1. NSCLC localmente avanzato
MARTA SCORSETTI M.D.
Direttore Radioterapia e Radiochirurgia
Istituto Clinico Humanitas 1 1

2. 2013
In patients with infiltrative stage III (N2,3) NSCLC and performance status 0-1 being considered for curative-intent treatment, combination platinum-based chemotherapy and radiotherapy (60-66 Gy) are recommended (Grade 1A)
Remark: Dose escalation of radiotherapy is not recommended (except in a clinical trial)
Remark: For patients with stage IIIB NSCLC, once daily thoracic radiotherapy plus platinum-based doublet chemotherapy is recommended

3. Why Did 74.0 Gy Fail? Speculation and Conjecture
W.J. Curran
A. Bezjak
H. Choy
Why Did 74.0 Gy Fail? Speculation and Conjecture
Walter J Curran, Jr, MD
Radiation Therapy Oncology Group Chairman
Executive Director, Winship Cancer Institute of Emory University
Georgia Research Alliance Eminent Scholar

4. RTOG 0617 Primary Objective
To compare the overall survival of patients treated with high-dose versus standard-dose conformal radiation therapy with concurrent chemotherapy.
To compare the overall survival of patients treated with cetuximab versus without cetuximab with concurrent chemoradiotherapy.

5. RTOG 0617: Trial Design Stratify: -RT Technique (IMRT vs 3D)
-Perf Status
(0 vs 1)
-Histology
(squam vs other)
-PET staging
(yes vs no) 5

6. RTOG 0617: Survival by RT Dose
18-Month Survival Rate
66.9%
53.9%
Median
Survival Time
28.7 months
19.5 months

7. RTOG 0617: Local Tumor Failure
18-Month Local Progression Rate
34.3%
25.1%

8. RTOG 0617: Distant Failure
18-Month Failure Rate
47.8%
42.4%

9. Hypothesis 1: Unbalanced Arms
Despite employing standard stratification features, some known or unknown features predictive for toxicity and/or treatment resistance were imbalanced between the arms.

10. Hypothesis 1: Unbalanced Arms
Stratification features employed:
RT Technique (IMRT vs 3-D Conformal RT)
Zubrod Performance Status
Use of PET in Staging
Histology (Squamous vs Non-Squamous)

11. Pretreatment Characteristics
60 Gy (n=213)
74 Gy (n=206)
Age (median)
 64
Gender
Male
59%
58%
Female
41%
42%
Race
Other
12%
14%
White
88%
86%
RT Technique
3DCRT
54%
53%
IMRT
46%
47%
PET Staging
91%
89%
Histology
Adenocarcinoma
39%
35%
Squamous
NSCLC NOS
19%
18%
AJCC Stage
Stage IIIA
Stage IIIB
67%
33%
64%
36%

12. Hypothesis 1: Unbalanced Arms
Any Unknown Features in Play?
Predictors of Treatment Resistance?
Predictors of Sensitivity to Toxicity?

13. 100 NSCLC Patients at U Michigan Kaplan-Meier Estimates of Overall Survival According to the Serum MicroRNA Signature
P = 0.001
Low risk (N=53)
MST = 36.6months
High risk (N=47)
MST = 13.3 months

14. Analysis of miRNA Signature and RT Dose Bi, …Kong, U Michigan
BED < 100Gy, low risk, MST = 33.4 Months (N=38)
BED < 100Gy, high risk, MST = 9.9 Months (N=33)
BED ≥ 100Gy, low risk, MST = 38.9 Months (N=15)
BED ≥ 100Gy, high risk, MST = 19.3 Months (N=14)
Log-rank P = 0.001
Patients with high risk miRNA signature benefited from high dose RT, while low risk pts did not.

15. Hypothesis 2: RT Delivery Issues
To meet RT dose constraints, less optimal RT was delivered to the 74 Gy arm patients, leading to poor RT dose distribution and an influence on toxicity and/or tumor control.

