Full Text CA-92-08
RFA:  CA-92-08
P.T. 34

  Medical/Diagnostic Imaging 

National Cancer Institute
Application Receipt Date:  May 21, 1992
Letter of Intent Receipt Date:  April 21, 1992
The Radiation Research Program (RRP), Division of Cancer Treatment
(DCT), of the National Cancer Institute (NCI), invites research grant
applications that advance current methods of imaging-based tumor
volumetric analysis for optimization of response assessment in
oncology.  The objective of this Request for Applications (RFA) is to
support meritorious research in the development of a
three-dimensional (3D) approach to serial quantitation of tumor
volume.  The proposed research is expected to improve clinical
management in oncology and to facilitate the development and
evaluation of anti-neoplastic drugs and other treatment modalities in
cancer patients.
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,
Quantitation of Tumor Response to Treatment:  A Three Dimensional
Approach, 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
Changes in tumor volume in response to anti-neoplastic treatment
constitute important criteria for the evaluation of therapeutic
efficacy in cancer patients.  Reliable quantitation of changes in
tumor volume is of great importance for detecting biologic activity
of the administered therapy in individual patients.  It has also been
pointed out that "the ability to compare results of clinical trials
depends upon consistent definitions of tumor response and the use of
reliable and reproducible methods of tumor measurements"(1).
Generally, clinical investigations in oncology depend heavily upon
two-dimensional radiologic techniques to determine tumor response to
treatment.  The major focus of this proposal is to optimize
mathematical analysis of tumor volume based on three-dimensional (3D)
radiologic images in order to enhance evaluation of therapeutic
efficacy of various treatment modalities/regimens in cancer patients
and to facilitate comparison of clinical trials.
Although the role of diagnostic imaging modalities in detection and
delineation of neoplasms has been extensively studied, a fully
adequate approach to serial evaluation of tumor response to treatment
has not been developed.  Until the present time, it has been
difficult to obtain accurate tumor measurements and volumetric
analysis of tumor response to treatment usually has been subjective
and qualitative rather than quantitative in nature.  Indeed, errors
in tumor measurements have been described among the major factors
limiting the interpretability of response rates(2).  Major
limitations in the accuracy and reliability of tumor measurements
stem from the two-dimensional nature of imaging data display
currently used for tumor volume analysis.  Tumor response to
treatment, however, is a complex three-dimensional phenomenon, and
the use of two-dimensional imaging techniques is frequently
inadequate for its full evaluation.  The Diagnostic Imaging Research
Branch (DIRB) workshop entitled "3D Data Display and Analysis for
Cancer Treatment Planning" (July, 1990) confirmed the need for
accurate tumor measurements in oncology and concluded that 3D
approach is optimal for time-series volumetric tumor analysis.
At the DIRB workshop, the state-of-the-art in 3D imaging research in
oncology was examined, and future research directions were discussed
and prioritized.  This workshop demonstrated that 3D imaging can
provide unique information for spatial tumor display and tumor
volumetric analysis, that cannot be obtained by any other means.
Further, the was consensus among the participants that there are two
closely intertwined basic scientific areas of highest priority to the
future advancement of tumor volumetric analysis:  (1) automated
segmentation, or "tumor edge definition"; and (2) multimodality image
registration (e.g. computerized tomography (CT), positron emission
tomography (PET), conventional and metabolic chemical shift magnetic
resonance imaging (MRI), immunoimaging).
Automated segmentation and multimodality image registration are
critical generic basic research topics in computer science that have
not been adequately supported by government agencies or by the
computer industry.  Indeed, there is a need to develop automated
image segmentation in contrast to currently used manual delineation
of tumor margins in order to facilitate the process of measurement
and to minimize errors.  If automated image segmentation were
developed, the process of tumor volume measurement may become a
routine part of oncologic patient evaluation, similarly to the
currently routine measurement of cardiac ejection fraction in
cardiovascular clinic.  Utilization of computer vision was identified
as one of the promising potential avenues for the advancement of
automated image segmentation.  Another research area that has been
identified as an area of major importance for the field of 3D image
analysis is multimodality image registration, the specific goal of
which is to combine high resolution anatomic information provided by
such modalities as CT and proton MRI with biologic, metabolic,
physiologic and cell marker information obtained from PET,
conventional Nuclear Medicine, immunoimaging, multinuclear MRI/MRS,
and other modalities.  It has been pointed out that scientific
advances in multimodality image registration would result in improved
diagnostic specificity as compared to a single modality approach to
tumor imaging and, consequently, it may become possible to
differentiate foci of viable tumor from (and/or within) scar,
necrosis, edema, inflammation and other processes.  Thus,
advancements in multimodality image registration are expected to
improve specificity and accuracy of tumor volumetric analysis.
The specific goal of this proposal is the development and
optimization of a quantitative analysis of tumor response to
treatment based on 3D medical imaging.  The proposed research will
stimulate the achievement of optimal tumor volumetric analysis by
means of the development of advanced approaches to two critical basic
computer science topics, automated image segmentation and
multimodality image registration, and their validation and testing.
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
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 must 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, 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 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
