Full Text CA-92-02


NIH GUIDE, Vol. 21, No. 8, February 28, 1992

RFA:  CA-92-02

P.T. 34

  Diagnosis, Medical 
  Medical/Diagnostic Imaging 

National Cancer Institute

Letter of Intent Receipt Date:  March 24, 1992
Application Receipt Date:  May 26, 1992


The Radiation Research Program (RRP), Division of Cancer Treatment
(DCT) of the National Cancer Institute (NCI), invites applications for
cooperative agreements to establish a multi-institutional scientific
group to optimize staging and follow up of pediatric solid tumors and
ovarian cancer.


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,
Radiologic Diagnostic Oncology Group IV: Ovarian Cancer and Pediatric
Solid Tumors, 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 "Healthy People 2000" (Summary Report:
Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone


Non-profit and for-profit organizations and institutions, governments
and their agencies, and foreign and domestic institutions are eligible
to apply.  Applications from minority individuals and women are
encouraged.  In order to participate in this program, applicant
institutions must demonstrate, or meet the
following requirements:

A. Requirements for Participating Institutions

1. A commitment to participate in multi-institutional protocols and
documentation of the facilities and professional personnel available to
conduct cooperative imaging trials.  This includes assignment of
appropriate specialists required by each protocol including, but not
limited to, radiologists, surgeons and pathologists, in order to ensure
complete patient evaluation.

2. Individual applicant institutions must demonstrate the availability
of state-of-the-art instrumentation and the capacity to perform various
procedures.  Specifically, this RFA solicits applications that compare
various imaging techniques for the detection of ovarian cancer and
pediatric solid tumors.  Each member institution is not expected to
participate in protocols in both pediatric solid tumors and ovarian
cancer, but a given institution must possess equipment suitable for the
developed protocol.  In order to be qualified for these protocols,
applicant institutions must have the instruments, facilities, and
capabilities for performing the specified studies outlined below.

a. The Ultrasound scanner should be 5 megahertz or larger.

b. The magnetic resonance (MR) scanner field uniformity must be
assured.  Applicants must provide documentation, using data from
phantoms or patients, of the signal-to-noise ratio, the contrast
resolution, the spatial resolution, field uniformity and other
pertinent information about the whole body MR scanners and surface
coils (when applicable) intended to be used in this study.  The study
section will review and evaluate the technical quality of MR images in
every application.

c. The computer tomography (CT) scanners must be third or fourth
generation high resolution units.

d. Applicant institutions must be able to correlate imaging data with
pathology and CT-directed biopsies as designed by the protocol.

3. The presence of expertise for review and evaluation of the quality
of images and the existing procedures for quality control of imaging
equipment, imaging technique, and image interpretation must be

4. The availability of qualified support personnel to ensure timely and
accurate data retrieval and reporting is necessary.

5. The availability of sufficient expertise and the potential for
adequate patient accrual must be demonstrated by the grantee
institutions.  Applicants must show the ability to organize, conduct,
and monitor clinical trials in radiology.

6. The organizational plan must be presented for personnel and
facilities capable of performing and supporting the administrative
functions of a cooperative group member conducting imaging trials in

B. Eligibility requirements for the Headquarters

1. Expertise in the design and coordination of multi-institutional
cooperative clinical trials including interactions with participating

2. Capability to provide educational workshops and ongoing training for
group participants in order to ensure the development of scientifically
valid results in the most efficient manner.

3. Capacity to develop and implement an administrative and management
structure for the RDOG IV including criteria for membership, an
Executive Committee, a Quality Assurance Committee, a Protocol and a
Research Strategy Committee that will assume responsibility for
randomized studies and set the priorities for protocol development.

4. Capacity for monitoring performance of studies and producing timely
reports on the quality of data for relevant diagnostic imaging
modalities including, but not limited to, image interpretation and
related information, sensitivity and specificity of imaging modalities.

5. Expertise in the development of experimental design for
statistically valid multi-institutional imaging trials.

6. Availability of facilities and professional personnel with expertise
in data management and analysis and the ability to participate in
cooperative clinical trials to provide centralized statistical


Support of this program will be through the cooperative agreement
(UO1), an assistance mechanism in which substantial NCI programmatic
involvement with the recipient during performance of the planned
activity is anticipated.  The nature of NCI staff involvement is
described in the Section "Terms of Cooperation."  Applicants will be
responsible for the planning, direction, and execution of the proposed
project.  Except as otherwise stated in this RFA, 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.

