current controversies in radiation therapy for lung …...radiation therapy for lung cancer optimal...
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Current Controversies in
Radiation Therapy for Lung
Cancer
Optimal RT Dose :RTOG 7301
n = 378, stage III, KPS ≥ 50
RTOG-7301: Survival/Response
Total Number Median 2-Yr.
n Dose (cGy) Fractions (mos.) (%)
93 4,000 10(S) *(1-2-1) 8.5 10
97 4,000 20(C) 10.6 11
91 5,000 25(C) 9.5 19
84 6,000 30(C) 10.8 19
60 Gy in 6 weeks became the
standard dose for Stage III NSCLC
in the 70’s …80’s and 90’s
Overview of 74 Gy vs 60 Gy Dose
(Phase I/II Trials)
RTOG 0617- A 7501
Randomized Phase III Comparison of Standard-Dose (60 Gy)
Versus High-Dose (74 Gy) Conformal Radiotherapy with
Concurrent and Consolidation Carboplatin/Paclitaxel +/-
Cetuximab In Patients with Stage IIIA/IIIB Non-Small Cell Lung
Cancer (NSCLC)NCI Sponsored Cooperative Groups: RTOG, NCCTG, CALGB
Jeffrey D Bradley, Rebecca Paulus, Ritsuko Komaki, Gregory A. Masters, Kenneth Forster, Steven E. Schild, Jeffrey Bogart, Yolanda I. Garces, Samir
Narayan, Vivek Kavadi, Lucien A Nedzi, Jeff M. Michalski, Douglas Johnson, Robert M MacRae, Walter J Curran, and
Hak Choy
Bradley A-7501, ASCO ‘13
RTOG 0617 Overall Survival
Surv
ival R
ate
(%
)
0
25
50
75
100
Months since Randomization
0 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 months20.3 months
2 year Survival Rate
57.6%
44.3%
Bradley A-7501, ASCO ‘13
60 Gy
74 Gy
7
My Perspective on RT Dose and
RTOG 0617 60Gy
68Gy
63G
y
74G
y
More is not necessarily better (60 Gy > 74 Gy)
Less is “more” and clearly less toxic
1970 2014
CONVERT trialConcurrent ONce-daily VErsus twice-daily RadioTherapy:
A 2-arm randomised controlled trial of concurrent chemo-
radiotherapy comparing twice-daily and once-daily
radiotherapy schedules in patients with limited-stage small
cell lung cancer and good performance status
Corinne Faivre-Finn1, Michael Snee2, Linda Ashcroft3, Wiebke Appel4, Fabrice Barlesi5, Adi Bhatnagar6, Andrea Bezjak7, Felipe
Cardenal8, Pierre Fournel9, Susan Harden10, Cecile Le Pechoux11, Rhona McMenemin12, Nazia Mohammed13, Mary O'Brien14,
Jason Pantarotto15, Veerle Surmont16, Jan Van Meerbeeck16, Penella Woll17, Paul Lorigan1, Fiona Blackhall1
1. The University of Manchester, Institute of Cancer Sciences, Manchester, UK; 2. St James Hospital, Leeds, UK; 3. MAHSC-CTU, The Christie
NHS Foundation Trust, UK; 4. Royal Preston Hospital, UK; 5. CHU de Marseille, France; 6.Southampton General Hospital, UK; 7.Canadian Cancer
Trials Group, Princess Margaret Cancer Center, Toronto, Canada; 8. GECP , Institut Català d'Oncologia, Barcelona, Spain; 9. GFPC, Institut de
Cancérologie de la Loire, France; 10. Addenbrookes Hospital, Cambridge, UK; 11. Institut Gustave Roussy, Villejuif, France; 12. Freeman Hospital,
Newcastle-upon-Tyne, UK; 13. Beatson Cancer Centre, Glasgow, UK; 14. Royal Marsden Hospital, Surrey, UK; 15. Ottawa Health Research
Institute, Canada; 16. Universiteit Gent, Belgium; 17. Weston Park Hospital, Sheffield, UK
ASCO 2016, Presented by: Prof C Faivre-Finn
@finn_corinne
Study design multinational, phase III randomized study
