The Science of Radiation Oncology: Innovative Approaches€¦ · The Science of Radiation Oncology: Innovative Approaches Sunday, September 24, 1:00-2:00pm PT Moderator: Brian Czito,

The Science of Radiation Oncology: Innovative Approaches

ASTRO News BriefingSunday, September 24, 2017

ASTRO News BriefingThe Science of Radiation Oncology: Innovative ApproachesSunday, September 24, 1:00-2:00pm PTModerator: Brian Czito, MD, FASTRO, Duke University

Consolidative radiotherapy for limited metastatic non-small cell lung cancer (NSCLC): A randomized phase II trialPuneeth Iyengar, MD, PhD, University of Texas, Southwestern

Analysis of outcomes using external beam radiotherapy plus high dose rate brachytherapy (4x7 Gy or 2x9 Gy) for cervix cancer in a multi-institution trial

May Abdel-Wahab, MD, PhD, FASTRO, International Atomic Energy Agency

Phase II 5-arm trial of ipilimumab plus lung or liver stereotactic radiation for patients with advanced malignanciesJames Welsh, MD, MD Anderson Cancer Center

Long-term results of RTOG 0617: A randomized phase III comparison of standard dose versus high dose conformal chemoradiotherapy +/- cetuximab for stage III NSCLC

Jeffrey Bradley, MD, FASTRO, Washington University, St. Louis

Circulating tumor DNA analysis during radiotherapy for localized lung cancer predicts treatment outcomeAadel Chaudhuri, MD, PhD, Stanford University in Palo Alto, California

Consolidative Radiotherapy for Limited Metastatic Non-Small Cell Lung Cancer (NSCLC): A

Randomized Phase II Trial

P. Iyengar, V. Tumati, D. Gerber, Z. Wardak, C. Ahn, R. Hughes, J. Dowell, N. Cheedella, L. A. Nedzi, K. D. Westover, S. Pulipparacharuvil, H. Choy, and R. D. Timmerman

University of Texas Southwestern Medical Center, Dallas, TX

Background

• Lung cancer claims the most cancer-specific deaths of any tumor type

• Up to 70% of stage IV NSCLC patients achieve partial response or stable disease following first-line cytotoxic systemic therapy, but durability is poor, with disease progression occurring 3-4 months after treatment ends

• Research on other metastatic cancers suggests potential benefit from adding local therapy to maintenance systemic therapy for limited metastatic NSCLC

Stage IV NSCLC Patients

Any 1st Line Chemotherapy

Study Schema

CR

Progression

Partial Response

Stable Disease

Less than or Equal to

6 Locations of Disease =

Randomization

Maintenance Chemotherapy

SAbR to all sites of metastatic Main Chemo

disease and amenable primaries if feasible

(Hypofractionation to primary

if central and/or mediastinal LN metastases)

Primary End Point – PFS

Secondary End Points – OS, Toxicity, Patterns of Failure

All metastatic sites and primaries were treated with SAbR if feasible. Central primary disease and mediastinal

LN mets were treated with either SAbR or hypofractionated radiation (45Gy in 15Fx).

Study Schema

Patient & Tumor Characteristics

Results: ToxicityMaintenance Chemotherapy Only Arm – 2 Grade 3, 1 Grade 4, no Grade 5 events att.

SAbR + Maintenance Chemotherapy Arm – 4 Grade 3, no Grade 4/5 events att.

Results: Patterns of Failure

5 sites in 4/14 patients 13 sites in 10/15 patients

SAbR + Maintenance (N=14) Maintenance Only (N=15)

Sites of Progression No. No.

Brain 1 4

Liver 2 0

Lung 0 8

Bone 1 1

Pancreas 1 0

In Field 0 7

Results: Progression-Free Survival

Median PFS 9.7 months

Median PFS 3.5 months

Conclusions/Summary1. Metastatic NSCLC patients treated with only systemic therapy have

similar PFS if disease is limited or more widely dispersed.

