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The GO2 trial - SIOGThe GO2 trial Dr Peter S Hall 1 Sponsor: The University of Leeds Funder: Cancer...
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Opmising chemotherapy for frail or elderly paents with advanced gastric or oesophageal cancer The GO2 trial 1 Dr Peter S Hall Sponsor: The University of Leeds Funder: Cancer Research UK PS Hall, D Swinson, JS Waters, S Falk, R Roy, T Tille, J Nicoll, S Cummings, SA Grume, K Kamposioras, E Katona, G Velikova, RD Pey, HI Grabsch, MT Seymour on behalf of the GO2 Invesgators [email protected]
Transcript of The GO2 trial - SIOGThe GO2 trial Dr Peter S Hall 1 Sponsor: The University of Leeds Funder: Cancer...
Optimising chemotherapy for frail or elderly patients with advanced gastric or
oesophageal cancer
The GO2 trial
1Dr Peter S Hall
Sponsor: The University of Leeds
Funder: Cancer Research UK
PS Hall, D Swinson, JS Waters, S Falk, R Roy, T Tillett, J Nicoll, S Cummings, SA Grumett, K Kamposioras, E Katona, G Velikova, RD Petty, HI Grabsch, MT Seymour
on behalf of the GO2 Investigators
• Disclosures– None
Background
• The median age of gastric and oesophageal (GO) cancer
diagnosis > 75 years old.1
• Many patients are frail.
• …however “standard” chemo schedules were developed in
trials of mostly fit patients with median age <65 years2.
3
1. Cancer Research UK. CancerStats. https://www.cancerresearchuk.org/health-professional/cancer-statistics/2. Cunningham D, Starling N, Rao S, et al. New England Journal of Medicine 2008;358(1):36-46
Dr Peter S Hall [email protected]
administered dose
administered dose
patient’s drug exposure
patient’s drug exposure
efficacy and toxicity effects
efficacy and toxicity effects
consequences for the patient
consequences for the patient
pharmacokinetics
pharmacodynamics
impact
standard oncology trial outcome measures:
RECIST response, PFS, CTCAE adverse events, OS, …
…do not properly reflect our (both doctors’ and patients’) goals
standard oncology trial outcome measures:
RECIST response, PFS, CTCAE adverse events, OS, …
…do not properly reflect our (both doctors’ and patients’) goals
we need good clinical trials to ask these questions in:• the fit and very old• the frail and ‘somewhat elderly’• patients with comorbidities
…i.e. all the patients who are often treated but rarely offered enrollment in trials
• Developing better assessment of patients:– Comprehensive Health Assessment (CHA) in the oncology clinic
– nurse and patient modules, 20-40 mins total
– frailty, comorbidity, symptoms, functioning, psychological QL
• Developing better assessment of outcomes:– Overall Treatment Utility (OTU)
– “Am I glad I decided to go ahead with this treatment?”
– combines: survival, non-progression, clinical benefit, patient satisfaction, adverse events and maintenance of QL
FOCUS2 321GO GO2
80% FU80% FU
80% OxFU80% OxFU
80% Cap80% Cap
80% OxCap80% OxCap
80% EOxCap80% EOxCap
80% OxCap80% OxCap
80% Cap80% Cap
100% OxCap100% OxCap
80% OxCap80% OxCap
60% OxCap60% OxCap
60% OxCap60% OxCap
BSCBSC
RR
R1
R2
FOCUS2CRC
321GOOG
GO2OG
Overall Treatment Utility (OTU) asks 2 questions
Dr Peter S Hall
Good Intermediate Poor
Question1
Clinicianconsidered effective
• Radiological progression• Clinical progression• Deterioration QoL
Clinician scores benefit
Clinician does not score benefit
Clinician does not score benefit
AND OR AND
Question 2
Patient found treatment tolerable
• Toxicity• Interference in daily life• Worth it
Patient scores benefit
Patient does not score benefit
Patient does not score benefit
OR death
