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APPENDIX VII: UPDATE ON PROGRESS IN RESPONDING TO RECOMMENDATIONS OF THE
1992 WORKSHOP

July 1, 1999

In April 1992, the NIH sponsored a scientific workshop entitled "NIH Workshop on Long-Term Effects of Exposure to Diethylstilbestrol (DES)." Recommendations made at that workshop fell into five general categories: I. Epidemiologic studies; II. Basic science research; III. Studies of vaginal clear cell cancer; IV. Clinical studies of pregnancy outcomes in DES daughters; and V. Education and outreach efforts. An additional category, VI. Other, was included for items that did not fall within the five main categories. The recommendations are listed in outline form under each of the categories.

In June 1994 and July 1998, two follow-up meetings of NIH staff members were held to track the implementation of the recommendations from the 1992 workshop. Updates from both of these meetings are included. Since the complete report from the June 1994 meeting is attached (see the following update dated June 30, 1994), only a brief summary has been included under each category.

  1. Epidemiologic studies

    2. 1992 Recommendations:

    1. Support registries of DES-exposed individuals as a resource for epidemiologic research.

      • Support follow-up of identified cohorts of DES-exposed individuals and controls.
      • Encourage collaboration between existing registries for key analyses where larger sample size is required for statistical power.
      • Increase numbers of registered individuals by:
        • Linking mothers and offspring in existing DES registries and recruiting unregistered members of mother-child pairs identified through these registries.
        • Registering newly identified individuals with a history of DES exposure.

    2. Use DES registries as a resource to:

      • Define the risk of ovarian, breast, uterine, and cervical cancer in DES daughters and the risk of testicular and prostate cancer in DES sons.
      • Define the role of hormonal exposure in later life (i.e., oral contraceptives, tamoxifen, replacement estrogens, drugs that induce ovulation) in modifying cancer risks.
      • Assess the effects of DES on fertility, reproduction, and gonadal senescence.
      • Assess the association between in utero DES exposure on immune-mediated disease and psychosexual development.
      • Assess the effects of DES on infants born to DES sons and daughters.

    Update:  1994

    1. Registries of DES-exposed individuals were identified.

      • In response to a Request for Proposal (RFP), contracts to study DES-exposed cohorts were awarded to five centers in September of 1992.
      • The majority of the mothers, daughters, and sons identified for the study were from previously identified cohorts.
      • New subjects were identified through familial linkages from existing registries (e.g., sons and daughters of mothers from the former Mothers' Study).
      • Attempts to identify a cohort of DES "grandchildren" were underway.

    2. Plans were developed for the use of DES registries.

      • Principal investigators (PI's) of the centers met with NCI Project Officers in November 1992 to discuss study methods and to design follow-up questionnaires.
      • The questionnaires included the following topics: cancer risks, fertility and reproductive outcomes, and autoimmune disorders.

    Update: 1998

    1. Efforts in the current NCI contracts have been focused in three areas.

      • Analyzing data that were collected in the first combined follow-up of the cohorts.
      • Conducting a second combined follow-up to obtain additional information.
      • Initiating approved sub-studies within the cohort to address other related issues of concern.

    2. Results from studies conducted under the NCI contracts were released in 1999.

      • The report on the cancer experience of DES daughters was released in 1998.
      • The reports on the cancer experience of DES sons and DES mothers, dysplasia of the uterine cervix in daughters, and the reproductive experiences of DES daughters will be completed in 1999.

  2. Basic science research

    3. 1992 Recommendations:

    1. Develop a mechanism to identify and make available human tissue specimens, serum, and leukocytes from DES-exposed individuals for basic research.

    2. Develop transplant-derived cell lines from patients with DES-induced CCAC of the vagina to permit in vitro testing of steroid receptors and drug sensitivity.

    3. Further develop in vivo methods and animal models to screen for adverse effects following prenatal exposure to DES and other environmental endocrine disruptive compounds.

    4. Basic research efforts should include:

      • Definition of molecular markers in DES-induced vaginal CCAC and precancerous lesions.
      • Definition of the role of co-factors in the development of cervical dysplasia in DES daughters.
      • Assessment of the influence of in utero DES exposure on the developing immune, musculoskeletal, endocrine, and central nervous systems.
      • Elucidation of factors regulating normal mesenchymal/epithelial interactions in the developing genital tract and how these are affected by exposure to DES.
      • Study of primitive and classical hormone receptors.
      • Study of derivatives of Müllerian epithelium in males exposed to DES in utero.
      • Study of the genotoxic effect of estrogen on paramesonephric epithelium in the developing female reproductive tract.

