Evaluation and management of Stage III Non-Small Cell Carcinoma Lung including Radiotherapy planning. On a Radiation Oncologist Perspective. MD Radiotherapy discussion - CMC, Vellore

1. MANAGEMENT OF
LOCALLY
ADVANCED NSCLC
DR BOAZ VINCENT
14.07.2017

2. EPIDEMOLOGY
 Lung cancer is the leading cause of cancer death in
the world
WORLD INDIA
New cancer cases 13 % 6.9 %
Cancer related mortality 19% 9.3%
Lung cancer: Prevalent trends & emerging concepts,
Indian J Med Res 141, January 2015, pp 5-7

3. Risk Factors
 Active Cigarette Smoking
 Other causal agents:
 Second hand smoking
 Ionizing radiation (including radon)
 Occupational exposures (arsenic, chromium, nickel, asbestos)
 Indoor and outdoor pollution
 Additional risk indicators: age, male sex, family history, acquired lung
disease

4. Screening
 At least 6 large RCTs evaluated lung cancer screening with CXR, and
none showed a mortality benefit to screening
 Screening with low dose CT – Reduced mortality
 Average dose 2 mSv.
 Eligible patients:
 55-74 years
 30 pack years of smoking; if quit, then within 15 years
 53,454 randomized to 3 annual LDCTs vs. 3 annual CXRs

6. • 20% relative reduction in lung cancer mortality
• 6.7% relative reduction in all-cause mortality

7. 35%
50%

8. Routes of spread
 Local extension –
o pleural surfaces, chest wall, ribs, and mediastinal structures
o Apical tumours – Superior sulcus syndrome, SVCO
o Recurrent Laryngeal Nerve - Vocal Cord paralysis
o Phrenic Nerve – Diaphragmatic paralysis
 Regional LNs – Hilar, Interlobar, mediastinal
 Distant metastases

11. Lung – AJCC 8Th Edition
T1 Tumour 3 cm or less
T1mi Minimally invasive adenocarcinoma
T1a Tumour 1 cm or less
T1b Tumour more than 1 cm but not more than 2 cm
T1c Tumour more than 2 cm but not more than 3 cm
T2 Tumour more than 3 cm but not more than 5 cm; or tumour with any of the
following features:
Involves main bronchus without involvement of the carina, or
invades visceral pleura or associated with atelectasis or obstructive
pneumonitis
T2a Tumour more than 3 cm but not more than 4 cm
T2b Tumour more than 4 cm but not more than 5 cm

12. Lung – AJCC 8Th Edition
T3 Tumour more than 5 cm but not more than 7 cm or directly invades:
parietal pleura, chest wall, phrenic nerve, or parietal pericardium; or
separate tumour nodule(s) in the same lobe.
T4 Tumour more than 7 cm or of any size that invades any of the following:
diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal
nerve, oesophagus, vertebral body, carina; or separate tumour nodule(s) in
a different ipsilateral lobe to the primary
N Category- No Change
M Category
M1a Separate tumour nodule(s) in a contralateral lobe; tumour with pleural or
pericardial nodules or malignant pleural or pericardial effusion
M1b Single extrathoracic metastasis in a single organ
M1c Multiple extrathoracic metastasis in a single or multiple organs

14. Right Lung
Upper-1,2,3,4,7
Middle-1,2,3,4,7
Lower-1,2,3,4,7,8,9
Left Lung
Upper-4,5,6,7
Lower-4,5,6,7,8,9

15. Work up

16. RADIOLOGICAL
INVESTIGATIONS
 Chest X ray
 CT scan - Base of the neck to below adrenal glands
 Tumour size, mediastinal & vascular invasion
 Lymph node involvement
 Estimate the proximal extent of the tumour within the
airways.
 Distant mets
 Sensitivity is 64% and specificity is 74%
 Bone Scan
 MRI

17. PET CT SCAN
 Confirm staging
 Detecting metabolically active intrathoracic LNs
 Any occult distant metastaic disease
 Sensitivity & specificity for staging is 83 and 91%,
respectively.
 PPV is ~80% (false-positive rate ~10–20%)
 NPV is ~95% (false-negative rate ~5–16%)

