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ANZGOG – 0701
Symptom Benefit Study
Measuring the Benefit of Palliative
Chemotherapy in women with platinum
refractory/ resistant ovarian cancer
ANZGOG AGM, 2 April 2009, Noosa
NHMRC Clinical
Trials Centre
Study Background
• The aim is to develop a method to measure the benefit of
chemotherapy, which takes into account BOTH subjective and
objective responses
• Document time to symptom progression as an additional endpoint as
well as symptom benefit
• Better insight into patterns of care and reasons for treatment with
platinum resistant or refractory ovarian cancer
• Develop a prognostic index that better defines outcomes and test in a
separate group
ANZGOG AGM, 2 April 2009, Noosa
NHMRC Clinical
Trials Centre
Objective
• Stage 1: To determine the symptoms and
aspects of HRQL that are rated most severe,
troublesome in patients and identify best
instruments to use in stage 2
• Stage 2: To determine the proportion of women
benefiting from palliative chemotherapy as
defined by a clinically significant improvement in
HRQL scores and improvement of symptoms
and time to symptom progression.
ANZGOG AGM, 2 April 2009, Noosa
NHMRC Clinical
Trials Centre
Makhija S et al. Proc
ANZGOG AGM, Noosa 2 April 2009
ASCO 2007;Abstract 5507
NHMRC Clinical
Trials Centre
Study Schema
During Trial
Stage1
Target Population
>18yrs
platinum resistant/
refractory epithelial
ovarian cancer
ECOG 0-3
Able to commence
treatment within 2wks
of registration
Ability to complete
QoL forms
independently
R
E
G
I
S
T
E
R
• Complete QoL
questionnaires at
each cycle
• 20 subjects will
participate in
additional QoL
telephone interviews
Stage2
Determine the optimal
QoL forms from Stage1
Longer follow-up
Prognostic data collected
at baseline
ANZGOG AGM, 2 April 2009, Noosa
Data
Collection
4 Treatment
cycles
or
Disease
progression
Proposed
longer
follow-up for
Stage 2
NHMRC Clinical
Trials Centre
Lung Cancer as a Model
Close parallels between platinum resistant/ refractory ovarian cancer
and recurrent NSCLC and SCLC in terms of response rates and survival
ANZGOG AGM, 2 April 2009, Noosa
NHMRC Clinical
Trials Centre
Fig 1. Survival in weeks
TOPOTECAN VS. CAV
von Pawel, J. et al. J Clin Oncol; 17:658 1999
Copyright © American Society of Clinical Oncology
Symptom improvement compared with baseline in patients with SCLC treated with
i.v. topotecan or CAV
Symptom
i.v. topotecan %
CAV %
p value
Anorexia
32
16
0.042
Chest pain
25
17
0.371
Cough
25
15
0.160
Dyspnea
28
7
0.002
Fatigue
23
9
0.032
Hemoptysis
27
33
0.706
Hoarseness
33
13
0.043
Insomnia
33
19
0.085
Interference with daily activities
27
11
0.023
Jassem et al.
2002 [33]
Osoba et al.
1985 [36]
Fernandez et al.
1989 [38]
Hardy et al.
1989 [39]
Ellis et al.
1995 [34]
Tummarello et al.
1995 [37]
Cullen et al.