ASCO 2016, Presented by: Prof C Faivre-Finn
RT 45Gy/30F/19D
Lim
ite
d S
tag
e S
ma
ll C
ell
SD,PR,CRPCI
If<SD no PCI
Registration
Randomisation
Restage
Chemotherapy
Radiotherapy
D1 D3 D22 D24 D43 D45 D64 D66
Twice-daily (BD) thoracic RT
D1 D3 D22 D24 D43 D45 D64 D66
RT 66Gy/33F/45D
Once-daily (OD) thoracic RT
Stratification factors• Centre• No. of cycles chemo: 4
vs.6 • PS: 0,1 vs. 2
RTP after randomisationRT started on D22 cycle 1• 3DCRT or IMRT• No ENIQA programme
Chemotherapy4 to 6 cycles • Cisplatin 25mg/m2 D1-3
or 75mg/m2 D1• Etoposide 100mg/m2
D1-3
Overall survival
Presented by: Prof C Faivre-Finn
Median follow-up: 45 months
Overall
survival
(n=543)
BD OD Log-rank
Median
(months)
30 (24-34) 25 (21-31)
p=0.15
1-year 83% (78-87) 76% (71-
81)
2-year 56% (50-61) 51% (45-
57)
3-year 43% (37-49) 39% (33-
45)
Primary objective-survival at 2 yearsTrial hypothesis
Expected survival BD arm 44%Projected survival OD arm 56%
@finn_corinne
HR for death OD group =1.17 95% CI 0.95-1.45
AE
CTCAE v3.0 Arm
0
n (%)
1-2
n (%)
3-5
n (%)
P
(0,1,2 vs3,5)
OesophagitisBD
OD
48 (18.9)
63 (25.7)
159 (62.6)
135 (55.1)
45 (18.5)
47 (19.2)0.85
PneumonitisBD
OD
198 (78.0)
187 (77.3)
51 (20.1)
49 (20.2)
5 (2.0)*
6 (2.4)*0.70
Symptom Arm 0 1-2 3 4 p0,1,2 vs 3,4
Dermatitis BDOD
233 (94.0)216 (92.7)
15 (6.0)17 (7.3)
- - -
Oesophagitis BDOD
219 (88.3)191 (81.6)
29 (11.7)39 (16.7)
-4 (1.7)
-0.06
Oesophagealstricture/fistula
BDOD
240 (91.8)226 (97.0)
8 (3.2)6 (2.6)
-1 (0.4)
-0.48
Pulmonaryfibrosis
BDOD
125 (50.6)120 (52.6)
119 (48.2)106 (46.5)
3 (1.2)2 (0.9)
-1.00
Pneumonitis BDOD
171 (69.0)154 (67.0)
71 (28.6)70 (30.4)
5 (2.0)5 (2.2)
1 (0.4)1 (0.4) 0.90
Myelitis BDOD
247 (99.6)223 (96.5)
1 (0.4)*8 (3.5)*
- - -
Other BDOD
92 (37.4)99 (42.7)
131 (53.3)113 (48.7)
20 (8.1)18 (7.8)
3 (1.2)2 (0.9) 0.78
Acute & Late Toxicity
Immunotherapy is HOT!
Lung cancer clinical trials
Keynote 001 Pembrolizumab Trial: Percentage of Cells Expressing PD-L1
Garon, EB; NEJM, 2015
2nd line Patients: Check mate 017Nivolumab vs. Docetaxel
Brahmer, J; NEJM, 2015
Radiation Therapy and the Abscopal Effect
Patient has visible tumor A, B, C, …
A
B
C
Radiation Therapy and the Abscopal Effect
Patient has visible tumor A, B, C, …
Treat tumor A alone with radiationA
B
C
Radiation Therapy and the Abscopal Effect
Patient has visible tumor A, B, C, …
Treat tumor A alone with radiation
Tumors B, C, … regress
A
B
CC
Radiation Therapy and the Abscopal Effect
Patient has visible tumor A, B, C, …
Treat tumor A alone with radiation
Tumors B, C, … regress
First described in 1953
Shown to be immune mediated over a decade ago
A
B
C
RT Can Augment Immune Response
Shiao and Coussens. J Mammary Gland Biol Neoplasia. 2012.
Abscopal Effects
The Immune Mediated Abscopal Effect
Treatment of one tumor triggers the response of other (or all) tumors
IF this occurred in a reliable way, it would be extremely important
–Alas, it dose not
Mostly described in retrospective single patient case reports rather than
prospective series
Abscopal Effects of Radiation Therapy
Postow et al. N Engl J Med. 2012;366:925-931.
Abscopal Effects of
Radiotherapy After
Immunotherapy
Grimaldi et al. Oncoimmunology. 2014;3:e28780.