This RFA is a one-time solicitation.  Future unsolicited competitive
continuation applications will compete as research project applications
with all other investigator-initiated applications and be reviewed by
the Division of Research Grants (DRG).  If the NCI determine 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 according to the procedures described


Approximately $800,000 in total costs per year for three years will be
committed to fund applications that are submitted in response to this
RFA.  It is anticipated that six to eight  institutions plus the
Headquarters component will be funded to establish the RDOG IV.  This
funding level is dependent on the receipt of a sufficient number of
applications of high scientific merit.  The total project period for
applications submitted in response to the present RFA may not exceed
three years.



The Radiologic Diagnostic Oncology Group (RDOG) was formed in September
1987, in response to an RFA.  The RDOG objective is timely evaluation
of current and emerging imaging modalities in the management of
patients with cancer.  The development of multi-institutional clinical
trial groups allows rapid patient accrual within a short period of
time.  This in turn assures rapid evaluation and optimization of
imaging techniques for diagnosis, staging, and serial monitoring of

Since the time of its establishment, RDOG clinical research has been
important for the development of optimal imaging algorithms for
prostate and lung cancer (RDOG I) and pancreatic and colon cancer (RDOG
II).  Four protocols are currently underway in ten academic centers in
this country.  Recently, an RFA (RDOG III) was issued to study
musculoskeletal and head and neck tumor imaging, and seven new
institutions have been funded.  The results of each RDOG study should
have a direct and immediate impact on patient care.  Additionally,
considerable health care cost saving is expected due to elimination of
unnecessary diagnostic studies.

The RDOG has had a significant impact on clinical research in
Radiology.  This is the first time that multi-institutional clinical
trials in diagnostic imaging have been conducted in a centrally
coordinated fashion with strict quality control and analysis of
cost-effectiveness.  Ultimately, RDOG study findings would be useful
for the design of therapeutic protocols and formulation of clinical and
medical insurance reimbursement policy.  Moreover, the proposed
clinical trials may stimulate spin-off projects addressing a number of
questions that are not within the scope of the RDOG cooperative
agreement. Indeed, potential research projects may involve detailed
studies of MR tissue characterization, prognostic factors, and many
other important areas in clinical radiology research.

The specific focus of this solicitation is to expand the RDOG in order
to include pediatric solid tumors and ovarian cancer, which have been
recently identified as high priority research areas in clinical

Ovarian Cancer

Ovarian cancer is the leading cause of death among gynecologic
malignancies in the United States (1). Significant improvement in
patient survival requires optimization of diagnostic strategy for
ovarian cancer detection and staging combined with more effective
treatment regimens.

The need for accurate staging of ovarian cancer for treatment planning
is apparent.  Non-radiologic methods for ovarian cancer diagnosis
include pelvic examination and serum marker measurements.  Pelvic
examination, which has often been relied upon, is insensitive for small
tumors (2).  Although ovarian tumor markers, such as CA 125 antigen
detected in about 80 percent of non-mucinous epithelial ovarian
carcinomas, appear helpful as indicators of disease recurrence and
progression, their diagnostic value has been limited (3). Indeed,
targeting monoclonal antibodies to cell markers for ovarian cancer
diagnosis has been problematic due to heterogeneous tumor antigen
expression (4).

While non-invasive radiologic procedures, such as ultrasound, x-ray
computed tomography (CT) and MR imaging (MRI), have emerged as
potentially important diagnostic tools, their role in staging of
ovarian cancer has not been defined as yet.  Intravaginal ultrasound
has been reported to be useful for ovarian cancer screening by a number
of investigators (5,6,7,8).  However, one of the major problems of
intravaginal ultrasound is the limited characterization of ovarian
abnormalities, and the role of this technique in staging of ovarian
cancer is unclear.  Indeed, the main ultrasonographic criterion for the
differentiation of benign from malignant ovarian lesions is the size of
detected abnormality (with size greater than 10 cm indicating
malignancy with higher degree of certainty) (6).  More recently, flow
imaging (color Doppler) has been reported to enhance ultrasonographic
identification of potentially malignant ovarian masses through the
assessment of the intraovarian vasculature (e.g., neovascularization)
and blood flow impedance (9).

The role of CT and MRI in ovarian cancer staging has been difficult to
define due to rapid technologic and methodologic advances.  Although
introduction of CT has significantly improved the preoperative
determination of disease extent in patients with ovarian cancer, some
investigators reported that tumors smaller than 1 to 1.5 cm cannot be
accurately visualized and about 40 percent of patients with negative CT
scans have been found to have disease at the time of exploratory
laparotomy (10,11).  While MRI appears helpful for detection and
characterization of pelvic diseases, its role in the evaluation of
ovarian carcinoma has not been established (12).

Patients with ovarian cancer frequently have "second look" laparotomy
for accurate determination of the disease extent due to the critical
role of this information in treatment planning.  Thus, the RDOG IV
imaging data can be readily compared to the "gold standard" of surgical
and pathologic staging information.  It is expected that RDOG IV
studies will develop an optimal imaging strategy for ovarian cancer
staging and will help to define the role of radiologic procedures with
reference to surgical intervention in tumor staging.

