A prospective U.S. ovarian cancer screening study using the

risk of ovarian cancer algorithm (ROCA)

K. H. Lu, S. J. Skates, T. B. Bevers, W. Newland, R. G. Moore, L. Leeds, S. Harris,

O. W. Adeyinka, H. A. Fritsche, R. C. Bast

• Ovarian cancer is the most lethal gynecologic cancer

• Greater than 75% of cases present with advanced stage disease, when cure rates are < 30%

• If caught at Stage 1 or 2, cure rates are 60-90%

• No effective screening methods have been validated

Ovarian Cancer

• Prevalence of ovarian cancer in post-menopausal women is 1 in 2,500

• Minimal requirements for ovarian cancer screening in the general population

• To achieve a positive predictive value > 10%

• High sensitivity > 75%

• VERY high specificity > 99.6%

Ovarian Cancer

• CA-125• Limited sensitivity• False positives

• Transvaginal sonography (TVS)• Improved sensitivity• Increased false positive rate• Increased expense

• 2 stage strategy: • Risk of Ovarian Cancer Algorithm (ROCA)

incorporates age and CA-125. Risk re-calculated with each new CA-125 test

• Those with high scores referred to TVS

Limitations of CA-125 or TVS alone

AnnualCA 125

ROCAalgorithm

Two stage screening

Courtesy of U. Menon and I. Jacobs

AnnualCA 125

ROCAalgorithm

NORMAL or “LOW”

Two stage screening

Courtesy of U. Menon and I. Jacobs

AnnualCA 125

ROCAalgorithm

SURGERY

ABNORMAL or “HIGH”

NORMAL or “LOW”

Two stage screening

Courtesy of U. Menon and I. JacobsTVS

AnnualCA 125

ROCAalgorithm

SURGERY

ABNORMAL or “HIGH”

“INTERMED”

NORMAL or “LOW”

RepeatCA 125

Two stage screening

Courtesy of U. Menon and I. JacobsTVS

•The purpose of this study was to assess the specificity and positive predictive value (PPV) of a 2-stage screening strategy to detect ovarian cancer in post-menopausal women :

• Tailored to each individual woman’s baseline

• Only a small fraction of women referred to transvaginal sonography (TVS) and clinical evaluation

Purpose

• Prospective, single arm

• Initiated in 2001

• Multicenter

1. M. D. Anderson, Houston TX2. Women’s Hospital, Houston TX3. University of Texas Family Practice, Houston TX4. Women and Infants Hospital, Providence RI5. Baylor Sammons Breast Center, Dallas TX6. John Stoddard Cancer Center, Des Moines, IA7. Geffen Cancer Center, Vero Beach, FL

• Data center for study – Massachusetts General Hospital

Methods

• Eligibility criteria

• Post-menopausal women ages 50-74

• Have at least 1 ovary

• No significant family history of breast or ovarian cancer

• Cancer-free and no treatment in past 12 mos, aside from hormonal adjuvant therapy

Methods

•Women underwent annual CA-125 blood tests

•CA-125 II assayed centrally using ROCHE platform

•CA-125 values were analyzed with ROCA algorithm

•ROCA recommendation communicated to primary physician and patient

•TVS performed at study centers

•Based upon TVS and ROCA, decision for surgery made by physician at study center and patient

Methods

Results

• Total number of participants = 3,252 women

• Total number of screen years = 10,679 years

• Average number of screen years per woman = 3.3 years

• Median age 59, with a range of 50-74

•

Characteristic

n %

Ethnicity Caucasian Black Hispanic Asian Other

27502641396435

84.68.14.32.01.1

Ever pregnant 2594 86.8

Ever use OCP 2388 79.1

Ever use HRT 616 20.6

Hx breast cancer 428 16.6

Baseline characteristics

Results

Average annual rates:

• Normal risk “return in 1 year” = 92.6% • Intermediate risk “repeat CA-125 in 3 mos = 6.5%• High risk “TVS + referral” = 0.9%

Overall:

• Normal risk “return in 1 year” , n= 2666 (82%)• Intermediate risk “repeat CA-125 in 3 mos, n= 501

(15.4%)• High risk “TVS + referral” , n=85 (2.6%)