A 54-y-old male patient received 4 cycles of ipilimumab 3 mg/kg (June to August 2012) followed by palliative whole-brain radiotherapy (WBRT)
Figure 1. Patient survival according to abscopal responses. Kaplan-Meier curves depicting overall survival (OS) curves among patients who received RT after progression with ipilimumab, according to the presence or absence of an abscopal response (present in 11 patients and absent in 10 patients). Groups were compared using the log-rank test; P=0.002.
Grimaldi et al. Oncoimmunology. 2014;3:e28780.
Randomized, Double Blinded Phase III Trial of
Cisplatin and Etoposide Plus Thoracic Radiation
Therapy Followed by Nivolumab/Placebo for Locally
Advanced Non-Small Cell Lung Cancer
[RTOG Foundation 3505]
Alliance Foundation Trial (AFT-16)
Chemoradiation in Stage III Unresectable NSCLC
*Chemo/RT= carboplatin (AUC2) + paclitaxel 50 mg/m2 IV weekly x6 cycles +60 Gy qd x 30fxn§Consolidation chemotherapy = carboplatin AUC6 + paclitaxel 200 mg/m2 IV q21 days x 2 cycelsORR=objective response rate; PD=progressive disease; RT=radiotherapy; QoL=quality of life
Phase II/III trial of induction immunotherapy with atezolizumab for patients with unresectable stage IIIA
and IIIB NSCLC eligible for chemoradiotherapy with curative intent and whose tumors express PD-L1
Phase III Objectives and Endpoints:
1. Primary endpoint: OS
2. Secondary endpoint: PFS, safety, QoL
Chemo/RT + Consolidation Adjuvant Immunotherapy
Chemo/RT +
Conoslidation
4 total cycles of
Atezolizumab induction
Alliance Standard
Chemo/RT* regimen
Alliance Standard Chemo
Consolidation§
Atezolizumab
1200mg q3w for 1
year
NSCLC
Stage
IIIA &
IIIB
PDL1+
Primary Endpoints: ORR following induction, PFS following induction + chemo/RT
R A
N D
O M
I Z
E 2
:1
Atezolizumab
1200 mg IV
q3w
x4 cycles
Induction
Immunotherapy
Immunotherapy
+
SAbR(Stereotactic Ablated Radiation Therapy)
(SBRT)
i-SAbR
Is There a Role for Consolidative Stereotactic Body Radiation
Therapy Following First-line Systemic Therapy for Metastatic
Lung Cancer? A Patterns-of-Failure Analysis
Careful assessment of pattern of failure (POF)
–Local (L, existing sites) or distant (D, new sites)
–Brain mets scored separately
64 patients with stage IIIB-IV NSCLC
–Median time to progression = 3.9 months
L only failure in 64%, L+D in 27%, D only in 9%
–1st-line therapy fails to control gross disease in 91%
91%
A Phase II Trial of 2nd-line Erlotinib in Combination With Stereotactic
Body Radiation Therapy (SBRT) for Patients With Locally Advanced or
Metastatic Non-Small Cell Lung Cancer (NSCLC)
NSCLC1. Progressed after prior
systemic therapy2. ≤6 discrete lesions3. Eligible for erlotinib
and SBRT to all lesions4. “unscreened
Week 1Begin erlotinib
150 mg/d
Weeks 2-4Continue erlotinib
Begin SBRT to all involved sites of disease*
Post-SBRTErlotinib until disease progression or unacceptable toxicity
*VERY CONSERVATIVE SBRT DOSES, eg, 1 × 19 Gy, 3 × 11 Gy, 5 × 8 Gy.
Metastatic SBRT!
UTSW/U Denver Trial
028
Pattern of Failure Number (%) out of 23 patients
Sites of Failure by Patient:
Within SBRT treated area 1 (4)
Outside SBRT field 6 (26)
None 17 (74)
Distant Failure Sites
Liver 4 (17)
Brain 2 (9)
Pancreas 1 (4)
Lymph node 1 (4)
24 patients with stage IV NSCLC who had progressed through
platinum-based chemotherapy
Erlotinib and concurrent SBRT to all sites (up to 6)
J Clin Oncol. 2014 Oct 27
Untreated
029
J Clin Oncol. 2014 Oct 27
• 24 patients with stage IV NSCLC who had progressed through
platinum-based chemotherapy
• Erlotinib and concurrent SBRT to all sites (up to 6)
• Dramatically improved median PFS and OS compared to historical controls
Stage IV NSCLC Patients
Any 1st Line Chemotherapy
Randomized Phase II Trial Comparing Maintenance Chemotherapy vs
SBRT Followed by Maintenance Chemotherapy for
Stage IV NSCLC Patients with Limited Metastatic Disease
CR
Progression
Partial Response
Stable Disease
Less than or Equal to
6 Locations of Disease =
Randomization
Maintenance Chemotherapy
SBRT to all sites of disease Chemo
determined by CT or PET/CT
Patient off study – When progression by imaging cannot be adequately addressed by SBRT (either
from too many sites of disease progression or failures within previously treated sites with SBRT)
Primary End Point – PFS
Secondary End Points – OS, Toxicity, Biologic Correlates, Cost-Benefit Analysis, QoL
Longitudinal Biologic Correlates – Could include CTCs, Cytokines, Growth factors, Biopsy of
Recurrences and evaluation of SNPs, Deep Sequencing, etc.