Pediatric Solid Tumors

Non-central nervous system (CNS) pediatric solid tumors (e.g.,
neuroblastoma, Ewing's sarcoma, rhabdomyosarcoma) represent another
high priority research area in clinical radiology. The difficulties
with formulating an optimal approach to staging and follow-up of these
tumors stem, at least in part, from the limited number of patients at
a given institution. It is expected that the multi-institutional nature
of RDOG IV studies would allow for enhanced patient accrual and
development of the optimal approach to radiologic imaging of pediatric

Neuroblastoma is the most common extracranial nonlymphomatous solid
tumor in childhood (about 10 percent of all pediatric tumors) (13).
Primary sites of neuroblastoma are abdomen, posterior mediastinum, and
pelvis.  About half of patients with neuroblastoma have metastases to
bone marrow, liver, bone, or lymph nodes at the time of diagnosis.
While children under 12 months of age have a favorable prognosis even
when advanced disease is present, prognosis and treatment outcome in
neuroblastoma in older children (>1 year of age) are dependent on
extent of disease at the time of diagnosis (14). Indeed, metastatic
disease is almost invariably fatal in older children.  Treatment
approach to neuroblastoma should optimize outcome and minimize
treatment-induced morbidity.

Patients with limited neuroblastoma usually have surgical resection.
If there is no evidence of lymph node involvement or other evidence of
residual regional disease, additional interventions are not usually
warranted.  Older children with unresectable localized tumors may
benefit from combination chemotherapy, delayed surgical resection, and
radiation therapy.  Thus, accurate staging of neuroblastoma is
important for management of these patients.  It is expected that RDOG
IV studies will develop the optimal imaging approach to determine the
location and extent of the primary and metastatic neuroblastoma.

Among other non-CNS pediatric solid tumors, Ewing's sarcoma and
rhabdomyosarcoma have been identified as childhood malignancies
requiring further studies for the development of optimal imaging

Rhabdomyosarcoma accounts for about 5-10 percent of all pediatric solid
tumors (13), with the primary sites of lesions as varied as head and
neck (38 percent), genitourinary tract (21 percent), extremities (18
percent), trunk (7 percent) and retroperitoneum (7 percent).  The
extent of rhabdomyosarcoma at diagnosis is an important factor for
treatment planning.  Indeed, the role of surgery varies with the
primary site, size, and extent of the disease at presentation.  In
early stages of the disease, if patients are rendered disease-free by
surgery, radiation therapy is not required, while adjuvant chemotherapy
improves survival. In more advanced disease, radiation therapy is
usually necessary for local and regional control, and radiation fields
depend on the local disease extent and regional lymph node involvement.
The utility of systemic chemotherapy in patients treated with radiation
depends on the residual disease.  The relapse-free survival rates are
63-72 percent for patients with microscopic residual disease, 54-61
percent for patients with gross residual disease, and only 17-23
percent in patients with disseminated disease.  Thus, accurate staging
of the disease extent is critical for treatment planning and prognosis
in children with rhabdomyosarcoma.

Ewing's sarcoma is the second most common primary bone tumor of
childhood.  The characteristic feature of this tumor is the relatively
high incidence of metastatic disease (14-50 percent) at the time of
diagnosis.  While surgical procedure alone results in less than 10
percent long-term survival rates, systemic adjuvant chemotherapy for
preventing distant failure and radiation therapy for local control
increase long-term survival rates.  The choice between radiation
treatment and surgical intervention for a primary lesion are guided by
two major clinical end-points of therapy, tumor control and
preservation of function.  However, local control with primary
radiation and chemotherapy appears to depend on tumor size.  While
radiation therapy is a primary mode of treatment for most local
lesions, a very careful definition of irradiation fields is required in
order to maintain function. Thus, the accurate determination of the
local tumor extent on initial and follow-up radiologic images is
essential for management of Ewing's sarcoma.

It is expected that RDOG IV studies will evaluate relative accuracy of
radiologic modalities, such as CT, MRI, and other techniques, in the
determination of local and regional disease extent, and define the most
effective approach to diagnosis of metastatic spread in children with
neuroblastoma, rhabdomyosarcoma, and Ewing's sarcoma.


