- Non-small cell lung cancer is the most common malignancy worldwide and a leading cause of cancer death. It accounts for the majority (70-80%) of lung cancers. - Imaging techniques like CT scans are important for accurately assessing the primary tumor and detecting metastasis. Positron emission tomography (PET) CT is more sensitive than size-based criteria alone for detecting lymph node involvement. - Staging involves classifying the size and extent of the primary tumor and determining if the cancer has spread to lymph nodes or distant organs. Higher stages indicate larger primary tumors or spread beyond the lungs.

1. Non Small Cell Lung Cancer Moderator : Dr. R. Kapoor

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. Anatomy

4. Bronchopulmonary segments Independent anatomical & functional subunits of lungs Number: 10 in each lung Each segment has a centrally located: Segmental bronchus Segmental branch of pulmonary artery Segmental branch of bronchial artery The pulmonary veins and lymphatics are intersegmental in position. Early malignant pathology is usually confined to the segment from which it originates.

5. Lymphatic Drainage Level 1: Highest Mediastinal nodes Level 2: Upper paratracheal nodes Level 4: Lower paratracheal nodes Level 7: Subcarinal nodes nodes Level 8: Paraesophageal nodes Level 9: Pulmonary ligament nodes Level 10: Hilar nodes Level 11: Interlobar nodes Level 12, 13, 14: Lobar, segmental & subsegmental nodes

6. Lymphatic Drainage Level 6: Paraaortic nodes Level 5: Subaortic nodes Level 3A and 3P: Prevascular and retrotracheal nodes

7. Classification & Pathology

8. Pathology Primary Lung Cancer Non Small cell type (70% - 80%) Small Cell type (20% – 30%) Squamous cell (30 - 50%) Adenocarcinoma (20 - 40%) Large Cell (10 – 15%) Adenosquamous Carcinomas with sarcomatous elements Neuroendocrine Others Bronchial surface epithelial type Goblet cell type Clara cell type Type II alveolar cell type Bronchial gland type

9. Squamous cell carcinoma Squamous cell Carcinomas Arise centrally within the main, lobar, segmental or subsegmental bronchi. Extends into the lumen of the airway with invasion into the underlying wall. 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. Tend to be slow growing. Incidence of SCC appears to be decreasing relative to adenocarcinoma.

10. 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 .

11. Special types Bronchoalveolar carcinoma Considered as precursor leison to invasive adenocarcinoma. Growth along pre-existing alveolar structures without evidences of stromal, pleural, or vascular invasion and without metastasis ( lepidic growth pattern ). Right to left intrapulmonary shunt due to impaired gas exchange. Origin : Surfactant secreting Clara cells ?

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

13. Smoking: Association Incidence trends reveal a matching rise and fall with changes in smoking habits. Rising trend in women correlates with rising incidence of smoking in them Persistent smoking was associated with a 16-fold increase in cumulative lung cancer risk Risk is doubled if smoking commenced before age 15. Duration and intensity are both correlated the former in a exponential fashion. Cancer risk declines substantially after cessation. Even passive smoking is associated with an increased risk (25%) China has the largest number of young smokers in the world and the highest incidence! Use of filter cigarettes has been correlated with peripheral carcinogen deposition and association with adenocarcinoma. `` 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

14. Pathogenesis: Squamous type

15. Pathogenesis: Adenocarcinoma

16. Presentation

17. Incidence & Prevalence

18. 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

19. 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 Hyperamylesmia VIP induced diarrhea Hypertrichosis Hyperkeratosis Acanthosis nigricans Anemia, thrombocytopenia DIC Pure red cell aplasia Optic neuritis Autonomic neuropathy Eaton Lambert syndrome Cerebellar degeneration Gynecomastia Carcinoid Syndrome Cushing’s Syndrome SIADH

20. 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

21. Chest X ray

22. Imaging Plain X rays A tumor visible in a chest X ray has usually completed 75% of it’s natural history. Guides local radiotherapy Cheap follow-up assessment 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. Various nodal size criteria exist to predict likelihood of nodal mets. Pitfall : Pneumonitis cant be accurately distinguished. PET CT has a greater degree of sensitivity for detection of nodal disease that would be missed by size based criteria alone.

