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Romero IL, McCormick A, McEwen et al. 2012. Obstetrics & Gynecology, vol. 119:61-67
What does the descriptive epidemiology teach us?
Changes in Cancer Mortality Rates, 2006-2010. U.S.
Trend in Ovarian Cancer Incidence and Mortality Rates, California, 1988-2011
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
0
2
4
6
8
10
12
14
16
18
Incidence Rate Mortality rate
Year Dx or Death
Age Adjusted Rate/100,000
Age Adjusted Incidence and Mortality Rates of Ovarian Cancer in California, 2007-2011, by Race/Ethnicity
NH White NH Black Hispanic Asian/PI0
2
4
6
8
10
12
14
16 Incidence Rate Mortality Rate
Age Specific incidence Rates of Ovarian cancer In California, 2007-2011
00 yea
rs
01-0
4 ye
ars
05-0
9 ye
ars
10-1
4 ye
ars
15-1
9 ye
ars
20-2
4 ye
ars
25-2
9 ye
ars
30-3
4 ye
ars
35-3
9 ye
ars
40-4
4 ye
ars
45-4
9 ye
ars
50-5
4 ye
ars
55-5
9 ye
ars
60-6
4 ye
ars
65-6
9 ye
ars
70-7
4 ye
ars
75-7
9 ye
ars
80-8
4 ye
ars
85+ y
ears
0
10
20
30
40
50
60
Age Specific Rate
Age Dx
Rate/100,000
Age Specific incidence rate of Ovarian Cancer in California, 1988-2011, by Race/Ethnicity
00 yea
rs
01-0
4 ye
ars
05-0
9 ye
ars
10-1
4 ye
ars
15-1
9 ye
ars
20-2
4 ye
ars
25-2
9 ye
ars
30-3
4 ye
ars
35-3
9 ye
ars
40-4
4 ye
ars
45-4
9 ye
ars
50-5
4 ye
ars
55-5
9 ye
ars
60-6
4 ye
ars
65-6
9 ye
ars
70-7
4 ye
ars
75-7
9 ye
ars
80-8
4 ye
ars
85+ y
ears
0
10
20
30
40
50
60
70
NH White NH Black Hispanic Asian/PI
Age Dx
Rate/100,000
Age Adjusted Ovarian Cancer Incidence Rates in California, 2007-2011, by County of Residence
Age Adjusted Ovarian Cancer Mortality Rates, 2007-2011, in California, By County of residence
What does the analytic epidemiology teach us?
What “risk factors” alter risk of ovarian cancer?
Risk Factors for Ovarian Cancer by Strength of Evidence
What is the distribution of stage at diagnosis for ovarian cancer and why is this important for survival?
Ovarian Cancer Stage Distribution, SEER Data, 2004-2010 (N=33,841)
Localised Regional Distant Unstaged0
10
20
30
40
50
60
70
1518
61
6
Percent
Percent Dx
Five Year Relative Survival, Ovarian Cancer, U.S., SEER Data, 2004-2010, by Stage at Diagnosis
Localized Regional Distant Unstaged0
10
20
30
40
50
60
70
80
90
100
Stage at Dx
Percent Surviving 5 Years
Five Year Relative Survival, Ovarian Cancer, U.S. SEER Data, 2006-2010
Diagnosis 1-Year 2-Year 3-Year 4-Year 5-Year0
10
20
30
40
50
60
70
80
90
100100
75.4
63.9
55.5
49.545.2
Years Since Diagnosis
Percent Surviving
Type II Diabetes
• It is estimated that two in five women born in the United States in the year 2000 will have type II diabetes diagnosed during their lifetime.
• Available data suggest that ovarian cancer patients with type II diabetes have decreased survival.
• It is biologically plausible that hyperinsulinemia and hyperglycemia induced by type II diabetes promotes tumorigenesis.
• Hypergylcemia provides a nutrient rich microenvironment for rapidly dividing cancer cells, which have elevated metabolic demands and consume glucose at a higher rate than normal cells.
Proportions of the California Female Population, Age > 45 years, Ever Diagnosed with Diabetes (2011-2012 CHIS data)
SJV California0
5
10
15
20
25
All Race/Ethnic Groups Hispanics Only
Area of Residence
Percent of the Population
Metformin
• Metformin is the most commonly prescribed drug for the treatment of type II diabetes. Metformin reduces both insulin and glucose levels.
• In ovarian cancer preclinical studies, metformin inhibits proliferation of cancer cell lines in a dose-dependent fashion (Gotlieb, 2008) and in a time dependent manner (Rattan, 2009).
Frequency of Metformin prescription, U.S., 2012 (Lindsley, ACS. Chem Neuroscience, 2013, 4, 1133-1135).
