Transcript 2006_files/Wong ASCO 2006 Cost analysis slides

Direct Cost Survival Analysis of
Treatment of Metastatic Colorectal
Cancer
Yu-Ning Wong1, Neal J. Meropol1, Daniel Sargent2,
Richard Goldberg3, J. Robert Beck1
1Fox Chase Cancer Center, Philadelphia, PA; 2Mayo Clinic,
Rochester, MN; 3University of North Carolina, Chapel Hill, NC
Abstract
Background:
Patients with metastatic colorectal cancer (mCRC) treated with 5Fluorouracil plus
leucovorin (5FU/LV) have a median life expectancy (LE) of approximately12 months. The
addition of irinotecan, oxaliplatin, bevacizumab and cetuximab has increased LE
significantly. Although they have been widely adopted, little is known about the financial
impact of these new drugs.
Methods:
Using published reports and aggregate data from NCCTG 9741, we developed a Markov
Model which assumes forward progression through up to three lines of therapy compared
to 5FU/LV alone. Patients who do not die of toxicity (tox) transition through supportive
care prior to death. State changes are based on progression and dose-limiting toxicity.
Drug costs are based on Average Sales Price. No other direct or indirect costs are
included. Dose modifications for toxicity are defined as 80% of standard doses. Sensitivity
analyses (SA) were performed on key variables.
Results:
LE, total drug costs, and cost-effectiveness (CE) ratios compared to single line-5FU/LV
and FOLFOX for 9 commonly used treatement sequences are presented below. SA show
that results are sensitive to progression rates,drug costs and length of time on supportive
care. Changes in 1st line tox rates have a greater impact on final results than changes in
2nd or 3rd line therapy tox rates.
Conclusions:
Using drug costs alone, this model shows sequential combination therapy including all
available agents to cost $2000-$2800K/week life gained ($100-$145K/year) compared to
both 5FU/LV and FOLFOX. For clarity only 9 strategies are presented, but the model
presented will contain multiple sequences consisting of 1-3 lines of therapy. Refined tox
data, associated costs and quality of life adjustments are needed for realistic comparisons
among specific combinations. Combination therapy may have CE ratios similar to other
currently accepted intensive medical interventions. These data can help inform
discussions of how the cost of care impacts patients, providers, and societies.
Background
Since 1996, four new agents have been introduced for the
treatment of mCRC
Median life expectancy has increased from 12 months to greater
than two years
Survival of patients has improved due to the availability of
treatment with 5FU/LV, irinotecan- and oxaliplatin- containing
regimens.1
Possible Treatment Sequences for
Metastatic Colorectal Cancer
First Line
FOLFIRI or IFL +
Bevacizumab
First Line
FOLFOX
Bevacizumab
First Line
5FU/LV +
Bevacizumab
Second Line
FOLFOX
Second Line
Irinotecan
Cetuximab
Second Line
Irinotecan or
FOLFIRI
Second Line
FOLFOX
Second Line
Irinotecan or
FOLFIRI
Third Line
Cetuximab+/Irinotecan
Third Line
FOLFOX
Third Line
Cetuximab+/Irinotecan
Third Line
FOLFIRI or
Irinotecan
Third Line
Cetuximab+/Irinotecan
Modified from the 2006 NCCN Guidelines
for Treatment of Metastatic Colon Cancer.
In addition, the option of single line
cetuximab following irinotecan is included
as a treatment sequence, in accordance
with its FDA indication.
Fourth Line
Cetuximab +/Irinotecan
Treatment Related Costs have increased
with Introduction of New Agents
Cost of 6 months of commonly prescribed regimens for a 70 kg, BSA 1.7m2 patient 2
5FU/LV (Mayo Regimen, every 4 weeks)
$96
Infusional 5FU/LV (De Gramont, every 2 weeks)
$352
Capecitabine 1250 mg/m2 bid daily x14 days every 3 weeks
$11,648
Irinotecan 350 mg/m2 every 3 weeks
$30,100
Irinotecan 125 mg/m2 weekly x 4 every 6 weeks
$21,500
FOLFIRI every 2 weeks
$23,572
FOLFOX every 2 weeks
$29,989
Bevacizumab every 2 weeks
$23,897
Cetuximab, load followed by weekly dosing alone or with irinotecan
$52,131
Issue of Cost Effectiveness is Debated
Historical: $50,000/QALY (cost of one year of dialysis in the 1970s)
Institute of Medicine Report 2003: Hidden Costs, Value Lost:
Uninsurance in America: $160,000 for a year in perfect health
NEJM 2005 Analysis of ICDs--$100,000/QALY3
Project Aim
To measure the added costs and changes to life expectancy
associated with newly developed combination regimens compared
to 5FU/LV
To examine what variables (ie progression, toxicity, drug costs, have
the greatest impact of CE ratios)
Model Design
Legend:
Progressive Disease on
therapy
P
Stable Disease on
Front Line Rx
Toxicity on therapy leading
to either discontinuation
or resumption of therapy
T
Stable Disease on
Second Line
Rx
T
P
Start
Change therapy
T
Choice of Front
Line Therapy
P
Stable Disease on
Third Line
Rx
P
Change therapy
T
Supportive Care
Dead
Stylized Markov Model
Patients enter at time of choice of front line therapy and
transition from state to state at one week intervals. Ovals
represent disease states. Rectangles represent decision
points. Bold lines represent remaining in the current state
for an additional cycle. Dashed lines represents returning to
previous line of therapy after developing toxicity, either at
current dose or with dose and/or schedule modification.