16. RTOG 0617: Dosimetric Data Distribution
60 Gy (n=203)
Mean (Median)
74 Gy (n=197)
GTV Volume (cc)
125 (92)
 129 (96)
Heart V5 (%)
47 (46)
46 (46)
Heart V50 (%) (4)
11 (6)
Lung V20 (%)
29  (29)
31 (32)
Esophagus Dose (Gy)
25 (25)
30 (29)
Esophagus V60 (%)
15 (13)
26 (26)
Mean Margin CTV to PTV (mm)
8 (7)

17. As scored by institution No significant difference
RTOG 0617 Definitely, Probably, or Possibly Related to Treatment (CTCAE Version 3.0)
Standard Dose: 60 Gy
High Dose: 74 Gy
(n=213)
Grade
(n=206) 3 4 5
Worst non-hematologic 98
(46%) 21
(10%) 2
(1%) 95 23
(11%) 10
(5%)
Worst overall 99
(47%) 57
(27%) 86
(42%) 65
(32%)
Grade 5 Events
(n=2)
(n=10)
As scored by institution
No significant difference
1 Pulmonary
1 Sudden death
2 Pulmonary
1 Thrombosis
1 Upper GI Hemorrhage
1 Pulmonary Hemorrhage
1 Pneumonia NOS
1 Esophageal
1 TE fistula
1 Sepsis
1 Death NOS

18. Esophagitis Standard Dose: 60 Gy High Dose: 74 Gy Esophagitis/
Dysphagia
(n = 213)
(n = 206)
Grade 2
198 (93%)
163 (79%)
Grade 3
15 (7%)
43 (21%)
p-value
0.0003

19. Per Protocol vs. Not per protocol
Multivariate Cox Model
Covariate
Comparison (RL)
HR (95% CI)
p-value
Radiation dose
60 Gy v 74 Gy
1.51 (1.12, 2.04)
0.007
Histology
Non-squam v Squam
1.31 (0.99, 1.75)
0.061
Max esophagitis grade
<3 vs ≥3
1.52 (1.06, 2.20)
0.024
Heart Contour
Per Protocol vs. Not per protocol
0.67 (0.47, 0.96)
0.029
GTV
Continuous
1.001 (1.000, 1.002)
0.038
Heart V50(%)
1.017 (1.004, 1.030)
0.008
Backwards Selection: Exit criteria p>0.10
Two-sided p-values
Removed from model: Age (continuous), overall RT review (per protocol vs. not per protocol), and lung V5 (continuous)

20. What might have happened?
74 Gy given over too long an interval?
Possibly.
Unreported Toxicity?
Chemotherapy delivery/compliance?
No evidence of this
RT compliance; GTV misses?
Under review
Heart dose

21. Hypothesis 3: Pt-Reported Outcomes (PRO) may help
Patient-reported outcomes were effectively collected in the trial and may be illuminating.

22. RTOG 0617 PRO Methods
QOL was collected prospectively via a validated lung cancer instrument: Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI)
FACT-TOI = Physical Well Being (PWB) + Functional Well Being (FWB) + Lung Cancer Subscale (LCS)
Data was collected at baseline, 3 months & 12 months via clinically meaningful changes of >2 points for PWB, FWB or LCS, or >5 points for TOI

23. Change in Lung Cancer Symptoms (LCS)
LCS Decline

24. Results: Baseline FACT and OS
Baseline QOL (whether PWB, FWB, or FACT-TOI) also predicted for survival in multivariate analysis, p=<0.02 independent of RT dose assignment.
Every 10 points higher on the FACT-TOI at baseline corresponded to a 14% decreased risk of death
Is this the unknown variable not used in stratification?