2. Local therapy in the form of SAbR improves PFS nearly three-fold for limited metastatic NSCLC patients.

3. Failure patterns shift to distant rather than local sites.

4. Does local therapy help with OS? Phase IIIR to follow.

5. Can local therapy questions in metastatic NSCLC settings add to our knowledge of how distant disease develops?









Analysis of Outcomes Using External Beam Radiotherapy Plus High Dose Rate Brachytherapy (4x7 Gy or 2x9 Gy) for Cervix Cancer in a Multi-

institution Trial

J. Hendry1, G. W. Jones2, U. M. Mahantshetty3, G. Sarria4, N. W. da Motta5, E. Fidarova6, M. Abdel-Wahab6, R. R. Prasad6, A. Polo6, and E. Zubizarreta6

1Macclesfield, United Kingdom, 2The Cancer Centre Eastern Caribbean, Antigua & Barbuda, 3Tata Memorial Hospital, Mumbai, India, 4Radioncologia - AUNA, Lima, Peru, 5HSR/iSCMPA, Porto

Alegre, Brazil, 6International Atomic Energy Agency (IAEA), Vienna, Austria

13

The IAEA is an independent intergovernmental science and technology organization within the United Nations family.

Serves as the global focal point for nuclear cooperation worldwide

Objective: To enhance capabilities in Member States to address needs related to the prevention, diagnosis and treatment of health problems through the development and

application of nuclear and related techniques within a quality assurance framework.

Background

• 8 in 10 patients with locally advanced cervical cancer live in lower- or middle-income countries

• Radiation therapy is an essential components of management of cervical cancer

• Prospective, multicenter, international randomized trial to confirm the effectiveness of high-dose brachytherapy, or internal radiation therapy, for managing locally advanced cervical cancer

• Histologically confirmed cervix cancer• FIGO stage IIB or IIIB• Age over 18 years• ECOG 0-2 or Karnofsky status ≥ 50• No contraindications for chemotherapy• Adequate bone marrow/renal function• Electrolytes within normal limits• Expected good compliance for FU• Written informed consent

R

Arm1: [EBRT 2Gy x 23fx] + [HDR 7Gy x 4fx]

Arm2: [Arm 1] + [CDDP day 1 of each EBRT w]

Arm3: [EBRT 2Gy x 23fx] + [HDR 9Gy x 2fx]

Arm4: [Arm 3] + [CDDP day 1 of each EBRT w]

EBRT (all arms)✦ 2D planning✦ AP-PA or 4-field technique✦ Prescription at midplane or

isocenter

HDR Brachytherapy✦ 2D planning✦ Arms 1 and 2: 7Gy at point A x 4fx✦ Arms 3 and 4: 9Gy at point A x 2fx

Chemotherapy (arms 2 and 4)• CDDP 40mg/m2 up to

maximum of 80mg• Day1 of each week during

EBRT

Trial Design

Recruiting centerAdministrationData management

CENTER TOTAL CASES

Mumbai (India) 257

Lima (Perú) 147

Cape Town (South Africa) 76

Porto Alegre (Brazil) 53

Bahawalpur (Pakistan) 32

Rabat (Morocco) 19

FYRM (Skopje) 18

Participating Centers

Study armOS

%, (95% CI)CSS

%, (95% CI)LRF

%, (95% CI)Grade ≥ 3 AE%, (95% CI)

Arm17Gy x 4 fx

62 (53-70) 70 (61-78) 19 (13-27) 16 (9-29)

Arm2[Arm1] + CDDP

73 (64-80) 81 (72-87) 13 (8-21) 14 (8-24)

Arm39Gy x2 fx

68 (59-76) 74 (65-81) 26 (19-34) 5 (2-10)

Arm4[Arm3] + CDDP

65 (56-73) 71 (63-78) 29 (22-38) 8 (4-14)