The major thrust of this RFA is to develop the optimal imaging strategy
for ovarian cancer and non-CNS pediatric solid tumors and to assess the
impact of improved diagnosis on patient management and health care
costs.  It is expected that the following goals will be achieved:

(1) Improved staging of ovarian cancer and pediatric solid tumors

(2) Definition of the general role, indications, comparative accuracy,
and proper sequence and timing of imaging procedures

(3) Comparison of the role of radiologic procedures as compared to
surgical exploration in the evaluation of disease extent

(4) The impact of optimized imaging on treatment decisions, local
disease control, and patient survival


Terms of Cooperation

A. Nature of Participation by NCI Staff

All RRP staff assistance, advice and support, as described throughout
these Terms of Cooperation, will be communicated to awardees by the
Associate Director, RRP (ADRRP), or designee.  In all cases, the role
of the NCI is to assist and facilitate but not to direct research

1. RRP as a Scientific Resource for NCI-supported Clinical

The ADRRP, or designee, will serve as a resource available to awardees
for specific scientific information with respect to clinical trial
design.  The staff will assist the RDOG IV institutions as appropriate
in developing information concerning the scientific basis for specific
research protocols and also will be responsible for advising the group
of the nature and results of relevant studies being carried out
nationally or internationally.  The ADRRP, or designee will participate
in planning and strategy meetings, when indicated, of the RDOG IV
institutions.  At these meetings, RDOG IV institutions, assisted by the
ADRRP, or designee, will review relevant information and establish and
prioritize the outstanding research questions.

2. RRP Assistance in Protocol Development

The protocol must be a study document mutually acceptable to the RDOG
IV and to the ADRRP.  Communication at the various stages of protocol
development is encouraged.  The ADRRP, or designee, will be available
to assist the group in developing a mutually acceptable protocol,
consistent with the research interests, abilities, and strategic plans
of the group and of the NCI.  The ADRRP will assist the RDOG IV
institutions in protocol design as may be appropriate by providing
information regarding:  (a) the existence and nature of concurrent
clinical trials in the area of RDOG IV research, pointing out possible
duplication of effort, and (b) relevant data concerning imaging
research.  The ADRRP, or designee, will also comment on the scientific
rationale and value of the proposed study, the design, the statistical
requirements, and the implementation of the study, if indicated.

All protocols for submission to NCI must be preceded by a letter from
the RDOG IV Chairperson to the ADRRP describing the hypothesis
investigated, the general design of the contemplated trial, and
relevant information on accrual capabilities to document feasibility.
The ADRRP will then formally review and provide a program response to
these concepts, commenting on study originality and programmatic
interest.  This preliminary review will expedite protocol development
and implementation and facilitate agreement on study priority and

3. RRP Review of Proposed Protocols

All the RDOG IV scientific protocols will be reviewed by the ADRRP.  Ad
hoc reviewers, external to the NCI, will be utilized whenever the need
for a specific additional expertise is  identified by the ADRRP.  For
all protocols, the ADRRP, or designee, will provide the RDOG IV
Chairperson with a written consensus review that describes recommended
modifications and other suggestions as appropriate.

The major considerations relevant to protocol review by the NCI
include:  (a) the strength of the scientific rationale supporting the
study, (b) the medical importance of the question being posed, (c) the
avoidance of undesirable duplication with other ongoing studies, (d)
the appropriateness of study design, (e) a satisfactory projected
accrual rate and follow-up period, (f) patient safety, (g) compliance
with federal regulatory requirements, (h) adequacy of data management,
(i) appropriateness of patient selection and follow-up, evaluation, and
assessment of complications/toxicity.

If a proposed protocol is disapproved by the NCI, the specific reasons
for lack of approval will be communicated by the ADRRP to the RDOG IV
Chairperson as a consensus review within 45 days of receipt of the
proposed protocol.

Disagreements arising pursuant to protocol disapproval may be submitted
to an arbitration panel.  An arbitration panel composed of one RDOG IV
nominee, one ADRRP nominee, and a third member with clinical trials
expertise chosen by the other two will be formed to review the NCI
decision and recommend an appropriate course of action to the ADRRP.
These special arbitration procedures in no way affect the awardee's
right to appeal an adverse determination in accordance with PHS
regulations at 42 CFR Part 50, subpart D, and HHS regulations at 45 CFR
Part 16.

The RDOG IV will not expend NCI funds to conduct any study not approved
by the NCI unless the disapproval has been modified by the arbitration
process outlined above.

4. RRP Study Monitoring

The ADRRP, or designee, will review RDOG IV mechanisms for study
monitoring (see section Responsibilities of Awardees, RDOG IV

5. RRP Review of Data Management and Analysis

The ADRRP, or designee, will review RDOG IV mechanisms established by
the RDOG IV Headquarters for data management and analysis (see section
Responsibilities of Awardees, RDOG IV Headquarters).  The ADRRP, or
designee, when deemed appropriate, will make recommendations to the
RDOG IV Group Chairperson for assuring that data collection and
management procedures are adequate for quality control and analysis and
sufficiently uniform across the RDOG IV participating institutions.
Any disagreements between NCI and RDOG IV members relating to data
management and analysis that cannot be resolved by bilateral
discussions will be submitted to the same arbitration process
previously outlined.

