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SOCCARa Phase II Trial of Sequential Versus
Concurrent Chemotherapy and Radiotherapy Using an Accelerated Hypofractionated Radiation Schedule in Stage III NSCLC
J Maguire, R McMenamin,N O’Rourke, C Peedell, M Snee,
S McNee, V Kelly
overview
• development of SOCCAR chemo- radiotherapy regimen
• SOCCAR trial
• where next………….?
SWOG 88 - 05
45 Gy
CDDP CDDP CDDP CDDP
VP16 VP16
Platinum 50 mg/m2 days 1, 8, 29, 36Etoposide 50 mg/m2 days 1-5, 29-33
Albain KS, Rushi VW et alJCO 1995
Problems with concurrent chemo-radiotherapy in NSCLC
• TOXICITY – radical radiotherapy and full dose chemotherapy at the same time
• oesophagitis, pneumonitis, sepsis
• initial US studies reported 10% treatment related mortality
• PATIENT SELECTION CRITICAL
Accelerated Repopulation is a major cause of local treatment failure
radical RT in 28 days may ↓ effects
55Gy/20f/26-28d a standard UK regimen
Liverpool 1996 - 2004
Concurrent Chemo-RT - development
• 20 fractions in 4 weeks
• initially CDDP 20 mg/m2 1-5, 16-20
• dose escalation 45, 47.5, 50, 52.5, 55 Gy
• weekly Vinorelbine added 2003
PS 0-1 (78.8%)
PS 2 (18.8%)
PS 3 (2.4%)
ChemoRT (Liverpool, not SOCCAR)
Performance Status
IIIB (74.5%)
IIIA (7%)
IIB (12.8%)IV (3.2%)
IB (2.5%)
Stage
ChemoRT (Liverpool, not SOCCAR)
Liverpool (not SOCCAR)Stage III NSCLC PS 0-1 concurrent chemoRT
Survival by RT dose (not randomised)
Months
55Gy/20 52.5Gy/20 <52.5Gy/20n= 64 37 17Med. 30.3 m 15.5 m 19.4 m1 year 72.4% 62.2% 64.7%2 year 57.4% 43.2% 29.4%3 year 46% 40.5% 23.5%
55 Gy/20
52.5 Gy/20
<52.5Gy/20
%
concurrent ChemoRT adjuvant chemo vs no adjuvant chemo
Stage 3 PS 0-1 (Liverpool, not SOCCAR, non-randomised)
160140120100806040200
1.0
.8
.6
.4
.2
0.0
months
%
chemo
no chemo
chemo no chemomedian 26.6 m 14.6 m1 yr 84% 75%2 yr 52.4% 43.7%3 yr 43.3% 43.7%5 yr 31.9% 31.2%
p= NS
Liverpool Lung Cancer Unit
1997 - 2004 68 patients
Toxicity oesophagitis G1 48.4%
G2 27.4% G3 6.5%
neutropenic sepsis 5
treatment related deaths 0
Pulmonary function after Chemo-RT
Patients
FEV 1
SOCCAR - Aims
1. Provide definitive answer to question: is concurrent Chemo-RT superior? 2. Enable UK centres to gain experience with concurrent Chemo-RT in controlled setting of phase III multicentre trial
trial funding and disclosure
• Funding: CRUK
• Sponsor: University College London
• Trial administration: UCL cancer trials centre
• Supported by British Thoracic Oncology Group
Maguire, J: research support and speakers honoraria:
Pierre Fabre, Astra Zeneca;advisory boards: Eli Lilly
McMenamin,R: speakers honoraria: Pfizer; advisory boards: Bayer, GSK; support for meetings: GSK, Ibt, Ferring, Boeringer
O’Rourke, N: support for meeting Roche
Peedell, C: nil
Snee, M nil
McNee, S nil
Kelly, V: support for meeting Pierre Fabre
Cancer Research UK & UCL Cancer Trials Centre
SOCCAR
Endpoint Survival at 2 years
Secondary endpoints
QOLLocal controlHealth economics
SOCCAR – patient selection
• PERFORMANCE STATUS
activities in past few days no allowance for age activity diary and review if
equivocal
SOCCAR – patient selection 2
• Staging CT + PET scans required - one within 4 weeks of randomisation Use additional techniques if you have them e.g. US guided neck node bx 4D radiotherapy planning
