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

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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