Full Text CA-92-05


NIH GUIDE, Volume 21, Number 16, May 1, 1992

RFA:  CA-92-05

P.T. 34

  Urogenital System 
  Clinical Trial 

National Cancer Institute

Letter of Intent Receipt Date:  June 1, 1992
Application Receipt Date:  August 26, 1992


The Radiation Research Program (RRP), Division of Cancer Treatment
(DCT), of the National Cancer Institute (NCI) invites applications for
cooperative agreements to carry out National Collaborative Radiation
Therapy Trials:  3-D Dose Escalation Study for Prostate Cancer.  The
objectives of the present solicitation are (1) to conduct Phase I, II,
and III clinical trials to test the efficacy of using 3-D conformal
radiation therapy (3DCRT) in a dose escalation study for the treatment
of prostate cancer, and (2) to collect 3-D dose distributions and data
on radiation-induced damage to normal tissues.

The decade of the 1980s brought unprecedented advances in computer
hardware and software for the development and implementation of 3-D
techniques in radiation therapy treatment planning and treatment
delivery.  The new 3-D technology has the potential to deliver higher
radiation doses to tumor targets with no increase in normal tissue
morbidity.  The potential benefit to the cancer patient is improved
local control, fewer complications to normal tissues, and longer
survival.  A potential risk is that tight, conformal fields will
underdose occult tumor at the margins of the fields.

Multi-institutional trials are supported by the NCI for the conduct of
clinical trials to establish the efficacy of new therapies and new
approaches for the treatment of cancer.  The objective of this Request
for Applications (RFA) is to support multicenter cooperative clinical
trials carrying out a dose-escalation study in the treatment of
prostate 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,
National Collaborative Radiation Therapy Trials:  3-D Dose Escalation
Study for Prostate Cancer, 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 for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and 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.

Requirements for the Operations and Statistical Center

o  Expertise in the design and coordination of multi-disciplinary,
multi-modality cooperative clinical trials.

o  Capacity to develop and implement a structure for a Cooperative
Group, including criteria for membership, and to provide leadership to
an Executive Committee (see SPECIAL REQUIREMENTS, Section B2).  The
Executive Committee will assume responsibility for setting the
priorities for the development and coordination of protocol design and
implementation, quality control, and formulation of a research

o  Expertise in the design of guidelines for statistically valid
studies planned for multi-institutional trials.

o  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

o  Demonstrated capabilities for monitoring the performance of 3DCRT
studies and for providing that information to the Executive Committee
for the development of new research strategies.  These capabilities
shall include availability of facilities and professional personnel
with expertise in 3-D treatment planning and 3DCRT treatment delivery
and verification techniques for the necessary monitoring of the dose
escalation studies for quality control.

o  Demonstrated capability to exchange magnetic tape of patient data,
tumor and treatment volume contours, normal tissue contours, and dose
distributions over the volume irradiated between institutions.  These
data will be the basis for the monitoring of the clinical studies for
quality control and provide data for the 3-D database of normal tissue

o  Demonstrated capability for incorporating 3-D data obtained from
dose distributions correlated with anatomical structure (e.g.,
dose-volume-histograms) into a standard database for the recording of
radiation injury as a function of dose and volume.  This database will
be designed such that it can be made available to other researchers and
serve as a resource for developing mathematical models that describe
normal tissue complication probabilities as a function of volume

Requirements for Radiotherapy Centers

o  Radiotherapy Center applications must demonstrate a commitment to
participate in multi-institutional protocols and document the existence
and commitment of facilities and professional personnel available to
conduct cooperative therapy trials.  This includes assignment of
appropriate specialists who may be required to carry out the research,
including such diverse specialties as, but not necessarily limited to,
radiologists, radiotherapists, surgeons, pathologists, physicists,
statisticians, dosimetrists, data managers, and radiation therapy
technicians, in order to ensure availability of the timely and complete
information, expertise, and skills needed for patient treatment
planning, radiation therapy treatments and evaluation.

o  Radiotherapy centers must demonstrate the capability to plan 3-D
treatment, deliver treatment, and verify portal in a 3DCRT environment.
Specific capabilities will include, as a minimum, 3-D representations
of tumor and target/treatment volumes and normal tissues and
beam's-eye-view representations for treatment planning, non-conformal
beam planning and treatment delivery, and treatment portal verification
for each beam.