6. Access to Data

The NCI will have access to all data generated under this cooperative
agreement and may periodically review the data. Data must also be
available for external monitoring as required by agreement between the
NCI and the FDA relative to the responsibility of the NCI as a study
sponsor.  The awardee will retain custody and primary rights to the
data consistent with current HHS, PHS, and NIH policies.

7. RRP Involvement in Protocol Closure

The ADRRP, or designee, will review RDOG IV mechanisms for interim
monitoring of results and will monitor protocol progress.  The ADRRP
may request that a protocol study be closed to accrual for reasons
including:  (a) insufficient accrual rate; (b) achievement of the
original accrual goal; (c) poor protocol performance; (d) patient
safety; (e) conclusive study results; and (f) emergence of new
information that diminishes the scientific importance of the study.
The NCI will not permit expenditures of NCI funds for a study after
requesting closure (except for patients already on-study).  For any
study closure, NCI will establish an arbitration process for
institutions that wish to appeal protocol closure.  This process will
be identical to that described above for protocol disapproval.

If the RDOG IV wishes to close accrual to a study prior to meeting the
initially established accrual goal, the RDOG IV Chairperson must submit
the interim results and written justification to NCI staff for review
and approval. Unresolved disagreements between NCI staff and the RDOG
IV institutions regarding the appropriateness of early study closure
will be arbitrated by the process outlined above.

8. RRP Involvement in Investigational Device and Agent Management

a. If applicable, RRP staff will advise the RDOG IV institutions of
specific requirements and changes in requirements concerning
investigational device and/or agent management that the FDA may
mandate. Investigators performing trials under RDOG IV cooperative
agreements will be expected, with RRP assistance, to comply with all
FDA monitoring and reporting requirements for investigational devices,
if applicable.

b. Investigators performing NCI funded clinical trials will be advised
by NCI staff of potential studies that will be relevant to new avenues
of cancer diagnosis.  When this involves an investigational device
and/or agent, the clinical information must be acceptable to the FDA.
With ADRRP assistance, the RDOG IV institutions will develop protocols
to obtain such information needed, if applicable, for the projects.

9. RRP Review of Procedures for Compliance with Federally Mandated

RRP staff will review procedures established by the RDOG IV
Headquarters for monitoring of compliance and assurance to meet FDA
regulatory requirements for studies involving investigational
devices/agents, if applicable, and Office for Protection from Research
Risks (OPRR) requirements for the protection of human subjects by all
RDOG IV institutions (see section Responsibilities of Awardees, RDOG IV

10. RRP Review of Progress

Performance of each RDOG IV member and affiliate will be reviewed
annually by the ADRRP, or designee, on the basis of the information
provided at the progress review meetings, annual and semi-annual
reports.  Each RDOG IV institution must submit an annual progress
report.  Annual and semi-annual reports submitted to the NCI shall
contain highlights of progress made during that period and will
include, at a minimum, summary data on protocol performance by each
RDOG IV member and affiliate and other relevant data.  In addition,
periodic accrual information may be requested by the NCI for all active
studies whenever deemed appropriate.  A system for providing such
information in a timely manner must be in place.

Support recommended for the remainder of the project will be contingent
upon favorable review by the ADRRP, or designee, of the progress of the
project and sufficient patient accrual.  Insufficient patient accrual,
or noncompliance with the terms of award, including these Terms of
Cooperation, may result in a reduction of budget, withholding of
support, or termination of the award.

B. Responsibilities of Awardees

It is the responsibility of the awardee to develop the details of the
research design including definition of objectives and approaches,
planning, implementation, analysis, and publication of results,
interpretations and conclusions of studies.  The awardee, with ADRRP or
designee assistance, shall develop RDOG IV research goals, develop
protocols for clinical cancer research in accord with the awardee's
research interests, abilities and goals, and submit to the NCI for
review and approval prior to implementation.

