1. Multidisciplinary approach to lung cancer
Kamil Konopka
Department of Oncology, University Hospital in Cracow

2. Lung cancer epidemiology
Most common malignancy worldwide
14% of all new cancers are lung cancers
Lung cancer (NSCLC&SCLC) is the second most common cancer in both men and women (excluding skin cancers)
Lung cancer is the leading cause of cancer deaths in men and women; about 1 out of 4 cancer deaths are from lung cancer
Estimations in USA for 2017 are:
- about new cases
- about deaths from lung cancer

3. Epidemiology

4. Etiology & risk factors
Smoking – responsible for more than 80% of lung cancer, smoking 20 cigarettes per day increases one’s risk of cancer 20-fold;
Second-hand smoke - 30% increased risk
Asbestos – especially when combined with smoking (90-fold increased risk)

5. Lung cancer risk
American Cancer Society, 2012

6. Lung cancer survival
About 16% people with lung cancer survived 5 years after diagnosis

7. Lung cancer
How to improve survival rates?

8. LUNG CANCER SCREENING R The National Lung Screening Trial (NLST)
People with high-risk of developing lung cancer
age
at least 30 packyears
former smokers, who stopped smoking within the last 15 years
n=53454
Low-dose CT
1x/year R
Radiography
1x/year
National Lung Screening Trial Research Team.N Engl J Med 2011; 365:

9. LUNG CANCER SCREENING The National Lung Screening Trial (NLST)
20.0% decrease in mortality from lung cancer was observed in the low-dose CT group as compared with the radiography group.
National Lung Screening Trial Research Team.N Engl J Med 2011; 365:

10. Lung cancer symptoms Cough – 80% of symptomatic pts,
Dyspnea, stridor, haemopytsis
Reccuring pnaeumonia – bronchi obstruction
Pleural effusion (exudate)
Chest pain
Shoulder and arm pain
Horner’s syndrome
Unilateral diaphargm paresis
Zwężenie źrenicy, zwężenie szpary powiekowej, zapadnięcie galki ocznej do oczodołu

11. Lung cancer – diagnostic procedures and staging
History and physical examination
Chest X-ray
CT scan – chest and upper abdomen (liver and adrenal glands), mediastinal lymph nodes
PET–CT – distant metastases, mediastinal lymph nodes (+/-)
Histology/cytology:
- central tumors – bronchoscopy
- peripheral tumors – transthoracic needle biopsy, thoracotomy

12. Lung cancer – diagnostic procedures and staging
PET scan
Treatment strategy change in up to 40% of patients

13. Lung cancer – diagnostic procedures and staging
Mediastinoscopy – mediastinal lymph nodes biopsy (N1 vs N2)
EBUS (endobronchial ultrasound) i EUS (endoscopic ultrasound)
Thoracoscopy and thoracocentesis
EUS
EBUS

14. Lung cancer staging UICC TNM 8th edition (January 2017): Chest CT scan
PET-scan
Recommended brain MRI
Needle aspiration under EBUS/EUS:
cN2: abnormal mediastinal nodes
cN1: hilar nodes
cN0: if central tumor or size >3 cm
Mediastinoscopy if EBUS/EUS are negative but high suspicion for nodal involvement
In 8th edition Staging is based on

15. Lung cancer staging – TNM 8th edition

16. Lung cancer - histopathology
Non-small cell lung cancer (NSCLC) 87%
-adenocarcinoma !!!
-squamous cell carcinoma
- Large cell carcinoma
- NOS carcinoma
Small cell lung cancer (SCLC) 13%

17. Lung cancer – histopathology & smoking

18. Lung cancer
Stage
Very early
Early
Late

19. Lung cancer - treatment
Stage I – IIIA - surgery

20. NSCLC treatment - surgery

21. NSCLC treatment - surgery
VATS (video-assisted thoracoscopic surgery)
- peripheral tumors up to 6 cm
- minimally invasive surgery
- eligibility - stages I to IIIA
- less pain after operation
- better quality of life

