Transcript Diapositiva 1 - Oncologia Toracica

NSCLC
localmente
avanzato
MARTA SCORSETTI M.D.
Direttore Radioterapia e Radiochirurgia
Istituto Clinico Humanitas
[email protected]
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
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
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.
RTOG 0617: Trial Design
Stratify:
-RT Technique
(IMRT vs 3D)
-Perf Status
(0 vs 1)
-Histology
(squam vs other)
-PET staging
(yes vs no)
RTOG 0617: Survival by RT Dose
Survival Rate (%)
100
18-Month
Survival
Rate
75
66.9%
53.9%
50
Median
Survival Time
Dead Total
90
213 28.7 months
Standard (60 Gy)
High dose (74 Gy) 117 206 19.5 months
25
HR=1.56 (1.19, 2.06)
0
0
Patients at Risk
Standard
213
High dose
206
3
207
197
p=0.0007
6
9
12
15
Months since Randomization
190
178
177
159
161
135
141
112
18
108
87
RTOG 0617: Local Tumor Failure
Local Progression Rate (%)
100
Fail
65
Standard (60 Gy)
High dose (74 Gy) 81
75
HR=1.37 (0.99, 1.89)
Total
213
206
18-Month
Local
Progression
Rate
p=0.0319
50
34.3%
25.1%
25
0
0
Patients at Risk
Standard
213
High dose
206
3
205
197
6
9
12
15
Months since Randomization
187
170
165
134
137
105
113
80
18
85
62
RTOG 0617: Distant Failure
Distant Failure Rate (%)
100
Fail
Total
97
213
Standard (60 Gy)
High dose (74 Gy) 104 206
75
HR=1.15 (0.87, 1.51)
18-Month
Failure Rate
p=0.1576
50
47.8%
42.4%
25
0
0
Patients at Risk
Standard
213
High dose
206
3
205
193
6
9
12
15
Months since Randomization
175
161
145
126
115
93
94
73
18
73
54
Hypothesis 1: Unbalanced Arms
Despite employing standard stratification features,
some known or unknown features predictive for
toxicity
and/or
treatment
imbalanced between the arms.
resistance
were
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
Age (median)
60 Gy
(n=213)
64
74 Gy
(n=206)
64
Gender
Male
Female
59%
41%
58%
42%
Race
Other
White
12%
88%
14%
86%
RT Technique
3DCRT
IMRT
54%
46%
53%
47%
PET Staging
91%
89%
Histology
Adenocarcinoma
Squamous
NSCLC NOS
39%
42%
19%
35%
47%
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 Michigan
Kaplan-Meier Estimates of Overall Survival According to the
Serum MicroRNA Signature
P = 0.001
100
OS(%)
80
Low risk (N=53)
MST = 36.6months
60
40
20
High risk (N=47)
MST = 13.3 months
0
0
12
24
36
48
Months
60
72
84
96
Analysis of miRNA Signature and RT Dose
Bi, …Kong, U Michigan
100
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)
OS(%)
80
Log-rank P = 0.001
60
40
20
0
0
12
24
36
48
60
72
84
96
108
Months
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
74 Gy
(n=203)
(n=197)
Mean (Median) 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)
8 (7)
8 (7)
Mean Margin CTV to PTV (mm)
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)
Grade
3
4
5
3
4
5
Worst non-hematologic
98
(46%)
21
(10%)
2
(1%)
95
(46%)
23
(11%)
10
(5%)
Worst overall
99
(47%)
57
(27%)
2
(1%)
86
(42%)
65
(32%)
10
(5%)
Grade 5 Events
-As scored by institution
-No significant difference
(n=2)
1 Pulmonary
1 Sudden death
(n=10)
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
Multivariate Cox Model
Covariate
Comparison (RL)
HR (95% CI)
p-value
60 Gy v 74 Gy
1.51 (1.12, 2.04)
0.007
Non-squam v Squam
1.31 (0.99, 1.75)
0.061
<3 vs ≥3
1.52 (1.06, 2.20)
0.024
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
Radiation dose
Histology
Max esophagitis grade
Heart Contour
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)
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)
p=0.024
50%
46%
p=0.7
39%
40%
LCS
Decline
36%
31%
30%
74 Gy
60 Gy
20%
10%
0%
3 months
12 months
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
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
Altered fractionation
60 Gy/30 fr
Week-end Week-end Week-end Week-end
1O Gy
31,5 Gy
24 Gy
22,5 Gy
20 Gy
12 Gy
15 Gy
Week-end Week-end Week-end Week-end Week-end
Weekly D
5 days
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
Split course:2 wks
CCTG=60Gy/40 fr
DD : 2X1,5 Gy
NSCLC-Patient characteristics (n=2,000)
Conventional RT=944 pts
Modified RT=1056pts
Disease
Patients
• Performance Status%
• Age
%
• 0
42
– <60
28
• 1
58
– 60-69
42
• Stage
%
– 70+
30
• Gender (male)
75%
• I / II
• IIIA
• IIIB
17
43
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, cisplatinetoposide or carboplatin-paclitaxel)
Overall survival NSCLC
No. Deaths / No. Entered
Exp. RT
Conv. RT O-E
Category
Trial
Variance
Hazard Ratio
HR [95% CI]
Very accelerated RT
PMCI 88C091
PMCI 88C091 CT
CHART
ECOG 2597
CHARTWEL
CHARTWELCT
vs 60/3wks
48/4860Gy/6wks
52/53
-0.8 BID 24.3
60Gy/6wks
vs
60/3wks
51/51
56/56
6.0 CT 25.6
60Gy/6wks
vs 54 Gy/12d
316/338
217/225
-29.4 TD120.7
64Gy/6,4Wks
vs 57,6Gy/2,5wks
TD
51/60
55/59
-7.4
25.8
66
Gy
vs
60Gy/2,5wks
TD
132/150
132/150
0.2
65.8
66
Gy
vs
60Gy/2,5wks
CT
TD
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 72Gy/8wks
27/29 vs 72/5,5wks
-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
35/35vs 60/40/6wks
-7.0
15.7
60Gy/30/6wks
SC
NCCTG 942452
111/125
108/121
-2.6
54.6
60Gy/30/6wks
vs 60/40/6wks
SC
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
60Gy/30/6wks
vs 69,6/6wks
BID
Subtotal
155/163
Total
964/1056
Test for heterogeneity: 29 = 9.74
Test for interaction:
156/163
2
3
= 0.17
-6.4
885/944 -55.2
2
p = 0.37 I = 8 %
p = 0.98
76.9
443.7
0.92 [0.74;1.15]
0.88 [0.80;0.97], p=0.009
0.25
1.00
4.00
Experimental RT
| Conventional RT
better
better
Overall and Progression-Free Survival NSCLC
100
Modified radiotherapy, overall survival
Conventional radiotherapy, overall survival
Modified radiotherapy, progression-free survival
Conventional radiotherapy, progression-free survival
Survival (%)
80
60
40
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
19.7
20
0
15.9
0
10.5
9.1
1
2
3
4
Time from randomisation (Years)
10.8
8.3 5.1
4.9
5
>6
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
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
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
• 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 reRT)
• 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).
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!
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
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)
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