Full Text CA-93-12


NIH GUIDE, Volume 22, Number 7, February 19, 1993

RFA:  CA-93-12

P.T. 34

  Cell Lines 

National Cancer Institute

Letter of Intent Receipt Date:  March 31, 1993
Application Receipt Date:  May 5, 1993


The Extramural Programs Branch, Epidemiology and Biostatistics
Program, Division of Cancer Etiology, National Cancer Institute (NCI)
invites cooperative agreement applications from investigators to
participate, with the assistance of the NCI, in epidemiologic and
interdisciplinary studies to follow-up patients with
diethylstilbestrol (DES)-associated clear cell adenocarcinoma of the
cervix or vagina.


The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Follow-Up of Patients with DES-Associated Clear Cell Adenocarcinoma,
is related to the priority area of cancer.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington DC 20402-9325 (telephone 202-783-3238).


Applications may be submitted by domestic and foreign non-profit and
for-profit institutions, public and private, such as colleges,
universities, hospitals, research laboratories, units of State and
local governments, and eligible agencies of the Federal Government.
Applications from minority and women investigators are encouraged.


Support of this program will be through the Cooperative Agreement
(U01), an assistance mechanism in which substantial NCI programmatic
involvement with the recipients during performance of the planned
activity is anticipated.  The nature of NCI staff involvement is
described in SPECIAL REQUIREMENTS and Terms and Conditions of Award.
Applicants will be responsible for the planning, direction, and
execution of the proposed project.  Awards will be administered under
PHS grants policy as stated in the Public Health Service Grants
Policy Statement, DHHS Publication No. (OASH) 90-50,000, revised
October 1, 1990, and in this RFA.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete as research project
applications with all other investigator-initiated applications and
be reviewed by the Division of Research Grants (DRG).  However, if
the NCI determines that there is a sufficient continuing program
need, the NCI will invite recipients of awards under this RFA to
submit competitive continuation cooperative agreement applications
for review.

Because the nature and scope of the research proposed in response to
this RFA may vary, it is anticipated that the size of an award will
vary also, and that the average award will be in the range of
$100,000 to $300,000.  The total project period for applications
submitted in response to the present RFA should not exceed four
years.  The earliest feasible start date for the initial awards will
be September 30, 1993.


Approximately $850,000 in total costs per year for four years will be
committed to specifically fund applications which are submitted in
response to this RFA.  It is anticipated that four to eight awards
will be made.  This funding level is dependent on the receipt of a
sufficient number of applications of high scientific merit.  Although
this program is provided for in the financial plans of the National
Cancer Institute (NCI), the award of cooperative agreements pursuant
to the RFA is also contingent upon the availability of funds at the
time the awards are made.



Diethylstilbestrol (DES) is a synthetic estrogen that was frequently
prescribed for threatened abortion in several areas of the United
States from 1945 to 1955.  It is estimated that there may have been
up to 4 to 6 million Americans (mothers, daughters, sons) exposed to
DES.  In 1971, an epidemiologic study reported that the risk of
development of a rare form of malignant vaginal and cervical cancer,
clear cell adenocarcinoma (CCA), was related to intrauterine exposure
to DES.

Subsequently, 21 cases of CCA in DES-exposed daughters were reported
to a newly established registry for the monitoring of this specific
disease.  Much of the data concerning vaginal and cervical CCA in DES
daughters comes from the registry developed by Dr. Arthur Herbst.  As
of March 1992, 587 patients with CCA of the cervix or vagina had been
reported.  Patients are classified into four separate categories
according to their exposure status: (1) those having a documented
history of DES exposure, (2) those with documented exposure to other
hormones, (3) those having no history of hormonal exposure, or (4)
those with unknown exposure.  Exposure data are confirmed through
1989. In total, 352 (60 percent) of registrants have a documented
history of DES exposure.  The peak incidence occurs between ages 15
and 25, and ranges from age seven to 42.  The lifetime risk of
vaginal CCA appears low, between 1 in 1,000 and 1 in 10,000 of those

A recent incidence study of CCA in Connecticut demonstrated that (1)
previously estimated incidence rates for CCA were low, and as many as
half of incident cases were not correctly reported to the local
cancer registry, and (2) incidence rates for CCA have not declined
but have been stable since 1975, emphasizing the need for continued
clinical and epidemiologic studies of the etiology and clinical
course of CCA.

