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MARTA SCORSETTI M.D.
Direttore Radioterapia e Radiochirurgia
Istituto Clinico Humanitas
NSCLC localmente avanzato
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
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
W.J. Curran
A. Bezjak
H. Choy
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.
Stratify:
-RT Technique (IMRT vs 3D)
-Perf Status(0 vs 1)
-Histology(squam vs other)
-PET staging(yes vs no)
Stratify:
-RT Technique (IMRT vs 3D)
-Perf Status(0 vs 1)
-Histology(squam vs other)
-PET staging(yes vs no)
RTOG 0617: Trial Design
RTOG 0617: Survival by RT Dose
Surv
ival
Rat
e (%
)
0
25
50
75
100
Months since Randomization0 3 6 9 12 15 18
Patients at RiskStandardHigh dose
213206
207197
190178
177159
161135
141112
108 87
Dead
90117
Total
213206
HR=1.56 (1.19, 2.06) p=0.0007
Standard (60 Gy)High dose (74 Gy)
Median Survival Time
28.7 months19.5 months
18-Month Survival Rate
66.9%
53.9%
RTOG 0617: Local Tumor Failure
18-Month Local Progression Rate
25.1%
34.3%
Loca
l Pro
gres
sion
Rat
e (%
)
0
25
50
75
100
Months since Randomization0 3 6 9 12 15 18
Patients at RiskStandardHigh dose
213206
205197
187170
165134
137105
113 80
85 62
Fail6581
HR=1.37 (0.99, 1.89)
Total213206
p=0.0319
Standard (60 Gy)High dose (74 Gy)
RTOG 0617: Distant Failure
Dis
tant
Fai
lure
Rat
e (%
)
0
25
50
75
100
Months since Randomization0 3 6 9 12 15 18
Patients at RiskStandardHigh dose
213206
205193
175161
145126
115 93
94 73
73 54
Fail97104
HR=1.15 (0.87, 1.51)
Total213206
p=0.1576
Standard (60 Gy)High dose (74 Gy)
18-Month Failure Rate
42.4%
47.8%
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.
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)
Pretreatment Characteristics
60 Gy(n=213)
74 Gy(n=206)
Age (median) 64 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 42% 47% NSCLC NOS 19% 18%
AJCC Stage Stage IIIA Stage IIIB
67%33%
64%36%
Hypothesis 1: Unbalanced Arms
Any Unknown Features in Play?
Predictors of Treatment Resistance?
Predictors of Sensitivity to Toxicity?
100 NSCLC Patients at U MichiganKaplan-Meier Estimates of Overall Survival According to the
Serum MicroRNA Signature
0 12 24 36 48 60 72 84 960
20
40
60
80
100
Months
OS
(%)
P = 0.001
Low risk (N=53)MST = 36.6months
High risk (N=47)MST = 13.3 months
Analysis of miRNA Signature and RT DoseBi, …Kong, U Michigan
0 12 24 36 48 60 72 84 96 1080
20
40
60
80
100
Months
OS
(%)
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.
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.
RTOG 0617: Dosimetric Data Distribution
60 Gy(n=203)
Mean (Median)
74 Gy(n=197)
Mean (Median)
GTV Volume (cc) 125 (92) 129 (96)
Heart V5 (%) 47 (46) 46 (46)
Heart V50 (%) 7 (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) 8 (7)
RTOG 0617Definitely, Probably, or Possibly Related to Treatment
(CTCAE Version 3.0)
Standard Dose: 60 Gy High Dose: 74 Gy
(n=213)
Grade
(n=206)
Grade
3 4 5 3 4 5
Worst non-hematologic98
(46%)
21
(10%)
2
(1%)
95
(46%)
23
(11%)
10
(5%)
Worst overall99
(47%)
57
(27%)
2
(1%)
86
(42%)
65
(32%)
10
(5%)
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
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
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(%) Continuous 1.017 (1.004, 1.030) 0.008
Backwards Selection: Exit criteria p>0.10Two-sided p-valuesRemoved from model: Age (continuous), overall RT review (per protocol vs. not per protocol), and lung V5 (continuous)
Multivariate Cox Model
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
– Under review
Hypothesis 3: Pt-Reported Outcomes (PRO) may help
Patient-reported outcomes were effectively collected
in the trial and may be illuminating.
