Heart Separate tumour nodule in same lobe – MALIGNANT pleural / pericardial effusion
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
Staging: AJCC 2002 5 yr overall survival Stage TNM 80% T N M IA T1 N0 M0 IB T2 N0 M0 60% IIA T1 N1 M0 50% IIB T2 N1 M0 T3 N0 M0 T3 N1 M0 30% T1-T3 N2 M0 20% T4 N0-N2 M0 IIIA IIIB T1-T4 IV N3 N0-N3 M1 67% 55% 55% 45% 40% 22.50% 10% 7.50% M0 T1-T4 70% 2.50% 0% IA IB IIA IIB IIIA IIIB IV
Chart illustrates the descriptors from the 7th edition of the TNM staging system for lung cancer. 2010;30:1163-1181
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 T3 disease. • T3N0M0 is lumped into stage IIB – Prognosis of patients with chest wall disease significantly better than other T3 category tumors even after complete resection. – Even those T3 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.
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
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 widespread 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.
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~ Limited disease Extensive disease 5 years 18-24 months 10 months • SCLC without treatment < 3 months
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
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 )
SCLC LD Standard of treatment Cisplatin 80 mg/m2 d1 Etoposide 120 mg/m2 d1-3 Q3wk x 4 Thoracic Radiotherapy 45 Gy 1.5 Gy/fraction bid 3 wk Turrisi et al. NEJM 1999
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%
Surgery
Surgical Aspects in Lung Cancer Management • How fit is the patient ? • What is the stage, histology, and exact size and location ? • Diagnostic • Is the patient for • Treatment – Diagnosis – Treatment – Palliation – – – – Bronchoscopy VATS Mediasteinoscopy Mediasteinotomy – Wedge – Lobectomy – Combined wedge and lobectomy – Pneumonectomy • Palliation – Effusions
Surgery : PFT based algorithm Surgery Type Lobectomy /Lesser Pneumonectomy FEV1 > 1.5 L FEV1> 60% DLCO > 60% FEV1 > 2 L FEV1> 60% DLCO > 60% •V/Q scan •Calculated Post operative FEV1 & DLCO Operate > 40% < 40% Exercise study V02 max < 15 ml/kg/min Operate Average risk V02 max > 15 ml/kg/min Medically inoperable
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 Ettinger et al. Oncology. 1996;10:81-111. Stage I 10% Stage IV 40% Stage IIIB 15% Stage II 20% Stage IIIA 15%
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.
THORACOTOMY Posterolateral Anterolateral Lateral Mini Muscle sparing
SEGMNENTECTOMY WEDGE RESECTION • Small peripheral tumour confined to an anatomic segment. • Non anatomic and definitive therapy only in poor risk patients. • Patient has limited pulmonary reserve. • 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. • 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, • CALBG ( cancer & leukemia Group B ) - Trial of lobectomy vs sublobar resection. • ACOSOG – Trial sublobar resection vs sublobar resection + implanted radiation seeds.
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)
LOBECTOMY • 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. BILOBECTOMY • 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 centralproximity of the origins of superior segmental and middle lobe bronchi • Interlobar vascular vascular or nodal involvement.
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
Fewer complications • • 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%) Hoksch1 Less pain Walker2 Better quality of life Sugiura3 Better PFTs Nakata4 Less pneumonia Whitson5 Earlier recovery Demmy6 Easier for octogenarians McVay7
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
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 therapydue to extent of their disease they need pneumonectomy Extended Pneumonectomy • Intrapericardial pneumonectomy • Supra aortic pneumonectomy • Carinal pneumonectomy
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.
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
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.
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, nodenegative, totally resectable, and, after careful evaluation with MRI, does not involve the spinal canal.
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.
Preliminary Supraclavicular Exploration • Dissection of: – – – – – Posterolateral (Shaw - Paulson) Anterior cervicothoracic (Dartevelle) Hemi-clamshell (Burt) Anteroposterior “hook” (Niwa) VATS - Posterior Supraclavicular nodes S.C. artery Brachial plexus Scalene muscles Phrenic nerve • Adverse prognostic factors: – Horner’s syndrome – N2, N3 disease – Incomplete resection • 9% 5yr survival
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)
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)
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
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 N2 or any N3 disease.