Epidemiology of Ovarian Cancer With Reference to
the Role of Metformin
CCRA Meeting, November 7, 2014
Paul K Mills, Ph.D., Kristine McLane, B.S., Cynthia Cortez, B.S., Soe Naing, MD, Maria
Arambula, MD and Theresa Gipps, MD
Institutional Review Board and Funding
• Approval for the study was received from CMC IRB: Approval #2012026, March, 2012
• Funding generously provided from: Central California Faculty Medical Group, Maria Arambula, MD, P.I.
Ovarian Cancer-Metformin Study: Methodology
• Retrospective Cohort Study Design• Inclusion Criteria: Epithelial Ovarian
cancer patients (ICD-O-3 =56.9) diagnosed 2001-2010 at CRMC, Fresno, California• Exclusion criteria: Non-invasive
pathology, non-epithelial malignancies, non ovarian primary cancer that metastasized to ovary.
Ovarian Cancer-Metformin Study: Predictors, Outcomes and Analysis.
• Primary Predictor Variable: Metformin Exposure
• Primary Outcome Variable: Time to recurrence and time to death.
• Analyses: Simple descriptive analysis of means, standard deviations and proportions with use of Student’s t test and chi-square to compare groups. Survival analysis using Kaplan –Meier and Cox Proportional hazards regression.
• Statistical significance set at p<=0.05, two-sided tests.
Data Sources, Data Collection, Coding and Quality Control
• Four primary data sources: Epic (post-2009), Last Word, EMR and paper medical records.
• Data dictionary developed, standardized data abstracting and coding techniques were developed by two trained research coordinators (Kristine M and Cynthia C.).
• Results recorded on excel spreadsheets, analysis performed using IBM/SPSS, version 21.
Results
Characteristics of the Study Cohort, Histology
Histology Number (N=220) Percent
Serous 98 44.5
Mucinous 23 10.5
Endometrioid 24 10.9
Clear Cell 7 3.2
Adenocarcinoma, NOS
53 24.1
Carcinoma, NOS 15 6.8
Total 220 100
Characteristics of the Cohort, Demographics, Labs and Follow-up (means, medians and SD)
Variable Mean SD
Age at Dx (N=220) 59.1 14.6
BMI (N=199) 29.7 6.8
Blood Glucose at Dx (N=186) 120.3 37.7
CA-125 at Dx (N=142) 1,361.3 (mean)288.5 (median)
3394
Follow-up, Dx to Last f.u. 845 days (median)
Follow-up, Dx to death (N=122)
497.5 days (median)
Characteristics of the Study Cohort, Race/Ethnicity
Race/Ethnicity Number (N=220)
Percent
Non-Hispanic White 145 65.9
Non-Hispanic Black 7 3.2
Hispanic 56 25.5
Asian/Pacific Islander 12 5.5
Total 220 100
Characteristics of the Cohort, Stage at Diagnosis
Stage at Diagnosis
Number (N=220) Percent
Localized 49 22.3
Regional 17 7.7
Remote 88 40
Distant Metastasis 62 28.2
Unknown 4 1.8
Total 220 100
Characteristics of the Cohort, Smoking
Smoking Status Number (N=220) Percent
Never Smoker 149 67.7
Current Smoker 22 10
Past Smoker 38 17.3
Unknown 11 5
Total 220 100
Characteristics of the Cohort, Treatment Related Variables
Variable Number (N=220)
Percent
ASA Class
No Surgery 47 21.3
Class I-II 52 23.6
Class II-IV 41 18.6
Unknown 80 36.4
Platinum Chemo. Rx
None 61 27.7
Rec’d 77 35.0
Unknown 82 37.3
Taxane Chemo Rx
None 60 27.3
Rec’d. 77 35.0
Unknown 83 37.7
Characteristics of the Cohort, Diabetes
Status Number (N=220)
Percent
Non-Diabetic 159 72.3
Diabetic 48 21.8
Unknown Diabetes Status 13 5.9
Total 220 100
Characteristics of the Cohort, Metformin Use/Exposure
Metformin Use Number (N=220)
Percent
No Metformin Exposure 179 81.4
Metformin taken at or after Ca Dx 18 8.2
Metformin taken only prior to Ca Dx 4 1.8
Unknown Status 19 8.6
Total 220 100
Characteristics of the Cohort, Vital Status at End of Follow-up
Vital Status at End of Follow-up
Number (N=220)
Percent
Alive 90 40.9
Known Dead 122 55.4
Dead, Ovarian Ca 29 13.2
Dead, Other Cause