An estimated 20 new cases and 10 to 15 recurrent cases of CCA are
diagnosed annually in the United States.  These estimates, probably
conservative, are based on data from the Herbst registry and from a
recent survey of Gynecologic Oncology Group members.  In the Herbst
registry, approximately 90 percent of newly diagnosed patients are
classified as having stage I or stage II disease.  Survival for
patients with stage I disease is high if conventional therapy is
employed; 10-year survival rates approach 90 percent.  The assessment
of women with early-stage disease has proven particularly
problematic, as primary surgery and radiation therapy result in a
high proportion of survivors, but also in significant long-term
morbidity, loss of reproductive and sexual function, and altered body
image.  Sequelae of CCA are clearly profound and long lasting.

Overall, CCA has recurred in 19 percent of cases referred to the
Herbst registry.  While the recurrences of CCA are rare after five
years, they have appeared 10 years and longer after initial
diagnosis.  These findings emphasize the need for long-term follow-up
of CCA patients.

Recent evidence has renewed interest in the continued follow-up of
CCA patients, who are just entering the at-risk age range for most of
the hormonally-related tumors (e.g., breast).  A recent case-control
study of DES-associated CCA found that both height and body mass had
significant dose-response relationships with this disease.  Estrogen
levels are known to be associated with increased body mass and
height; thus, endogenous hormonal factors may be acting as promoters
for CCA.  The relationship of exogenous hormones and related agents
(e.g., oral contraceptives, agents used to induce ovulation,
tamoxifen, replacement estrogens) with CCA remains to be explored.

Results of in vitro and animal studies suggest that exposure to DES
during in utero and neonatal development may turn on persistent
overexpression of protooncogenes associated with mitosis (such as
c-fos or c-jun), resulting in altered tissue responsiveness to
hormones, either during puberty or later in life.  This, in turn, may
result in unregulated cell growth that can have teratogenic or
carcinogenic effects.  In addition to oncogenes, growth factor genes,
such as transforming growth factor-alpha and epidermal growth factor,
and a group of genes recently termed natural reporter genes for
estrogen action, including the gene for lactoferrin, have been shown
to be overexpressed following developmental exposure to DES.

Two Department of Health and Human Services (DHHS) task forces
devoted to the DES issue (1978 and 1985) have strongly recommended
the continued follow-up of established cohorts.  Congress expressed
its concern in the FY 1992 appropriations bill with the following
language:  "The Committee is concerned that despite scientific cause
to investigate, DES research has declined.  The Committee intends for
longitudinal studies of the DES-exposed to be a priority of the NIH."
The FY 1993 Senate Appropriations Subcommittee Report states, "NCI is
expected to work closely with organizations representing DES victims
in developing and implementing the national education programs and
longitudinal studies mandated by [this] legislation."

An NIH workshop on the long-term health effects of DES was held in
Falls Church, Virginia, on April 22-24, 1992, in which NCI
participated as a co-sponsor.  The FY 1993 Senate Appropriations
Subcommittee Report states, "The Committee requests NCI ... to
implement the recommendations stemming from the DES conference in
April..."  This RFA responds to recommendations made by workshop
participants regarding research on unresolved issues about
DES-associated malignancies.

Research Goals and Scope

The primary objectives of these Cooperative Agreements are:

(1) to continue follow-up of documented CCA patients and continue
accrual of incident cases to further define the age-incidence curve,
the survival rate, the recurrence rate, the incidence of second
primary cancer(s), and the incidence of other health outcomes; and

(2) in women with CCA, 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.

Investigators and organizations that have participated in
documentation of cases of CCA with data on treatment and systematic
follow-up for health outcomes, and other interested investigators,
are encouraged to respond to this RFA and to participate in
cooperative studies of CCA.  These studies may include assessment of
the completeness of case identification, confirmation of diagnosis,
validation of data on DES and other hormonal exposures, evaluation of
health status, and gathering of information useful for future
follow-up. Interdisciplinary collaborations are encouraged to provide
additional expertise in, for example, molecular biology or behavioral

It is anticipated that through cooperation in the follow-up of study
participants, collaborations can be established and resources made
available for other research initiatives to evaluate a range of
questions regarding CCA.  Applicants are encouraged to consider
feasible approaches to the following additional research objectives
that stem from the recommendations made by participants in the NIH
workshop on DES.  Utilization of existing CCA registry data can be
maximized through:

(1)  Development and maintenance of a mechanism to permit access to
specimens, serum, and leukocytes from vaginal and cervical CCA

(2)  Conduct of molecular studies on archival specimens from CCA
patients where serial biopsies are available.