•

Study-directed surgeries

8 surgeries 5 early stage cancers

• 3 high grade invasive• Stage IC• Stage IC• Stage IIB

• 2 borderline (LMP)• Stage IA• Stage IA

3 without ovarian cancer•2 benign ovarian tumors •1 with no ovarian abnormality (2 months later found to have early stage endometrial cancer)

Study-directed surgeries

Study Directed Surgeries (n=8)

PtAge at entry

1st CA125

# annual CA125

CA 125 resulting in “High

Risk”

TVS results Symptoms Findings at surgery

1 68 29 1 74 abnormal No Stage 1 serous LMP

2* 64 9 6 15 abnormal No Stage 1 serous LMP

3* 63 12 2 24 abnormal No Benign (cystadenoma)

4* 55 12 3 22 abnormal No Stage IIB high grade invasive cancer

5* 53 13 318

170

#1: normal

#2: abnormalGI Stage IC high grade invasive cancer

6 69 75 0 75 abnormal No Benign (cystadenoma)

7 65 19 3 340 abnormal No Stage IC high grade invasive cancer

8 60 45 0 59 abnormal No1st surgery: no ovarian disease (sigmoid nodule with necrotic component); 2nd surgery: endometrial cancer

* Detected by ROCA only, and not by CA-125 >35

Stage IIB high grade invasive cancerStage IC high grade invasive cancer Stage IC high grade invasive cancer

Examples of CA 125 trends

Patient classified as “Low Risk”Patient classified as “Low Risk”

Specificity and Positive Predictive Value

• Specificity 99.9%, 95%CI [99.7%, 99.98%]

• Positive predictive value 37.5%, 95% CI [11.1%, 100%]

- No more than 3 operations to detect 1 case of invasive ovarian cancer

• Study was not powered to determine sensitivity

- 2 borderline cases were not detected by ROCA algorithm

- 0 invasive ovarian cases were missed

Discussion

• United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

– randomized 200,000 post-menopausal women, with 50,000 undergoing 2-stage ROCA algorithm screening

– prevalence data from 1st screen published in Lancet Oncology 2009

• UK (prevalence data) and US ovarian cancer screening trials demonstrate similar proportions of women triaged:

– “Normal risk” annual CA125 (90.9% vs 92.6%)– “Intermediate risk”, repeat CA125 in 3 mos (8.6% vs 6.5%)– “High risk”, TVS and referral (0.5% vs 0.9%)

Discussion

• UK (prevalence data) and US ovarian cancer screening trials:

• Specificity (99.8% vs 99.9%)

• PPV for invasive cancer (35.1% vs 37.5%)

• Stage distribution in UK (prevalent cases):

16 of 34 (47%) invasive cancers were Stage 1, 2

• Stage distribution in US (incident cases):

3/3 (100%) invasive cancers were Stage 1, 2

Conclusions• In this 9-year screening trial of 3,252 women over age

50, the ROCA algorithm followed by TVS demonstrated very few false positives (specificity = 99.9%)

• Fewer than 1% of women required a TVS each year

• Overall, the positive predictive value was 37.5%, which greatly exceeded the goal of 10%; i.e. no more than 3 operations will be required to detect 1 invasive ovarian cancer

• 5 ovarian cancers were detected, all early stage (3 invasive, high grade and 2 borderline)

Conclusions

• 2-stage strategy for ovarian cancer screening is feasible in a U.S. population.

• Not practice-changing at this time- await the results of the definitive trial that

examines mortality as an endpoint, which is currently ongoing in the United Kingdom

• Future directions- 4 marker panel (CA-125, HE4, CEA, VCAM)- “Point of contact” assay

• Trial Participants

• Mary Hernandez, RN• Deepak Bedi, MD• Cynthia Deverson• Connie Teodoro• Nora Horick, PhD• Charlotte Sun, PhD• Pati Berger, RN• Cindy Brizard• Veronica Solano• Cristina Vaida, RN

• Funded by the M. D. Anderson Ovarian Cancer Specialized Program of Research Excellence P50 – CA083639

• Golfers Against Cancer

• Tracey Jo Wilson Foundation

• Mossy Foundation

• Shader Family Foundation

• Norton Fund

Acknowledgements