10 4.5
Dead, Unknown Cause
83 37.7
Unknown Vital Status 8 3.6
Total 220 100
Comparisons of the Study Groups
Variable Non-Diabetic (n=159)
Diabetic, no Metformin Use (N=18)
Diabetic, Metformin Use (N=18)
p-value
Age at Dx (mean, SD)
57.3 (14.3) 65.8(14.5) 64.1( 15) 0.02
Race/Ethnicity
NHW 111 (.69) 8 (.44) 8 (.44) .005
NHB 4 (.02) 1 (.06) 1 (.06)
Hispanic 37 (.23) 9 (.50) 5 (.28)
Asian/PI 7 (.04) 0 4 (.22)
BMI (Kg/M2) 28.8 (5.9) 30.6 (7.1) 28.9 (6.1) 0.64
Gravidity (mean)
2.6 (2.2) 3.4 (3.1) 5.3 (4.2) 0.02
Parity (mean)
2.2 (1.9) 2.9 (2.5) 4.9 (3.7) 0.004
Comparisons of Study Groups
Variable No Diabetes (N=159)
Diabetic, no Metformin (N=18)
Diabetic with Metformin (N=18)
P-value
FIGO Stage
I 38 (23.9) 3 (16.7) 3 (16.7) 0.16
II 10 (6.3) 4 (22.2) 3 (16.7)
II 67(42.10 9 (50.0) 6 (33.3)
IV 43 (27.0) 2 (11.1) 6 (33.3)
Histology 0.64
Serous 74 (46.5) 6 (33.3) 7 (38.9)
Mucinous 18 (11.3) 2 (11.1) 1(5.6)
Endometriod 18 (11.3) 3 (16.7) 1 (5.6)
Clear cell 6 (3.8) 1 (5.6) 0 (0.0)
Carcinoma, NOS
43 27.0) 6 (33.3) 9 (50.0)
Treatment Related Variables in Study Groups
Variable Non-Diabetics (N=159)
Diabetics, no Metformin (N=18)
Diabetes, with Metformin (N=18)
P-Value
ASA Class
I-II 38 (23.9) 5 (27.8) 7 (38.9) 0.28
II-IV 34 (21.4) 3 (16.7) 2 (11.1)
No Surgery 25 (15.7) 7 (38.9) 5 (27.8)
Not recorded 62 (39.0) 3 (16.7) 4 (22.2)
Platinum
Received 63 (39.6) 3 (16.7) 6 (33.3) 0.11
None 44 (27.7) 8 (44.4) 3 (16.7)
Not recorded 52 (32.7) 9 (50.0) 11 (61.1)
Taxane
Received 62 (39.0) 4 (22.2) 6 (33.3) 0.31
None 44 (27.7) 7 (38.9) 3 (16.7)
Not recorded 53 (33.3) 9 (50.0) 11 (61.1)
All Cause Mortality Proportions Among Three Exposure Groups (N=122 deaths)
No
Diabe
tes
DM/N
o M
etfo
rmin
Diabe
tes/M
etfo
rmin
0
0.2
0.4
0.6
0.8
% Dead at End of F.U.
Median Survival Time, Date of Diagnosis until date of Recurrence or Death, CRMC, Epithelial Ovarian Cancer Patients, 2001-2010
Non Diabetic (N=134) Diabetes, no Metformin (N=15)
Diabetes, Metformin (N=15)
0
100
200
300
400
500
600
700
800
900
1000
579
765
893
Comparison Groups
No. of Days
P=0.549
Life table estimates of progression–free survival among three groups of epithelial ovarian cancer patients, CRMC, Fresno,
2001-2010. (log rank test p=0.549)
P=0.05
Cox Regression estimates of survival without recurrence outcomes among epithelial ovarian cancer patients, adjusted for age at diagnosis. The two groups are ovarian cancer patients with type II diabetes using Metformin (n=16) and ovarian cancer patients with or without type II diabetes not using Metformin (n=149). (p = 0.393)
Cox Regression Model Hazard Ratios for Progression-Free and Overall Survival
Variable Progression Free Survival
Overall Survival
DM/Metformin Status
Hazard ratio Hazard Ratio
Non-Diabetic 1.00 1.00
Diabetic, no metformin 1.18 (.63-2.20)
O.83(.40-1.67)
Diabetic, metformin 0.85 (.45-1.58)
0.92(.46-1.79)
Limitations/Conclusions
• This is not a randomized clinical trial and sample size is limited.
• Data quality issues are important, and it is important to recognize the limitations of medical records as a source for research data.
• Among 220 epithelial ovarian cancer patients at CRMC, Fresno, approximately 72% had never been diagnosed with diabetes, 8 % had diabetes but no metformin exposure and, 8% had exposure to the drug metformin.
• Metformin users were older, more likely to be Hispanic and to be of higher parity and gravity than non metformin users.
• Survival among ovarian cancer patients exposed to metformin was not statistically different from those not exposed, although there was a suggestive improvement in survival in metformin users in younger aged women.
The French Lilac plant, Galega officinalis