o  The presence of expertise for review and evaluation of the treatment
plans and treatment delivery for 3DCRT and the existence of procedures
for quality control of the radiotherapy treatments must be

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

o  Sufficient numbers of patients must be available and enrolled in
meaningful trials.  Applicants must show the ability to recruit these
patients to group studies and to maintain follow-up of the patients
after treatment. (see STUDY POPULATIONS.)

o  The availability of personnel and facilities capable of performing
and supporting the administrative functions of a cooperative group
member conducting therapy trials in cancer must be demonstrated.

o  Demonstrated capability of magnetic tape exchange  of patient data,
tumor and treatment volume contours, normal tissue contours and dose
distributions over the volume irradiated with the Operations Center.


The mechanism for this award is a cooperative agreement (U01).  Such
assistance programs involve substantial participation of NCI staff
during the performance of this project.  The nature of NCI staff
participation is described under 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 determines that
there is sufficient programmatic 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
in the section "Terms of Cooperation".


Approximately $750,000 in total costs per year for four years will be
committed to fund applications that are submitted in response to this
RFA.  The NCI anticipates a single award for funding an Operations and
Statistical Center and up to four to five awards to Radiotherapy
Centers for a period of four years. It is estimated that the award for
the Operations and Statistical Center will be about $400,000 and the
remaining funds will be to the radiotherapy centers.  The 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 NCI, the award of cooperative agreements in
response to this RFA is also contingent upon the availability of funds
for this purpose.


The objective of this RFA is to support multicenter cooperative
clinical trials to conduct disease-specific Phase I and II studies
using 3DCRT techniques that will define a new maximum tolerated dose
(MTD) beyond standard radiation therapy for prostate cancer treatments.
Should the Phase II results be sufficiently convincing that a new MTD
has been reached, the Cooperative Group will proceed to Phase III
trials, in which 3DCRT will be compared with best standard conventional
therapy for prostate cancer.  The Cooperative Group, through the
Executive Committee, will also define protocols for scoring radiation
injury as a function of dose and volume to the normal tissues at risk
for this disease, which is to be incorporated into a new three-
dimensional (3D) database for future reference and use by scientific
investigators.  The design, structure, and maintenance of the 3D
database is a research objective of this RFA.

The Division of Cancer Treatment, NCI, intends to support these trials
by awarding cooperative agreements to selected institutions that have
the capability to plan and deliver 3D conformal radiation therapy, and
to a single organization or institution that is capable of coordinating
the multi-institutional studies and serving as a data management and
analysis center.


There are approximately 122,000 new cases of prostate cancer in this
country each year.  It is the second-most common cancer among men and
results in about 32,000 deaths annually.  Radiation therapy is commonly
used in the curative management of the disease, and it is estimated
that approximately 40-50 percent of the cases are treated with
radiation therapy.  The Patterns of Care studies funded by the National
Cancer Institute in 1973, 1978 and 1983 (1516 patients) showed that
excellent 5- and 10-year survival for patients treated with radiation
therapy is achieved for T1 or early stage B patients (1).  Patterns of
Care 10-year survival data showed that Stage A of the disease is
locally controlled with radiation therapy at the 97-98 percent level.
Stages A2 and B patients with negative lymph node dissections show
freedom from recurrence that is equal to those results from radical
surgery.  Local control is less effective for more advanced disease,
however, with a 67-69 percent 10-year survival rate found for Stage C.
Approximately 40 percent of the prostate cancer cases diagnosed each
year are Stage C.

The Patterns of Care analyses demonstrated a dose-response effect in
the recurrence-free outcome for the Stage C patients that was not shown
in Stage A and B patients.  Doses of greater than 70 Gy (or 7000
centigray) reduce the recurrence of disease in Stage C patients to 24
percent from a rate of 36 percent for patients receiving doses of 65 Gy
or less.  There was no dose-response effect observed for Stage B or
Stage A.  Complication rates, however, increase when doses of greater
than 70 Gy are delivered.  The Patterns analyses showed a doubling of
complication rates from 3.5 percent to about 7 percent when doses of 70
Gy are used.  A retrospective study of patients treated in the
Netherlands without field blocking showed a 60 percent complication
rate for doses greater than 75 Gy (2).  Such treatment techniques
without the use of field blocks treats normal tissues to the same dose
as the tumor target, which resulted in a high complication rate in the
Netherlands study.   The use of 3DCRT "conforms" the radiation field
precisely to the treatment volume and thereby focuses the radiation on
the target, sparing normal tissues.

