This document discusses the management of locally advanced lung cancer. It provides information on the epidemiology, risk factors, anatomy, patterns of spread, diagnostic workup, staging, and management approaches for resectable stage III disease. Management involves induction chemotherapy or chemoradiation followed by surgery with postoperative radiotherapy or chemotherapy, depending on pathological findings. The evidence from clinical trials supports the use of multimodality therapy with chemotherapy and radiation for improved outcomes in resectable locally advanced non-small cell lung cancer.

1. MANAGEMENT OF LOCALLY
ADVANCED LUNG CANCER
PRESENTED BY DR FARAZ BADAR
MODERATOR : DR KUSHAL NARANG
DATED : 07/12/2019

2. EPIDEMIOLOGY
• Accounts for 11.6% of the total cases of cancer and 18.4 % of the
cancer-related deaths (Globocan 2018)
• Males  Most commonly diagnosed cancer. Leading cause of cancer
death.
• Females  Fourth most commonly diagnosed cancer. Second leading
cause of cancer death.
• The overall 5-year survival rate  18%.
• INDIA 2nd most common cancer in males.

3. RISK FACTORS
• Majority of cases attributable to cigarette smoking. (80% - 90%)
• The smoker to non-smoker ratio ~ 20:1
• Exposure to secondhand smoke  30% increase in risk from
secondhand smoke exposure associated with living with a smoker
• Indoor radon exposure
• Exposure to occupational carcinogens  asbestos, arsenic, and
polycyclic aromatic hydrocarbons.

4. ANATOMY
• Conical in shape
• Apex projecting upward into the
neck for 2 to 3 cm above the
clavicle.
• Base sitting on the diaphragm
• Costal surface along the chest wall
• Mediastinal surface that is molded
to the heart and other mediastinal
structures
• Visceral pleura cover the lungs.
• Parietal pleura cover the inside of
the chest cavity.

7. BRONCHOPULMONARY SEGMENTS
• Smallest functionally independent area of the lung.
• Can be safely resected without affecting adjacent structures.
• Trachea  Main Bronchi  Lobar bronchi  segmental bronchi.
• Segmental bronchi supply Bronchopulmonary segment.
• Pyramidal in shape, with an apex toward the lung root and a base at
the pleural surface.
• 10 BPS in each lung.

8. LYMPHATIC DRAINAGE
• International Association for the Study of Lung Cancer (IASLC) has
proposed a new lymph node map
• Endorsed by the American Joint Committee on Cancer (AJCC)
• 14 levels of intrapulmonary, hilar, and mediastinal lymph nodes
stations.
• Compartmentalized the stations into zones  prognostic
implications.

10. LYMPH NODE STATION
NUMBER
DESCRIPTION
1 Low cervical, supraclavicular, and sternal notch nodes
2 Upper paratracheal nodes
3 Prevascular and retrotracheal nodes
4 Lower paratracheal nodes
5 Subaortic (aorto-pulmonary Window)
6 Para-aortic nodes (ascending aorta or phrenic)
7 Subcarinal nodes
8 Paraesophageal nodes (below carina)
9 Pulmonary ligament nodes
10 Hilar nodes
11 Interlobar nodes
12 Lobar nodes
13 Segmental nodes
14 Subsegmental
N1 NODES

11. PATTERNS OF SPREAD
• At diagnosis, 15%  localized to the primary site, 22% regional lymph
node spread, and 56%  Distant metastasis.
• NSCLC  50% of patients presented with localized or locally advanced
disease and 50 % with advanced disease.
• SCLC  20% to 30% present with locally advanced disease, and 70% to 80%
present with advanced disease.
• Two patterns of spread can be identified
• 1) LOCOREGIONAL (intrathoracic)  Direct invasion
• 2)DISTANT (extrathoracic)  Lymphatic/vascular invasion