Number of events 177 deaths 136 deaths 121 failures 44 with AE

2-tailed p-value log-rank 4-arms

0.18 0.17 0.004 0.56

2-tailed p-value log-rank 2-groups (‡)

HDR = 0.6Chemo = 0.2

HDR = 0.4Chemo = 0.2

*HDR = 0.0008**Chemo = 0.6

**HDR = 0.3**Chemo = 0.5

** 25 v 19 events* 78 v 43 events** 62 v 59 events

OS: overall survival; CSS: cause specific survival; LRF: loco regional failure; AE: pelvic adverse effects gastrointestinal, genitourinary or gynaecological

(‡) HDR: [Arm1+Arm2] vs. [Arm3+Arm4]; Chemo: [Arm2+Arm4] vs. [Arm1+Arm3]

(†) Median follow-up 4y; maximum follow-up 7y

Five-Year Results by Treatment Arm

LOCO-REGIONAL FAILURE SITE of 181 FAILURES

p=0.004

LRC (%) 95%CI

Arm1+Arm2 (7Gy x 4fx) 88 84-92

Arm3+Arm4 (9Gy x 2fx) 77 72-82

p value 0.0008 0

Sub-group analysis (dose-effect)

60

355

23

4

1818

Median time to LRF= 0.97 y (n = 121)

4-arm log-rank p=0.004Chemo vs. no-chemo p=0.66

4HDR vs. 2 HDR p=0.0008

DISTANTMedian time to DF= 1.65 y (n = 119)

4-arm log-rank p=0.31Chemo vs. no-chemo p=0.068

4HDR vs. 2 HDR p=0.88

REGIONAL

Trial Results by Treatment Arm

LOCAL

ALL CAUSE MORTALITY CAUSE-SPECIFIC MORTALITY

p=0.18 p=0.17

Trial Results by Treatment Arm

Conclusions

• A dose-effect relationship is implied by a 11% reduction in local failure (4x7 superior to 2x9 HDR).

• However, no statistical difference in overall survival or cause-specific survival.

• Also no statistical difference in grades 3-5 GI, GU and GYN chronic side-effects attributable to treatments occurring in the absence of relapse (local, nodal or distant).

• Not enough statistical power to detect significant effect of CDDP among arms.

• If resources are severely limited and 2x9 Gy is used, a small decrease in local control can be expected.









Phase II 5-arm Trial of Ipilimumab Plus Lung or Liver Stereotactic Radiation for Patients with

Advanced Malignancies

J. W. Welsh1, C. Tang1, P. de Groot1, A. Naing1, U. Raju1, S. Shaaban1, J. Y. Chang1, T. Cushman1, J. Heymach1, R. Dadu1, M. E. Cabanillas1, K. Hess1, E. Massarelli2, V. Subbiah1, S. Fu1, V. Papadimitrakopoulou1, D. R. Gomez1, S. M. Hahn1, R. U. Komaki1, and D. Hong1

1The University of Texas MD Anderson Cancer Center, Houston, TX2City of Hope, Houston, TX

Questions1) Dose2) Sequencing3) Tumor location

Study Design

Characteristics All patients(n=100)

Group 1: LiverConcurrent(n=20)

Group 2: LiverSequential(n=20)

Group 3: LungConcurrent(n=20)

Group 4: LungSequential(n=20)

Group 5: Liver/Lung 60/10Sequential(n=20)

SexMale

Female51 (51%)49 (49%)

911

137

713

911

137

Median age (range)

58 (22-82) 57 (39-77) 59 (31-77) 56 (29-79) 60 (31-82) 58 (22-80)

EthnicityWhiteAsianBlackOther

88 (88%)2 (2%)7 (7%)3 (3%)

19

1

18

2

1514

1811

18

11

Primary HistologyAdenocarcinoma

SCCOthers

58 (58%)12 (12%)30 (30%)