Failure of Local Control

The objective of this RFA is to focus on two factors that are
recognized as the causes of local failure with radiation therapy:  (1)
failure to appreciate the true anatomical extent of the tumor; and (2)
failure to deliver tumoricidal doses due to the limitations of the
radiation tolerance of the normal tissues involved.  The limitations of
conventional treatment planning, as practiced routinely during the last
decade, are generally recognized to be the following:

o  Definitions of the tumor target volume are incomplete.

o  Tumor and normal tissue boundaries are only approximated. (For
example, treatment planning is generally carried out on only a few
representative CT slices: the mid-field plane slice and one or two
other slices.  The superior and inferior boundaries of the treatment
field are typically determined from the x-ray simulation film.)

o  Beam apertures or radiation field boundaries are simplified.

o  Treatment planning isodose displays may not display dose throughout
the entire volume.

o  Plan evaluation and optimization are often based on a limited number
of planar isodose displays without full dose-volume information.

3-D Treatment Planning Research

Since 1982, the Radiation Research Program of the National Cancer
Institute has supported multi-institutional collaborative working
groups in treatment planning that have focused research efforts on 3-D
treatment planning evaluation, beginning with the Collaborative Working
Group for the Evaluation of Treatment Planning for Particle Beam
Radiotherapy from 1982-86.  The work of this group of contractors was
then modified, improved and expanded by the Collaborative Working Group
on the Evaluation of Treatment Planning for External Photon Beam
Radiotherapy, funded from 1984-87 (3).  The Collaborative Working Group
for High Energy Electron External Beam Treatment Planning was funded
from 1986-89.  All of these collaborative working groups in 3-D
treatment planning advanced the field dramatically, and the result has
been the development of a new technology. Embraced by the leading
radiotherapy departments and institutions in the country as a major
technological advance for the treatment of cancer, 3-DCRT  is now ready
to be tested in a clinical environment.

3DCRT Characteristics

The basic characteristics of a 3-D planning system have been described
elsewhere (3).  The application of a 3-D planning system, coupled with
the necessary modifications and enhancements to traditional
conventional methods for treatment delivery and verification,
constitutes a  3DCRT environment.  Its basic characteristics can
generally be described as follows:

o  Tumor or treatment targets are defined as volumes, showing the full
extent in all slices in three dimensions. Typically, they are generated
by a radiotherapist drawing or outlining the two-dimensional contours
on each CT slice throughout the tumor region.  Depending on the
thickness of the CT slice for the treatment planning scan, the study
may contain contours on 10-20 or more CT slices.

o  Normal structures are defined as volumes; they are not limited to
single points or a single contour on one CT slice.  In 3-D conformal
therapy, tumor contours, treatment volumes and normal tissue anatomical
structures, particularly those at risk during the radiation therapy
treatment, are entered on the entire set of CT slices that comprise the
study--up to as many as 50 CT slices.

o  Treatment planning then proceeds in a 3-D environment---namely the
manipulation of the target and anatomical structures as volumes.  An
important advance with this technology is the development of the
beam's-eye-view, which shows the projection of the tumor from a
particular beam direction, allowing for the precise shaping of the
treatment portal from any arbitrary beam angle, thereby enabling the
planner to minimize radiation damage to local adjacent structures.

o  Radiation dose calculations are modeled in three dimensions, taking
into account the effect of inhomogeneities.  Dose- volume-histograms
are calculated that show the dose as a function of volume, either as an
integral plot or a differential plot, in both the target volumes and in
the organs and normal tissues at risk.  Using theoretical models that
predict complication probabilities, it is possible to use the
dose-volume-histogram to assist in the evaluation of competing plans.

o  3-D conformal therapy requires accurate and precise positioning of
the patient and immobilization during treatment.  The task of
reproducibility becomes much more important when the treatment
technique reduces the volume of normal tissues at risk.  Over a six to
seven week course of treatment, reproducibility of the patient
treatment position must be verified through careful portal imaging and
verification techniques.


Terms of Cooperation

A.  Nature of Participation by NCI Staff

The role of the NCI staff is to assist and facilitate, but not to
direct the research activities.