1. RDOG IV Headquarters

The Principal Investigator of the Headquarters institution will serve
as the RDOG IV Chairperson.  The RDOG IV Headquarters, under the
leadership of the RDOG IV Chairperson, will be responsible for the
coordination of protocol development, quality control and study
monitoring, data management and analysis, adherence to requirements
regarding investigational device management (when applicable) and
federally mandated regulations, protocol and performance reporting, and
recommendations for resource adjustments.  All the scientific and
administrative decisions related to the RDOG IV-funded activities and
made by the RDOG IV institutions or affiliates will be communicated to
the ADRRP or designee by the RDOG IV Chairperson.  The RDOG IV
Chairperson will communicate the results of the NCI protocol reviews to
the RDOG IV institutions.

a. Study Monitoring

The RDOG IV Headquarters, under the leadership of the RDOG IV
Chairperson, is responsible for establishing a mechanism for study
monitoring to assure accurate and timely knowledge of the progress of
each study through:

o tracking and reporting of patient accrual and adherence to defined
accrual goals;

o ongoing assessment of case eligibility and evaluability;

o  timely review and assessment of patient data;

o  if applicable, rapid reporting of procedure-related morbidity and
measures to ensure communication of this information to all parties;

o  if applicable, interim evaluation and consideration of measures of
outcome, as consistent with patient safety and good clinical trials

o  timely communication of results of studies; and

o  a method of providing, upon NCI request, summary of the imaging
methodology sensitivity/specificity and, when appropriate, morbidity

b. Data Management and Analysis

The RDOG IV Headquarters, under the leadership of the RDOG IV
Chairperson, will develop procedures to ensure that data collection and
management are:  (a) adequate for quality control and analysis; (b) as
simple as appropriate in order to encourage maximum participation of
physicians entering patients and to avoid unnecessary expense; and (c)
standardized among the RDOG IV participating institutions. Any
disagreements between RRP and RDOG IV members relating to data
management and analysis that cannot be resolved by bilateral
discussions will be submitted to the same arbitration process
previously outlined.

c. RDOG IV Compliance with Federally Mandated Regulations

The RDOG IV Headquarters, under the leadership of the RDOG IV
Chairperson, is responsible for establishing procedures for all RDOG IV
institutions to comply with DHHS and FDA regulatory requirements for
studies involving investigational devices/agents, if applicable, and
the OPRR requirements for the protection of human subjects.  These
procedures include:

o methods for assuring that each protocol is reviewed by the
responsible Institutional Review Board (IRB) prior to patient entry,
and that each protocol is reviewed at least annually by the IRB while
the protocol is active in accordance with 45 CFR 46, Protection of
Human Subjects.

o if applicable, a system for assuring timely reporting of all serious
and unexpected complications to the ADRRP, or designee.

d. Progress Review

The RDOG IV Headquarters, under the leadership of the RDOG IV
Chairperson, will have a mechanism in place for assessing performance
of its members, with particular attention to accrual of an adequate
number of eligible patients onto group trials, timely submission of
required data, conscientious observance of protocol requirements,
authorship, and participation in group leadership.  This mechanism will
include a procedure for the RDOG IV Chairperson to recommend to the NCI
an adjustment of funds within the group as appropriate for the level of
participation in group activities including, but not limited to,
accrual. Financial adjustments may be made by NCI at the time a non-
competing continuation [Type 5] award is negotiated.  The RDOG IV
Chairperson, Principal Investigator from each RDOG IV institution and
the ADRRP, or designee, shall meet twice a year to review RDOG IV
progress, establish priorities, and plan future activities.  The
frequency of such meetings may be increased if it is deemed necessary.

2. Membership in RDOG IV

NCI funding is contingent upon the institution remaining a member of
the RDOG IV.

3. Planning Procedures

It is anticipated that decisions on all RDOG IV activities will be
reached by consensus of the group under the leadership of the RDOG IV
Chairperson who will be responsible for communication with the ADRRP or

4. Attendance Requirements

It is required that a Principal Investigator, or designee, from all
RDOG IV members participate at all meetings and workshops relevant to
their protocol(s).

5. Protocol Development

All RDOG IV institutions are expected to participate in the development
of new and revised protocols under the leadership of the RDOG IV
Chairperson.  The RDOG IV Chairperson will submit such protocols in a
timely fashion for review and approval by NCI.

6. Conduct of Research and Patient Accrual

Awardees are expected to conduct pertinent clinical imaging studies
consistent with approved applications and post-award procedures.
Awardees also are expected to provide timely results from sufficient
numbers of patients.  All new and revised protocols must be submitted
by the RDOG IV investigators to the appropriate IRB within 30 days of
the date of the written approval from the RDOG IV Chairperson.
patients may not be entered into new or revised protocols until the
protocol has been reviewed and approved by the IRB in accordance with
45 CFR 46, Protection of Human Subjects.

7. Progress Review

The RDOG IV Chairperson, the Principal Investigator from each RDOG IV
institution and the ADRRP, or designee, shall meet twice a year to
review RDOG IV progress, establish priorities, and plan future
activities.  The frequency of such meetings may be increased if it is
deemed necessary.