1325

1235

938

1118

1334

Patient Characteristics

AE Conc Lung Conc Liver Seq Lung Seq Liver Seq 60/10

GIT:Colitis

ObstructionAbdominal Pain

DiarrheaAST/ALT increase

Lipase IncreaseBilirubin Increase

4 (4%)1 (1%)1 (1%)

2 (2%)1 (1%)

1 (1%)

2(2%)

2 (2%)

1 (1%)1 (1%)

2 (2%)

5 (5%)1 (1%)

Endocrine:HypophysitisTSH increase

1(1%)1 (1%)

1 (1%) 1 (1%)

Chest:Pneumonitis

Chest PainDyspnea

1 (1%)2 (2%) 1 (1%)

1 (1%)

Rash maculo-popular

2 (2%) 2 (2%)

Adverse Events (G3, no G4-5) (n=100)

• Median PFS:

5 months

• Median OS:

12 months

26

Treatment Response

Concurrent liver Liver Sequential Concurrent Lung Sequential Lung Sequential 60/10

irPD

irPR/iRCR

irSD

14 (73%)

1(5%)

4 (21%)

11 (68%)

1(6%)

4 (25%)

8 (42%)

3 (16%)

8 (42%)

7 (36%)

3(16%)

9 (47%)

9 (47%)

2 (10%)

8 (42%)

Clinical Benefit

5(26%) 5 (31%) 11 (58%) 12 (63%) 10 (52%)

26-63%5-16%

Response to Treatment

Non-XRT treated tumor responseClinical benefit SD+PR+CR

45/95= 47%

Reduction in size 31/95 =32%

Abscopal Response in Lung

7-7-2106 3-13-2017

Tumor got low dose scatter

No low dose = No Abscopal

7-7-2106 3-13-2017

No Abscopal









Long-Term Results of RTOG 0617: A Randomized Phase 3 Comparison of Standard

Dose (60 Gy) versus High Dose (74 Gy) Conformal Chemoradiation Therapy +/-

Cetuximab for Stage III NSCLC

J. D. Bradley1, C. Hu2, R. U. Komaki3, G. Masters4, G. R. Blumenschein5, S. E. Schild6, J. A. Bogart7, K. M. Forster8, A. Magliocco9, V. S. Kavadi10, S. Narayan11, P. Iyengar12, C. G. Robinson1, R. B. Wynn13, C. D.

Koprowski14, M. R. Olson15, J. Meng16, W. J. Curran Jr17, and H. Choy12

1Washington University School of Medicine, Department of Radiation Oncology, St. Louis, MO, 2Johns Hopkins University School of Medicine, Division of Biostatistics and Bioinformatics, Baltimore, MD, 3Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX,

4Medical Oncology Hematology Consultants, Philadelphia, PA, 5Thoracic Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 6Mayo Clinic Arizona, Phoenix, AZ, 7SUNY Upstate Medical University, Syracuse, NY, 8University of South Alabama, Mobile, AL, United

States, 9Moffitt Cancer Center, Tampa, FL, 10Texas Oncology, Fort Worth, TX, United States, 11Michigan Cancer Research Consortium CCOP, Ypsilanti, MI, 12University of Texas Southwestern Medical Center, Dallas, TX, 13University of Pittsburgh Medical Center, Pittsburgh, PA, 14Christiana Care Health System,

Newark, DE, 15Baptist Medical Center, Jacksonville, FL, 16Ottawa Cancer Center, Ottawa, ON, Canada, 17Department of Radiation Oncology, WinshipCancer Institute of Emory University, Atlanta, GA

• Early results of the randomized phase III trial published in Lancet Oncology in 2015 showed a median overall survival of 22.9 vs 28.7 months in high-dose vs standard arms, respectively.

• Multiple secondary analyses have been reported on patient-reported quality of life (Movsas et al; JAMA Oncol 2016), institutional volume (Eaton et al; JNCI 2016), and benefits of IMRT (Chun et al; JCO 2017).