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%. • 2nd primary lung cancers are known to occur at a rate of 1% per year in survivors.
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.
RT: Advanced Disease • Aim: – To achieve local control due to high probability of death due to progression of systemic disease. • Indications: – T3 disease – N1 or small N2 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: – T4 disease – Extensive N2 or N3 disease – Distant metastasis – Weight loss > 12% of body weight – > 50% of normal working time spend in bed.
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.
IMRT
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 .
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.
Intraoperative Brachytherapy ● Mostly used for Stage IIIA disease - ● close or positive margins Improved local control
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
Chemotherapy & Targeted therapy
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.
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. 22% Gemcitabine 25% Paclitaxel 29% Vinorelbine 30% Irinotecan 25% Mitomycin C 27% Vinbasltine 23% Ifosfamide 21% Cisplatin 0% 10% 20% 30% 40%
y Advanced Non-Small-Cell Lung Cancer: 2013 GUIDELINES First-line Therapy: 2013 Column A Cisplatin Carboplatin Column B Vinorelbine Gemcitabine Paclitaxel Docetaxel Pemetrexed Nab-paclitaxel Irinotecan Column C Bevacizumab Cetuximab? Column D Erlotinib Crizotinib 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) National Comprehensive Cancer Network clinical practice guidelines in oncology: Non-small-cell lung cancer (v2.2013). www.nccn.org
Contenders for Second Line and Beyond • Non-small cell lung cancer –pemetrexed –gefitinib • Small cell lung cancer –topotecan
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.
Gefitinib: Mechanism of Action EGF/TGFα R R Extracellular Membrane Intracellular Proliferation Growth factors Chemotherapy/ radiotherapy sensitivity EGFR-TKI  K K  EGFR-TKI Signalling Cell survival (anti-apoptosis) DNA Angiogenesis Metastasis R, epidermal growth factor receptor
Stereotactic Radiation for Lung Cancer (SBRT) • • • • • • • • • 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 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
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 1 diaphram. 3 months post-RFA
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
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
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
Wayne McLaren as the Marlboro man (1976) Dying from Lung Cancer (1992) Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor 81
Death is a natural event
THANK YOU
Surgical Resection of the Lung Standard of Care For Peripheral Nodules 1940’s 1960’s 1990’s Pneumonectomy Lobectomy ?Segmentectomy/Wedge (and adjuvant local/systemic Rx)
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
Lobectomy vs Limited Resection 120 100 80 60 40 20 0 Lobectomy Limited Resection 10 8 12 0 96 84 72 60 48 36 logrank p=0.088 (one-tailed) 24 0 12 % Survival Time to death (from any cause) by treatment Ginsberg and Rubinstein Ann Thorac Surg
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
Wedge vs Lobectomy for Stage I NSCLC 120 % Survival 100 80 Wedge Lobectomy 60 40 p=0.889 20 0 0 10 20 30 40 50 60 Landreneau, et.al., J Thorac Cardiovasc Surg 1997;113:691-700
Wedge vs Lobectomy for Stage I NSCLC Open WR VATS WR Vs. Lobe 0 0 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* Op Mortality (%) P< *- 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
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
Results 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 93, 73, 68, 60% 96, 82, 70, 67% p=ns 29 (28.4) 22 (23%) p=ns 65% 53% p=ns Survival % 1, 2, 3 and 4 year Systemic Recurrence Pre-op FEV 1% predicted The FEV 1 did not change postoperatively in the sublobar resection with brachytherapy group in the interval of follow-
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
Lobectomy vs Sublobar Resection 5 Year Cancer Specific Survival “Stage I” 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 0 “Okada, M, et al J Thorac Cardiovasc Surg. 2005 Jan;129(1):87-93”

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Lung cancer

  • 1.
    LUNG CANCER- TREATMENTRECENT ADVANCES & RESULTS Presenter- Dr.Jyotindra singh NIMS,HYDERABAD Non Small Cell Lung Cancer
  • 2.
    Introduction • Most commonmalignancy 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 Incidenceper 100,000 3.8 India 12.1 26.6 China 67.5 13.3 Japan 44.6 12.9 22 120 100 22 80 51.2 60 33.5 40 55.7 Males Females Male Female 2002 2000 1998 1996 1994 1992 1990 0 1988 80 1986 60 1984 40 1982 20 1980 0 20 1978 USA 1976 UK 1974 Sweden
  • 4.