(3)  Development of a transplant-derived cell line of CCA to permit
in vitro testing of steroid receptors and drug sensitivity.

(4)  Conduct of genetic studies of family members (parents, siblings,
children) of patients with DES-associated malignancy, in order to
define molecular markers of carcinogenesis.

(5)  Establishment of consensus as to reasonable guidelines for the
primary treatment of CCA patients aimed at more conservative surgical
approaches and morbidity reduction.

(6)  Studies of the emotional effects of DES exposure in survivors of
DES-associated vaginal CCA, including coping mechanisms, body image,
sexuality, and transgenerational relationships.


The Terms and Conditions of Award, below, will be included in all
awards issued as a result of this RFA.  It is critical that each
applicant include specific plans for responding to these terms.
Plans should describe how the applicant will comply with the program
staff involvement as well as how all the responsibilities of awardees
will be fulfilled.

This initiative is designed to enhance cooperation between
investigators and the NCI.  The role of the NCI will be that of the
provider of technical assistance; however, in order to assess
applicant ability to conduct research projects under the conditions
of this cooperative agreement, applicants must demonstrate their
understanding of the research process and their responsibilities as a
partner in the cooperative agreement.  Investigators will be
responsible for selecting appropriate patient/control populations and
recruiting participants for this study.  Each applicant should
propose the study design most appropriate for this project.  This
might include a description of the characteristics of the population
to be selected.  Evidence should be presented indicating the
likelihood of recruiting study participants.  This should include
data on the likelihood of subject availability for interview.
Evidence should be presented indicating the feasibility of achieving
significant participation rates in this group.  Applicants should
discuss any factors which they believe should exclude a participant
from the study.

Applicants should discuss: (a) what data should be collected, (b)
how, when, where and by whom the data are to be collected, (c) the
numbers of study subjects to be enrolled, (d) data management
procedures, (e) the procedures for assuring timeliness, completeness
and accuracy of the data, and (f) plans for data analyses.

Under the Cooperative Agreement, a partnership will exist between the
recipient of the award and the NCI.  The role of the NCI will be to
provide technical assistance to the awardees.  The following Terms
and Conditions pertaining to the scope and nature of the interaction
between the NCI and the investigators will be incorporated in the
Notice of Award.  The Terms and Conditions described in this section
are in addition to, and not in lieu of, otherwise applicable OMB
administrative guidelines; HHS grant administration regulations at 45
CFR 74 and 92, and 42 CFR 52; other, HHS, PHS, and NIH grant
administration policy statements and other NCI administrative terms
of award.

Terms and Conditions of Award

Nature of Participation of NCI Staff

The NCI Program Coordinator will be the Chief, Extramural Programs
Branch, EBP, DCE, NCI, or Assignee.

The NCI Program Coordinator or Assignee will:

o  Participate in the Steering Committee that oversees study conduct;

o  Assist in the development of the protocol, which specifies the
methods of research to be followed;

o  Serve as liaison, helping to coordinate activities among the

o  Assist in the preparation of questionnaires, medical record
abstracts, and other data recording forms;

o  Assist in the monitoring of field data collection, helping to
ensure standardization in methods across study centers;

o  Assist in the analysis of the pooled data;

o  Assist in the interpretation and reporting of the collected

o  Monitor study progress.  This may include periodic site visits for
discussions with awardee research teams, observation of field data
collection and management techniques, fiscal review, and other
matters.  Decisions for continued funding will be based on overall
study progress, as well as sufficient patient and/or data accrual,
cooperation in carrying out the research (e.g., attendance at
Steering Committee meetings, implementation of group decisions,
compliance with reporting requirements), and maintenance of a high
quality of research, which will allow pooling of data and comparisons
across Cooperative Agreements for common data elements. The inability
of a cooperative agreement recipient to meet the performance
requirements, or significant changes in the level of performance, may
result in an adjustment of funding, withholding of support,
suspension or termination of the award;

o  Assist by providing advice in the management and technical
performance of the investigation;

o  In conjunction with grants management, provide advice on
administrative issues, including funding.

The project will be viewed as a partnership between the NCI and the
several participating institutions, with the goal of gaining
understanding of this cancer problem.