12. PATTERN OF LYMPH NODAL INVOLVEMENT
• Lymph node level involvement depends
on the location of the primary tumor#
• Right upper and middle lobe tumors 
Station 4 (Lower paratracheal)
• Right lower lobe tumors  Station 7
(subcarinal)
• Left upper lobe tumors  Station 5
(subaortic)
• Left Lower lobe tumors  Stations 7
and 9. subcarinal and pulmonary
ligament nodes
• Stations 4, 5, and 7 are the most
commonly involved
#  Kotoulas CS, Foroulis CN, Kostikas K, et al. Involvement of lymphatic metastatic spread in non-small cell lung cancer
accordingly to the primary cancer location. Lung Cancer 2004;44:183–191.

13. Contralateral lung, liver, bone, adrenals, and brain are the
most frequent sites of distant disease

14. CLINICAL FEATURES
• COUGH  most common presenting symptom.
• HEMOPTYSIS  25% of patients. Either due to tumor invading a blood vessel or bleeding
from fragile neo-vasculature.
• WHEEZING  Due to progress of central airway involvement.
• SHORTNESS OF BREATH
• CHEST PAIN  due to direct extension to the mediastinum, parietal pleura, or chest wall.
• HOARSENESS OF VOICE recurrent laryngeal nerve involvement.
• HICCUPS  due to phrenic nerve involvement  progress to u/l paralysis of diaphargm
• FULLNESS IN HEAD, SWELLING OF FACE AND ARMS due to superior vena cava
obstruction. (more common in small cell lung cancer)
• PANCOAST'S SYNDROME
o shoulder pain + brachial plexopathy + horner's syndrome.
o char by severe radicular pain in the distribution of ulnar nerve.
o seen in superior sulcus tumors.

15. SYNDROME FOUND IN CLINCIAL FEATURES
SIADH SCLC  headache, muscle cramps, anorexia, and
decreased urine output.
 results in hyponatremia
 If untreated cerebral edema
Cushing Syndrome SCLC, CARCINOID muscle weakness, weight loss, hypertension,
hirsutism, and osteoporosis.Hypokalemic alkalosis and
hyperglycemia are usually present.
Hypercalcemia Squamous cell carcinoma (m/c) >
Adenocarcinoma> Small cell lung cancer
 anorexia, nausea, vomiting, constipation, lethargy,
polyuria, polydipsia, and dehydration.
LEMS SCLC  Proximal muscle weakness that improves with
repeat testing (rising from a sitting position)
HPO Adenocarcinoma  Clubbing, symmetrical, painful arthropathy of
ankles, knees, wrists, and elbows

16. PATHOLOGY
• ADENOCARCINOMA Most common histology, 38% of all lung
cancers. Majority are peripheral.
• SQUAMOUS ~20% of all lung cancers. Majority are centrally
located.
• SMALL CELL CARCINOMA 13% of all lung cancers, almost always
associated with smoking
• OTHER: Consists of other rare histologies and other neuroendocrine
carcinomas such as large cell or carcinoid.

17. DIAGNOSTIC WORKUP
• Complete History (elicit tobacco use)and physical examination
• Laboratory studies  CBC, KFT, LFT, Serum electrolytes including calcium,
PFTs
• Chest X-ray
• CECT scan of the thorax and abdomen  include the entire liver and
adrenal glands
• PET CT  Higher sensitivity and specificity for nodal disease.
• High rates of false positives and false negatives.
SENSITIVITY SPECIFICITY
FDG PET 81% 90%
CT 59% 79%

18. • MRI brain indicated in stage II or higher disease (NCCN)/ MRI of thorax for superior
sulcus tumors to check for brachial plexus invasion/ MRI spine for symptomatic
patients to rule out cord compression.
• Bronchoscopy  Advantage  Direct visualization
• Endobronchial Ultrasound  stations 2, 3, 4, 7 and 10 could be examined.(Superior
mediastinal/subcarinal/ hilar)
• Mediastinoscopy  Can evaluate stations 2, 4, and 7.
• Chamberlain procedure (Anterior mediastinotomy)  to evaluate nodes in stations
5 and 6.(Subaortic and paraaortic)
• CT guided biopsy  for peripherally-located lesions, or at sites of distant disease.

