1) For operable stage III NSCLC patients with resectable tumors, preoperative chemoradiotherapy followed by surgery may improve survival outcomes compared to surgery or chemoradiotherapy alone. 2) For stage III NSCLC patients with N2 nodal involvement who have undergone complete resection, postoperative radiotherapy does not provide a survival benefit and can increase toxicity. 3) For unresectable locally advanced stage III NSCLC patients, concurrent chemoradiotherapy improves survival compared to radiotherapy alone and should be the standard of care. Adding consolidation immunotherapy after chemoradiotherapy may provide additional benefits.

1. (Un)Operable-(Un)resectable Stage III
NSCLC:
What’s place for (chemo)radiotherapy ?

2. Questions
• Preoperative irradiation
• Postoperative irradiation
• Exclusive irradiation
2

3. PREOPERATIVE RADIOTHERAPY
3

4. Randomisation
Dose 45 Gy in 5 weeks
Chemotherapy:
CDDP
VP16
75% of the patients were
operated on
- 38 patients radiological
response
- 28 patients (73%) total
pathological response
4

5. Sulcus superior carcinoma
5

6. Results= overall survival
6
All patients : plateau at 2 years = 55%
Patients operated on : plateau at 2 years = 70%

7. Conclusions and French
guidelines
• This trial showed the strength
of the combination of
radiotherapy, chemotherapy
and the surgery for operable
patients with a resectable
sulcus superior tumor.
• This is included in the 2021
French recommendations
(publication soon!)
7

8. Stage IIIA operable patients
RT or CT with resectable
tumor
8

9. Patients and treatments
• Eligible patients
– Pathologically proven, locally advanced T1–3N2M0, stage IIIA/N2
– Staging by PET-CT and brain MRI
– N2 be proven by mediastinoscopy or endobronchial ultrasonography,
endoscopic ultra sonography, or bronchoscopy with transbronchial fine-
needle aspiration
• Chemotherapy
– 3 cycles of cisplatin and docetaxel every 3 weeks
• Sequential Radiotherapy
– 44 Gy in 15 fractions over a 3 weeks period (2.9 Gy / fraction)
9
Cisplatin 100mg/m² J1
Docetaxel 75mg/m² J1
x 3 cycles
arm RTCT
117 patients
arm CT
113 patients
SURGERY
SURGERY
Cisplatin 100mg/m² J1
Docetaxel 75mg/m² J1
x 3 cycles
Sequential
Radiotherapy
44Gy en 15 x 2.9 Gy

10. Randomisation
10
2001-2012
23 centers
228 patients
0.9 patients / yr

11. Results
11
9% 19%
RTC :12.8 months (95% CI 9.7–22.9)
CT: 11.6 months (8.4–15.2)
HR 1.1, 95% CI 0.8–1.4, p=0.67
Median overall survival
- RTCT: 37.1 months
(95% CI 22.6–50.0)
- CT: 26.2 months
(95% CI 19.9–52.1)
HR 1.0, 95% CI 0.7–1.4

12. Conclusion
• Despite good local and regional control, RT-
CT failed to demonstrate a role in neo-
adjuvant treatment
– Dose ?
– No concurrent chemo-RT?
– Number of patients per arm? Time for
inclusion – number of centers -
heterogeneity
12

13. RT-CT + surgery vs CT + surgery
13

14. Method
14

15. RT-CT + surgery vs CT + surgery
15

16. RT-CT + surgery vs CT + surgery
16

17. Conclusions
• In this metaanalysis combinaison of the three
therapies seems unuseful:
– RT can be avoided in RT-CT + S
– But :
• old studies
• Small number of patients per trials
17

18. POSTOPERATIVE
RADIOTHERAPY (PORT)
18

19. Littérature:Issue of N2 patients
• 2 meta-analysis 1998/2016
• One cohort analysis 2006
• One randomized analysis 2020
19

20. Post Operative Radiation
Therapy
Post-Operative RadioTherapy Overview (Lancet
1998)
• 2128 pts : 808 pts stage III included in 9
randomized trials
Surgery alone (1072 pts)
2-yr OS: 55%
surgery + PORT(1056 pts)
2-yr OS: 48%
PORT, Lancet 1998

21. Analyse par sous-groupe
Hazard Ratio
RT better No RT better
0.0 0.5 1.0 1.5 2.0
0
1
2
Nodal Status
Stage 1
2
3
Test for trend
c2
(1)=13.194, p=0.0003
Test for trend
c2
(1)=5.780, p=0.016
PORT, Lancet 1998
Deletere effect

22. Cohort of 7465 pts operated-on Stages II, III
NSCLC SEER Data base
N0 pts N2 pts
N1 pts
All pts
Port Port
Port
Port
Surgery + PORT: improvement of overall survival for N2 patients (p<.004)
5 yr OS
S 41%,
Port 31%
5 yr OS
S 20%,
Port 27%
5 yr OS
S 34%,
Port 30%
3 yr OS
S 47%,
Port 41%
Lally and al, JCO 2006

23. Retrospective study of PORT after complete surgery
• Large number of patient
• Similar conclusions than the 1998 metaanalysis
for N0 and N1
• Improvement for N2? But numerous factors
were not studied in the analysis

24. Issue of N2 patients
24

25. Method
• Period of inclusion 1965-2016
• Individual data of 11 trial with individual data
• 2343 participants (1511 deaths)
25

26. Main results
26
(HR) of 1.18 (95% CI 1.07 to 1.31)
An 18% relative increase in risk of death
An absolute detriment of 5% at two years (95%CI: 2% to 9%)
Reducing overall survival from 58% to 53%.