Nature of Participation of Cooperative Agreement Recipients

The recipients of Cooperative Agreement awards will cooperate with
each other and the NCI in the conduct of this research.  Each awardee

o  Designate the Principal Investigator or assignee to participate in
the Steering Committee to oversee conduct of this study.  This
committee will meet periodically during the course of the study.  The
first meeting will be called by the NCI Program Coordinator shortly
after award of the agreements.  Subsequent meetings will be planned
and scheduled at this meeting;

o  Cooperate in the development of a common study protocol and study
documents.  The study documents may include questionnaires, medical
record abstract forms and field procedures manuals.  Each awardee
will need to implement and comply with the study protocol, but
additional elements could be appended by individual institutions to
address issues of unique interest or capabilities in each center;

o  Establish and maintain quality control in all data and materials
collection and management procedures.  Strategies for the analyses of
the pooled data will be developed jointly by the awardees and NCI;

o  Submit progress reports every year to the NCI Program Coordinator,
and periodic supplementary reports if requested;

o  Cooperate in the reporting of the study findings.  Collaborative
publications among awardees and the NCI are anticipated, with plans
for joint publication of pooled data to be developed by the Steering
Committee prior to the end of year 2 of the award.

Terms of Cooperation

A Steering Committee will be the main oversight body of the study and
will be composed of the Principal Investigators or assignees from the
awardee institutions and the NCI Program Coordinator or assignee.
The Committee likely will meet approximately twice yearly.
Accordingly, respondents must request sufficient funds within the
submitted budgets to accommodate expenses for one to two participants
at these meetings.  Major scientific decisions regarding the core
data will be determined by the Steering Committee.  All investigators
selected will need to be able and willing to implement the core data
collection method and strategy collaboratively decided upon by the
Steering Committee.  Additionally, the investigators must be able to
implement the strategy specifically designed for their study
population.  An organizational meeting of the Steering Committee will
be convened early after award by the NCI Program Coordinator.  A
Chairperson, other than the NCI representative, will be selected by a
vote of the members.  Research results will be disseminated by means
of peer-reviewed publications that will be planned and prepared by
award recipients, with assistance as needed from NCI program staff.

In the event of a major scientific/programmatic disagreement between
the NCI and the awardees that cannot be resolved by appropriate
negotiations, an ad hoc arbitration panel will be assembled to
consist of one awardee nominee, one NCI nominee, and a third member
with appropriate expertise chosen by the other two.  This NCI
arbitration process in no way affects the awardees' right to appeal
an adverse determination under the terms of 42 CFR Part 50, Subpart
D, and 45 CFR Part 16.

The NCI will have rights of access to the data under this cooperative
agreement.  The awardees will retain custody and primary rights to
the data consistent with current HHS, PHS and NIH policies.



NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
women in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale must be provided.  NIH policy does not allow
funding such applications unless the justification is compelling.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale
for its choice.  In addition, gender and racial/ethnic issues should
be addressed in developing a research design and sample size
appropriate for the scientific objectives of the study.  This
information should be included in the form PHS 398 (rev. 9/91) in
Sections 1-4 of the Research Plan AND summarized in Section 5, Human
Subjects.  Applicants are urged to assess carefully the feasibility
of including the broadest possible representation of minority groups.
However, NIH recognize that it may not be feasible or appropriate in
all research projects to include representation of the full array of
United States racial/ethnic minority populations (i.e., Native
Americans (including American Indians and Alaskan Natives),
Asian/Pacific Islanders, Blacks, Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.
However, if an applicant proposes that there is justification for
conducting a study where there will be limited minority participation
or inclusion of only one racial/ethnic group, a strong scientific
rationale or other well-supported justification must be provided.
The IRG/TEG will be instructed to evaluate the merit of such
justifications.  Appropriate justification will not adversely affect
the assigned score.  The ADAMHA/NIH will not fund/award such
applications unless the justification is compelling.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these


Prospective applicants are requested to submit, by March 31, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name and address of the Principal Investigator, the
names of other key personnel, the participating institutions, and the
number and title of the RFA in response to which the application may
be submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains is helpful in planning for the review of
applications.  It allows NCI staff to estimate the potential review
workload and avoid conflict of interest in the review.  The letter of
intent is to be sent to:

Dr. Kumiko Iwamoto
Division of Cancer Etiology
National Cancer Institute
Executive Plaza North, Suite 535
Bethesda, MD  20892
Telephone:  (301) 496-9600
FAX:  (301) 496-9146


Applicants are encouraged to submit and describe their own ideas on
how to best meet the goals of this announcement.  Advantages and
disadvantages of the proposed approaches should be discussed, and the
plans for establishing collaborations should be described.
Applications are to be submitted on form PHS 398 (rev. 9/91),
available at most institutional offices of sponsored research and
from the Office of Grants Inquiries, Division of Research Grants,
National Institutes of Health, Westwood Building, Room 449, Bethesda,
MD 20892, telephone 301/496-7441.  The format and instructions
applicable to research grant applications must be followed.