19. AJCC STAGING OF LUNG CANCER, 8TH EDITION
T1
• Tumor 3 cm or less in greatest
dimension, surrounded by lung or
visceral pleura, without bronchoscopic
evidence of invasion more proximal
than the lobar bronchus (i.e., not in the
main bronchus)
• T1a Tumor is ≤1 cm in greatest
dimension
• T1b Tumor  >1 cm but ≤2 cm in
greatest dimension
• T1c Tumor >2 cm but ≤3 cm in
greatest dimension

20. T2
• Tumor >3 cm but <5 cm or having any of the
following features:
• Involves the main bronchus regardless of
distance to the carina, but without involvement
of the carina
• Invades visceral pleura
• Associated with atelectasis or obstructive
pneumonitis that extends to the hilar region,
involving part or all of the lung
• T2 tumors with these features are classified as
• T2a  < 4 cm or if the size cannot be
determined and
• T2b  if >4 cm but <5 cm.

21. T3
• Tumor >5 cm but <7 cm in greatest
dimension or directly invading any of
the following:
• Parietal pleura
• Chest wall (including superior sulcus
tumors)
• Phrenic nerve
• Parietal pericardium
• Separate tumor nodule(s) in the same
lobe as the primary

22. T4
• Tumor >7 cm or tumor of any size invading one
or more o f the following:
• Diaphragm
• Mediastinum/heart/ great vessels
• Trachea
• Recurrent laryngeal nerve
• Esophagus
• Vertebral body
• Carina
• Separate tumor nodule(s) in an ipsilateral lobe
different from that of the primary

23. • N1 ipsilateral peribronchial /hilar lymph nodes and intrapulmonary nodes
• N2  ipsilateral mediastinal/subcarinal lymph node(s)
• N3  contralateral mediastinal/contralateral hilar/ipsilateral or contralateral
scalene, or supraclavicular lymph node(s)

24. • M0  No distant metastasis
• M1 Distant metastasis
• M1a  Separate nodules in contralateral lobe/ Pleural nodules
and/or Malignant pleural/pericardial effusion.
• M1b  Single extrathoracic metastasis in single organ and/or single
non-regional lymph node
• M1c  Multiple extrathoracic metastasis

25. STAGE GROUPING: TNM SUBSETS, 8TH EDITION

26. STAGE III
Resectable Unresectable
Preop chemo or
chemoRT chemoRT RT only
surgery
PORT + adj. CT
MANAGEMENT OVERVIEW

27. MANAGEMENT OF RESECTABLE
STAGE III DISEASE

28. INDUCTION CHEMOTHERAPY
• Neoadjuvant versus Adjuvant Taxol/Carbo Hope trial
(NATCH)#
• 624 patients with Stage IA (>2 cm), IB, II, or T3N1
• Randomization Neoadjuvant versus adjuvant versus
surgery alone arms
• Chemotherapy 3cycles of carboplatin–paclitaxel
• Results  Neoadjuvant arm had a trend toward better
DFS than surgery alone arm (not significant)
• Subset analysis of only stage II-T3N1  5-year DFS was
36.6% in the neoadjuvant arm and 25% in the surgery
arm (HR 0.81, P = .07).
• The adjuvant arm showed less benefit than the
neoadjuvant arm.

29. PREOPERATIVE CONCURRENT
CHEMORADIATION : INT-0139 TRIAL

30. POST OPERATIVE RADIOTHERAPY
• Indications  pN2 disease and microscopically positive margins
• Evidence for PORT
• PORT Meta-Analysis(Burdett S et al., Lung Cancer 2005) Subset
analysis showed a detriment to PORT in resected stages I–II disease
but no adverse effect in N2 disease.
• SEER Analysis (Lally BE et al., JCO 2006)  For N2 subset, PORT was
associated with better OS (HR 0.85) but detrimental for N0-N1.
• Reanalysis of the ANITA trial (Douillard JY et al., IJROBP 2008)
PORT improved survival for both observation and chemotherapy arms
in pN2 patients.

