Chemoprevention of Chemoprevention of Ovarian Cancer: Is Ovarian Cancer: Is There a Role for Diet There a Role for Diet and Physical Activity and Physical Activity Interventions? Interventions? David S. Alberts, M.D.
Mar 30, 2015
Chemoprevention of Chemoprevention of Ovarian Cancer: Is There a Ovarian Cancer: Is There a Role for Diet and Physical Role for Diet and Physical
Activity Interventions?Activity Interventions?
David S. Alberts, M.D.
Background• The five year relative survival rate for ovarian cancer The five year relative survival rate for ovarian cancer
between 1996 and 2002 was 45%*between 1996 and 2002 was 45%*– For regional and distant disease, 5 year survival rates For regional and distant disease, 5 year survival rates
are 69% and 305, respectively*are 69% and 305, respectively*• More than 70% of women who experience a clinical CR More than 70% of women who experience a clinical CR
on primary chemotherapy experience disease on primary chemotherapy experience disease recurrence and ultimately die**recurrence and ultimately die**
• Efforts to identify lifestyle modifications that may Efforts to identify lifestyle modifications that may modulate disease incidence and progression remain modulate disease incidence and progression remain limitedlimited
• The role of diet and specific dietary constituents in The role of diet and specific dietary constituents in ovarian cancer survival is not clearly understoodovarian cancer survival is not clearly understood– Diet and exercise remain potential modifiable risk Diet and exercise remain potential modifiable risk
factors for this diseasefactors for this disease
* American Cancer Society, Cancer Facts and Figures 2007, Atlanta: American Cancer Society; * American Cancer Society, Cancer Facts and Figures 2007, Atlanta: American Cancer Society; 2007 **Bosetti C et al. Curr. Opin. Obstet. Gynecol., 2007 **Bosetti C et al. Curr. Opin. Obstet. Gynecol., 14:14:13, 200213, 2002
Comparison of incidence of invasive ovarian cancer, invasive endometrial cancer, and other invasive cancers between intervention
and comparison groups in the Women’s Health Initiative (WHI) Dietary Modification Trial
Incidence per 1000 person-years (# of cases) Cancer site Intervention Comparison P HR (95% CI) Ovary 0.36 (57) 0.43 (103) .03 0.83 (0.60 to 1.14)* Breast 4.15 (655) 4.52 (1072) .09 0.91 (0.83 to 1.01) Colorectal 1.27 (201) 1.18 (279) .29 1.08 (0.90 to 1.29)
Background-Diet
•Supports low fat diets in the primary prevention of ovarian cancer (WHI Supports low fat diets in the primary prevention of ovarian cancer (WHI n=48,835 post-menopausal women)n=48,835 post-menopausal women)
Prentice R, Thomson CA, et al. JNCI, 99:1534, 2007Prentice R, Thomson CA, et al. JNCI, 99:1534, 2007
* Hazard ratio was 0.60 (955 CI = 0.38 to 0.96, p=0.03 for the follow-up over the last 4 years (4.0-8.1 years)
WINS Relapse Rate Curve (All)
Follow-up time (Years)
Re
lap
se
Ra
te
0 1 2 3 4 5 6 7 8 9 10
0.0
0.05
0.10
0.15
0.20
0.25
0.30
YEARS
PA
TIE
NT
S (
%)
Diet Control HR, 95% CI P-value* 96/975 181/1462 0.76, 0.60-0.98 0.034
Diet 975 949 907 807 647 490 342 201 96 Control 1462 1416 1352 1197 965 756 529 326 151
* From adjusted Cox proportional hazards model including: stratification factors, ER status, tumor size, and surgery (mastectomy/lumpectomy), p value = 0.067 by unadjusted log rank test
Absolute difference 1%
3% 3% 3% 4% 7%
Chlebowski RT et al., J. Natl. Cancer Inst., Chlebowski RT et al., J. Natl. Cancer Inst., 98:98:1767, 20061767, 2006
WINS Relapse Rate Curve(for ER -)
Follow-up time (Years)
Re
lap
se R
ate
0 1 2 3 4 5 6 7 8 9 10
0.0
0.05
0.10
0.15
0.20
0.25