27. Secondary trends
27

28. Conclusions
• Trials over a period of 40 years
• Old techniques
• Old machines
Are not no arguments to discredit results of
metaanalysis
28

29. Post operative N2 irradiation
29

30. RANDOMISATION
30
501 patients
Stade III pN2 R0
Neoadjuvant or adjuvant
CT allowed
Conformational 3D-RT
54 Gy / 27 fractions
252 patients
Follow-up
249 patients
End-point : 3-yr disease-free survival

31. PORT vs No PORT for N2
operated on patients
31

32. Overall survival
PORT noPORT
3-yr 66.5% 68.5%
Disease death 69.4% 86.1%
Cardiovascular death 16.2% 2%
32

33. Conclusion
• Definitively no PORT is required for N2
patients, operated-on, with R0 resection
33

34. French guidelines
34

35. WHERE IS RADIOTHERAPY?
35

36. Places of radiotherapy
• Incomplete resection
• Inoperable – unresectable patients
36

37. PORT for incomplete
resected Patients
37

38. Incomplete resection
• 1 cohort analysis
– Result of the treatment
• 1 randomised trial
– Management before « incomplete »
resection
38

39. Patients
• National Cancer Data Base
• Lobectomy or pneumectomy
• App. 1900 patients R1 or R2 resection
• 3395 included patients
– 1207 (35.6%) received PORT
– dose 50-74 Gy
39

40. Results
40
All patients N0 patients
N1 patients N2 patients

41. CT followed by surgery or RT
41

42. Randomisation
• 579 pts, "unresectable" N2
NSCLC received 3 cycles of
induction Pt-based chemo
• Nonprogressors after
chemotherapy
– RT or surgery
42

43. Results
• Surgery  increase Local
Control but no difference in 5yr-
OS (~15%) or Median Survival
(16.5 mo)
• Surgery  increase Toxicity-
related mortality (9% vs. <1%)
43
Progression-free survival

44. Conclusions
• Surgery did not improve OS or PFS
• Given low morbidity and mortality, RT
should be preferred modality
• RT arm used older techniques of 3DCRT and included
elective nodes
• Surgery arm included 47% pneumectomies
• only 50% had R0 resection
44

45. « NON OPERABLE » – « NON
RESECTABLE » PATIENTS
CONCURRENT OR SEQUENTIAL
RT-CT ?
45

46. Metaanalysis 1
• 19 randomised trials (2728 patients)
– Concurrent chemoradiotherapy versus
radiotherapy alone
• 6 randomised trials (1024 patients)
– concurrent versus sequential chemoradiation
O’Rourke N et al. Cochrane Database of Systematic
Reviews 2010
46

47. Results
• RT-CT vs RT
– Reduced overall risk of death (HR 0.71, 95% CI 0.64 to
0.80)
– Reduced overall progression‐free survival at any site (HR
0.69, 95% CI 0.58 to 0.81)
• Concurrent vs sequential RT-CT
– Improvement of overall survival (HR 0.74, 95% CI 0.62 to
0.89)  10% absolute survival benefit at 2 years.
– More treatment‐related deaths (4% vs 2%) no statistical
significance (RR 2.02, 95% CI 0.90 to 4.52).
– increased severe oesophagitis with concurrent treatment
(RR 4.96, 95%CI 2.17 to 11.37)
47

48. Metanalysis 2
48

49. Results
49
 Concurrent CT-RT
- 3-yr OS  +5.7%
- 5-yr OS  +4.5%
six trials
1205 patients

50. Conclusions
• Concurent chemotherapy and
radiotherapy should be proposed to
inoperable and no resectable patients
50

51. French guidelines
51

52. CONSOLIDATION TREATMENT
52

53. Consolidation treatment
53

54. Patients
54

55. Results
55

56. Conclusion
• In inoperable patients, unresectable tumor,
with IIIA-B tumor adding Durvalumab lead to
improve progression-free and overall
survival
56

57. French guidelines
57

58. Conclusion of the conclusions
• There is not opposition between surgery and
radiotherapy – we are not in the same fields
• Surgery can cure operable patients with resectable
tumor IIIA tumors
– We can cure together (RT + Surgery) advanced
superior sulcus tumor
• Radiotherapy (with chemo) try to cure inoperable or
unresectable IIIA tumors (and IIIB)
• Consolidation treatments can not replace bad
selection of patients and an non-optimal treatment
(non adapted radiotherapy)
58