Support of this program will be through the National Institutes of
Health (NIH) individual research grant (R01). 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.  Generally, 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 determines that there is a sufficient continuing
program need, a request for competitive continuation applications
will be announced.
Approximately $500,000 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 three awards will be made.  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 earliest feasible start date for the initial awards
will be March 1, 1993.  Although this program is provided for in the
financial plans of the NCI, the award of grants pursuant to this RFA
is also contingent upon the availability of funds for this purpose.
Applications may be submitted by domestic and foreign for-profit and
non-profit, public and private organizations, such as universities,
colleges, hospitals, laboratories, units of State or local
governments, and eligible agencies of the Federal Government.
Applications from minority individuals and women are encouraged.
In order to participate in this program, applicant institutions must
demonstrate or meet the following requirements:
o  A commitment to participate in research devoted to the 3D approach
to tumor volumetric analysis.  This includes assignment of
appropriate specialists required by this research, including, but not
limited to, radiologists, medical, surgical and radiologic
oncologists, and pathologists, to ensure the development and
validation of tumor volumetric analysis.
o  Individual applicant institutions must demonstrate the
availability of state-of-the-art instrumentation and the capacity to
perform various imaging procedures.  To be qualified for these
protocols, applicant institutions must have the imaging and computer
equipment, facilities, and capabilities for performing the specified
1.  The ultrasound scanner should be 5 megahertz or larger.
2.  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) that are intended for use in the study.
3.  The CT scanners must be third or fourth generation high
resolution units.
4.  Applicant institutions must be able to correlate imaging data
with pathology as designed by the protocol.
o  The presence of expertise for 2D and 3D optimal image acquisition,
reconstruction, processing, display, and analysis must be
o  The availability of qualified support personnel to ensure timely
and accurate data retrieval and reporting is necessary.
Upon receipt, applications initially 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 eligibility criteria
stated in the RFA is an NCI program staff function.  Applications
will be judged to determine how well they meet the goals and
objectives of the program as described in the RFA.  Applications
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 relevance of proposed
research to the RFA may be directed to program staff as described in
the INQUIRIES section.
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 (triage) 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 by the National Cancer Advisory Board
considers the special needs of the Institute and the priorities of
the National
Cancer Program.
Applications will be reviewed on the basis of the following criteria:
o  Scientific, technical, or medical significance and originality of
the proposed research in the area of tumor volumetric analysis.
o  Appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research.
o  Qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research.
o  Evidence of the ability to conduct successful research in imaging
and computer science.
o  Evidence of the ability of the applicant to complete scientific
projects in the area of imaging and computer science of substantial
scientific merit in a reasonable period of time.
o  Availability of appropriate facilities, equipment, and
instrumentation to ensure that the institution is capable of
performing innovative research in the area of 3D image display and
The budget will not be considered as a review criterion. Based on the
actual budgetary needs for the conduct of the approved research, the
review group will recommend an appropriate budget and a period of
support for each approved application.
The research grant application form PHS 398 (rev. 10/88, reprinted
9/89) must be used in applying for these grants.  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, and from the NCI program director named below.
The application must include a sample protocol for three-dimensional
tumor volumetric analysis and its validation.
The RFA label available in the latest revision of 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 four signed, exact photocopies, in one package to
the DRG at 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
Bethesda, MD  20892
Applications must be received by May 21, 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 wither 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.
Prospective applicants are asked to submit, by April 21, 1991, 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 should be sent to:
Faina Shtern, M.D.
Chief, Diagnostic Imaging Research Branch
Radiation Research Program
National Cancer Insitute
Executive Plaza North, Suite 800
Bethesda, MD  20892
Telephone:  (301) 496-9531
FAX:  (301) 480-5785
Written and telephone inquiries concerning the objectives and scope
of this RFA and inquiries about whether or not specific proposed
research would be appropriate are encouraged and are to be directed
to Dr. Faina Shtern at the above address.  The Program Director
welcomes the opportunity to clarify any issues or questions from
potential applicants.
Direct inquiries regarding fiscal matters to:
Marian F. Focke
Grants Administration Branch
National Cancer Institute
Executive Plaza South, 242
Bethesda, MD  20892
Telephone:  (301) 496-7800, extension 46
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) Grossman SA and Burch PA.  Quantitation of tumor response to
treatment.  Seminars in Oncology, Vol. 15, No 5, 1988:  pp. 441-454.
(2) Simon RM.  Design and conduct of clinical trials, in DeVita VT,
Hellman S, Rosenberg SA (eds):  Cancer.  Philadelphia, J.B.
Lippincott, 1985, pp. 329-350.

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