0.30
P-value from adjusted Cox proportional hazard model
Diet 205 196 182 166 135 105 77 45 25 Control 273 205 230 203 163 133 88 55 26
Control ------Diet _____
Diet Control HR, 95% CI P-value28/205 59/273 0.58,0.37-0.91 0.018
Absolute difference:6%
8% 11% 11%6%
YEARS
PA
TIE
NT
S (
%)
Chlebowski RT et al., J. Natl. Cancer Inst., Chlebowski RT et al., J. Natl. Cancer Inst., 98:98:1767, 20061767, 2006
Pierce JP et al., J. Clin. Oncol., 25:2345, 2007Pierce JP et al., J. Clin. Oncol., 25:2345, 2007
Women’s Health Eating and Living Study re-analysis women who followed both diet and exercise recommendations had lower
recurrence and better survival rates
Background-Diet
• Population based ovarian cancer case-control Population based ovarian cancer case-control across 3 Australian states( 1990-1993)across 3 Australian states( 1990-1993)
• 609 women with invasive epithelial ovarian cancer609 women with invasive epithelial ovarian cancer• Diet assessed with food frequency questionnaireDiet assessed with food frequency questionnaire• Deaths identified though state cancer registries Deaths identified though state cancer registries
and national death indexand national death index
Nagle, Christina M et al. Int J Cancer, 106:264, 2003Nagle, Christina M et al. Int J Cancer, 106:264, 2003
Dietary Influences on Survival After Ovarian Cancer
Christina M. Nagle1, David M. Purdie1,2, Penelope M. Webb1,2, Adele Green1,2, Philip W. Harvey1 and Christopher J. Bain1
1School of Population Health, University of Queensland, Brisbane, Australia2Queensland Institute of Medical Research, Brisbane, Australia
Dietary Intake Total Crude 5-year survival % (SE%)
Adjusted Hazard ratio (95% CI)
P trend
All vegetables <3.9 serves 201 44 (4) 1.0
3.9-5.56 serves 201 43 (4) 1.08(0.82-1.42 >5.56 serves 207 50 (3) 0.75 (0.57-0.99) 0.01
Cruciferous vegetables <0.41 serves 201 42 (4) 1.0
0.41-0.83 serves 203 44(4) 0.87(0.67-1.13) >0.83 serves 205 49(4) 0.75(0.57-0.98) 0.03
Nagle CM et al., Int J Cancer, Nagle CM et al., Int J Cancer, 106:106:264, 2003264, 2003
Dietary Influences on Survival after Ovarian Cancer
Increased intake of lactose and galactose have specifically been identified to increase ovarian cancer risk in select populations by both Cozen
et al. and Nagle et al.
Cozen W et al., Cancer Causes Control., Cozen W et al., Cancer Causes Control., 13:13:113, 2002 & Nagle CM et al., Int J Cancer, 113, 2002 & Nagle CM et al., Int J Cancer, 106:106:264, 2003264, 2003
Possible a Priori “Harmful” Prognostic Factors for Ovarian Cancer
Daily Intake Total Crude 5-year survival % (SE%)
Adjusted Hazard ratio
(95% CI)
P trend
Lactose <13.6 g 199 48 (4) 1.0
13.6-20.17g 204 47 (4) .99(0.75-1.31 >20.17g 206 40 (3) 1.32 (0.99-1.75) 0.04
Effects of Food Groups on Survival from Epithelial Ovarian CancerLong-term Follow up of a Cook County Case Control Study*
Food Median Hazard Group Servings/Week N Ratio p-valueVegetables0<7 4.5 54 1.00 <0.05
7<14 10.0 1.38 0.49 <0.01
14+ 18.6 149 0.59 <0.05Cruciferous Vegetables0<1 0.5 83 1.00 <0.051<3 1.9 144 0.56 <0.013+ 5.0 114 0.84 0.43Red Meats0<1 0.2 73 1.00 <0.051<4 1.5 218 1.90 <0.014+ 5.0 50 2.82 <0.01Milk (all types)0 0.0 58 1.00 <0.05>0<7 2.0 170 1.80 <0.057+ 10.5 113 2.15 <0.01
*Dolecek, TA, Davis FG, Campbell RT, Joslin CE. Diet and survival from ovarian cancer among women in Cook County, IL. Am. J. Epidemiol. 2008.
Kushi LH et al., Am J Epidemiol, Kushi LH et al., Am J Epidemiol, 149:149:21, 199921, 1999
Relative risks and 95% confidence intervals of ovarian cancer among 29,083 postmenopausal women, Iowa Women’s Health Study, 1986-1995
Category Range of intake (# of servings)
Cases (no.)