23. 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.

24. Staging & Prognosis

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

26. 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.

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

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

29. 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

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

31. 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 0 M 0 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. Depth of invasion another important variable that is ignored. Tumors invading the vagus or phrenic nerves have prognosis similar to stage IIIB patients! 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.

32. 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

33. Prevention & Screening The most cost effective method of lung cancer prevention is to stop smoking. Chemoprevention strategies in primary and secondary lung cancers have not been fruitful. Addition of β carotene actually increased incidence & mortality in patients with high risk factors e.g. smoking. CARET trial and ATBC lung cancer prevention trials . Screening of lung cancer was initiated with CXR and sputum cytology Disadvantages : Early detection failed to improve prognosis even in high risk groups. False positive results may be as high as 5% in CXR Both are relatively insensitive to early stages. The prevalence in the population is not high enough to justify routine mass screening. 3 major randomized trials have failed to provide evidence of any benefit from screening. In USA non-contrast spiral CT is being evaluated as a screening tool in the high risk group.

34. Surgery

35. 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. At least nodal sampling should be performed, if not complete lymphadenectomy.

36. 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)

37. 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

38. 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

39. 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.

40. Results T 1 tumors : Five-year overall survival: 82%. 10 year overall survival: 74%. T 2 tumors : Five-year overall survival: 68%. 10 year overall survival: 60% Morbidity : 15% reduction in spirometric values in lobectomy 35% - 45% reduction after pneumonectomy. Mortality : 7% perioperative mortality for pneumonectomy. 4% perioperative mortality for lobectomy

41. 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% Ludwig lung cancer study group. Ann Surg 1987; 250: 67 – 71 . 5 survival in clinical N2 negative nodes: 27 % 5 survival in clinical N2 positive nodes : 8 % Martin et al. Ann Surg 1983; 198 (3): 386 – 97. 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.

42. Radiotherapy

43. 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. Surgical oncology facilities are not available widely. Associated comorbidities and poor lung function make patients not suitable for surgery. Advanced age and poor socioeconomic status make RT an attractive treatment option.

44. Treatment techniques Treatment for cure As definitive treatment alone (or with chemotherapy). As adjuvant treatment post surgery. Treatment for local control with limited probability of survival. Treatment for relief of symptoms , when the disease is too locoregionally advanced for control. Treatment in special situations : Treatment for superior sulcus tumors. Treatment for SVCO. Local palliative treatment Brachytherapy.

45. Curative radiotherapy Indications for curative definitive radiotherapy : Histologically proven squamous cell carcinoma. Medically inoperable patients with localised tumors. Unimpaired functional status with or without symptoms (WHO < 2). Weight loss lesser than 6%. No evidence of distant metastasis. Contraindications for curative definitive radiotherapy are: SVC syndrome. Paralysis of recurrent laryngeal nerve. Paralysis of phrenic nerve. Pleural or pericardial effusions. Extensive infection including abscess formation Destructive involvement of chest wall. Superior sulcus tumors

46. Technique Patients should be treated in supine position unless indicated otherwise. Dose: 60 Gy in 30 # over 6 weeks Both cobalt or LINAC can be used with equal efficacy. Energy range is choosen to be 6 – 10 MV Lung correction factor should be applied during the calculations especially if manual calculation is being done. Co 60 & 4MV  4% per cm of lung tissue 10 MV  2% per cm of lung tissue 20 MV  1% per cm lung tissue

47. Field Selection Parallel opposed anterior and posterior fields are used. The primary disease should be encompassed with the 2 cm margin of normal-appearing lung. In upper and middle lobe or hilar disease, the inferior margin is situated 5 to 6 cm below the carina. In upper lobar disease the superior margin should cover the ipsilateral supraclavicular fossa. In lower lobe disease, inferior margin extends to the vertebral origin of the diaphragm. Width of the mediastinal field encompasses the vascular shadow, or the lymphadenopathy, whichever is wider. Field margins should be such that, the tumor lies within the field during inspiration and expiration.

