Management of locally advanced (Stage III) NSCLC has undergone drastic changes.

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