OTU scores in GO2OTU scored in all 514 patients in the chemotherapy randomisation:
factor contributing to OTU n /514 %
Survival patient died before 11 wk assessment 80 16%
Q1 Alive @ 11 weeks
radiological progression 58 11%
clinical evidence of progression 77 15%
deterioration in QL score§ 178 35%
Q2 Alive @ 11 weeks
SAR or SUSAR 82 16%
“Interfered with my daily activities” 207 40%
“Was not worthwhile” 105 20%
§ fall of >16% from baseline global QL score, EORTC QLQ-C30
Elements of OTU Survival
Yes: 434 pts
Effective 273
Tolerated 196 Not tolerated 77
Not effective 161
Tolerated 72 Not tolerated 89
No: 80 pts
Poor OTU169
Poor OTU169
Intermediate OTU149
Intermediate OTU149
Good OTU196
Good OTU196
Q1
Q2
Level A (100%) Level C (60%)
Level B (80%)
Level A (100%) Level C (60%)
Level B (80%)
PFS
OS
Level A (100%) Level B (80%) Level C (60%)
poorOTU38%
intermed.OTU26%
good OTU36%
poorOTU31%
intermed.OTU34%
good OTU35%
poorOTU29%
intermed.OTU27%
good OTU43%
OTU to compare treatment arms
Question 1: Efficacy
Level A Level B Level C0
102030405060708090
100
Effective
No prog but QoL
Clin prog no rad prog
Rad prog
Question 2: Tolerability
0102030405060708090
100
TolerableNot worth it aloneToxicity but not interfereInterfere
Leve
l A
Leve
l B
Leve
l C0
102030405060708090
100
Dead
Alive
Alive at 11 weeks
Baseline CHA to aid decision makingClinico-pathological factors Age, gender, PS,
comorbidity, disease characteristics
Quality of life EQ-5D
GHS/ Qol C-30
EORTC QLQ fatigue score
Symptoms OG-25 symptoms
Function ADL/ IADL
Get Up and Go test
Standard of care bloods FBC, U&E, LFTs
Specialist bloods BNP, CA19.9, CEA
Frailty assessment 9 [email protected]@nhs.net
Patient collectedPatient collectedNurse interviewNurse interview
Frailty assessment
16Dr Peter S Hall
• 9 domains• Definition of frailty– Moderately frail 1-2
domains– Severely frail >2
Domains Cut pointsWeight loss Weight loss (> 3kg in 3m) | BMI
(<18.5)
Mobility Timed up and go test (>10 seconds)
Falls 2 or more falls in 6m (EORTC G8)
Cognition Mild or severe dementia diagnosis
Function One or more impairment in IADL
Social Place of residence (Requires 24 hour care)
Mood EQ5D question (feelings today)
Fatigue EORTC QLQ Fatigue Score
Polypharmacy Prescribed regular medications (>4)
Baseline CHA to aid decision-making
...as a predictor of treatment benefit – univariate– CHA elements correlating with risk of worse OTU at 9 wk
Factor p
Age (>75 vs <75) 0.63
Frailty (>3/9) 0.003
WHO PS (0-1, 2, >2) 0.21
Distant mets (y/n) 0.13
Histology (sq/other)
0.87
Site (oes/OGJ/stom)
0.72
Anxiety/depression 0.56
Fatigue 0.12
Weight loss 0.29
Factor p
Get-up-and-go 0.60
Dementia/MCI 0.004
ADL/IADL impairment
0.02
EQ-VAS impairment 0.02
QLQ-C30 Global 0.02
EQ-5D Pain 0.14
Anxiety/depression 0.56
OG-25 Taste 0.01
Number of symptoms
0.15
Factor p
raised BNP (/pro) 0.0005
raised CEA/CA19.9 0.02
raised WBC 0.04
raised NLR 0.01
raised plts 0.27
low albumin 0.02
low Hb 0.11
raised urea 0.03
raised bilirubin 0.78
Baseline CHA to aid decision-making
...as a predictor of treatment benefit – univariate– CHA elements correlating with risk of worse OTU at 9 wk
Factor p
Age (>75 vs <75) 0.63
Frailty (>3/9) 0.003
WHO PS (0-1, 2, >2) 0.21
Distant mets (y/n) 0.13
Histology (sq/other)
0.87
Site (oes/OGJ/stom)
0.72
Anxiety/depression 0.56
Fatigue 0.12
Weight loss 0.29
Factor p
Get-up-and-go 0.60
Dementia/MCI 0.004
ADL/IADL impairment
0.02
EQ-VAS impairment 0.02
QLQ-C30 Global 0.02
EQ-5D Pain 0.14
Anxiety/depression 0.56
OG-25 Taste 0.01
Number of symptoms
0.15
Factor p
raised BNP (/pro) 0.0005
raised CEA/CA19.9 0.02
raised WBC 0.04