48. 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  dose escalation impossible Two techniques of respiratory gating are: Breathhold techniques : Active : Using valves and spirometers Passive : Voluntary breath holding (used in PGI) Synchronized gating technique : Uses free breathing with synchronized beam delivery.

49. IMRT : Institutional example

50. IMRT : Institutional example PTV Esophagus Spinal Cord

51. Results Till date phase I / II trials available for 3DCRT 3 yr overall survival in early stage I/II disease 29% (Hayman et al). 50 -60% patients still fail at distant sites.

52. Problems of IMRT in lung Suitability of patients for curative radiation therapy. High incidence of mediastinal nodal involvement even in stage I tumors. Complex tumor movement with breathing and cardiac cycle. Difficulty in assessing proper CTV – Is it pneumonitis or tumor? Intrinsic radiation sensitivity of the lungs and poor pretreatment lung function. Inability to include the mediastinum if dose escalation is desired. Lack of clinically validated predictors of lung toxicity in IMRT with its characteristic inhomogeneous dosage. According to AAPM & ASCO IMRT in lung tumors should not be considered outside research settings at present.

53. Results: Stage I Comparison for crude survival data presented by Fletcher et al reveals the 3 year survival rate of 10% in less advanced tumors. Presently patients with T1 tumors can expect a 3 yr actuarial survival probability in the range of 20% - 30% . 40% - 33% 50% 60 Gy Noordijk et al 3% 54% 32% 47% 38% % T1 - - 21% 60 Gy Talton et al 43% - 24% 64 Gy (Median) Sibley et al 16% 22% 17% 60 Gy (Median) Sandler et al 34% 42% 31% 60 – 65 Gy Krol et al 27% 33% 19% 63 Gy (Median) Kaskowitz et al Intercurrent death 3 yr CSS 3 yr OS Dose Authors

54. Patterns of failure: Early stage Definitive RT alone results in local failure in 33% -45% patients. Lower doses (40Gy) result in local failure in 44% - 50% patients. LeChevalier et al have reported 83% -85% pathological local failure rates in patients treated with dose of 65 Gy. Incidence of distant mets 75% -80% Local tumor control however yields a significantly better survival (22%) at 3 yrs as compared to local failure (10%). Perez et al IJROBP 1986;12:539 – 47

55. Better Surgical results: Why? As a curative modality radiotherapy fares poorly in studies as: Most patients excluded from surgical series have serious medical comorbidities. Pathological staging is not done  37% upstaging by pathological staging can be the reason for stage wise better survival in lung cancer in surgical series. Both modalities are for local control and surgery results in quicker and more through eradication of a small localised disease. Consideration of long term and short term toxicity result in the inability to deliver an actual curative dose in RT trials. The mobility of these tumors may be another reason for their apparent poorer result.

56. 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.

57. Technique For local control where patient is expected to die of systemic disease: ~ 60-80% patients die from distant metastasis in this subgroup making radical treatment futile. Supraclavicular fossa should be incorporated if involved or in upper lobar tumors. Usually a dose of 30Gy in 15# over 3 weeks is followed by 2-3 weeks gap. Further therapy is then individualized. 20 Gy in 10# is given in the second course over 1 week. In certain selected situations 30 Gy / 10# in 2 weeks may be prescribed in the event of a very good response and good GC.