SOCCAR - chemotherapy
• Cisplatinum/vinorelbine
anti-emetics as per local practice
antibiotics required days 9 - 20
SOCCAR - radiotherapy
• conformal
• GTV + min. 1.5cm circumferential,
1.5 cm sup-inf. margins
• V20 lung ≤ 30%
• no more than 12 cm oesophagus in PTV
21
pathologically confirmed
NSCLC stage III , PS 0-1,
CT± mediastinoscopy, PET-CT
unsuitable for surgeryCONCURRENT ARM SEQUENTIAL ARM
cisplatinum 80mg/m2 day 1
vinorelbine 25mg/m2 day 1,
8 4 cycles
55Gy/20f/4weeks
cisplatinum 80mg/m2 weeks
1,4
vinorelbine 15mgs/m2
weekly
cisplatinum 80mg/m2 day 1
vinorelbine 25mg/m2 d 1, d 8
2 cycles
4 weeks
55Gy/20f/4weeks
4 weeks
SOCCAR Trial Design
SOCCAR - inclusion criteria
• histological or cytological confirmation• staging by CT±mediastinoscopy, PET-CT• judged inoperable by thoracic surgeon• PS 0 – 1• v20 ≤ 30%, ≤ 12cm oesophagus in PTV• FEV1 ≥ 1L, TLCO ≥ 50%• conformal or 4D RT planning
starting position (2006)
• historically poor UK lung cancer survival
• minimalist and over-conservative approach to treatment
• long diagnosis to treatment times
• limited experience with concurrent chemoradiation
• 3/12 centres pre trial use of con regimen
problems at the start……
• introducing a new technology
• European Clinical Trials Directive
• “adverse publicity”
demographics
• 130 patients, median age 62 (range 39 - 77)• 61% male, 39% female• 64% sq, 27% adeno• 3 excluded (2 stage IV, 1 too extensive )
• wt loss > 5% 16% con, 20% seq• N3 8.6% con, 10% seq• >70yrs 8pts con, 10pts seq
acceptable toxicity (O’Rourke et al WLC 2011)
toxicities
• SAEs 46% vs 47%
• 15 grade 4 toxicities (8 con vs 7 seq)
• G3 oesophagitis: 8 con vs 1 seq (no grade 4 oesophagitis)
• confirmed treatment related deaths 2 con vs 1 seq
deaths in first 6/12 3 con, 2 seq
SOCCAR NSCLC Stage III PS 0 - 1
Months
CON SEQ n 67 59median 27.4 m 18.6 m1 year 73.1% 83.1%2 year 54% 42%3 year 38% 27%5 year 33.6% NR
Local PD 10% 22%
Con
Seq
%
Concurrent Schedules ComparedCancer Research UK & UCL Cancer Trials Centre
• Trial %2ys RT CT %TRM G3/4oes • pts Gy/f
SOCCAR 2010 70 54 55/20 cis/vin 4 17%
Jeremic 1996 65 43 69.6/58/6w carbo/etop 0 8Belderbos 2006 66 39 66/24 daily cis 1.5 17 Fournel 2005 100 39 66/33 cis/etop 10 32 Curran 2003 201 37 60/30 cis/vbl 3 25 Huber 2006 99 36 60/30 wkly taxol 0 13 Furuse 1999 156 34.6 56/28spli cis/vind 0.6 3 Zatloukal 2004 51 34 60/30 cis/vin 0 18 Belani 2005 92 29 66/33 carbo/tax ? 31
conclusions
Cancer Research UK & UCL Cancer Trials Centre
• 55Gy/20f/26-28d with concurrent cisplatinum and vinorelbine is a highly effective treatment for stage III NSCLC, PS 0-1
• 2 year survival in concurrent group > 50%
• In comparison of 16 RCTs, 1733 patients treated on concurrent CTRT, this treatment ranks top on survival with comparable tolerability
SOCCAR Concurrent ChemoRT
n=67median 27.4 mth1 year 73.1%2 yr 54%3 year 38%5 year 33.6%
Months
%
Liverpool 55Gy/20 + chemo Pre-SOCCAR
n=65median 35.5m1 year 79.5%2 yr 61.2%3 year 49%5 year 33.7%7 year 29.5%
Months
%
Pre-SOCCAR Pilot study (excluding Liverpool) 55 Gy/20 + concurrent cis/vin
Survival
Months
n= 61 median 26.8 m1 ye ar 64.9%2 yea r 52.1%3 year 43.3%
%
Concurrent ChemoRT 55Gy / 20 f with cisplatinum and vinorelbine
Months
%
SOCCAR
Liverpool
Pilot exc.