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
Change in Lung Cancer Symptoms (LCS)
LCS Decline
0%
10%
20%
30%
40%
50%
3 months 12 months
46%
39%
31%36%
74 Gy
60 Gy
p=0.024
p=0.7
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?
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
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
Cécile Le Péchoux
Altered fractionation
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-en
d W
eek-en
d W
eek-en
d W
eek-en
d
Week-en
d W
eek-en
d W
eek-en
d W
eek-en
d W
eek-en
d
Weekly D
1O Gy
31,5 Gy
24 Gy
22,5 Gy
20 Gy
12 Gy
15 GySplit course:2 wks
60 Gy/30 frDD = 2 Gy*ECOG 64 GyCHARTWEL 66 Gy
NSCLC-Patient characteristics (n=2,000)
Patients• Age %
– <60 28– 60-69 42– 70+ 30
• Gender (male) 75%
Disease• Performance Status %
• 042
• 158
• Stage %• I / II 17• IIIA 43• IIIB 40
• Histology (squamous) 60%
Conventional RT=944 pts Modified RT=1056pts
• 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)
Very accelerated RT
CategoryTrial
No. Deaths / No. Entered
Exp. RT Conv. RT O-E Variance Hazard Ratio HR [95% CI]
Experimental RTbetter
| Conventional RTbetter
PMCI 88C091 48/48 52/53 -0.8 24.3PMCI 88C091 CT 51/51 56/56 6.0 25.6CHART 316/338 217/225 -29.4 120.7ECOG 2597 51/60 55/59 -7.4 25.8CHARTWEL 132/150 132/150 0.2 65.8CHARTWELCT 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
Subtotal 26/29 27/29 -1.4 13.2 0.90 [0.52;1.54]Hyperfractionated RT - identical total dose
NCCTG 902451 34/39 35/35 -7.0 15.7NCCTG 942452 111/125 108/121 -2.6 54.6
Subtotal 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 -6.4 76.9
Subtotal 155/163 156/163 -6.4 76.9 0.92 [0.74;1.15]
Total 964/1056 885/944 -55.2 443.7
Test for heterogeneity: 29
= 9.74 p = 0.37 I2 = 8 %
2 pTest for interaction: 3 = 0.17 = 0.98
0.88 [0.80;0.97], p=0.009
0.25 1.00 4.00
Overall survival NSCLC
60Gy/6wks vs 60/3wks BID60Gy/6wks vs 60/3wks CT
60Gy/6wks vs 54 Gy/12d TD64Gy/6,4Wks vs 57,6Gy/2,5wks TD
66 Gy vs 60Gy/2,5wks TD66 Gy vs 60Gy/2,5wks CT TD
72Gy/8wks vs 72/5,5wks
60Gy/30/6wks vs 60/40/6wks SC60Gy/30/6wks vs 60/40/6wks SC
60Gy/30/6wks vs 69,6/6wks BID
Modified radiotherapy, overall survivalConventional radiotherapy, overall survivalModified radiotherapy, progression-free survivalConventional radiotherapy, progression-free survival
Su
rviv
al (
%)
0
20
40
60
80
100
Time from randomisation (Years)0 1 2 3 4 5 >6
10.5
4.99.1 5.1
15.9
19.7
10.88.3
Overall and Progression-Free Survival NSCLC
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
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: 60-66 Gy with platin based ccCTRT still the standard
Four-dimensional Gallium-68 perfusion PET/CT scans can improve radiotherapy planning through functional avoidance of lungShankar Siva Peter MacCallum Cancer Centre Melbourne
14 patientsRT 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
MO23 RADIOTHERAPY II
• 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
Background• High local recurrence rates in stage III NSCLC
– PD on imaging: 30-40 %– 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
Question 1: Is it safe?
• 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
• 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).
• 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!
Conclusion: Is it safe?
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
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
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
• 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)
Future directions
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