    Update: 1994

    1. The Chemical and Physical Carcinogenesis Program's (CPCP) FY94 research grant portfolio included 13 DES grants totaling $1.5 M.

    2. In September 1993, the CPCP published a Program Announcement entitled "Breast Cancer: Etiology and Prevention" which was expected to yield research proposals related to DES.

    3. Under the provisions of the cooperative agreement with The University of Chicago, Dr. Arthur Herbst's group planned to conduct a review to determine the availability of archival specimens for molecular studies. (More details on the agreement are included under Section III. Vaginal Clear Cell Cancer Patients--Update 1994).

    Update: 1998

    1. Research projects associated with DES are often part of studies involving hormonal carcinogenesis.

      • Many times the research associated with DES is done in combination with other hormones (e.g., testosterone, etc.) and the investigator is interested in the effects as related to various cancers including prostate, breast, etc.
      • The research focus on hormones has historically been associated with receptor mechanisms and the ability to stimulate cellular proliferation.
      • In the area of hormonal carcinogenesis, investigators are beginning to understand the estrogen metabolic pathway. This research could lead to a better understanding of hormone effects associated with other diseases (i.e., Parkinson's).
      • It would be an important issue to determine what research efforts directly or indirectly relate to DES research as NCI or Congress define it.

    2. National Institute of Environmental Health Sciences (NIEHS) researchers and their collaborators have published the results of a study on the female offspring of mice exposed to DES during gestation. Their studies have shown that fertility of females whose "grandmothers" had received DES during pregnancy exhibited normal fertility. However, an increased incidence of malignant reproductive tract tumors, including uterine adenocarcinoma, was noted in these female descendants of DES-exposed animals, and the range and prevalence of tumors increased with age.

    3. A tissue repository is being established with the consideration of other biological specimens under the provisions of Dr. Herbst's Cooperative Agreement.

  3. Studies of vaginal clear cell cancer

    4. 1992 Recommendations:

    1. Support registry efforts for follow-up of vaginal clear cell cancer patients.

    2. Review recent data from the Society of Gynecologic Oncologists survey and the American College of Surgeons tumor registry database on vaginal clear cell cancer.

    3. Use registry data to define:

      • The age-incidence curve, survival rate, and recurrence rate of vaginal clear cell cancer and the incidence of second primary cancers (vaginal clear cell and other cancers).
      • The effect of exogenous hormones and pregnancy on the incidence, survival, and recurrence of vaginal clear cell cancer.

    4. Develop a consensus for the primary treatment of women with stage I/II vaginal clear cell cancer aimed at organ preservation and morbidity reduction.

    5. Conduct Phase II clinical trials to define the role of new agents such as taxol in the treatment of patients with stage III/IV and recurrent vaginal clear cell cancer.

    6. Assess the impact of cancer and cancer treatment on clear cell vaginal cancer survivors including: coping mechanisms, body image, sexuality, child bearing, the development of intimacy, and mother-daughter relationships.

    Update: 1994

    1. In September 1993, a cooperative agreement for $450,000 was awarded to Dr. Arthur Herbst at the University of Chicago for continued follow-up of patients with DES-associated CCAC.

      • The objectives of the cooperative agreement were:
        • To continue follow-up of documented CCAC patients and continue accrual of incident cases to further define the age-incidence curve, survival, recurrence rate, the incidence of second primary cancer(s) and the incidence of other health outcomes; and
        • To ascertain data on exposure to DES, other hormones, and other relevant factors, and to assess the determinants of survival, recurrence, and other health outcomes in women with CCAC.
      • The group planned to conduct a study of the emotional effects of DES exposure in survivors of DES-associated vaginal CCAC.

    2. The Gynecologic Oncology Group (GOG) developed a Phase II protocol to evaluate Taxol ® in the treatment of recurrent non-squamous cell carcinoma of the vagina and cervix including DES-associated CCAC.

    Update: 1998

    1. The University of Chicago's Registry for Research on Hormonal Transplacental Carcinogenesis has been reactivated and newly diagnosed cases are being added.

      • The Registry consists of a cohort of about 600 diagnosed CCAC cases in women who were DES-exposed in utero.
      • Updated and additional clinical and epidemiologic data are being collected.
      • Two collaborative teams have demonstrated that early menarche may be associated with CCAC risk and that prevalence of human papillomavirus is not elevated.

    2. At the 1992 Falls Church meeting, the consensus of the treatment panel was that primary therapy should be individualized, based on the size and location of the cancer, as well as each woman's reproductive plans.