31. POST OPERATIVE CHEMOTHERAPY
• 4,584 patients included on five PRTs of
adjuvant Chemotherapy in NSCLC.
• MFU  5.2 years.
• Overall HR of death was 0.89 (p =
.005), corresponding to 5-year
absolute benefit of 5.4%.
• Benefit of adjuvant chemotherapy
varied with stage  detrimental for
stage IA (HR 1.4), nonsignificant for IB
(HR 0.93), and beneficial for stage II
(HR 0.83) and III (HR 0.8).
• Conclusion: Chemotherapy confers
survival advantage in stage II/III NSCLC

32. POST OPERATIVE CHEMORADIOTHERAPY
• Recommended if gross
disease was left behind at
surgery and variably
recommended if microscopic
disease was left behind at
surgery.
• No phase III evidence.
• Evidence comes from ECOG
3590 and RTOG 9705 studies
• Both are phase II trials

33. MANAGEMENT OF
UNRESECTABLE STAGE III DISEASE

34. SEQUENTIAL CHEMORADIOTHERAPY
• CALGB 8433
• Phase III randomized trial of 155 patients
• Unresectable stage III NSCLC
• RANDOMISATION  Radiotherapy alone to 60 Gy or to induction
chemotherapy with cisplatin and vinblastine followed by radiotherapy
to 60 Gy.
• RESULTS  Median survival improved with induction chemotherapy
to 13.7 months versus 9.6 months with radiotherapy alone (P =
.0066).
• The 5-year survival improved from 6% to 17% with induction
chemotherapy

35. CONCURRENT CHEMORADIOTHERAPY
• Standard of care for fit patients.
• Evidence shows better outcomes with concurrent approach compared to
sequential chemoradiation.
• West Japan Lung Cancer Study Group (Furuse K et al., JCO 1999)
• 320 stages II–III patients
• RANDOMISATION  Sequential vs. concurrent CRT.
• Concurrent arm  CDDP/vindesine/MMC with split-course RT (28 Gy * 2).
• Sequential arm  same chemo → RT (56 Gy conventional, nonsplit
course).
• RESULTS  There was better OS and PFS in patients with concurrent CRT.
• MS was 16.5 months vs. 13.3 months
• 5-yr OS was 15.8% vs. 8.9% .

36. RTOG 9410
• 610 pts randomized to 3 arms
• Sequential (Dillman regimen with RT to 63
Gy) (arm 1)
• Concurrent CRT (to 63 Gy) (arm 2) and
• Concurrent hyperfractionated RT (1.2
bid/69.6 Gy) + chemo (arm 3).
• Chemo was CDDP/vinblastine (except EP
for arm 3).
• RESULTS  Definitive concurrent CRT (arm
2) had a better outcome in MS (17 months)
vs. 14.6 months (arm 1) or 15.6 months
(arm 3) and 5-yr OS (16% vs. 10% vs. 13%).
• ↑ toxicity in the concurrent CRT arm.

37. • Evaluated data from six clinical trials involving 1,205 patients.
• Median follow-up  6 years
• RESULT  Significant benefit favoring concurrent over sequential
chemotherapy and radiotherapy with respect to OS (HR 0.84, P = .004),
• Absolute increase in survival of 5.7% (from 18.1% to 23.8%) at 3 years and
4.5% at 5 years.
• PFS also improved (HR 0.90, P = .07).
• Concurrent chemoradiotherapy decreased locoregional progression (HR 0.77,
P = .01), although not distant progression.
• Increase in acute esophageal toxicity (grades 3 and 4) from 4% to 18% with a
relative risk of 4.9 (P <.001).

