MARTA SCORSETTI M.D.

Direttore Radioterapia e Radiochirurgia

Istituto Clinico Humanitas

marta.scorsetti@humanitas.it

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