18. Getting tissue from thorax
 Sputum cytology
 Bronchoscopy
 Endobronchial ultrasound
 Esophageal ultrasound
 Transthoracic biopsy
 Mediastinoscopy
 Electromagnetic navigation
 VATS

19. Pathology
 ADENO CA – Neoplastic gland formation or intra-
cytoplasmic mucin
 SQUAMOUS CELL CA – Presence of Keratin
production or intra cellular desmosomes
 ADENO SQUAMOUS- Greater than 10% malignant
glandular and squamous components

20. Immunohistochemistry

21. DRIVER MUTATIONS
 Somatic gene alterations
 Occurs in genes encoding for proteins which are
critical in cell growth and survival
 1. EGFR – 15% - US ; up to 62% - Asians
Non smokers
Erlotinib, Gefitinib, osemertinib

22. 2. ALK Mutation(Anaplastic Lymphoma Kinase)
 4% in US
 Non smokers and younger patients
 Crizotanib, Ceritinib, alectinib
3. ROS1 translocation 1-2 %
 Adenocarcinoma, young, never smokers
 Crizotinib

23. MANAGEMENT OF STAGE III NSCLC
1. UNRESECTABLE
2. RESECTABLE

24. UNRESECTABLE NSCLC
 T4 or N2 disease
 Concurrent chemo radiotherapy is now the standard of
care in unresectable Stage III

25. Unresectabe - RT alone
Perez at al , IJROBP 1986
• Compared 60 Gy , 50 Gy, 40 Gy and 40 Gy Split course
• Found wit 60 Gy
• Higher complete response – 24%
• Intra-thoracic tumor control – 57%
• 3 year overall survival – 15%

26. With 60 Gy
• Higher complete
response – 24%
• Intra-thoracic tu
control – 57%
• 3 year OS – 15%

27. Chemo + RT Vs RT alone
 Although dose escalation was achievable and
appeared to be associated with improvements in local
control in locally advanced NSCLC, the dominant
pattern of failure was distant dissemination in about
75% to 80% of patients.
 To address the issue of systemic therapy was
considered

30. • Six trials were received (1,205 patients).
• Median follow-up was 6 years.
• Significant benefit of concomitant Rx on overall survival),
• with an absolute benefit of 5.7% at 3 years
• and 4.5% at 5 years.
• For progression-free survival – better with concuurent chemo RT
• No effect on distant progression
• Increased acute esophageal toxicity (grade 3-4) from 4% to 18%
• No significant difference regarding acute pulmonary toxicity

32. Optimal chemotherapy
regime?

33. • Identified patients treated with EP and CP with
concurrent radiotherapy - 2001 to 2010.
• Survival rates were compared
Conclusion :
• Patients treated with
EP versus CP had
similar overall
survival, but EP was
associated with
increased morbidity.

34. Optimal dose

35. Interpretation
• 74 Gy in 2 Gy fraction
with conc chemo was
not better than 60 Gy,
and might be
potentially harmful.
• Addition of cetuximab
to concurrent chemRT
provided no benefit in
OS

37. Un-resectable Stage III - Summary
 Concurrent chemo-radiotherapy is preferred
 Optimal chemotherapy is an open question
 Randomized evidence supports a total dose of 60Gy in 2Gy
daily fractions with concurrent chemotherapy
 Sequential chemo-radiation, and radiation alone are options in
less-fit patients

38. RESECTABLE STAGE III
 In carefully selected patients with limited stage IIIA disease
that can be completely resected, initial surgery is often the
treatment of choice
 Examples include T3N1 disease, or T4 disease due to
multiple tumor nodules in one lung

39. POST OP CHEMOTHERAPY
• Individual patient data pooled from the five largest trials
(4,584 patients) of cisplatin-based chemotherapy in
completely resected patients conducted after 1995