38. MOULD AND SCAN
• Supine position with hands over head
• Thermoplastic cast
• Knee support
• Appropriate head rest
• Scan limit Cricoid cartilage to the superior aspect of the L2
• Slice thickness  3mm
• 4D-CT scan is recommended.
• Active breathing coordinator (ABC) system  optional
• Specific planning-PET-CT scan  preferably in planning position

39. 2D PLANNING
• For 2D planning: -2cm margin around any gross tumor and 1cm
margin around regional lymph node groups
• Upper lobe tumors- I/L supraclavicular and subcarinal lymph nodes to
be included.
• Middle and lower lobe tumors- entire mediastinum from the thoracic
inlet to the diaphragm. Fields: AP-PA portals till spinal cord tolerance
(~40Gy).
• Boost of 20Gy by shrinking field technique after spinal shielding..
• Dose: 60Gy in 30# over 6 weeks (RTOG 73-01 trial).

40. CONFORMAL PLANNING
GTV #
• Primary tumor , clinically positive lymph
nodes seen either on the planning CT (>
1 cm short axis diameter) or on
pretreatment PET/CT scan (SUV > 3), and
any known involved nodal level found on
mediastinoscopy or biopsy
• In case of a collapsed lobe or lung
segment  use PET/CT to distinguish
tumor.
• Use lung window to delineate primary
tumor surrounded by lung tissue.
• Mediastinum window for primary tumor
surrounded by mediastinum/chest wall
and lymph nodes
#  Nestle U et al. ESTRO ACROP guidelines for target volume definition in the treatment of locally advanced non-small cell lung
cancer. Radiother Oncol (2018), https://doi.org/10.1016/j.radonc.2018.02.023

41. CTV
• CTV primary  GTV + 6–8 mm margin
depending on histology (edited for
adjacent natural barriers)
• CTV node  Two options:
• Option 1 (lymph node stations)
inclusion of the whole pathologically
affected lymph node station
• Option 2 (geometric expansion)
geometric expansion of nodal GTV to
CTV in analogy to the primary tumor
(3mm for size < 2 cm; 8mm for size >
2cm).

42. PTV
• PTV = CTV + ITV + margin for set up errors
• Manual editing of the PTV should not be performed.
• For the specific motion-related uncertainties 
• 1. Delineation of an internal target volume (ITV): it includes all CTV
positions during the breathing cycle as per ICRU 62.
• 2.Application of respiratory-synchronised techniques, such as gating
or tracking, with use of system-specific PTV margins

43. DOSE AND FRACTIONATION#
#  NCCN guidelines Version 1.2020

44. NORMAL TISSUE CONSTRAINTS IN
CONVENTIONALLY FRACTIONATED CTRT

45. CONCURRENT CHEMOTHERAPY/RT REGIMENS
- Carboplatin AUC 5 day 1; pemetrexed 500mg/m2 on day 1 every 21 days
for 4 cycles (non-squamous).
- Cisplatin 75mg/m2 day 1; pemetrexed 500mg/m2 on day 1 every 21
days for 3 cycles (non-squamous).
- Paclitaxel 45-50 mg/m2 weekly; Carboplatin AUC 2 (nonsquamous)
- Cisplatin 50mg/m2 days 1, 8, 29 and 36; etoposide 50mg/m2 days 1-5
and 29-33 (squamous).

46. CHEMOTHERAPY REGIMENS FOR NACT AND
ADJUVANT THERAPY
• Cisplatin 75mg/m2 day 1; pemetrexed 500mg/m2 on day 1 every 21 days for 3 cycles (non-
squamous).
• Cisplatin 75mg/m2 day 1; gemcitabine 1250mg/m2 days 1 and 8, every 21 days for 4
cycles.(Squamous)
• Cisplatin 50mg/m2 days 1 and 8; vinorelbine 25mg/m2 days 1, 8, 15, 22, every 28 days for 4
cycles.
• Cisplatin 100mg/m2 day 1 ; vinorelbine 30mg/m2 days 1, 8, 15, 22, every 28 days for 4 cycles.
• Cisplatin 100mg/m2 day 1; etoposide 100mg/m2 days 1-3, every 28 days for 4 cycles.