• Current presentation reports mature 5-year data

Background

Eligibility Criteria

• Newly diagnosed, unresectable Stage IIIA/B NSCLC; patients who present with N2/N3 disease and an undetectable NSCLC primary tumor were also eligible

• No supraclavicular or contralateral hilar adenopathy

• Zubrod 0/1

• Age ≥ 18

• FEV1 ≥ 1.2 liters/second or > 50% predicted

• ANC ≥ 1,000, platelets ≥ 100,000, Hgb ≥ 10.0 g/dl

• Serum creatinine within normal institutional limits, or creatinine clearance ≥ 60 ml/min, bilirubin within normal institutional limits; AST and ALT < 2.5 X IULN

• Signed informed consent

Esophagitis and Pulmonary Toxicity

Standard Dose: 60 Gy High Dose: 74 Gy

Esophagitis N=218 N=207

Grade 1-2 202 (93%) 164 (79%)

≥Grade 3 16 (7%) 43 (21%)

P value <0.0001

Pneumonitis

≥Grade 3 15 (7%) 9 (4%)

P value 0.258

Any pulmonary

≥Grade 3 45 (21%) 40 (19%)

P value 0.734

Overall Survival by RT Level

Time (years) Standard Dose: 60 Gy High Dose: 74 Gy

% Alive (95%CI) # at risk % Alive (95% CI) # at risk

5 year OS 32.1% (25.8, 38.6) 54 23.0% (17.5, 29.0) 37

Dead/Total 150/218 163/207

Median Survival 2.4 years (2.0, 3.2): 28.7 months 1.7 years (1.5, 2.0): 20.3 months

Log-rank P-value

(1-sided)

0.0036

Hazard ratio (95% CI) 1.35 (1.08, 1.69)

*Median follow-up time: all patients 2 yearssurviving patients 5.6 years

Overall and Progression-free Survival by RT Dose

Multivariable Cox Model for Overall Survival Covariate Comparison Dead/

Total RL

Dead/Total

Group 2

HR (95% CI) p-value*

Radiation Level Standard Dose (RL) vs.

High Dose132/196 14/188 1.30 (1.02, 1.66) 0.0315

Tumor Location LLL or central node (RL)

vs. Neither LLL nor

central node

172/226 107/158 0.86 (0.67, 1.11) 0.2395

Institution Accrual

Volume

1-3 patients (RL) vs. ≥ 4

patients

122/149 157/235 0.74 (0.58, 0.95) 0.0170

Maximum related

esophagitis/

dysphagia grade

Maximum grade < 3 (RL)

vs. Maximum grade ≥ 3

230/328 49/56 1.54 (1.12, 2.12) 0.0079

Volume of PTV

(log-transformed)

Continuous 279/384 1.323 (1.041, 1.680) 0.0219

Heart V5 Continuous 279/384 1.008 (1.002, 1.013) 0.0051

RL=reference level, HR=hazard ratio, CI=confidence interval, LLL=lower left lobe

*2-sided p-value

Heart V5 based on heart contour performed centrally at NRG (Gore, ASTRO 2016)

Conclusions

• Mature 5-year follow-up data confirm that a dose of 60 Gy was superior to 74 Gy for overall survival for stage III NSCLC.

• The use of cetuximab was of no benefit.

• The 5-year overall survival rate of 32% is a new benchmark for chemoradiation for Stage III NSCLC.

• Other important factors predicting overall survival were institutional accrual volume, maximum esophagitis/dysphagia grade, volume of PTV, and heart dose.