Liverpool SOCCAR Pilotn 65 67 61median 35.5 m 27.4 m 26.8 m 1 year 79.5% 74% 64.9%2 year 61.2% 54% 52.1%3 year 49% 38% 43.3%5 year 33.7% 33.6%7 year 29.5%
what next………?
• needs to be relevant internationally
• ? relevance of individualised dose escalation for some patients (but tumour size critical)
improving efficacy concurrent chemoRT: dose escalation and cetuximab?
RTOG 0617: four arm study
• Arm A 60Gy + carbo/taxol• Arm B 74Gy + carbo/taxol• Arm C 60Gy + carbo/taxol+ cetuximab• Arm D 74Gy + carbo/taxol + cetuximab
RTOG 0617 – interim analysis ASTRO October 2011
survival 60Gy 74Gy
one year 81% 70.4%
median 21.7m 20.7m p= 0.02
What next?
• eligible patients should have concurrent chemoradiotherapy
• next UK study should have SOCCAR regimen standard arm vs conventional fractionation
• national agreement to compare 55Gy/20f with 64Gy/32f
with concurrent cisplatinum/vinorelbine
BIG LUNG TRIAL: PROPOSAL 2012Patient with inoperable stage II/III NSCLC
suitable for radical treatment
Fit for concurrent treatment
Fit for sequential treatment
Clinician judgement
CARSON
Randomised phase III comparison of SOCCAR 55Gy/20 fractions vs
66/33 + concurrent Cis/Vinorelbine
ASCaN
Randomised phase II pick the winner comparison of CHART-ED,
IDEAL, I-START, ISO-A-IMRT v standard sequential treatment
(cisplatin chemo x 4 followed by 55Gy in 20 fractions)
- ASCaN -
A Randomised Phase II study of Accelerated Sequential Chemo-
radiotherapy in NSCLC
CI: Mathew Hatton
-CARSoN -
Conventional Against Reduced Fractionation of
Sensitised Radiotherapy in NSCLC
CI: Joe Maguire
CARSON - DESIGN
fit for concurrent chemoRT
SOCCAR regimen 55 Gy in 20 fractions + concurrent Cis/Vinorelbine
66 Gy in 33 fractions + concurrent Cis/Vinorelbine
Randomisation ratio:
1 1
CARSON - DESIGN• Randomised phase III non-inferiority trial
•Aims to rule out the possibility that the SOCCAR regimen increases the death rate by more than 17.5% relative to 66Gy in 33 fractions
•this corresponds approximately to retaining half the benefit of going from sequential to concurrent treatment
• 2.5% 1-sided level of statistical significance
• 580 patients (80% power)
•Final selection between arms based on toxicity/HE
CARSON - DESIGN
•Aims to rule out the possibility that the SOCCAR regimen increases the death rate by more than 17.5% relative to 66Gy in 33 fractions
• Rule out reducing median OS by >3 months (assuming 20 months median on standard)
• The design assumes that the SOCCAR regimen will actually reduce the death rate by at least 10%
• Assumes median OS on SOCCAR will be 22.2 months compared to 20 months on standard (actual median in SOCCAR 27 months)
CARSON - DESIGN• Other design options
•Superiority in terms of OS – but the SOCCAR regimen perhaps has advantages even if OS is the same
• Standard non-inferiority design in terms of OS – but this is very large and probably undeliverable. If SOCCAR has a small survival advantage this is overpowered.
•Use HE as a primary end-point – difficult to design and also demonstrating non-inferiority in terms of OS was crucial
conclusions
• 55Gy/20f/26-28d with concurrent cisplatinum and vinorelbine is a feasible and effective treatment for stage III NSCLC, PS 0-1
• 2 year survival in concurrent group > 50%
• SOCCAR confirms the value of an accelerated hypofractionated radiotherapy schedule as a therapeutic approach in NSCLC
• major opportunity for follow on trial now!