  • 5.
    Pathology Primary Lung Cancer SmallCell type (20% – 30%) Non Small cell type (70% - 80%) Bronchial surface epithelial type Squamous cell (30 - 50%) Goblet cell type Adenocarcinoma (20 - 40%) Clara cell type Large Cell (10 – 15%) Type II alveolar cell type Adenosquamous Bronchial gland type Carcinomas with sarcomatous elements Neuroendocrine Others
  • 6.
    Squamous cell carcinoma Incidenceof 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.
  • 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 inthe 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 medicalexamination, 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<5mmexcellent,>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. • • RET MET Central tumours- higher incidence of LN metastasis. ROS1 EGFR KRAS No known genotype BAC (variant)- higher incidence of LN involvement . ALK • Neuroendocrine differentiation,WDFA –poor prognosis. BRAF HER2 PIK3CA ,
  • 12.
    Risk Factors • Smoking •Genetic predisposition – Genetic trait : Li Fraumeni syndrome (P53 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 & B12 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 Cough Central growth Hemoptysis Dyspnea /Wheeze Pneumonitis Symptoms Pain Cough Peripheral growth Dyspnea Hoarseness Lung abscess Dysphagia Diaphragmatic palsy Regional Spread Horner’s Syndrome SVC syndrome Pancoast syndrome
  • 14.
    Signs • Signs directlycaused 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 SIADH Cushing’s Syndrome Carcinoid Syndrome Gynecomastia Cerebellar degeneration Eaton Lambert syndrome Autonomic neuropathy Optic neuritis Pure red cell aplasia DIC Anemia, thrombocytopenia • Paraneoplastic syndromes: Acanthosis nigricans – Cancer cachexia (MC) – Hypercalcemia – HPOA & clubbing Hyperkeratosis Hypertrichosis VIP induced diarrhea Hyperamylesmia
  • 15.
    Investigations • Investigations toconfirm 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 Xrays – 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.
  • 18.
    Bronchoscopy Most valuable invasiveinvestigation 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.
  • 20.
    Staging • T1: – 3cm 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 Mediastinalpleura Pericardium Main bronchus <2cm to carina – Complete atelectasis / obstructive pneumonitis of entire lung
  • 23.
    Staging • T4: – – – – – – Carina Vertebrae Great Vessel Esophagus Heart Separatetumour nodule in same lobe – MALIGNANT pleural / pericardial effusion
  • 24.
    Staging • N0: – Noregional 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 5yr overall survival Stage TNM 80% T N M IA T1 N0 M0 IB T2 N0 M0 60% IIA T1 N1 M0 50% IIB T2 N1 M0 T3 N0 M0 T3 N1 M0 30% T1-T3 N2 M0 20% T4 N0-N2 M0 IIIA IIIB T1-T4 IV N3 N0-N3 M1 67% 55% 55% 45% 40% 22.50% 10% 7.50% M0 T1-T4 70% 2.50% 0% IA IB IIA IIB IIIA IIIB IV
  • 26.
    Chart illustrates thedescriptors from the 7th edition of the TNM staging system for lung cancer. 2010;30:1163-1181
  • 27.
    Staging Controversies • Tumorsize cutoff of 3 cm. – Several authors have demonstrated the prognostic value of size > 5 cm and recommend it be incorporated in T3 disease. • T3N0M0 is lumped into stage IIB – Prognosis of patients with chest wall disease significantly better than other T3 category tumors even after complete resection. – Even those T3 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 lungcarcinoma • 15 – 25 % of all lung cancers • Almost exclusively in smokers • Distinguished from NSCLC by: – Rapid doubling time – High growth fraction – Early development of widespread 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-limiteddisease: 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~ Limited disease Extensive disease 5 years 18-24 months 10 months • SCLC without treatment < 3 months
  • 31.
    PROGNOSTIC FACTORS • The hostfactors 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 ofchemo & 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 Standardof treatment Cisplatin 80 mg/m2 d1 Etoposide 120 mg/m2 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%
  • 36.
  • 37.