Multivariable-adjusted relative
risk
95% confidence
interval Green Leafy Vegetables
1 <2/week 48 1.00 2 2-3/week 23 0.80 0.47-1.35 3 4-5/week 48 0.87 0.56-1.34 4 >5/week 22 0.44 0.25-0.79
p for trend 0.01 Dairy Products
1 >9/week 28 1.00 2 8-14/wek 34 1.25 0.72-2.18 3 15-23/week 38 1.65 0.96-2.85 4 >23/week 39 1.76 0.99-3.13
p for trend 0.03
Summary-Diet
• Select dietary constituents have been suggested to Select dietary constituents have been suggested to reduce ovarian cancer risk. reduce ovarian cancer risk. – Green leafy vegetables (RR=0.44 - 1.00, p for Green leafy vegetables (RR=0.44 - 1.00, p for
trend, 0.01) Iowa Women’s Health Study*trend, 0.01) Iowa Women’s Health Study*– Cholesterol intake (RR=1.00-1.55; p for trend, Cholesterol intake (RR=1.00-1.55; p for trend,
0.06) Iowa Women’s Health Study*0.06) Iowa Women’s Health Study* • Consumption of greater than four eggs/week Consumption of greater than four eggs/week
(RR=1.00 -1.81, p for trend, 0.04)*(RR=1.00 -1.81, p for trend, 0.04)*• Increased risk associated with egg intake was Increased risk associated with egg intake was
corroborated in Australian women**corroborated in Australian women**
*Kushi LH et al., Am. J. Epidemiol., *Kushi LH et al., Am. J. Epidemiol., 149:149:21, 1999 21, 1999
**Pirozzo S et al., Cancer Epidemiol Biomarkers Prev, **Pirozzo S et al., Cancer Epidemiol Biomarkers Prev, 11:11:1112, 20021112, 2002
Summary-Diet– Protective effects for high vegetable intake (RR= Protective effects for high vegetable intake (RR=
0.61 for three servings per day versus less than 0.61 for three servings per day versus less than one, (CI: 0.38-0.97) *one, (CI: 0.38-0.97) *• Case (n=605) control (N=3899) study of newly Case (n=605) control (N=3899) study of newly
diagnosed epithelial ovarian cancerdiagnosed epithelial ovarian cancer– These findings are supported in the widely These findings are supported in the widely
recognized WCRF/AICR report that also evaluated recognized WCRF/AICR report that also evaluated diet and ovarian cancer**diet and ovarian cancer**
*Riman T et al., Eur. J. Epidemiol., *Riman T et al., Eur. J. Epidemiol., 19:19:1011, 20041011, 2004**Glade MJ et al., Nutrition, **Glade MJ et al., Nutrition, 15:15:523, 1999523, 1999
Background-Physical Activity
• Mechanisms by which physical activity may Mechanisms by which physical activity may exert protective effectexert protective effect– Improving immune functioningImproving immune functioning– Reduction of ovarian estrogen production (via Reduction of ovarian estrogen production (via
delay of menarche and reduction of cycling in delay of menarche and reduction of cycling in young women)young women)
– Reducing body fat (thereby reducing fat-produced Reducing body fat (thereby reducing fat-produced estrogens along with potential for storage and estrogens along with potential for storage and turnover of fat-soluble carcinogens)turnover of fat-soluble carcinogens)
– Increasing sex-hormone binding globulins Increasing sex-hormone binding globulins – reducing circulating insulin and glucosereducing circulating insulin and glucose– Reducing activity of COX-2 and levels of Reducing activity of COX-2 and levels of
prostaglandins in ovarian epitheliumprostaglandins in ovarian epithelium
Relative Risks and 95% Confidence Intervals for Ovarian Cancer in Relation to Leisure-Time Physical
Activity: Iowa Women’s Health Study, 1986-2000
Increased risk of ovarian cancer development among women with the Increased risk of ovarian cancer development among women with the highesthighest levels of physical activity levels of physical activity
Anderson JP et al., Cancer, Anderson JP et al., Cancer, 100:100:1515, 20041515, 2004
Variable Number of Cases
Multivariable-adjusted RR
95% confidence
interval
P value
Frequency of Moderate Physical Activity (times per week) Rarely/Never 45 1.00 Reference 0.25
1 49 0.75 0.50-1.14 - 2-4 69 0.98 0.66-1.44 - >4 57 1.17 0.78-1.75 -
Frequency of Vigorous Physical Activity (times per week) Rarely/Never 177 1.00 Reference <0.01
1 17 0.84 0.50-1.43 - 2-4 14 1.03 0.58-1.80 - >4 11 2.38 1.29-4.38 -
Relative Risks and 95% Confidence Intervals for Ovarian Cancer in Relation to Baseline Anthropometric
Variable: Iowa Women’s Health Study, 1986-2000
Increased risk of ovarian cancer development among women with higher Increased risk of ovarian cancer development among women with higher waist-to-hip ratioswaist-to-hip ratios
Anderson JP et al., Cancer, Anderson JP et al., Cancer, 100:100:1515, 20041515, 2004
Variable Number of Cases
Multivariable-adjusted RR
95% confidence
interval
P value
Waist-to-hip ratio ≤ 0.78 41 1.00 Reference 0.14
0.78-0.83 73 1.79 1.19-2.63 - 0.84-0.89 47 1.17 0.76-1.81 -
>0.89 61 1.54 1.05-2.40 -
Significantly reduced risk of ovarian cancer among women in the highest tertiles of Significantly reduced risk of ovarian cancer among women in the highest tertiles of moderate, recreational activitymoderate, recreational activity
Odds Ratios for Ovarian Cancer Associated With Moderate and Vigorous Recreational Physical Activity, Overall and by
Menopausal Status, NECSS Study, Canada, 1994-1997
Pan SY et al., Int. J. Cancer, Pan SY et al., Int. J. Cancer, 117:117:300, 2005300, 2005
All Women (n=2,577)
Recreational physical activity (MET units/week)
Cases (n) Controls (n) Multivariable-adjusted
OR 95% CI Moderate (tertiles)
0-7.49 168 712 1.00 7.50-24.16 160 712 0.89 0.69-1.17
≥ 24.17 114 711 0.67 0.50-0.88 p for trend 0.006
Vigorous 0 131 740 1.00
>0-4.15 177 698 1.14 0.87-1.50 ≥ 4.16 134 697 0.93 0.70-1.24
p for trend 0.56
The Netherlands Cohort Study Reported an Inverse Association Between Moderate Physical Activity and
Ovarian Cancer Risk
• Same study looked at using participation in sport Same study looked at using participation in sport (competition) as a marker for vigorous activity (competition) as a marker for vigorous activity finding no association of vigorous activity with finding no association of vigorous activity with ovarian cancer risk. ovarian cancer risk.
