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.