    3. The NCI-sponsored Gynecologic Oncology Group currently has open a phase II trial of paclitaxel (Taxol ®) for women with advanced, persistent, or recurrent CCAC of the cervix and vagina.

      • Since March 1994, eight patients with CCAC have been enrolled.
      • An additional 12 to15 patients are needed before statistical analysis can be carried out.

    4. The small number of women diagnosed with CCAC of the vagina and cervix preclude phase III trials at this time.

  4. Clinical studies of pregnancy outcomes in DES daughters

    5. 1992 Recommendations:

    1. Conduct clinical studies to identify risk factors for premature delivery in DES daughters.

    2. Define the role of tocolytic agents and cerclage in prevention of premature delivery.

    Update: 1998

    Studies of DES daughters indicate an increased risk for premature births and ectopic pregnancies (Endocrinology 7:124, 1987).

  5. Education and outreach efforts

    6. 1992 Recommendations:

    1. Develop comprehensive educational programs for health providers and the general public concerning adverse health effects associated with DES exposure.

    2. Disseminate recommendations for cancer screening and obstetrical care to health professionals and DES-exposed persons.

    Update: 1994

    1. In September 1993, the NCI launched the National DES Education Program with grants in five geographic regions.

      • One purpose of the grants was to design, implement, and evaluate a program to increase health information about DES exposure.
      • A second purpose was to improve early detection, diagnosis, and treatment of several medical conditions associated with DES exposure.

    2. Baseline surveys were developed for consumers and health care providers on knowledge, attitudes, screening behaviors, and medical conditions of DES exposure.

    3. The five grantees were working together to develop joint hot-line materials, including brochures, question-answers, resource directories, etc.

    Update: 1998

    1. The work of the NCI National DES Education Program based on the original Requests for Announcement (RFA) is now complete.

    2. Principal investigators (PI) responsible for the five grants met on June 16, 1998 at the National DES Education Program meeting chaired by Dr. Sherry Mills to present their findings.

      • Each PI will prepare a scientific paper based on his/her own findings.
      • Some of the papers have already been submitted for publication.
      • The paper regarding the baseline results for both patients and physicians should be completed soon.

    3. The research included the preparation and distribution of educational materials for the physicians and patients.

      • Educational booklets were printed for distribution. [Partially funded by National Institute of Child Health and Human Development (NICHD) and Office of Research on Women's Health (ORWH), NIH]
      • In addition to the hard copies, the information is also available on the "Cancer Network" (http://http://dccps.nci.nih.gov/ACSRB/pubs/DES_Pubs/directory.html) and through the DES Action group.
      • A reference booklet prepared for physicians is now complete and will be distributed in the near future.

    4. In conclusion, the results indicate that the focus for education on DES should be targeted to the physicians.

    5. The identification of resources available to the lay person should be widely disseminated and identified for practitioners and exposed persons.

      • This includes printed materials and support from the DES Action group.
      • In addition, the DES Action group also maintains a 1-800 phone number.

    6. Discussions are underway between the Office of Women's Health (OWH)/Public Health Services (PHS) and Centers for Disease Control and Prevention (CDC) about shifting the responsibility of the DES education and outreach component to the CDC. This activity was previously managed through NCI grants.

    7. The ORWH, NIH is actively involved in encouraging medical schools and nursing programs to add materials about DES to their educational curriculum.

  6. Other

    7. 1992 Recommendations:

    1. Coordinate efforts to support DES research at the National Institutes of Health, and to track the implementation of recommendations made at the DES Workshop.

    2. Hold additional DES Workshops to discuss and disseminate new research findings.

    Update: 1994

    1. The June 30, 1994 follow-up meeting was held to review the tracking of recommendations.

    2. Part of the program of a workshop that was planned for September 1994 entitled "Dietary Phytoestrogens: Cancer Cause or Prevention?" was to explore the role of estrogenlike compounds in the etiology and prevention of cancer using DES as a prototype.

    1998

    1. On July 1, 1998, another follow-up meeting was held to review the current status of research on DES and the response to the original recommendations.

    2. The NCI and the ORWH, NIH, will consider collaborating together on a follow-up NIH workshop in the summer of 1999.

    3. From an international perspective, the ORWH, NIH, will investigate the possibility of DES research as a potential future agenda item at a meeting of the U.S. Office of Women's Health and the Mexico Commission on Women's Health.

National Cancer Institute Diethylstilbestrol (DES) Update

June 30, 1994



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