raised NLR 0.01
raised plts 0.27
low albumin 0.02
low Hb 0.11
raised urea 0.03
raised bilirubin 0.78
12 of 27 factors p
redictive for O
TU on univariate analysis
Baseline CHA to aid decision-making {Provisional}...as a predictor of treatment benefit – multivariable model
- Best fit of baseline characteristics vs OTU at 9 wk
Factor Cut point Odds ratio
Test statistic
P-value
Age ≥75 1.01 0.00 1.0
Frailty 3+ domains 1.87 5.61 0.018
VAS (EQ-5D) <50 1.99 4.47 0.034
BNP or NT-Pro BNP ≥ULN 2.40 10.25 0.001
CEA or CA19-9 ≥ULN 2.39 7.10 0.008
Dose reduction for GFR
<50/ 1.5 ULN 4.09 8.54 0.003
Ordered logistic regression multi-variable model. • Likelihood ratio p<0.0001, Score p<0.0001, Wald
p<0.0001
Provisional Decision Aid
Age Dose reduction for renal BNP or NT- CEA >3ug/ml or VAS <50 Frailty Poor GoodProp<75 No No No No Not/Slightly frail (0-2)
>=75 No No No No Not/Slightly frail (0-2)
<75 No No No No Severely frail (≥3)
<75 No No No Yes Not/Slightly frail (0-2)
>=75 No No No No Severely frail (≥3)
>=75 No No No Yes Not/Slightly frail (0-2)
<75 No No Yes No Not/Slightly frail (0-2)
<75 No Yes No No Not/Slightly frail (0-2)
>=75 No No Yes No Not/Slightly frail (0-2)
>=75 No Yes No No Not/Slightly frail (0-2)
<75 Yes No No No Not/Slightly frail (0-2)
<75 No No Yes No Severely frail (≥3)
<75 No No Yes Yes Not/Slightly frail (0-2)
<75 No Yes No No Severely frail (≥3)
<75 No Yes Yes No Not/Slightly frail (0-2) <40 35 4<75 Yes No No Yes Not/Slightly frail (0-2)
<75 Yes No Yes No Not/Slightly frail (0-2)
>=75 Yes Yes Yes Yes Severely frail (≥3) 90 3 9
55
1740
125
<20
<30
<50
75 19<10
2160
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Provisional Decision Aid Simplified
Variables Proportion of Patients Probability of Good OTU
All favourable 19% 75%
Severely frail or QoL 21% 60%
Either TM or BNP/ NT-ProBNP 30% 55%
Dose reduction alone or2 other variables with full dose
21% 35-40%
Dose reduction + 1 other variable
1% 25%
All unfavourable 9% 3%
TM = tumour markerQoL measured by EQVD VAS
22Click to edit Author Name
Key points
Treatment recommendations• Doublet chemotherapy delivered at significantly lower doses delivers
better patient experience without sacrificing efficacy
Assessing patients• CHA is deliverable and may inform decision making
• Decision aid includes both clinical and lab elements (e.g. frailty and BNP)
•Novel trial end points • OTU may provide more patient centred information than
conventional oncology endpoints
• Heavily influenced by patient reported [email protected]
Further work……• Validate and refine
–Criteria for frailty and decision tool with other data sets
–Test established frailty criteria using OTU as an endpoint
–Qualitative research to further refine OTU
• Explore
–Mechanisms of why BNP (/pro) correlation with poor outcomes
–Dose minimisation in other cancer sites, younger fitter patients, in
combination with novel [email protected]
All 321 GO investigatorsMatt Seymour, Peter Hall,
Simon LordMichelle Collinson
Helen MarshallMarc Jones
Helen HowardGalina VelikovaAlan Anthoney
Rajesh Roy, Jo DentSue Cheeseman, Kim Last
CTRU LeedsYorkshire CRN
55 patients and their families
All the GO2 Investigators Matt Seymour, Peter Hall,
Justin Waters, Helen Marshall, David Cairns, Russell Petty, Raj Roy,
Stephen Falk, Jon Wadsley, Simon Lord, Christine
Allmark, Cat Handforth, Ann Crossley, Heike Grabsch, Galina Velikova, Kostas
Kamposoras, Jonathan Nicoll, Tania Tillett, Sharon
Ruddock, Eszter Katona , Helen Howard
CTRU Leeds, NIHR CRN558 patients and their
families
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