• Women who reported sport participation (i.e. Women who reported sport participation (i.e. vigorous physical activity) tended to differ from the vigorous physical activity) tended to differ from the overall population: taller, lower BMI, greater daily overall population: taller, lower BMI, greater daily alcohol intake, and fewer childrenalcohol intake, and fewer children
Biesma RG et al., Cancer Causes Control, 17:109, 2006Biesma RG et al., Cancer Causes Control, 17:109, 2006
GOG-225 GOG-225 Can Diet and Physical Can Diet and Physical
Activity Modulate Ovarian Activity Modulate Ovarian Cancer Progression Free Cancer Progression Free
Survival?Survival?
Study ChairStudy ChairDavid S. Alberts, M.D.David S. Alberts, M.D.
Study Co-ChairsStudy Co-ChairsCynthia Thomson, Ph.D., R.D., C.O.N.S.Cynthia Thomson, Ph.D., R.D., C.O.N.S.
Janet Foote, Ph.D.Janet Foote, Ph.D.Robert Mannel, M.D.Robert Mannel, M.D.
Quality of Life Co-ChairQuality of Life Co-Chair Karen Basen-Engquist, Ph.D, MPHKaren Basen-Engquist, Ph.D, MPH
StatististicianStatististicianMarion Piedmont, M.S.Marion Piedmont, M.S.
Translational ScientisistTranslational ScientisistZoe Miner, Ph.D.Zoe Miner, Ph.D.
Biomarkers StudiesBiomarkers Studies
Schema-GOG-225Schema-GOG-225
Ovarian Cancer Diagnosis: Successful first line treatment consolidation
Comparison Lifestyle
Intervention Lifestyle: 6 servings of fruits and
vegetables (incl. 1 cruciferous), low
fat, (weight control )+ 4000 additional steps
daily
2:1intervention: comparison
Progression-free survival (@ 2 years)
RANDOMIZE
Primary Objective
• Determine if disease-free women who Determine if disease-free women who completed therapy for Stage III-IV completed therapy for Stage III-IV ovarian or primary peritoneal cancer ovarian or primary peritoneal cancer randomized to a healthy lifestyle randomized to a healthy lifestyle intervention have increased intervention have increased progression free survival compared to progression free survival compared to those randomized to usual care.those randomized to usual care.
Secondary Objective
• Determine if women in the intervention group Determine if women in the intervention group have improved general quality of lifehave improved general quality of life– Measured by General Health subscale of Measured by General Health subscale of
RAND-36 RAND-36 • Determine if women in the intervention group Determine if women in the intervention group
have improved physical functioning have improved physical functioning – Measured by the Physical Functioning Measured by the Physical Functioning
subscale of RAND-36 and the GSRS-IBSsubscale of RAND-36 and the GSRS-IBS
Eligibility Criteria
• Diagnosis of epithelial ovarian or primary Diagnosis of epithelial ovarian or primary peritoneal carcinomaperitoneal carcinoma– Stage III or IV at diagnosisStage III or IV at diagnosis
• Completion of all primary chemotherapy and Completion of all primary chemotherapy and consolidation therapy > 12 weeks prior to consolidation therapy > 12 weeks prior to enrollment and < 24 months from enrollment enrollment and < 24 months from enrollment
• Complete remissionComplete remission– No clinical evidence of persistent or recurrent No clinical evidence of persistent or recurrent
disease based on CA-125 and CT scan. disease based on CA-125 and CT scan.
• GOG Performance Grade of 0, 1, or 2.GOG Performance Grade of 0, 1, or 2.