58. Technique For symptom palliation the dose and fractionation is tailored to the condition depending upon the life expectancy: Treatment schedules choosen: If life expectancy is > 3-4 months : 30 Gy in 10# over 2 weeks If life expectancy is from days to 3 months : 20 Gy in 5# over 1 week 8 Gy in single fraction. 1 st schedule better as option for a 2 nd course kept open if needed.

59. Why a Split Course? Majority of our patients are treated with a split course as: Disease is too advanced at presentation to attempt a cure. Allows healing of acute toxicity in between two courses. The split allows the patient to return home and thus is more comfortable for the patient. Response evaluation may be done at the beginning of the second course allowing further treatment selection. We can give simultaneous treatment for any bone or brain mets that the patient may develop during the second course. The theoretical fear of tumor repopulation leading to local failure during the gap is offset by the limited life span and higher probability of death from distant metastasis in these patients.

60. RT results: Split Course Split course RT is criticized due to the radiobiological claim of tumor repopulation during the break. However in two randomized studies by Holsti et al (1980) and Lee et al (1976) no survival advantage of continuous course RT could be demonstrated. In another series by Perez et al ( RTOG 73-01 ), the survival for patients receiving split course was comparable after 4 years to those receiving a continuous regimen (stage I/II). However they also reported a lower in field control rate for split course regimen.

61. Special Situations SVC Syndrome Patient should be started on decongestive measures prior to starting radiotherapy. I/V steroids Moist Oxygen Bronchodilators RT induced edema can exacerbate symptoms in the first few days Doses will depend upon the GC of the patient. Usual doses : 30 Gy in 10# in 2 weeks 20 Gy in 5 # in 1 week 8 Gy in SF Regimen selected depends on patient age and GC.

62. Superior Sulcus Tumors In patients with painful apical syndrome only : 30 Gy / 10 # Superior border kept at C 5 level Inferior border 5 cm below carina Laterally include the full width of the upper 4 ribs . Medially entire mediastium. Pt should be assessed for possible Sx after this course. The contraindications for Sx are mentioned later on.

63. SST: Results Preoperative RT : 50% - 60% become operable after preoperative RT. 5 yr Survival in this group was 30% - 40% which was better than the group who couldn't undergo operation. Martini et al found that preoperative RT also improved the complete resectability rates (from 9% to 40%). Postoperative RT : Like in other situations no survival benefit has been found. However difficulty in obtaining clear resection margins make post operative RT necessary with an aim to improve local control.

64. Inoperable SST Surgery is contraindicated in patients with: Horner’s Syndrome Rib destruction Brachial plexus involvement. Major vessel involvement. Treatment goal is palliation of symptoms. RT/CCT are the main therapeutic modalities.

65. Dose Intensification Rationale : Adding to local control in early disease adds to a survival advantage. Premise : Intensification of dose in temporal or quantitative fashion will translate into a better local control. Basic data : ( Fletcher et al ) Dose required for eradication of malignant squamous cell lung cancer encountered usually varies from 80 – 100 Gy . Implication : We should be in the steep portion of the dose response curve with a steep rise in local control with a small increase in dose. Problem : High radiation sensitivity of lungs and surrounding normal tissue and the high incidence of death from systemic disease. Modalities : Hyperfractionation Chemoradiation Conformal avoidance

66. Hyperfractionation Aims to keep the dose per fraction low to avoid toxicity while giving a number of fractions per day to exploit the differential repair kinetics of malignant and normal cells. In two trials by Arrigada et al and Sause et al no survival benefit could be demonstrated over conventional fractionation. Further no benefit of dose escalation over 69.6 Gy could be appreciated in terms of local control or survival. Hyperfractionated accelerated radiotherapy (HART) in stage IIIA and IIIB patients has been evaluated by a phase II ECOG study. The results were: Median relapse free survival: 7 months 1 year relapse free survival: 23% Grade 3 acute toxicity: 30%

67. CHART & CHARTWEL CHART is a variant where 54 Gy were delivered in 1.5 Gy / # thrice daily over 12 continuous days. Results: 2 year survival 29% (Control – 20%) Local control 23% (Control – 15%) Acute radiation pneumonitis 10% (Control 19%) Severe esophagitis 19% (Control 3%) Late pulmonary fibrosis requiring treatment 16% (Control 4%) Saunders et al. Radiotherapy and Oncology 1999;52:137-148 New modality : CHARTWEL

68. Chemoradiation Administration of chemotherapy concurrently with radiation therapy theoretically improves local control by sensitizing the tumor to radiation, while simultaneously treating systemic disease, albeit at the expense of greater local toxicity.