Circulating Tumor DNA Analysis During Radiotherapy for Localized Lung Cancer Predicts

Treatment Outcome

A. A. Chaudhuri1, A. F. Lovejoy1, J. J. Chabon1, A. Newman1, H. Stehr1, D. J. Merriott2, J. N. Carter1, T. D. Azad1, S. Padda1, M. F. Gensheimer1, H. A. Wakelee1, J. W. Neal1, B. W. Loo

Jr1, A. A. Alizadeh1, and M. Diehn1

1Stanford Cancer Institute, Stanford, CA, 2Stanford University School of Medicine, Stanford, CA

Background• Circulating tumor DNA (ctDNA)

• Typically <1% of total cell-free DNA in cancer patients

• We recently developed an ultrasensitive method to quantitate ctDNA called Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq)1,2

• MRD = Minimal Residual Disease or Molecular Residual Disease• Prognostic biomarker important in the management of leukemia

• Currently no role in lung cancer management

• Hypotheses: • ctDNA analysis can detect MRD after definitive intent treatment of lung

cancer

• ctDNA MRD detection is prognostic for progression and survival

1Newman & Bratman et al, Nature Medicine, 2014

2Newman, Lovejoy & Klass et al, Nature Biotech, 2016

Study Design

Patient CohortParameter n = 41

Follow-up time (mo) 35.1 (6.9-56)

Age (y) 66.8 (47-91)

Gender

Male 28 (68%)

Female 13 (32%)

Smoking history

Yes 36 (88%)

No 5 (12%)

Pack-years 30 (0-150)

Stage

IA 1 (2%)

IB 7 (17%)

IIA 3 (7%)

IIB 4 (10%)

IIIA 15 (37%)

IIIB 11 (27%)

Histology

Adenocarcinoma 20 (49%)

Squamous carcinoma 15 (37%)

Small Cell 3 (7%)

NOS 3 (7%)

Local therapy

Radiotherapy 36 (88%)

Radiotherapy + Surgery 3 (7%)

Surgery 2 (5%)

Chemotherapy

Yes 28 (68%)

No 13 (32%)

Circulating DNA

ctDNA detected pre-tx 39 (95%)

Results: Patients with detectable ctDNA MRD have significantly worse outcomes

Patient Example: EGFR activating mutation detected by ctDNA MRD

Stage IB Adeno No recurrence Brain metRadiologyinterpretation

0 1 2 3 4 5 6 7

1

10

Time (Months)

EG

FR

L858R

(hG

E/m

L)

ND

Scan 2 Scan 3Scan 1

SA

BR

0.51 hGE/mL

Potential adjuvant treatment based on ctDNA MRD

0 6 12 18 240

20

40

60

80

100

Time from landmark (mo)

Fre

edom

fro

m

Pro

gre

ssio

n (

%)

Survival of Mid-tx (<28d from chemoRT start): FFP

> 0.1% ctDNA (n = 8)

< 0.1% ctDNA (n = 5)

P = 0.037

HR = 4.4

Cox Regression

P = 0.006

HR = 2.7

13 patients with ctDNA measured within 4 weeks of chemoRT start

Exploratory Analysis: Mid-treatment ctDNA levels correlate with future lung cancer progression

Conclusions and Future Directions

ctDNA detects MRD after definitive intent treatment for localized lung

cancer

ctDNA MRD detection after treatment correlated with significantly

worse progression and survival

ctDNA MRD may be useful for selecting patients for early

administration of targeted therapies

ctDNA levels may be prognostic at the mid-treatment time point

Potential for future studies that offer early therapeutic intervention

based on ctDNA quantitation









Q & A

Online attendees: Please use the Question function to submit questions.

ASTRO’s On-site Press Office in San Diego

Room 24B, San Diego Convention Center

September 24-26, 8am-5pm PT; September 27, 8am-12pm PT

Phone: 703-286-1600

Email: [email protected]

Slides, audio and hi-res photos will be available following the briefing at www.astro.org/AMpress

Interview Requests and Other Questions:

http://www.astro.org/AMpress

Documents

The Science of Radiation Oncology: Innovative Approaches€¦ · The Science of Radiation Oncology: Innovative Approaches Sunday, September 24, 1:00-2:00pm PT Moderator: Brian Czito,