8. Reporting Requirements

Reporting requirements will be in agreement with NCI procedures.
Annual progress reports will be submitted to the NCI and will include
at a minimum summary data on protocol performance by each awardee.
Interim reports of each activated and ongoing study shall appear in the
minutes of each RDOG IV meeting and shall include specific data on
patient accrual and, whenever appropriate, detailed reports of
device/agent-associated morbidity.  In addition, semi-annual accrual
information may be requested by the ADRRP, or designee, for all active
studies.  A system for providing such information in a timely manner
must be in place.

In addition to the annual progress report and detailed final report
currently required by research project grants and cooperative
agreements, awardees shall provide a semi-annual interim report six
months after the start date of each budget period.  The report shall
contain highlights of progress made during that period and will include
at a minimum summary data on protocol performance by each RDOG IV
member and other relevant data.

9. Publication of Data

Timely publication of major findings is encouraged. Publication and
oral presentation of work done under this agreement will require
appropriate acknowledgement of NCI support.  The NCI will have access
to all data generated under this cooperative agreement and may
periodically review the data.  The awardee will retain custody of and
primary rights to the data consistent with current DHHS, PHS, and NIH

C. These Terms of Cooperation are in addition to and not in lieu of
otherwise applicable OMB administrative guidelines, HHS grant
administration regulations at 45 CFR Part 74 and DHHS, PHS, and NIH
grants administration policies.



NIH and ADAMHA policy is that applicants for NIH/ADAMHA 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 must 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 should be provided.

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 must be
included in the form PHS 398 in Section 2, A-D of the Research Plan AND
summarized in Section 2, E, Human Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However, NIH
recognizes 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 or Alaskan Natives], Asian/Pacific Islanders, Blacks,

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 not but 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.

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 policies.


Prospective applicants are asked to submit, by March 24, 1992, 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 is being submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, it is requested
in order to provide an indication of the number and scope of
applications to be reviewed.

The letter of intent is to be sent to:

Dr.  Faina Shtern
Chief, Diagnostic Imaging Research Branch
Radiation Research Program
National Cancer Institute
Executive Plaza North, Suite 800
Bethesda, MD  20892
Telephone:  (301) 496-9531


The research grant application form PHS 398 (revised 9/91) is to be
used in applying for cooperative agreements.  These forms are available
at most institutional business offices and from the Office of Grants
Inquiries, Division of Research Grants, National Institutes of Health,
Room 449, Westwood Building, 5333 Westbard Avenue, Bethesda, MD 20892,
telephone (301) 496-7441, and from the NCI program director named

The application must include a sample protocol for ovarian cancer
and/or pediatric solid tumor diagnosis to illustrate the ability to
perform clinical research.

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 RFA number and
title must be typed on line 2 of the face page of the application form.

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

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

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

Division of Extramural Activities
National Cancer Institute
Westwood Building, Room 838
5333 Westbard Avenue
Bethesda, MD  20892

Applications must be received by May 26, 1992.  If an application is
received after that date, it will be returned.  If the application
submitted in response to this RFA is substantially similar to a 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.

Special Instructions for Preparation of Cooperative Agreement

General instructions for the preparation of the cooperative agreement
application are contained in the grant application form PHS 398
(revised 9/91).

Because the Terms of Cooperation, discussed above, 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
must describe how the applicant will comply with the program staff
involvement and how all the Responsibilities of Awardees will be


A.  Review Procedure

Upon receipt, applications will be reviewed by the 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 that are judged non-responsive will be
returned by the NCI, but may be submitted as investigator-initiated
research grants at the next receipt date.  Questions concerning the
responsiveness of proposed research to the RFA may be directed to
program staff listed under INQUIRIES.

If the number of applications is large compared to the number of awards
to be made, the NCI may conduct a preliminary scientific peer review to
eliminate those that are clearly not competitive.  The NCI will remove
from competition those applications judged to be noncompetitive for
award and notify the applicant and institutional business official.

Those applications judged to be both competitive and responsive will be
further 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 will be by the National Cancer Advisory Board.

B.  Review Criteria

1.  Applications for the Headquarters will be reviewed on the basis of
the following criteria:

o  Scientific merit and resources, appropriateness and adequacy of the
proposed approach to experimental protocol development and
biostatistical data processing.  The proposed methodology must exhibit
scientific soundness showing how the trials will be conducted to attain
the objectives.

o  Qualifications and research experience of the Principal Investigator
and staff including, but not limited to, previous experience with
administration of multi-institutional clinical trials in imaging
science.  These should include the experience of the proposed personnel
(statisticians, programmers, and data management staff) in the design,
monitoring, analysis, and reporting of cooperative multi-center
clinical trials.

o  Feasibility and merit of the proposed structure for RDOG IV
administration and data management including, but not limited to,
interactions with the RDOG IV participating institutions.