69. Sequential CCT +RT : Results A metaanalysis by the Institut Gustave-Roussy and the British Medical Research Council Cancer Trials Office showed a statistically significant, overall benefit with chemotherapy. The overall hazard ratio (HR) was 0.90 (p = 0.006) The absolute survival benefit was 3 per cent at 2 years and 2 per cent at 5 years! 12% 12 176 VCPC  RT  VCPC 4% 10 177 RT (65) LeChevalier 13% 12 mo 152 RT (69.6) 15% 13.2 mo 151 PV  RT (60) 6% 11.4 mo 149 RT (60) Sause et al (RTOG 88-08) 23% 13.8 mo 79 PV  RT (60) 11% 9.7 mo 77 RT (60) Dilman et al (CALGB) 3 yr OS Median Survival N Regimen Author

70. Concomitant CCT +RT : Results In the RTOG 9401 trial a concurrent CCT + RT approach resulted in improvement of survival from 14.6 to 17.1 months as compared to sequential approach. Other authors have also corroborated these results ( Furuse et al, Zatloukal et al). **Carboplatin and etoposide 21% 18 52 PE** (daily) +(64.8 , HF) 16% 13 56 PE** + (64.8 , HF) 6.6% 8 61 RT (64.8 , HF) Jeremic et al 26% - 102 P (daily) + RT (55) 19% - 98 P + RT (55) 13% - 108 RT (55) Shaake-Koning et al (EORTC) 18% 10.6 mo 104 P  RT (60-65) 13% 11.5 mo 111 RT (60 -65) Blanke et al 40% 16 mo 45 P+ RT (50) 25% 11 mo 50 RT (50) Soressi et al 2 yr OS Median Survival N Regimen Author

71. Recommendations Useful in patients with good general condition and performance status only. Single agent CCT is no better than radiation alone when used sequentially. Should be using a platinum based regimen as other regimens have not resulted in an improved survival ( Pujol et al ). Concurrent CCT is better than sequential but also leads to a greater toxicity ( RTOG 9401 results ). Higher levels of hematotoxicity should be anticipated before hand. Should be reserved for the trial setting because of the toxicity may not be routinely manageable.

72. PGI results Protocol : Cisplatin 30 mg/m 2 weekly with 50 Gy/25# vs RT 50 Gy/25# alone Despite the limited patient numbers the points emerging were: Patients had symptom severity similar to the palliative patients in the Langendijk study Symptom control was not different. Significantly more dysphagia in chemoradiation arm Paradoxically CR was lesser in the chemoradiation arm (? Less patients completing treatment due to toxicity)

73. 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 and improper fractionation and were conducted in the orthovoltage era.

74. Results Early Stage Disease post complete resection and node negative RT should be avoided as: Most patients die of systemic disease. Local control is excellent with surgery alone. Added toxicity dilutes any survival benefits. Van Houtte et al. IJROBP 1980; 6:983 – 86 PORT Meta-analysis Trialists Group. Lancet 1998;352:257 Negative surgical margins and positive mediastinal nodes Reduction in local recurrence was found in two major trials from 41% to 3% Patients with N2 disease experience better local control, survival and less distant mets but no advantage in N1 disease Stephens RJ. Br J Cancer 1996;74:632. No benefit as far as overall survival is concerned. LCSG. N Engl J Med 1986; 315 : 1377 – 81