    Surgical Aspects inLung Cancer Management • How fit is the patient ? • What is the stage, histology, and exact size and location ? • Diagnostic • Is the patient for • Treatment – Diagnosis – Treatment – Palliation – – – – Bronchoscopy VATS Mediasteinoscopy Mediasteinotomy – Wedge – Lobectomy – Combined wedge and lobectomy – Pneumonectomy • Palliation – Effusions
  • 38.
    Surgery : PFTbased algorithm Surgery Type Lobectomy /Lesser Pneumonectomy FEV1 > 1.5 L FEV1> 60% DLCO > 60% FEV1 > 2 L FEV1> 60% DLCO > 60% •V/Q scan •Calculated Post operative FEV1 & DLCO Operate > 40% < 40% Exercise study V02 max < 15 ml/kg/min Operate Average risk V02 max > 15 ml/kg/min Medically inoperable
  • 39.
    NSCLC: Stage atDiagnosis • 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 Ettinger et al. Oncology. 1996;10:81-111. Stage I 10% Stage IV 40% Stage IIIB 15% Stage II 20% Stage IIIA 15%
  • 40.
    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.
  • 41.
  • 42.
    SEGMNENTECTOMY WEDGE RESECTION • Smallperipheral tumour confined to an anatomic segment. • Non anatomic and definitive therapy only in poor risk patients. • Patient has limited pulmonary reserve. • 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. • 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, • CALBG ( cancer & leukemia Group B ) - Trial of lobectomy vs sublobar resection. • ACOSOG – Trial sublobar resection vs sublobar resection + implanted radiation seeds.
  • 43.
    Segmentectomy vs wedgerxn • 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)
  • 44.
    LOBECTOMY • Resection of alung 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. BILOBECTOMY • 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 centralproximity of the origins of superior segmental and middle lobe bronchi • Interlobar vascular vascular or nodal involvement.
  • 45.
    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
  • 46.
    Fewer complications • • 1281 Propensitymatched 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%) Hoksch1 Less pain Walker2 Better quality of life Sugiura3 Better PFTs Nakata4 Less pneumonia Whitson5 Earlier recovery Demmy6 Easier for octogenarians McVay7
  • 47.
    SLEEVE LOBECTOMY • Resectionof 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
  • 48.
    Pneumonectomy • The indications arecentral 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 therapydue to extent of their disease they need pneumonectomy Extended Pneumonectomy • Intrapericardial pneumonectomy • Supra aortic pneumonectomy • Carinal pneumonectomy
  • 49.
    CHEST WALL INFILTRATION • Tumorsinvading 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.
  • 50.
    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
  • 51.
    PERICARDIUM • Total resection ofthe 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.
  • 52.
    VERTEBRA • Vertebral body invasionis 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, nodenegative, totally resectable, and, after careful evaluation with MRI, does not involve the spinal canal.
  • 53.
    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.
  • 54.
    Preliminary Supraclavicular Exploration • Dissectionof: – – – – – Posterolateral (Shaw - Paulson) Anterior cervicothoracic (Dartevelle) Hemi-clamshell (Burt) Anteroposterior “hook” (Niwa) VATS - Posterior Supraclavicular nodes S.C. artery Brachial plexus Scalene muscles Phrenic nerve • Adverse prognostic factors: – Horner’s syndrome – N2, N3 disease – Incomplete resection • 9% 5yr survival
  • 55.
    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)
  • 56.
    Technique of MediastinalLymph 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)
  • 57.
    Complete Resection • Freeresection 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
  • 58.
    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 N2 or any N3 disease.
  • 59.
    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%. • 2nd primary lung cancers are known to occur at a rate of 1% per year in survivors.
  • 60.
    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.
  • 61.
    RT: Advanced Disease •Aim: – To achieve local control due to high probability of death due to progression of systemic disease. • Indications: – T3 disease – N1 or small N2 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: – T4 disease – Extensive N2 or N3 disease – Distant metastasis – Weight loss > 12% of body weight – > 50% of normal working time spend in bed.
  • 62.
    Advanced techniques • Recentinnovations – 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.
  • 63.
  • 64.
    Role of PostoperativeRadiotherapy • 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 .
  • 65.
    Brachytherapy • As farback 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.
  • 66.
    Intraoperative Brachytherapy ● Mostly usedfor Stage IIIA disease - ● close or positive margins Improved local control
  • 67.
    Cedars Brachytherapy • 3radiation 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
  • 68.