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

The Associate Director of the RRP, or his/her designee Program Director
(RRP/PD), will serve as a resource available to awardees for specific
scientific information with respect to clinical trial design and advise
the group of the nature and results of relevant national and
international studies.  The collective group of participating
institutions in this RFA, including the Operations and Statistical
Center, will be referred to as the Cooperative Group and the Principal
Investigator (PI) of the Operations and Statistical Center will be the
Group Chairperson.  The Executive Committee will consist of the PI's of
the Operations and Statistical Center and the Radiotherapy Centers.
Similar types of studies have found it beneficial to authorize an
Executive Committee to direct the research in accordance with the goals
and objectives of this initiative.  The RRP/PD will participate in
planning and strategy meetings of the Executive Committee when

2.  RRP Assistance in Protocol Development

a.  Protocol Design

The Associate Director, RRP, or his/her RRP/PD will participate in the
design of new studies and the development of protocols as needed,
assisting the awardees and facilitating the process, rather than
directing it, to assure that the proposed studies are in accord with
NCI and PHS research requirements and regulations.  The RRP/PD will
serve as a resource available to the Group for specific scientific
information with respect to protocol design and advise the group of the
nature and results of relevant national and international clinical

b.  Protocol Approval

Protocols will be submitted under the leadership of the Group
Chairperson to the Protocol Review Committee of the Clinical Therapy
Evaluation Program (CTEP) Protocol and Information office in a timely
fashion for review and approval by NCI. Protocols will be developed and
submitted and studies will be conducted in accordance with established
DCT Clinical Trials Cooperative Group Guidelines.

The major considerations relevant to protocol review by NCI include:
(a) 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 date management; (i)
appropriateness of patient selection and follow-up; and (j) evaluation
and assessment of complications/toxicity.

c.  Arbitration Process

If a proposed protocol is not approved by the RRP Program Director or
the Protocol Review Committee, the specific reasons for the disapproval
will be communicated to the Group Chairperson within 45 days of receipt
by the NCI.

The NCI will not permit expenditure of NCI funds for a protocol that
has not been approved.

Disagreements arising pursuant to protocol disapproval and/or other
scientific programmatic matters may be submitted to an arbitration
panel to determine the suitability of a protocol that has been
disapproved.  An arbitration panel composed of one Group designee, one
NCI designee, and a third member with clinical trials expertise chosen
by the other two designees will be formed to review the contested
decision(s). The arbitration panel will recommend an appropriate course
of action to the Director, DCT.  These special arbitration procedures
in no way affect the awardees' rights to appeal an adverse action in
accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS
regulations at 45 CFR Part 16.  The Group will not expend NCI funds to
conduct any study that has been disapproved by the NCI, unless the
disapproval has been modified by the arbitration process outlined

d.  Protocol Closure

The RRP/PD may request that a protocol study be closed to accrual for
reasons including:  (a) insufficient accrual rate; (b) achievement of
the original accrual goals; (c) patient safety; (e) conclusive study
results; (f) unacceptable toxicity; (g) further accrual will not add
information of scientific value; and (h) emergence of new information
that diminishes the scientific importance of the study in question.

Protocols shall not be terminated by the Group before reaching the
projected accrual target without the approval of the RRP/PD.  Such
approval will be based on a submission of an interim results report and
written justification for closing the study.  Unresolved disagreements
between NCI staff and the awardee institutions regarding the
appropriateness of early study closure will be arbitrated by the
process outlined in item 2.c. above.

3.  Review of Progress

Performance of the Group will be reviewed at least annually by the
RRP/PD on the basis of information provided at Group meetings, annual
progress reports, and interim reports.  The content of these reports is
described in the next section, Responsibilities of Awardees, Reporting
Requirements. Support recommended for the remaining project period will
be contingent upon annual favorable review by the RRP/PD of the
progress of the project and sufficient patient accrual to complete the
studies within the allotted time.  Insufficient patient accrual or
noncompliance with the terms of award, including these Terms of
Cooperation, may result in a reduction of the budget, withholding of
support, suspension or termination of the award.  Future support
recommended for the entire Group will be contingent upon favorable
review by NCI program staff of the progress of the Group as manifested
in part by sufficient patient accrual of the Group as a whole.  NCI
funding is contingent upon an awardee institution remaining as a member
of the Group.