75. Preoperative radiotherapy Preoperative irradiation was occasionally used in selected patients to: Reduce the bulk of tumor. Take care of subclinical spread beyond the surgical margins. Prevent dissemination by surgical manipulation. Use lower doses of radiation than those required postoperatively. However preoperative RT is no longer recommended as: Leads to unnecessary treatment delay. If surgical resection is not feasible, then efficacy of further radiation is lowered. Both randomized and nonrandomized data indicate that preoperative radiation alone does not improve the long-term survival 5 year survival rate was 14% after preoperative radiotherapy and 16% after immediate surgery Warram J, Preoperative irradiation of cancer of the lung: final report of a therapeutic trial. A collaborative study, Cancer. 1975 Sep;36(3):914-25 .

76. Radiotherapy: Toxicity The most common and significant radiation toxicity is radiation pneumonitis. Occurs in two forms: Acute (1-6 months). Late (months to years). While acute radiation pneumonitis responds to corticosteroids, late pneumonitis does not respond. Other toxicities encountered include, transverse myelitis, esophageal strictures or perforation. 60 61 62 Brachial plexus 47 50 50 Spinal cord 55 58 60 Esophagus 40 45 60 Heart 17.5 30 45 Lung 3/3 2/3 1/3 Organ TD 5/5 Volumes & Tolerance (Gy)

77. Radiation Pneumonitis Incidence of radiation pneumonitis is related to: Dose. Fractionation. Volume of lung irradiated. Pre-treatment pulmonary function. Administration of concurrent chemotherapy, especially Bleomycin. Asymptomatic radiological findings may be seen in 50% patients. Clinical radiation pneumonitis may develop in as many as 20% patients. Pathophysiology of Radiation Pneumonitis Latent phase: Loss of type 2 pneumocytes, Depletion of surfactant production and resultant protein translocation into the alveoli Edema of interstitial spaces Thickening of alveolar septa Acute clinical phase: Cough, dyspnea Loss of capillaries and collagen deposition Chronic restrictive changes

78. Radiation Pneumonitis Typical manifestations include fever, dyspnea, tachycardia and hypoxia. PFT reveals : Exercise induced oxygen desaturation (early change). Decreased diffusion capacity. X ray findings : B/L airway disease. Vertical (non segmental). Confined to portals. CT findings : Homogeneous slight increase in attenuation (2-4 mo) Patchy consolidation (1-12 mo) Non-uniform discrete consolidation (3 mo - 10 yrs) V/Q scans frequently reveal a perfusion defect!

79. Radiation pneumonitis: Predictors Dosimetric predictors: Mean lung dose. Volume of lung group receiving ≥ 20 Gy (V 20 ) Other predictors: Lower lobe treatment Pretreatment functional capacity Concurrent CCT Smoking (?) Peripheral location Increased serum TGF- β 24% >20 Gy 8% < 20 Gy Mean Lung dose 36% >40 % 13% 32 – 40% 7% 22 – 32% V 20 % toxicity ( ≥ Gr 2) Cutoffs Variable

80. 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.

81. Technique Uses Ir 192 remote afterloading HDR brachytherapy. The total length of endobronchial component with 2 cm margins on either side treated. Usual treatment length is 6-10 cm . Source is passed through a 6 F catheter placed transnasally under bronchscopic guidance. Dose prescribed is 8 Gy in 2# after XRT. Dose is prescribed at 1 cm from the central axis of the source.

82. Results In another previous series the duration of symptom relief was found to be 6 months when EBBT was added to XRT 30 Gy in 10# (Sharma et al). The most feared complication is massive hemoptysis which may occur in as many as 10% in some series. 5 – 7 months 94% 84% 91% 8Gy x 2# + XRT 30Gy 10Gy x 1# + XRT 30Gy 15Gy x 1# PGI results NA 88% 60% 60% 15 – 20 Gy x 1 Gollins NA 99% 85% 86% 10Gy x 3 ± XRT 60Gy 10Gy x 3 ± XRT 37.5Gy EBBT 7.5Gy x 3 Speiser 5 months 81% 81% 71% XRT 50 Gy  6 Gy x 3 Bedweinek Duration Hemoptysis Cough Dyspnea Symptom control Schedule Author

83. Chemotherapy & Targeted therapy

84. 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.