1988 [35]
Regimen
GP
BEP
PVM/I
MVbP
MVbP
PMVb
MIP
Overall response (%)
41
44
42
21
32
33
56
Overall symptom
improvement (%)a
—
—
—
67
69
54
—
Symptom improvement (%)
Anorexia
—
—
50
—
—
—
58
Cough
44
68
45
71
66
40
70
Dyspnea
36
31
78
65
59
66
46
Hemoptysis
75
78
91
—
—
100
92
Malaise
—
53
—
—
53
62
—
Pain
—
68
47
63
60
39
77
Weight loss
—
44
89
—
—
30
—
Non Small Cell Lung Cancer – Studies Gralla Oncologist 2004; 9:14-24
LCSS in relation to standard efficacy measures- Maximum Improvement
from baseline LCSS items- 2nd line therapy
De marinis et al JTO 3;1 2008
LCSC in relation to standard efficacy measures
De marinis et al JTO 3;1 2008
Lung Cancer Studies
●
●
Confirm that Symptom Benefit is a valid and
valuable endpoint
Correlation of Symptom Benefit with Response
and SD
●
Instruments sensitive to detect symptom benefit
●
Provides complimentary efficacy data
Current status
Fourteen sites open to recruitment
Twelve in Australia
Two in Canada
A further nine Australian sites are currently
awaiting final ethics approval
Total recruitment
46
26 Australia
20 Canada
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Baseline Demographics
Reason for treatment at enrolment
Symptom control/palliation + rising CA125 + radiological progression
28
Rising CA125 + radiological progression
9
Symptom control/palliation + rising CA125
6
Symptom Control + radiological evidence
1
Radiological Evidence only
1
Rising CA125 only
1
N = 46
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Baseline Demographics cont’d
Major symptoms reported at baseline:
1. Pain
2. Fatigue
3. Abdominal Bloating
ECOG
0 = 17
1 = 26
2= 2
3= 0
(N = 45 - missing data for one patient)
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Previous lines of chemotherapy
1 x line
2 x lines
3 x lines
4 x lines
5 x lines
7 x lines
18
8
9
5
2
1
N = 43
* Missing data on 3 x pts – awaiting response from sites
ANZGOG AGM, 2 April 2009, Noosa
NHMRC Clinical
Trials Centre
Majority Platinum Resistant
Compliance
All questionnaires were completed to a
very high compliance rate with few or no
missing data
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Death/Disease Progression
Cycle
2
Cycle
3
Deaths
4
1
Disease progression
1
6
Completed
34
22
Cycle
4
14
1 x pt. has withdrawn consent
3 x pts. off study due to site error
NB. Due to centralised data entry, there is a time lag in
receipt of CRFs
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Stage 1 QoL Questionnaires
1.
2.
3.
4.
5.
6.
7.
8.
Symptom Representation Questionnaire
FACT-O (includes FOSI)
EORTC QLQ-C30
EORTC QLQ-OV28
Patient Data Form
Expected and Perceived Benefit Scale
HAD Scale (Baseline & End of Treatment only)
Herth Hope Index (Baseline & End of Treatment only)
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Ovarian Symptom Benefit Study (OSBS)
Initial results and rationale for choosing the
FACT-O and revising the
Patient DATA Form – Ovarian as the
patient reported outcome measures (PRO)
for stage 2
Prepared by Madeleine King and
Martin Stockler on behalf of the
Ovarian Symptom Benefit Study Team
6 October 2009
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Background: What’s the problem?
•
OSBS stage 1 uses 4 questionnaires to measure
symptoms and/or quality of life:
1.
2.
3.
4.
•
•
Symptom Representation Questionnaire (SRQ)
Pt Disease & Treatment Assessment (Pt DATA Form)
FACT-O (including 8 items of FOSI)
QLQ-C30 + Ov28
items
66
48
39
58
The booklet was deliberately long and repetitive to
corroborate findings and help determine the
best subset of items for future studies
Interviews with 10 patients indicated that they neither
preferred nor disliked any particular questionnaires
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Substitutability of candidate
questionnaires
•
SRQ vs. Patient DATA Form
– designed to measure clinically important aspects of QOL
– similar layouts, 0 to 10 scales
– single-item scoring (rather than multi-item or domain scoring)
•
QLQ-C30/Ov28 vs. FACT-O
– designed to measure quality of life (QOL) in cancer clinical trials
– similar format and layout, similar response scales
– multi-item domains & scoring (QLQ-C30 incl. some single items)
•
We decided to choose for OSBS stage 2
– Either SRQ or Pt-DATA Form for individual symptoms
– Either QLQ-C30/Ov28 or FACT-O for multi-dimensional QOL
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
‘First filter’ analysis:
aims & methods
Aim
Determine which 4 PRO questionnaires to retain for stage 2
Analysis
1. Prevalence of each possible symptom in the
‘Top Three Most Noticed Symptoms in the last week’
(as asked by the Symptom Representation Questionnaire).