47. Sequential chemoRT regimens
- Cisplatin 100mg/m2 days 1 and 29; vinblastine 5mg/m2/weekly on
days 1,8, 15, 22, 29; followed by RT.
- Paclitaxel 200mg/m2 over 3hours on day 1; carboplatin AUC 6 over 60
minutes on day 1 every 3 weeks for 2 cycles followed by RT.

48. Concurrent chemoradiation followed by
chemotherapy
- Paclitaxel 45-50mg/m2 weekly; carboplatin AUC 2 with RT f/b 2 cycles
of paclitaxel 200mg/m2 and carboplatin AUC 6.
- Cisplatin 50mg/m2 days 1, 8, 29, 36; etoposide 50mg/m2 days 1-5,
29-33 with RT f/b cisplatin 50mg/m2 and etoposide 50mg/m2 x 2
cycles (category 2B).

49. Targeted Agents in Locally Advanced Disease
- Anti-EGFR agents:
a) monoclonal antibodies cetuximab and panitumumab.
b) TKIs- geftinib, erlotinib.
• ANTI- VEGF antibody Bevacizumab  for non squamous advanced
NSCLC
- Inhibits angiogenesis and metastasis by blocking VEGF induced
increase in capillary permeability
• Crizotinib  approved by FDA for patients with locally advanced or
metastatic NSCLC who are positive for ALK gene rearrangement.

52. Acute sequelae
• Acute radiation esophagitis usually begins in the 3rd week of
radiation.
• Cough is common but usually mild.
• Acute phase of radiation pneumonitis
• Skin reaction is mild to moderate

53. Late sequelae
1. Pneumonitis and pulmonary fibrosis
2. Esophageal stricture
3. Cardiac sequelae ( pericardial effusion, constrictive pericarditis,
cardiomyopathy),
4. Spinal cord myelopathy and brachial plexopathy.

54. RADIATION PNEUMONITIS
• RP may occur during fractionated treatment or up to 18 months afterward, with a
peak incidence at 2 to 6 months posttreatment.
• Presentation persistent nonproductive cough, dyspnea, low-grade fever, and
fatigue.
• CT scan may be normal or may be ground glass opacification (within 2 to 6
months), patchy consolidation (4 to 12 months), or fibrosis (10 months or more)
• PFTs  reduced lung volumes
• Risk of RP is <20% when the MLD is less than 20 Gy with conventional fractionation.
(QUANTEC)
• RTOG 0617  IMRT associated with 60 % decrease in high grade radiation
pneumonitis despite a higher proportion of stage IIIB and larger treatment volumes
compared to 3DCRT.
• Treatment  Steroids

55. TO CONCLUDE…
• Concurrent chemoradiation is recommended for patient with
inoperable stage III NSCLC (RTOG 9410, Auperin meta-analysis)
• Sequential chemoradiation or RT alone is appropriate for frail patients
unable to tolerate concurrent therapy. (CALGB 8433)
• Radiation has a role after surgery; however pre-operative RT has no
survival benefit in management of marginally resectable or
unresectable disease.
• Preoperative concurrent chemoradiation is an option for patients
with resectable stage IIIA (minimal N2 and treatable with lobectomy)
and is also recommended for resectable superior sulcus tumors.(INT-
0139 TRIAL)

56. • Preoperative chemotherapy and postoperative radiation is an
alternative for patients with resectable stage IIIA.
• In patients with clinical stage I/II upstaged surgically to N2+, PORT is
generally administered after post-op chemotherapy. For positive
resected margins, PORT with concurrent chemotherapy is
recommended. (RTOG 9705)

57. THANK YOU