22. Lung cancer
How could we improve survival?

23. NSCLC treatment – radiation tehrapy
Adjuvant Rth
- N2 positive ?
- R1 resection
- narrow margins ?

24. NSCLC treatment – adjuvant chemotherapy
Pisters KMW i wsp. J Clin Oncol 2007; 25:

25. NSCLC treatment – adjuvant chemotherapy
LACE meta-analysis
Adjuvant chemotherapy improves OS in NSCLC
Pignon J-P i wsp. J Clin Oncol 2008;26:

26. Lung cancer I-IIIA Standard treatment Operation
Adjuvant chemotherapy (>IB)
What if cancer is very small?

27. NSCLC treatment – radiation therapy
Stereotactic
Radiosurgery (SBS/SBRT)
Precise delivery of high doses of radiation to the limited volume of tissue in hypofractionated schedule
hang JY et al. Lancet Oncol 2015;16(6):

28. NSCLC treatment – radiation tehrapy (SBRT)
T1-T2 N0 M0
Peripheral tumors
Patients medically unfit to undergo surgery
Patients who declined surgery

29. NSCLC treatment – radiation tehrapy Patients unfit for surgery
SABR for stage I
Tumors >5cm and/or
moderately central
location, radical RT with
conventional schedules
Pooled analysis: SABR vs surgery
Postmus et al. Ann Oncol 2017
Chang et al. Lancet Oncol 2015

30. Lung cancer stage IIIA-IIIB
What if cancer is very big?

31. Lung cancer IIIA-IIIB
Stage
NeoCTH
CRTH

32. Loco-regional strategy
No enlarged N2 lymph nodes but central tumour or hilar LNs
Enlarged discrete N2 LNs
N0-N1 N2
Potentially resectable N2
Dedicated multidisciplinary assessment
Surgical multimodality treatment
Non-surgical multimodality treatment N3
Potentially resectable N2:
Single station N2
Indcution CT recommanded
No pneumonectomy
Postmus et al. Ann Oncol 2017

33. Loco-regional strategy
No enlarged N2 lymph nodes but central tumour or hilar LNs
Enlarged discrete N2 LNs
N0 -N1 N2 N3
Non-surgical multimodality treatment
Extensive mediastinal N2 infiltration
Unresectable N2
CTRT is SOC for stage IIIA-B
60-66 Gy, fractions, No PCI
Cisplatin-based CT
+ etoposide, vinorelbine, pemetrexed (non-sq)
Concomitant > sequential
2 to 4 cycles
Postmus et al. Ann Oncol 2017

34. Lung cancer treatment stage I-III
Diagnostic tests includes PET-CT and brain metastases
Stage I-II: surgery +/- adjuvant chemotherapy
- Rth is an option for unfit patients
Stage III: heterogenous
- Single station N2 without pneumonectomy – consider surgery
- Otherwise the standard is CTRT based on cisplatin
Adjuvant chemotherapy: T>4 cm or N+ disease, preferably with cisplatin
No molecular profile needed, no targeted therapies allowed

35. NSCLC treatment – stage IV
Palliative chemotherapy
Targeted therapies
Palliative radiotherapy
BSC

36. NSCLC treatment – palliative chemotherapy
Two drugs schedules based on cisplatin
PS 0-1
Similar outcomes for different chemotherapy regimens
Ramalingam i wsp. The Oncologist 2008;13(suppl 1):5–13

37. NSCLC treatment – palliative chemotherapy
J Clin Oncol 2008; 26:

38. NSCLC treatment – palliative chemotherapy

39. NSCLC treatment – palliative chemotherapy
Pemetrexed + cisplatin better in non-squamous cell lung carcinoma
- Gemcytabine + cisplatin better in squamous cell lung carcinoma

40. NSCLC treatment – palliative chemotherapy I line
Gemcitabine mg/m d 1,8
Cisplatin mg/m d q3w
all histologies
Vinorelbine mg/m d 1, 8
Cisplatin mg/m d q3w
Pemetrexed mg/m d 1
Cisplatin mg/m d q3w
non squamous NSCLC
Docetaxel mg/m d 1
Cisplatin mg/m d q3w
Paklitaxel mg/m2 (3 h) d 1
Carboplatin AUC d q3w
Optimal regimen for first line therapy is four cycles of platinum-based chemotherapy, in terms of tolerability and survival benefits.