Death is surrounded by multiple arrows to denote that it is
possible to enter this stage from any point on the model.
Model Assumptions
70 yo male 70 kg, 1.7 m2
Maximum of three lines of therapy
Evaluated at weekly intervals
Patients alive at the end of each interval get equal “credit”
One dose reduction allowed prior to changing therapy
Dose reduction/delay are translated into a 20% dose reduction
Costs only include drug costs (ASP)
Calculation of Probabilities
Survival=e-rate*time
Rate=(ln(0.5)/-Time in Months)/4.33
Rate=%/Number of weeks
Probability=1-e-rate*time
Results
Relationship between life
expectancy and cost of therapy
Cost Per Line of Therapy
Drug Cost
$0
$20,000
1) FOLFOX and Bevacizumab
2) Irinotecan
3) Irinotecan and Cetuximab
Regimen
$60,000
$80,000
$96,200
1) FOLFIRI and Bevacizumab
2) FOLFOX
3) Irinotecan and Cetuximab
$41,300
1) FOLFOX and Bevacizumab
2) Irinotecan
$25,500
$16,700
$33,600
1) FOLFIRI
2) FOLFOX
$45,000
$14,400
$13,700
$45,100
$94,500
$13,700
$19,300
$27,500
$184
1) Mayo (5FU/LV)
1st Line
2nd Line
3rd Line
$140,000
$41,800
$17,600
$88,200
1) FOLFOX
2) Irinotecan
3) Irinotecan and Cetuximab
$120,000
$25,500
$96,200
1) FOLFIRI and Bevacizumab
2) FOLFOX
3) Cetuximab
$100,000
$17,600
$88,200
1) FOLFOX and Bevacizumab
2) Irinotecan
3) Cetuximab
1) FOLFOX
$40,000
Supp Care
$160,000
$180,000
Time on Treatment By Regimen
Time on Treatment in Weeks
0
20
1) FOLFOX and Bevacizumab
2) Irinotecan
3) Irinotecan and Cetuximab
19
52
1) FOLFOX
2) Irinotecan
3) Irinotecan and Cetuximab
1) FOLFOX and Bevacizumab
2) Irinotecan
19
48
1) FOLFIRI
2) FOLFOX
21
37
7
17
17
37
1) FOLFOX
29
8
33
32
14
39
120
31
16
22
38
100
17
22
50
1) FOLFIRI and Bevacizumab
2) FOLFOX
3) Cetuximab
80
19
52
1) FOLFOX and Bevacizumab
2) Irinotecan
3) Cetuximab
Regimen
60
50
1) FOLFIRI and Bevacizumab
2) FOLFOX
3) Irinotecan and Cetuximab
1) Mayo (5FU/LV)
40
33
31
33
33
1st Line
2nd Line
3rd Line
Supp Care
140
Sensitivity Analyses (Two Way)
Incremental Cost Per Life Week Gained Compared to 5FU/LV alone when
Varying Toxicity of 1st Line FOLFIRI and Bevacizumab with Drug Costs
100%
90%
80%
C
o
s
t
70%
60%
50%
40%
o
f
D
r
u
g
s
30%
173%
156%
137%
117%
100%
81%
62%
44%
20%
25%
Toxicity Front Line Rx, Compared to Baseline
500-1000
1000-1500
1500-2000
2000-2500
2500-3000
This scenario varies cost of all four drugs with the toxicity of front line FOLFIRI/
Bevacizumab compared to baseline. This demonstrates that the incremental
cost per life week gained compared to 5FU/LV is more sensitive to drug costs
than toxicity profile of front line therapy.
Two Dimensional Sensitivity Analyses
•Two Dimensional Sensitivity Analyses
–Probabilistic
•Toxicity and Progression varied over beta distribution
•Cost varied over continuous distribution (between 20% and 100% of ASP)
–Microsimulation Trials (200 hypothetical patients)
Limitations
Model uses aggregate data from multiple studies
rather than patient level data
–Results in inconsistent toxicity data
–Only one dose reduction/delay
Capecitabine-containing regimens are not yet
incorporated (upcoming)
Conclusions
Our model suggests that the survival advantage afforded by new
therapies comes at treatment related costs that may exceed currently
accepted societal thresholds of cost effectiveness
The CE ratios are more sensitive to changes in drug costs rather than
improvement in clinical parameters (ie decrease in toxicity or increase
in TTP)
Cost effectiveness ratios may be improve with better methods of
treatment selection for individual patients
Cost effectiveness ratios may be improved if treatment with these
agents in the adjuvant setting prove to be effective in preventing
relapse
Acknowledgements
Dr.Wong is supported by R25 CA 057708 (FCCC) and an
ASCO Young Investigator Award
References
1.
2.
3.
Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with
advanced colorectal cancer improves with the availability of fluorouracilleucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol.
Apr 1 2004;22(7):1209-1214.
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