25. Why Did 74.0 Gy Fail? Still under many realms of investigation
74.0 Gy as delivered in this trial of this patient subgroup is associated with poorer survival than standard dose RT
The results provides greater support for more RT dose/volume investigations for stage III NSCLC

26. 26 26

27. 27 27

28. 28 28

29. 29 29

30. 30 30

31. 31 31

32. 32 32

33. 33 33

34. Contrasting results of altered fractionation in randomised trials
Cécile Le Péchoux
Contrasting results of altered fractionation in randomised trials
Over the years, several randomized trials evaluating ≠ altered fractionation schedules:
Contrasting results
Necessity of an individual patient data meta-analysis (IPD) to evaluate a potential benefit from modified fractionation radiotherapy schedules
Hyperfractionnated: higher number of fractions with smaller dose per fraction compared with conventional RT
Accelerated: reduced overall treatment time (OTT) compared with conventional fractionation and
Hyperfractionated and accelerated 34

35. Altered fractionation
Weekly D
1O Gy
31,5 Gy
24 Gy
22,5 Gy
20 Gy
12 Gy
15 Gy
60 Gy/30 fr
DD = 2 Gy
*ECOG 64 Gy
CHARTWEL 66 Gy
CHART=TD 54 Gy/36 fr
DD: 3X1,5 Gy
ECOG=TD 57,6 Gy/36 fr
DD : 1,5-1,8-1,5 Gy
CHARTWEL=60 Gy/40 fr
DD : 3X1,5 Gy
PMCI=60 Gy/30 fr
DD : 2X2 Gy
RTOG=69,6 Gy/58 fr
DD : 2X1,2 Gy
CCTG=60Gy/40 fr
DD : 2X1,5 Gy
5 days
Week-end Week-end Week-end Week-end Week-end
Week-end Week-end Week-end Week-end
Split course:2 wks

36. NSCLC-Patient characteristics (n=2,000)
Conventional RT=944 pts Modified RT=1056pts
Patients
Age %
<60 28
Gender (male) 75%
Disease
Performance Status %
Stage %
I / II
IIIA 43
IIIB 40
Histology (squamous) 60%
8 randomized trials: 2,000 pts (90% of all known randomized pts) between 1989 and 2005
4 trials with chemotherapy in the 2 arms (carboplatin, cisplatin-etoposide or carboplatin-paclitaxel) 36

37. Overall survival NSCLC
Very accelerated RT
Category
Trial
No. Deaths / No. Entered
Exp. RT
Conv. RT
O-E
Variance
Hazard Ratio
HR [95% CI]
Experimental RT
better |
Conventional RT
PMCI 88C091
48/48
52/53
-0.8
24.3
PMCI 88C091 CT
51/51
56/56
6.0
25.6
CHART
316/338
217/225
-29.4
120.7
ECOG 2597
51/60
55/59
-7.4
25.8
CHARTWEL
132/150
0.2
65.8
CHARTWELCT
40/53
47/53
-6.4
21.2
Subtotal
638/700
559/596
-37.8
283.4
0.88 [0.78;0.98]
Moderately accelerated RT
Gliwice 2001
26/29
27/29
-1.4
13.2
0.90 [0.52;1.54]
Hyperfractionated RT - identical total dose
NCCTG
34/39
35/35
-7.0
15.7
NCCTG
111/125
108/121
-2.6
54.6
145/164
143/156
-9.6
70.3
0.87 [0.69;1.10]
Hyperfractionated RT - increased total dose
RTOG 8808
155/163
156/163
76.9
0.92 [0.74;1.15]
Total
964/1056
885/944
-55.2
443.7
Test for heterogeneity: 2 9
= 9.74 p
= 0.37 I
= 8 %
Test for interaction: 3
= 0.17
= 0.98
0.88 [0.80;0.97], p=0.009
0.25
1.00
4.00
60Gy/6wks vs 60/3wks BID
60Gy/6wks vs 60/3wks CT
60Gy/6wks vs 54 Gy/12d TD
64Gy/6,4Wks vs 57,6Gy/2,5wks TD
66 Gy vs 60Gy/2,5wks TD
66 Gy vs 60Gy/2,5wks CT TD
72Gy/8wks vs 72/5,5wks
60Gy/30/6wks vs 60/40/6wks SC
60Gy/30/6wks vs 69,6/6wks BID

38. Overall and Progression-Free Survival NSCLC
Modified radiotherapy, overall survival
Conventional radiotherapy, overall survival
Modified radiotherapy, progression-free survival
Conventional radiotherapy, progression-free survival
Survival (%) 20 40 60 80
100
Time from randomisation (Years) 1 2 3 4 5
>6
10.5
4.9
9.1
5.1
15.9
19.7
10.8
8.3
In favor of modified RT
Absolute benefit OS
Absolute benefit PFS
At 3 yrs
3.8%
1.4%
At 5 yrs
2.5%
-0.2%
HR, p
0.88, p=0,009
0.94, p=0.19