41. NSCLC treatment – stage IV targeted therapy
Anti-EGFR
ALK- positive NSCLC
Immunotherapy

42. NSCLC - anti-EGFR treatment

43. NSCLC - anti-EGFR treatment
Erlotinib and gefitinib – 1st generation tyrosine kinase inhibitors (TKI)
Clinical predictive factors of response:
- female
- Asian
- never-smokers
- adenocarcinoma

44. NSCLC - anti-EGFR treatment

45. NSCLC - anti-EGFR treatment
IPASS trial Progression-free survival
Mok T. et al. Ann Oncol 2008;19(suppl 8)

46. NSCLC - anti-EGFR treatment
Afatinib – 2nd generation anti-EGFR TKI
 OS in 1st line treatment
LUX-LUNG3 TRIAL: afatinib vs cisplatin/pemetrexed
HR=0,54; p=0,0015
LUX-LUNG 6 TRIAL: afatinib vs cisplatin/gemcitabine
HR=0,64; p=0,0229

47. NSCLC - anti-EGFR treatment
Osimertinib – 3rd generation, irreversible EGFR TKI designed to both inhibit EGFR sensitizing and EGFR T790M resistance mutations
Clinically proven activity against CNS metastases

48. NSCLC - anti-EGFR treatment

49. NSCLC targeted treatment
Fusion gene
EML4-ALK
2-7% NSCLC patients
Crizotinib – oral ALK inhibitor

50. Immunotherapy

51. Immunotherapy Nivolumab Humanized IgG4 monoclonal antibody
Anti-PD-1 antibody enhancing autoimmune response of the “host”
Proved to be effective in 2nd line treatment of NSCLC
Both squamous and non-squamous NSCLC
19% of patients experienced complete or partial tumor shrinkage, effect lasted for an average 17 mo (in docetaxel group response lasted an average 6 mo only!!)

52. Immunotherapy

53. Immunotherapy
Improved OS in nivolumab arm (squamous NSCLC)

54. NSCLC treatment – radiation tehrapy
Palliative Rth: - bone metastases - brain metastases - local control of symptoms (cough, haemoptysis)

55. NSCLC treatment – BSC
Improved QoL and survival !!!

58. Small cell lung cancer (SCLC)
13% of all lung cancer cases
Neuroendocrine differentiation: positive staining for chromogranine, synaptophisine
Paraneoplastic syndromes due to neuroendocrine activity (Cushing`s syndrome, SIADH)

59. Small cell lung cancer (SCLC)
Large mass, hilar and mediastinal lymphadenopathy
In the most cases primary systemic disease (very high metastatic potential)

60. Small cell lung cancer (SCLC) - staging
Limited stage: confined to the chest and regional lymph nodes (1/3 pts)
Extensive stage: distant metastases (2/3 pts)

61. Small cell lung cancer (SCLC) – LD (limited disease) treatment
Chemoradiotherapy (EP regimen: cisplatin + etoposide)
- concurrent: - better outcomes
- higher toxicity
- sequential: - worse outcomes
- lower toxicity

62. Small cell lung cancer (SCLC) – LD (limited disease) treatment
Prophylactic Cranial Irradiation (PCI):
- after chemoradiation
- partial or complete response (PR/CR) in CT
- PS 0-1
- 3-5 weeks after the last administration of chemotherapy
3-year OS PCI group: 20,7%
no-PCI group: 15,3%

63. Small cell lung cancer (SCLC) – ED (extensive disease) treatment
70% of SCLC patients
SoC chemotherapy EP (cisplatin+etoposide)
4-6 cycles
If any response -> PCI
- decrease in incidence of symptomatic CNS metastases
- prolongs survival

64. Small cell lung cancer (SCLC) – ED (extensive disease) treatment
2nd line treatment:
- PD within 3 months – refractory disease
- PD 3-6 months – topotecan, CAV
- PD >6 months – EP re-induction

65. Thank you for your attention !