  • 69.
    Chemotherapy • Based uponthe 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.
  • 70.
    CCT regimens • Standardchemotherapy 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. 22% Gemcitabine 25% Paclitaxel 29% Vinorelbine 30% Irinotecan 25% Mitomycin C 27% Vinbasltine 23% Ifosfamide 21% Cisplatin 0% 10% 20% 30% 40%
  • 71.
    y Advanced Non-Small-Cell LungCancer: 2013 GUIDELINES First-line Therapy: 2013 Column A Cisplatin Carboplatin Column B Vinorelbine Gemcitabine Paclitaxel Docetaxel Pemetrexed Nab-paclitaxel Irinotecan Column C Bevacizumab Cetuximab? Column D Erlotinib Crizotinib 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) National Comprehensive Cancer Network clinical practice guidelines in oncology: Non-small-cell lung cancer (v2.2013). www.nccn.org
  • 72.
    Contenders for SecondLine and Beyond • Non-small cell lung cancer –pemetrexed –gefitinib • Small cell lung cancer –topotecan
  • 73.
    Targeted therapy • EGFRInhibitors – 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.
  • 74.
    Gefitinib: Mechanism ofAction EGF/TGFα R R Extracellular Membrane Intracellular Proliferation Growth factors Chemotherapy/ radiotherapy sensitivity EGFR-TKI  K K  EGFR-TKI Signalling Cell survival (anti-apoptosis) DNA Angiogenesis Metastasis R, epidermal growth factor receptor
  • 75.
    Stereotactic Radiation forLung Cancer (SBRT) • • • • • • • • • 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
  • 76.
    Stereotactic Body RadiotherapyVS 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
  • 77.
    Results- Tumor ResponseAfter 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 1 diaphram. 3 months post-RFA
  • 78.
    CALGB 14053 • Randomizedtrial 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
  • 79.
    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
  • 80.
    Conclusions • Minimally InvasiveLobectomy 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
  • 81.
    Wayne McLaren asthe Marlboro man (1976) Dying from Lung Cancer (1992) Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor 81
  • 82.
    Death is anatural event
  • 83.
  • 84.
    Surgical Resection ofthe Lung Standard of Care For Peripheral Nodules 1940’s 1960’s 1990’s Pneumonectomy Lobectomy ?Segmentectomy/Wedge (and adjuvant local/systemic Rx)
  • 85.
    Randomized Trial ofLobectomy 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
  • 86.
    Lobectomy vs LimitedResection 120 100 80 60 40 20 0 Lobectomy Limited Resection 10 8 12 0 96 84 72 60 48 36 logrank p=0.088 (one-tailed) 24 0 12 % Survival Time to death (from any cause) by treatment Ginsberg and Rubinstein Ann Thorac Surg
  • 87.
    Wedge Resection Versus Lobectomyfor Stage I (T1 N0 M0) Non-Small Lung Cancer Landreneau, et.al., J Thorac Cardiovasc Surg 1997;113:691-700
  • 88.
    Wedge vs Lobectomyfor Stage I NSCLC 120 % Survival 100 80 Wedge Lobectomy 60 40 p=0.889 20 0 0 10 20 30 40 50 60 Landreneau, et.al., J Thorac Cardiovasc Surg 1997;113:691-700
  • 89.
    Wedge vs Lobectomyfor Stage I NSCLC Open WR VATS WR Vs. Lobe 0 0 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* Op Mortality (%) P< *- 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
  • 90.
    Comparison Between Sublobar Resectionand 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
  • 91.
    Results 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 93, 73, 68, 60% 96, 82, 70, 67% p=ns 29 (28.4) 22 (23%) p=ns 65% 53% p=ns Survival % 1, 2, 3 and 4 year Systemic Recurrence Pre-op FEV 1% predicted The FEV 1 did not change postoperatively in the sublobar resection with brachytherapy group in the interval of follow-
  • 92.
    Lobectomy vs Sublobar Resection “Effectof 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
  • 93.
    Lobectomy vs Sublobar Resection 5Year Cancer Specific Survival “Stage I” 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 0 “Okada, M, et al J Thorac Cardiovasc Surg. 2005 Jan;129(1):87-93”

Editor's Notes

  • #80 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 23;2012(0):mms007–7.