85. 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.

86. Induction CCT Induction CCT is a sometimes used in stage III A patients to make them suitable for surgery  Downstaging is the intent of treatment. Disadvantage : Delay in initiation of radiotherapy if patient fails to respond to CCT Some patients otherwise suited for primary surgery may have disease progression during CCT itself. Approach remains valid in a very small selected group of highly motivated and affordable patients with good general condition preferably in a trial setting! 8 mo Mo 11 mo 64 mo Median Survival - - 30 Sx alone - 30% 30 IPM x 3  Sx Rosell et al 15% (3yr) - 32 Sx alone 56% (3yr) 35% 28 CEP x 3  Sx Roth et al Survival RR N Regimen Author

87. Adjuvant CCT Results : NSCLC-CG performed a metaanalysis examining survival in 9387 patients (7151 deaths) in 52 randomized clinical trials. Cisplatin-based chemotherapy regimens appeared to improve survival in patients undergoing resection by 5% but benefit was stastically insignificant. Survival benefit of 2-4% is expected against an expected mortality of 1-2% directly related to CCT toxicity. Relative chemoresistance of NSCLC makes the approach even more questionable.

88. Results : Advanced cases In the study reported from PGI : 33% patients couldn't take more than 1 cycle due to toxicity, lack of affordability or death. Survival was significantly correlated with performance status. Thus even in advanced disease RT probably a better option specially in most patients in our setup. 9.8% 5 mo 50% Cisplatin + Mitomycin + Ifosfamide Behra et al 37% 9.5 mo 30% Cisplatin + Vinorelbine 43% 9.9 mo 32% Cisplatin + Paclitaxel 37% 9.8 mo 30% Cisplatin + Gemcitabine Scagalotti et al 30% 7.2 mo 14% Vinorelbine 27% 7.4 mo 19% Cisplatin + Vindesine 35% 9.3 mo 30% Cisplatin + Vinorelbine LeChevalier et al 1 yr OS Median Survival RR Regimen Author

89. Summary of CCT evidence Evidence for any beneficial effect of CCT exists for patients with: WHO performance status 0 – 2 Age < 70 yrs. Platinum based regimens should be used and single agent CCT should be avoided (except in selected PS 2 patients) Adjuvant CCT after Surgery is not recommended without further evidence of its efficacy. Median prolongation of survival is approx 3.4 months in the palliative care setting but QOL is better than with BSC. Aggressive CCT regimens have failed to demonstrate a survival advantage over conventional regimens despite the cost and toxicity.

90. 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 .

91. Therapeutic approach NSCLC Stage I & II Fit Unfit Fitness for Sx Surgery RT ( ± CCT ) Stage IV Palliative RT / CCT Supportive care Hospice care Medication Brachytherapy Stage III Operable Inoperable Borderline Surgery Adjuvant RT ± CCT Induction CCT Fitness for Sx No

92. Conclusions Lung cancer remains a fatal disease in 70% - 80% patients affected. Surgery remains the gold standard treatment in patients with early resectable disease. Radiation has an important part to play in all stages & for radical treatment as well as palliation. In India however majority of patients present with advanced disease suited for palliation only. Alternate fractionation and chemoradiation are yet to prove their mettle in our setup. Systemic therapy remains ineffective and costly for this disease. Prevention through education and legislation remains the most cost effective way to reduce incidence and mortality.

93. Wayne McLaren as the Marlboro man (1976) Dying from Lung Cancer (1992)

94. Thank You