Non Small Cell Lung Cancer

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

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 smokingrelated mortality! • In India accounts for the commonest cancer in 3 leading cancer registries – Bhopal, Delhi & Mumbai.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Anatomy

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Lymphatic Drainage Level 1: Highest Mediastinal nodes Level 2: Upper paratracheal nodes Level 4: Lower paratracheal nodes Level 10: Hilar nodes Level 11: Interlobar nodes Level 12, 13, 14: Lobar, segmental & subsegmental nodes

Level 7: Subcarinal nodes nodes Level 8: Paraesophageal nodes Level 9: Pulmonary ligament nodes Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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

Level 5: Subaortic nodes

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Classification & Pathology

Pathology Primary Lung Cancer Non Small cell type (70% - 80%)

Squamous cell (30 - 50%)

Small Cell type (20% – 30%) Bronchial surface epithelial type 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

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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 ?

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Smoking: Association • • • • •

Incidence trends reveal a matching rise and

``fall A cigarette euphemism with changesis in a smoking habits.

for a Rising trend in women correlates with rising cleverly crafted product that incidence of smoking in them Persistent smoking wasright associated with a 16delivers just the amount of fold increase in cumulative lung cancer risk nicotine to keep its user addicted Risk is doubled if smoking commenced before age 15. for life before killing the person.'' Duration and intensity are both correlated the

former in a exponential fashion. Health director-general Gro •World Cancer risk Organization declines substantially after cessation. • Even passive smoking is associated with an Harlem Brundtland 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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Pathogenesis: Squamous type

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Pathogenesis: Adenocarcinoma

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Presentation

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

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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

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

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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

Hypertrichosis

Hyperkeratosis VIP induced diarrhea Hyperamylesmia

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Chest X ray

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Staging & Prognosis

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

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Staging • T3: – – – – –

Chest wall Diaphragm Mediastinal pleura Pericardium Main bronchus <2cm to carina – Complete atelectasis / obstructive pneumonitis of entire lung

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Staging • T4: – – – – – –

Carina Vertebrae Great Vessel Esophagus Heart Separate tumour nodule in same lobe – MALIGNANT pleural / pericardial effusion

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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 Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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 IV

T1-T4

N3

M0

T1-T4

N0-N3

M1

70%

67% 55% 55% 45%

40%

22.50%

10%

7.50%

2.50%

0%

IA

IB

IIA IIB IIIA IIIB IV

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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. – 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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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 Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Surgery

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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)

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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 Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Results • T1 tumors: – Five-year overall survival: 82%. – 10 year overall survival: 74%.

• T2 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

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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%. • 2nd primary lung cancers are known to occur at a rate of 1% per year in survivors. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Radiotherapy

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. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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. – Co60 & 4MV  4% per cm of lung tissue – 10 MV  2% per cm of lung tissue – 20 MV  1% per cm lung tissue

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

IMRT : Institutional example

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

IMRT : Institutional example

PTV

Esophagus

Spinal Cord

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Results: Stage I Authors

Dose

% T1

3 yr OS

3 yr CSS

Intercurrent death

Kaskowitz et al

63 Gy (Median)

38%

19%

33%

27%

Krol et al

60 – 65 Gy

47%

31%

42%

34%

Sandler et al

60 Gy (Median)

32%

17%

22%

16%

Sibley et al

64 Gy (Median)

54%

24%

-

43%

Talton et al

60 Gy

3%

21%

-

-

Noordijk et al

60 Gy

50%

33%

-

40%

• 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%. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

– 1st schedule better as option for a 2nd course kept open if needed.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

45% 40% 35% 30% 25% 20% 15% 10% 5% 0% 1 yr

2 yr

Continous

3 yr

4 yr

Split Course

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Special Situations SVC Syndrome • Patient should be started on decongestive measures prior to starting radiotherapy.

Symptomatic Relief from SVC Syndrome after RT

– 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

15% 15% 50% 20%

Excellent Minimal

Good No response

• Regimen selected depends on patient age and GC. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Superior Sulcus Tumors • In patients with painful apical syndrome only: – 30 Gy / 10 # – Superior border kept at C5 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. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Pain relief

Horner's Syndrome

3 yr Survival

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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%

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Sequential CCT +RT : Results Author

Regimen

N

Median Survival

3 yr OS

Dilman et al (CALGB)

RT (60)

77

9.7 mo

11%

PV  RT (60)

79

13.8 mo

23%

RT (60)

149

11.4 mo

6%

PV  RT (60)

151

13.2 mo

15%

RT (69.6)

152

12 mo

13%

RT (65)

177

10

4%

VCPC  RT  VCPC

176

12

12%

Sause et al (RTOG 88-08)

LeChevalier

• 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!