Median PFSSBRT – 292 daysMain – 105 days
MDACC Study
PFS Outcomes (updated data)
One patient inevaluable
(24 in each group)
Median PFS times:
No-LCT arm: 3.9 months
(95% CI 2.2-6.6 months)
LCT arm: 11.9 months
(95% CI 5.4 months-NA)
P-value = 0.005
0.0
00
.25
0.5
00
.75
1.0
0
Pro
gres
sio
n-F
re
e S
urviv
al P
ro
bab
ilit
y
24 2 0 0No LCT:
24 8 2 0LCT:
Number At Risk
0 1 2 3
Time in Years
LCT
No LCT
Presented by: Daniel Gomez, M.D.
Stage IV NSCLC Patients
1st Line Chemotherapy
SBRT for Limited Metastatic NSCLC in the
Consolidative Setting (NRG LU002)
Schema
Partial Response
Stable Disease
Maintenance Chemotherapy
SBRT to all metastases Maintenance Chemo
determined by CT or PET/CT
Primary disease treated with SBRT or
hypofractionation
Less than or Equal to 3 Sites of Metastatic Disease + Primary =
Randomization
Pemetrexed, Docetaxel, Erlotinib
Why SBRT works so well even in the
setting of Metastatic Lung Cancer ?
RT Can Augment Immune Response
Shiao and Coussens. J Mammary Gland Biol Neoplasia. 2012.
Abscopal EffectsHigh Dose SBRT
Conventional Therapy
o Standard Care
Proton therapy
o The Recent Technology
Radiation Oncology – Beyond Photon
How Proton is different than
X-rays/Photon ?
Mostly in the Physical property
Not much difference in Biology!
Dose Distribution Advantage
Discovered by Sir William Henry Braggin 1903
Provide a lethal dose to the tumor…
…while sparing the surrounding healthy
tissue
Effectiveness of Particle
Therapy
A Bayesian Randomization Trial of Intensity
Modulated Radiation Therapy (IMRT) vs.
3-Dimensional Passively Scattered Proton Therapy
(3DPT) for Locally Advanced Non-Small Cell
Lung Carcinoma
(clinicaltrials.gov identifier NCT00915005)
Zhongxing Liao, J. Jack Lee, Ritsuko Komaki, Daniel R. Gomez, Michael
O’Reilly, Pamela K. Allen, Frank Fossella, John V. Haymach, George R.
Blumenschein, Noah Chan Choi, Thomas F. Delaney, Stephen M. Hahn,
Charles Lu, James D. Cox, and Radhe Mohan
Supported in part by NCI grants P01 CA021230 and U19 CA021239.