39. Conclusions
Modified fractionation radiotherapy significantly improves overall survival in NSCLC
No significant effect on progression-free survival or loco-regional failure (BURDEN OF DISTANT FAILURE)
Increased acute esophageal toxicity (OR=2.44, p=0,01) in experimental treatments
Higher technology RT, better selection of patients: encouraging results in recent studies with better management of toxicity!
LARGE STUDIES NEEDED: Gy with platin based ccCTRT still the standard 39

40. MO23 RADIOTHERAPY II
Four-dimensional Gallium-68 perfusion PET/CT scans can improve radiotherapy planning through functional avoidance of lung Shankar Siva Peter MacCallum Cancer Centre Melbourne
How to adapt the treatment plan during the course of RT in case of perfusion modification? This is only an image at one time
Is it possible to perform this study on a large cohort and to correlate it with an evaluation of toxicity
14 patients
RT plan optimised to spare functionally perfused and high perfused lung volume
Conclusion : a large improvement was observed mainly for the treatment plan optimized to the high perfused lung volume

41. Background High local recurrence rates in stage III NSCLC
PD on imaging: %
Bronchoscopy series: 80 %
Most recurrences are irresectable
Low success rates with second line systemic treatment for local recurrences
15-25 % remissions
Median OS 4-8 months
Dramatic improvement of imaging and RT techniques (SBRT, VMAT …)
High-dose irradiation is technically feasible in selected patients 41 41

42. Question 1: Is it safe? Retrospective (except 1) Small series
Grade 5 aortic toxicity = 25 % with composite doses ≥ 120 Gy (vs. 0% for patients receiving <120 Gy) (p = 0.047) to 1 cm3 of the aorta (Evans et al. Radiother Oncol 2013).
Safe if
Accumulated V20 of the lungs is < 16 %
Accumulated Dmax to the heart < 115 Gy3
Accumulated Dmax to the trachea < 89 Gy3 and < 85 Gy3 to the oesophagus (Meijneke et al. Radiother Oncol 2013).
Retrospective (except 1)
Small series
Different treatments (primary and re-RT)
Short follow-up
Different second-line therapy
Different endpoints
Often no detailed DVH parameters available 42 42

43. Conclusion: Is it safe? Many uncertainties remain
Possibly safe when conservative constraints are used.
Repair possibilities: Many unknowns.
Use cumulative doses
Use elastic deformation algorithms
 Importance of patient information! 43 43

44. Question 2: Is it worthwhile?
Overall survival: Unclear
Median OS: 13 months after a median interval between primary therapy and RT for recurrence 19 months
Patients also receive systemic therapy
Progression-free survival  postpone systemic treatment: Likely
Median TTP (any place): 10 months
Quality of life: No data
Symptom control vs. palliative doses: Unclear 44 44

45. Question 3: Can we select patients for high-dose re-irradiation?
Probably (rational):
Good general condition
Single recurrence
Preferably suitable for SBRT
Doses and fractionation similar to those of primary lung cancer?
Lesion diameter < 3-4 cm
Cumulative doses to OAR below constraints for primary irradiation based on elastic deformation 45 45

46. General conclusion
In selected patients, high-dose re-irradiation may be considered
Most realistic aim in the majority of patients: postpone systemic treatment
Inform your patient about the uncertainties
 Obvious need for a randomised (phase II) trial 46 46

47. Future directions
Improve patients selection (Gene profile, microRNA signature)
Predictors of Sensitivity to Toxicity (IL-6, TGFβ….)
Improve protocol for delineation of target volume and OAR, increase RT dose/volume investigations
Well designed large randomized trials (No induction/consolidation chemotherapy) 47 47

48. PERSONALIZED MEDICINE: A PARADIGM SHIFT IN HEALTHCARE
The right treatment
At the right dose
For the right patient
At the right time
For the best outcome