4.  Access to Data

The NCI via the RRP/PD shall 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 HHS, PHS, and NIH policies.

B.  Responsibilities of Awardees

It is the responsibility of the awardees 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 the clinical studies.

1.  Group Chairperson

The PI of the Operations and Statistical Center will serve as
Chairperson of the Cooperative Group and will oversee the management
and direction of the Executive Committee.  The Group Chairperson will
be responsible for the logistics of Group meetings, for the
coordination of protocol development and protocol submission to NCI,
for communicating the results of NCI protocol reviews to the awardee
institutions, for the management and conduct of the clinical studies,
for quality control of the studies, for data management, for
coordinating group-related scientific and administrative decisions, and
for providing leadership to the Executive Committee.  The Group
Chairperson will be the principal point of contact for the  RRP/PD in
the conduct of this clinical trial.

2.  Executive Committee

The PI of the Operations and Statistical Center, the PI's of each of
the awardee institutions, and the RRP/PD constitute the Executive
Committee.  The Executive Committee will have the authority to create
committees it deems necessary for protocol design, for defining and
maintaining quality assurance, for collection and dissemination of the
data, and for the design, structure, and implementation of the 3-D
database (see 9 below).  The Executive Committee will have the
responsibility of implementing methods of assuring quality research
that is carefully monitored and controlled.  Such methods may include,
but not be limited to, the following:  setting standards for a minimum
number of evaluable cases submitted by awardee institutions,
maintaining quality control of the studies, termination of current
members whenever indicated, and defining principles governing admission
of new group members.

3.  Executive Committee Meetings

It is anticipated that all decisions of the Group will be reached by
Group consensus under the leadership of the Group Chairperson.  It is
required that the PI (or designee) of each awardee institution attend
all Executive Committee meetings.  Members of the Executive Committee
will meet at least twice a year at Group Headquarters to review
progress, establish priorities, and plan future activities.  For
purposes of developing a budget in response to this RFA, applicants
should assume a city in the Midwest.  At the time of award, travel
costs will be negotiated with awardees on the basis of actual location
of the Group Headquarters.

4.  Clinical Studies

a.  Protocol Development and Submission

It shall be the responsibility of the Group Chairperson to coordinate
protocol development and submit protocols to the NCI for approval as
described in the previous section, A. Nature of Participation by NCI
Staff.  The Group Chairperson may authorize meetings of the Executive
Committee for the purpose of discussions of protocol design, monitoring
of the studies, and quality assurance.  The Group Chairperson shall be
responsible for the logistics of Group meetings, for submitting
protocols to the NCI for approval, for communicating the results of NCI
protocol reviews to the awardee institutions, and for providing
leadership to the Executive Committee in the development of new

Protocols will be submitted by the Group Chairperson to the Protocol
Review Committee of the CTEP Protocol and Information office in a
timely fashion for review and approval by NCI.  Protocols will be
developed and submitted and studies will be conducted in accordance
with the "DCT Guidelines for Multicenter Investigational Agent Studies"
(available upon request from the RRP Program Director at the address
below) or in accordance with established DCT Clinical Trials
Cooperative Group Guidelines.

The major considerations relevant to protocol review by NCI are
contained under 2.b., Protocol Approval.

b.  Quality Assurance and Control

The Executive Committee will be responsible for overseeing and
monitoring data collections to ensure the highest possible quality
control of the clinical studies.  Such quality control issues may
include, but not be limited to, adequacy of tumor delineation and
target definition in three dimensions; portal image verification;
compliance with treatment planning protocols, specifically with respect
to treatment volume, including adequate margins in three dimensions;
adequacy of tumor coverage in three dimensions to the isodose line
prescribed in the protocol; adequacy of dose-volume-histogram
calculations; and adequacy of the documentation provided.
Non-compliance on the part of awardee institutions of quality control
standards as defined by the Executive Committee may be the basis for
excluding that institution from the Group.  Any disagreements between
the awardee institutions and the Executive Committee relating to data
management and analysis that cannot be resolved by bilateral
discussions will be submitted to the same arbitration process
previously outlined in Section 2.c, Arbitration Process under the Terms
of Cooperation.

c.  Protection of Human Subjects

It will be the responsibility of the PI of each awardee institution to
submit new and revised protocols to each appropriate Institutional
Review Board (IRB) within 30 days of the date of written notification
of NCI approval.  Each institution is responsible for ensuring that
each protocol is reviewed and approved prior to patient entry, in
accordance with 45 CFR, Part 46, Protection of Human Subjects.  Written
informed consent must be obtained prior to entry on the studies.  Each
protocol must be reviewed and approved at least annually by the
appropriate IRB while the protocol is active.