Randomized and Treated According
to Randomization Analysis
Comparative IMRT and 3DPSPT plans evaluated
N = 225
Treated with IMRTN=92
Preferred protons
N = 6
IMRT N = 105
Signed informed consent N= 274
Excluded from analysis N=49:1. Chemotherapy only : 12. Consented twice3. Closed to patient accrual: 34. Disease progression: 85. GTV movement > 2 cm: 16. Ineligible body weight: 17. Insurance denied: 88. No Chemo: 29. No good for proton: 110. Poor PFT : 411. Patient wants proton only: 212. Screening Failure: 4 (Stage I: 1 &
Stage IV:2)13. Surgery: 114. tumor too large: 115. TX at local facility: 116. Violation of the study: 417. Withdraw IC: 5
Plans randomizableN = 181
3DPT N = 76
Treated with 3DPT
N = 57
Insurance denied protons so treated with
IMRTN=15
3DPT betterN = 13
Off study due to Unacceptable plan
N =3
IMRT plan betterN = 28
Plans not randomizable
N=44
Off protocolN = 4
Off protocolN = 7
(3 insurance denial protocol)
Lung and Heart V5-V80
Lung V5 – V80
IMRT
Proton
0.2
.4.6
.81
Pe
rce
nt
V5 V10 V20 V30 V40 V50 V60 V70 V80
Heart V5 – V80
IMRT
Proton
0.2
.4.6
.81
Pe
rce
nt
V5 V10 V20 V30 V40 V50 V60 V70 V80
Note: Analysis carried out using the Wilcoxon rank-sum test (also known as Mann-Whitney Two Sample Statistic)
Radiation Pneumonitis
RP Grade IMRT 3DPT Total P values
N=92 N=57 N=149
0 65 36 101 0.36
1 9 4 13
2 12 11 23
3 4 6 10
4 0 0 0
5 2 0 2
Gr 0-2 86 51 137 0.54
Gr 3-5 6 (6.5%) 6 (10.5%) 12 (8.1%)
Median Time to RP:All = 4.3 month, IMRT= 4.5 month, 3DPT= 4.0 month (p=0.15)
Overall Survival
Whole Group IMRT vs. 3DPT
Cox Regression Analysis for OS
Variable HR p-value 95% CI Comparison
Age Continuous 1.03 0.012 1.01 1.06 Continuous
RT Dose >=74 0.62 0.036 0.39 0.97 <74Gy
GTV Continuous 1.002 0.02 1.000 1.003 Continuous
0.0
00
.25
0.5
00
.75
1.0
0
Pro
po
rtio
n
149 119(30) 76(31) 42(22) 28(5) 12(3) 1(2) Number at risk
0 12 24 36 48 60 72Analysis Time (Months)
0.0
00
.25
0.5
00
.75
1.0
0
Pro
po
rtio
n
57 43(14) 30(10) 18(10) 12(3) 5(3) 1(0)Proton92 76(16) 46(21) 24(12) 16(2) 7(0) 0(2)IMRT
Number at risk
0 12 24 36 48 60 72Analysis Time (Months)
MST=28.8 month MSTIMRT= 29.5 monthMST3DPT=26.1 monthP=0.30
RTOG 1308
Phase III Randomized Trial Comparing Overall Survival
after Photon versus Proton Radiochemotherapy for Inoperable Stage II-IIIB NSCLC
SCHEMA
S
T R A
T I
F Y
Stage
1. II 2. IIIA 3. IIIB
GTV Volume
1. ≤ 130 cc 2. > 130 cc
Histology 1. Squamous
2. Non-Squamous
Neoadjuvant Chemo
1. No 2. Yes
R A
N D
O M I
Z E
Arm 1: Photon
dose—Higher achievable dose
between 60-70 Gy, once daily plus platinum-based
doublet chemotherapy*
Arm 2: Proton dose—Higher
achievable dose between 60-70 Gy
(RBE), once daily plus platinum-based doublet
chemotherapy*
Both Arms: Consolidation
chemotherapy x 2 is allowed*
Target Accrual: 560, Accrual as of 1/15: 48
Conventional Therapy
o Standard Care
Proton therapy
o The Recent Technology
Heavy Ion Therapy
o The Most Advanced Technology
Radiation Oncology – Beyond Photon and Proton
Heidelberg Ion-Beam Therapy Center (HIT)
Perhaps, we can do better with
Heavy Ion Therapy (Carbon) !
3) Heavy Ions – have very sharp edges
Sharp Carbon
Proton or X-ray
Enhanced cell killing described by
Relative Biological Effectiveness
Common RBE values:
–X-ray (reference)1.0
–Protons 1.0 – 1.4
–Carbon 3 - 4
carbon proton
ProtonPhoton
Heavy ion
Heavy charged particles can overcome
radioresistance due to hypoxia
Aerobic Cells
Hypoxic Cells
PhotonProton
Carbon Ions
A Prospective Nonrandomized Phase I/II Study of Carbon Ion
Radiotherapy in a Favorable Subset of Locally Advanced Non–
Small Cell Lung Cancer (NSCLC)
Wataru Takahashi, et al. NIRS Cancer 2015;121:1321-7.
Review ArticleCarbon Ion Therapy for Early-Stage Non-Small-Cell Lung Cancer
Yusuke Demizu et al.
BioMed Research InternationalVolume 2014, Article ID 727962, 9 pages
“Even if you're on the right track, you'll get
run over if you just sit there”
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