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

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Ovarian cancer is the most lethal gynecologic cancer

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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

  • 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%


Limitations of CA-125 or TVS alone

  • CA-125

    • Limited sensitivity

    • False positives

  • Transvaginalsonography(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


Two stage screening

ROCA

algorithm

Annual

CA 125

Courtesy of U. Menon and I. Jacobs


Two stage screening

NORMAL or “LOW”

ROCA

algorithm

Annual

CA 125

Courtesy of U. Menon and I. Jacobs


Two stage screening

NORMAL or “LOW”

ROCA

algorithm

Annual

CA 125

ABNORMAL or “HIGH”

TVS

Courtesy of U. Menon and I. Jacobs

SURGERY


Two stage screening

NORMAL or “LOW”

ROCA

algorithm

Annual

CA 125

Repeat

CA 125

“INTERMED”

ABNORMAL or “HIGH”

TVS

Courtesy of U. Menon and I. Jacobs

SURGERY


Purpose

  • 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 transvaginalsonography (TVS) and clinical evaluation


Methods

  • Prospective, single arm

  • Initiated in 2001

  • Multicenter

    • M. D. Anderson, Houston TX

    • Women’s Hospital, Houston TX

    • University of Texas Family Practice, Houston TX

    • Women and Infants Hospital, Providence RI

    • Baylor Sammons Breast Center, Dallas TX

    • John Stoddard Cancer Center, Des Moines, IA

    • 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


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


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

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


Examples of CA 125 trends

Stage IC high grade invasive cancer

Stage IIB high grade invasive cancer

Stage IC high grade invasive cancer

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% vs6.5%)

      • “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


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