41. 5-year absolute
benefit of 5.4%
from chemotherapy

42. POST OPERATIVE
RADIOTHERAPY
 Why consider PORT?
 R1 resection (positive margins)
 R0 resection with positive nodes

43. PORT : Positive margins
• Patients with path stage N0-2 / stage II or III NSCLC
• Undergone a lobectomy or pneumonectomy with positive
surgical margins
• PORT – 50 to 74 Gy Vs observation
• Conclusion : PORT is associated with improved overall
survival

45. PORT in N2 nodes ??
 Still controversial
 Ongoing Trial EORTC 22055 – Phase III European
LUNG-ART randomized trial
 Dose is 54 Gy in 30 fractions

46. EORTC 22055

47.  Chemo RT followed by Surgery Vs Chemo RT alone-
 Intergroup 0139 (Lancet. 2009)
 Surgery arm – Better local control and PFS , No OS benefit
 Benefit those who underwent Lobectomy, high post operative
complications in pneumonectomy patients
 Chemo – Surgery Vs chemo followed by RT
 EORTC 08941
 Median survival and five-year overall survival rates were similar.
 RT is the preferred local treatment

48. Stage III resectable - summary

49. RADIOTHERAPY PLANNING

50. RTOG 0839
Immobilisation
 Patient is made to lie in a supine position with arms above or in an
akimbo position
 Immobilised using a VacLoc
 CT simulation is done in the same position
 CT images are aquired in 3mm/5mm cuts from level of cricoid
superiorly to include whole of liver inferiorly
 </=3mm slices are recommended throug the regions of gross
tumour, Enlarged LNs

51. Tumor volumes
GTV
Primary tumour + Gross nodes as visualised on CT/PET
(Nodes >1cm short axis diameter and/or with PET
uptake of suvMax of 3)
CTV
GTV + 0.5-1 cm margin - microscopic tumor extension.
All known levels of mediastinal nodal involvement
(defined both clinically and pathologically )
ITV / PTV

53. Simulation Techniques

54. OARs

55. PORT – LUNG ART Trial

56.  To start PORT as soon as possible after randomization.
 No concomitant chemotherapy is allowed.
 At least 10 days’ interval between the last day of chemotherapy
and PORT is requested – more in case of radio-sensitizing
chemotherapy.
 Dose - 54 Gy in 27 fractions of 2.0 Gy / fraction
 Treat once a day, 5 days per week.

57. Volume definitions
 rCTV in the mediastinum :
 Pathologic positive LN stations
 The bronchial stump, the homolateral hilar node region
will always be included in the rCTV.

58.  CTV in the mediastinum
 rCTV plus a margin corresponding to the upper and lower LN
station
 All LNs between two invoved noncontiguous node stations
will be included
 Because of the frequent involvement of subcarinal (LN7) and
paratracheal nodes (LN4) on surgical series, these stations
will also be systematically
 Left sided tumor - subaortic and PA nodes (LN 5 and 6)
should be included because they are very often involved
 Homolateral supraclavicular region will not be included
systematically in the CTV

59. PTV-
 Owing to organ movements and to setup uncertainties, an
additional margin of
 at least 0.5 cm (lateral, anterior, and posterior) and
 1 cm (superior and inferior) is recommended.

61. Right Lung
Upper-1,2,3,4,7
Middle-1,2,3,4,7
Lower-1,2,3,4,7,8,9
Left Lung
Upper-4,5,6,7
Lower-4,5,6,7,8,9

62. SEQUELAE OF THERAPY
Acute Sequelae
 Acute toxicities: Esophagitis, cough, skin reaction
 Acute radiation esophagitis: begins in the 3rd week of
R/T, approximately 30 Gy
 Nutritional status is compromised: N-G tube,
temporary gastrostomy
 Radiation pneumonitis:
Bed rest, bronchodilators, and steroids

63. SEQUELAE OF THERAPY
Late Sequelae
 Pneumonitis (10% grade 2 and 4.6% grade 3)
 Pulmonary fibrosis (20% grade 2 and 8% grade 3 or greater)
 Esophageal stricture
 Cardiac sequelae (pericardial effusion, constrictive
pericarditis, cardiomyopathy)
 Spinal cord myelopathy
 Brachial plexopathy.

64. Follow up

65. Thank You!!

66. CHART

67. HART