2. Summary statistics and histograms describing the
frequency distributions of items and domain scores for
each symptom at baseline
3. Changes from baseline in item and domain scores
Data
31 patients who completed QOL questionnaires at
baseline (pre-C1) AND (pre-C2 (AND/OR) pre-C3) by Jul ‘09
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Results: Top 10 Symptoms
of the ‘Three Most Noticed Symptoms in the last week’
at baseline
Rank
Symptom
No. who nominated
this symptom in her
Top 3 (n=31)
1
Fatigue
17
2
Pain - general
11
3
Abdominal bloating
10
4
Sleep disturbance
9
5
Nausea and vomiting
8
6
Appetite
7
7
Shortness of breath
6
8
Bowel disturbances (including constipation)
6
9
Pain - abdominal
5
10
Urinary problems
3
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Coverage of Top 10 symptoms by
candidate questionnaires
Symptom
SRQ
Pt DATA
FACT-O
FOSI
Fatigue
2
1
1
1
3
-
Pain - general
1
1
1
1
2
-
Abdominal bloating
1
1
1
1
-
1
Sleep disturbance
1
1
1
-
1
-
Nausea and vomiting
2
2
2
2
2
-
Appetite
1
2
1
-
1
1
Shortness of breath
1
1
-
-
1
-
Bowel disturbances
1
3
1
-
2
3
Pain - abdominal
-
1
1
1
-
1
Urinary problems
1
1
-
-
-
1
# items covering Top 10
12
15
9
6
12
9
Total # items in q’aire
24
18
39
8
30
28
50%
83%
23%
75%
40%
32%
%
ANZGOG AGM, Noosa 2 April 2009
QLQ-C30 QLQ-OV28
NHMRC Clinical
Trials Centre
Detailed example of overlap
Pain - general
Q’aire
Item stem
Response scale
SRQ
Pain
0 = did not have the symptom Single item
10 = as bad as I can imagine
Pt-DATA
Pain (all or anywhere)
0 = no trouble at all
10 = worst I can imagine
Single item
FACT-O
I have pain
0 = Not at all
1 = A little bit
2 = Somewhat
3 = Quite a bit
4 = Very much
One of 7 items in the
Physical Wellbeing
scale of the FACT
One of 8 items in the
FOSI
QLQ-C30
Have you had pain?
QLQ-C30
1 = Not at all
2 = A little
Did pain interfere with 3 = Quite a bit
4 = Very much
your daily
Scoring
These two items form
the pain scale of
the QLQ-C30
activities?
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Results at baseline (pre-cycle 1)
•
For each of the top 10 symptoms:
– we compared distributions and
summary statistics for similar items
– No major ceiling or floor effects
– Similar distributions for similar items
• Nothing to choose between questionnaires
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Change at Cycles 2 and 3
•
For each of the top 10 symptoms:
– we compared distributions and summary
statistics of change scores on similar items
– Mean change ~0 with large SD reflecting
improvements in some women and
deteriorations in others
– Comparable results across q’aires
• Nothing to choose between questionnaires
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Decisions
Retain modified Pt DATA Form – Ovarian to measure key symptoms
•
Enhance coverage of the Top 10
•
Allow measurement of both current status and change
•
Modifications by developer and OSBS investigators 
OSBS Recent Status Form
(after each cycle)
OSBS Change Form
(after every 2nd cycle)
•
Develop a separate Side Effects Form for net clinical benefit
Retain FACT-O (including FOSI) to measure QOL
FACT-O
•
Has fewer items: 39 (incl. 8 for FOSI) vs. 58 in the QLQC30/Ov28
•
Provides summary scores: overall QOL, Trial Outcome Index,
FOSI
•
Overall QOL based on all items
QLQ-C30
•
•
•
22 sub scales
Duplication of single-item symptoms with Pt DATA Form
Global QOL based on 2 items
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Prognostic Model
variables
No. of lines of therapy
Performance status
Volume of disease
Sites of disease
CA125 velocity
LDH; Hb; Albumin; Platelets
Inflammatory markers
Grade; histological subtype
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Platinum Resistant Ovarian Cancer
PFS
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Platinum Resistant Ovarian Cancer
OS
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Platinum Resistant Ovarian Cancer
Hypothetical Risk Groups
PFS
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Platinum Resistant Ovarian Cancer
Hypothetical Risk Groups
OS
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre
Discussion Points
• Comments and questions of study and
design- relatively fluid at present
• Comments on circulated CRF’s
• Which groups will join stage 2 study and
when ? Feasibility; Time Frame; Trials
Translations
Funding arrangements in different groups
ECRF’s and scanning of HRQOL forms
ANZGOG AGM, Noosa 2 April 2009
NHMRC Clinical
Trials Centre