2.  Applications for participating institutions will be reviewed on the
basis of the following criteria:

o  The overall qualifications of applicant institutions to the
requirement for membership in the collaborative group as stated in the
eligibility requirement for participants (see Eligibility

o  Adequacy of professional and support personnel.  Record or evidence
of willingness to work as a team with other group members and to
participate in group-generated and program-monitored protocols
according to their capacity.

o  Evidence of the ability to develop clinical trials in radiology.

o  Evidence of the ability of the applicant to complete imaging trials
of substantial scientific merit.  It is anticipated that different
institutions will have varying patterns of patient referral and
accession.  Applicants must show that they have the potential to
accomplish multi-center imaging trials of sound scientific quality in
a reasonable period of time.

o  Evidence of the ability to accrue an adequate number of patients.

o  Availability of appropriate facilities, equipment, instrumentation,
and other resources to ensure that each institution is capable of
performing innovative cooperative trials in cancer diagnosis.

o  Appropriateness of the proposed budget and duration in relation to
the proposed research.


The earliest feasible start date for the initial awards will  be
December 1, 1992.  In making funding decisions, the National Cancer
Advisory Board considers the special needs of the NCI and the
priorities of the National Cancer Program.  Although this program is
provided for  in the financial plans of the NCI, the award of
cooperative  agreements pursuant to this RFA is also contingent upon
the availability of funds for this purpose.


Written and telephone inquiries concerning the objectives and scope of
this RFA and inquiries about whether or not specific proposed research
would be responsive are encouraged and are to be directed to Dr. Shtern
at the address below.  Dr. Shtern welcomes the opportunity to clarify
any issues or questions from potential applicants.

Direct inquiries regarding programmatic issues to:

Dr. Faina Shtern
Chief, Diagnostic Imaging Research Branch
Radiation Research Program
National Cancer Institute
Executive Plaza North, Suite 800
Bethesda, MD  20892
Telephone:  (301) 496-9531

Direct inquiries regarding fiscal matters to:

Ms. Sara Stone
Grants Management Coordinator
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Suite 242
6120 Executive Boulevard
Rockville, MD  20852
Telephone:  (301) 496-7227, Extension 66
Facsimile:  (301) 496-8601


This program is described in the Catalog of Federal Domestic Assistance
Number 93.395, Cancer Treatment Research.  Awards are made under the
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.


(1) American Cancer Society, Massachusetts Division, Cancer Manual, 7th
Edition, 1986: 231-234

(2) American Cancer Society:  Cancer Statistics, Reprinted from Ca-A
Cancer Journal for Clinicians.  Ca 1989; 3:39

(3) Gargano G, Correale M, Abbate I, Falco G, De Frenza N, Lorusso V,
De Lena M, De Leonardis A. The role of tumor markers in ovarian cancer.
Clin.  Exp. Obst.  Gyn. Vol. 17 (1):  23-29, 1990

(4) Averette, et al. Ovarian Cancer Diagnosis, Staging and Treatment.
Cancer 65:703-708, 1990.

(5) Schoenfeld et al. Surgery in post-menopausal women-the value of
transvaginal sonography.  Surgical Endoscopy, Springer-Verlag, 1990:
pp.  108-113

(6) Rottem et al. Classification of ovarian lesions by high frequency
transvaginal ultrasonography.  J Clin Ultrasound. 18:  359-363, 1990.

(7) Higgins et al. Transvaginal sonography as a screening tool for
ovarian cancer.  Gynecologic Oncology 34, 402-406, 1989.

(8) Van Nagel et al. Transvaginal sonography as a screening method for
ovarian cancer:  a report of the first 1000 cases.  Cancer, Vol 65:
573-577, 1990.

(9) Bourne, T, Campbell S, Steer C, Whitehead MI, Collins WP.
Transvaginal colour flow imaging: a possible new screening technique
for ovarian cancer.  BMJ 299, 1989: 1367-1370

(10) Sanders RC, McNeil BJ, Finberg HJ.  A prospective study of
computed tomography and ultrasound in the detection and staging of
pelvic masses.  Radiology 1983; 146:  447-452

(11) Calkins AR, Stehman FB, Wass JL, et al.  Pitfalls in
interpretation of computed tomography prior to second-look laparotomy
in patients with ovarian cancer.  Br. J. Radiology 1987; 60:975-979

(12) Chang YC, Hricak H. Current status of MR imaging of the female
pelvis.  Crit Rev Diagn Imaging 1989; 29 (4): 337-356

(13) Simone JV, Cassady JR, Filler RM.  Cancers of childhood.  In
DeVita VT, Hellman S, Rosenberg SA (eds). Cancer:  Principles and
Practice of Oncology.  Philadelphia, JB Lippincott Co, 1982:  1254-1330

(14) American Cancer Society Cancer Manual, Massachusetts Division,
7th Edition, 1986: 336-337


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