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Concomitant CCT +RT : Results Author

Regimen

N

Median Survival

2 yr OS

Soressi et al

RT (50)

50

11 mo

25%

P+ RT (50)

45

16 mo

40%

RT (60 -65)

111

11.5 mo

13%

P  RT (60-65)

104

10.6 mo

18%

RT (55)

108

-

13%

P + RT (55)

98

-

19%

P (daily) + RT (55)

102

-

26%

RT (64.8 , HF)

61

8

6.6%

PE** + (64.8 , HF)

56

13

16%

PE** (daily) +(64.8 , HF)

52

18

21%

Blanke et al ShaakeKoning et al (EORTC) Jeremic et al

**Carboplatin and etoposide

• 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). Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

PGI results • Protocol: Cisplatin 30 mg/m2 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)

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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 longterm 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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Radiotherapy: Toxicity • The most common and significant radiation toxicity is radiation pneumonitis. • Occurs in two forms: – Acute (1-6 months). – Late (months to years).

TD 5/5 Volumes & Tolerance (Gy) Organ

1/3

2/3

3/3

Lung

45

30

17.5

Heart

60

45

40

Esophagus

60

58

55

Spinal cord

50

50

47

Brachial plexus

62

61

60

• While acute radiation pneumonitis responds to corticosteroids, late pneumonitis does not respond. • Other toxicities encountered include, transverse myelitis, esophageal strictures or perforation. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

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 Pathophysiology of Radiation Pneumonitis

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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!

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Radiation pneumonitis: Predictors • Dosimetric predictors: – Mean lung dose. – Volume of lung group receiving ≥ 20 Gy (V20)

• Other predictors: – Lower lobe treatment – Pretreatment functional capacity – Concurrent CCT – Smoking (?) – Peripheral location – Increased serum TGF-β

Variable V

20

Mean Lung dose

Cutoffs

% toxicity ( ≥ Gr 2)

22 – 32%

7%

32 – 40%

13%

>40 %

36%

< 20 Gy

8%

>20 Gy

24%

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Technique • Uses Ir192 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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Results Author

Schedule

Symptom control Dyspnea Cough

Hemoptysis

Duration

Bedweinek

XRT 50 Gy  6 Gy x 3

71%

81%

81%

5 months

Speiser

10Gy x 3 ± XRT 60Gy 10Gy x 3 ± XRT 37.5Gy EBBT 7.5Gy x 3

86%

85%

99%

NA

Gollins

15 – 20 Gy x 1

60%

60%

88%

NA

PGI results

8Gy x 2# + XRT 30Gy 10Gy x 1# + XRT 30Gy 15Gy x 1#

91%

84%

94%

5–7 months

• 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. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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%

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

30%

40%

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! Author

Regimen

N

RR

Survival

Median Survival

Roth et al

CEP x 3  Sx

28

35%

56% (3yr)

64 mo

Sx alone

32

-

15% (3yr)

11 mo

IPM x 3  Sx

30

30%

-

Sx alone

30

-

-

Rosell et al

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

1

Mo

8 mo

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. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Results : Advanced cases Author

Regimen

RR

Median Survival

1 yr OS

LeChevalier et al

Cisplatin + Vinorelbine

30%

9.3 mo

35%

Cisplatin + Vindesine

19%

7.4 mo

27%

Vinorelbine

14%

7.2 mo

30%

Cisplatin + Gemcitabine

30%

9.8 mo

37%

Cisplatin + Paclitaxel

32%

9.9 mo

43%

Cisplatin + Vinorelbine

30%

9.5 mo

37%

Cisplatin + Mitomycin + Ifosfamide

50%

5 mo

9 .8%

Scagalotti et al

Behra et al

• 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. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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.

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Therapeutic approach Fit

Surgery

Fitness for Sx

Stage I & II

Unfit RT (±

Inoperable NSCLC

Stage III

Induction CCT

Borderlin e Operabl e

Stage IV

CCT)

    

Surger y

Palliative RT / CCT Supportive care Hospice care Medication Brachytherapy

No

Fitness for Sx Adjuvant RT ± CCT

Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

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. Seminar on NSCLC, Department of Radiotherapy, PGIMER. Moderator : Dr. R. Kapoor

Wayne McLaren as the Marlboro man (1976)

Dying from Lung Cancer (1992)

Seminar on NSCLC, Department of Radiotherapy, PGIMER.93 Moderat

Thank You