The RFA label available in the application form PHS 398 must be
affixed to the bottom of the face page.  Failure to use this label
could result in delayed processing of the application such that it
may not reach the review committee in time for review.  In addition,
the number and title of the RFA must be typed on line 2a of the face
page of the application and YES must be checked.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, exact photocopies in one package to
the Division of Research Grants at the address below.  The
photocopies must be clear and single sided.

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, send two additional copies of the
application to:

Ms. Toby Friedberg, Referral Officer
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 650
6130 Executive Boulevard
Rockville, MD  20892

Applications must be received by May 5, 1993.  If an application is
received after that date, it will be returned without review.  If the
application submitted in response to this RFA is substantially
similar to a research grant application already submitted to the NIH
for review, but has not yet been reviewed, the applicant will be
asked to withdraw either the pending application or the new one.
Simultaneous submission of identical applications will not be
allowed, nor will essentially identical applications be reviewed by
different review committees.  Therefore, an application cannot be
submitted in response to this RFA that is essentially identical to
one that has already been reviewed.  This does not preclude the
submission of substantial revisions of applications already reviewed,
but such applications must include an introduction addressing the
previous critique.


Upon receipt, applications will be reviewed by the Division of
Research Grants (DRG) for completeness.  Incomplete applications will
be returned to the applicant without further consideration.
Evaluation for responsiveness to the program requirements and
criteria stated in the RFA is an NCI program staff function.
Applications which are judged non-responsive will be returned by the
NCI, but may be submitted as investigator-initiated regular research
grants at the next receipt date.  Questions concerning the
responsiveness of proposed research to the RFA should be directed to
program staff.

Those applications judged by the NCI to be responsive will be
evaluated according to the review criteria stated below for
scientific and technical merit by an appropriate peer review group
convened by the Division of Extramural Activities, NCI.  The second
level of review by the National Cancer Advisory Board considers the
special needs of the Institute and the priorities of the National
Cancer Program.

Applications should be responsive to the stated purpose and
objectives of the RFA.  Criteria for review of applications are as

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications, research experience, and time availability of the
Principal Investigator and staff, particularly, but not exclusively,
in the area of the proposed research;

o  availability of and access to a suitable patient population;

o  availability of resources necessary to perform the research;

o  ability to carry out common protocol;

o  willingness to work cooperatively with other awardees and NCI

o  adequacy of enrolled numbers of study subjects;

o  adequacy of proposed data to be collected and procedures for data
handling, managing, and preparing for analyses.

The review group will also examine the proposed budget and will
recommend an appropriate budget and period of support for each
recommended application.


The earliest anticipated date of award is September 30, 1993.
Applications will compete for available funds with all other
recommended applications. The following will be considered for making
funding decisions:

o  quality of the proposed project as determined by peer review;

o  availability of funds;

o  program balance among research areas.


Written and telephone inquiries concerning the RFA and the
opportunity to clarify any issues or questions from potential
applicants are welcome.

Direct inquiries regarding programmatic issues to:

Kumiko Iwamoto, M.D. or
G. Iris Obrams, M.D., Ph.D.
Extramural Programs Branch
National Cancer Institute
Executive Plaza North, Suite 535
Rockville, MD  20892
Telephone:  (301) 496-9600

Direct inquiries regarding fiscal matters to:

Ms. Kelli Newball
Grants Management Specialist
National Cancer Institute
6120 Executive Boulevard
Executive Plaza South, Suite 243
Rockville, MD  20892
Telephone:  (301) 496-7800, ext. 61


This program is described in the Catalog of Federal Domestic
Assistance No. 93.393, Cancer Cause and Prevention Research.  Awards
are made under authorization of the Public Health Service Act, Title
IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42
USC 241 and 285) and administered under PHS grants policies and
Federal Regulations 42 CFR Part 52 and 45 CFR Part 74.  This program
is not subject to the intergovernmental review requirements of
Executive Order 12372 or Health Systems Agency review.


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