5.  Conduct of Research and Patient Accrual

Awardees are expected to provide timely results from a sufficient
number of patients as required by the NCI approved protocols and the
Executive Committee recommendations.

6.  Study Monitoring

The Operations and Statistical Center, under the leadership of the
Group Chairperson, is responsible for establishing a mechanism for
study monitoring to ensure quality control of the studies and accurate
and timely knowledge of the progress of each study through:

a.  Tracking and reporting of patient accrual and adherence to defined
accrual goals and protocol requirements.

b.  Ongoing assessment of case eligibility and evaluability.

c.  Assuring that each participating institution's IRB has reviewed and
approved each new and revised protocol prior to patient entry.

d.  Timely review and assessment of patient data.

e.  Rapid reporting of treatment-related morbidity and measures to
ensure communication of this information to all parties.

f.  Interim evaluation and consideration of measures of outcome, as
consistent with patient safety and good clinical trials practice.

g.  Timely communication of results of studies.

7.  Reporting Requirements

Annual progress reports will be submitted by the PI of each awardee
institution to the NCI through the Group Chairperson describing their
participation in the study, the accomplishments at that institution,
and the number of patients entered into the study.  Each awardee
institution must submit to the Group Chairperson a biannual report of
patient accrual and treatment-associated morbidity. Determination of
adequate patient accrual will be based on plans developed by the PI's
in their Executive Committee roles (see B.2., Executive Committee, and
B.4.b., Quality Assurance and Control).

The Group Chairperson shall submit an annual report summarizing the
accomplishments of the Cooperative Group and the Executive Committee.
The report shall contain (1) highlights of progress made during the
period regarding the important issues of this study, such as protocol
development, 3-D database design, magnetic tape exchange; (2)
documentation of patient accrual to the studies; and (3) reports of
treatment-associated toxicity.  Minutes of the Executive Committee
meetings, protocols developed, and other supplementary material as
deemed appropriate, will be included as appendices.

8.  Publication of Data

Timely publication of major findings is encouraged.  Topics of
publications and authorship will be decided upon by the Executive
Committee under the leadership of the Group Chairperson.  Data
generated in these studies remains the property of the awardee
institution, consistent with current HHS, PHS, and NIH policies, but
publication and oral presentation of work done under this agreement
will require appropriate acknowledgement of NCI support.  The NCI,
through the RRP/PD, will have access to all data generated under this
cooperative agreement and may periodically review the data.

9.  3-D Database

It is the responsibility of the Operations and Statistical Center, in
collaboration with the Executive Committee, to design and implement a
database for the incorporation of 3-D dose/volume data that will be
maintained and made available to scientific researchers.  One of the
potential uses of such a database is the development of models that can
predict normal tissue complication probabilities on the basis of the
partial irradiation of an organ.  The maintenance of the database
beyond the lifetime of this award will be based on sufficient
programmatic need as determined by the NCI (see MECHANISM OF SUPPORT).

C.  The Terms of Cooperation described in this section are in addition
to, and not in lieu of, otherwise applicable Office of Management and
Budget administrative guidelines, HHS Grant Administration regulations
at 45 CFR, Part 74, and other HHS, PHS and NIH grant administration
policy statements.


POPULATIONS  (Considerations of women in the NIH and ADAMHA policy do
not apply for this RFA.)

NIH and ADAMHA policy is that applications for NIH/ADAMHA clinical
research grants and cooperative agreements will be required to include
minorities 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 in studies of diseases, disorders and conditions which
disproportionately affect them.  This policy is intended to apply to
males of all ages.  If minorities are excluded or inadequately
represented in the clinical research of this RFA, a clear and
compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of the racial/ethnic group, together with a rationale for its
choice.  In addition, 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 the Research Plan, 1-4, and
summarized in 5, 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 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 tissue from 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, 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 minorities.

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
minorities in the study design is inadequate to answer the scientific
question 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 June 1, 1992, a letter
of intent that includes a descriptive title of the proposed research,
the name and address of the PI, 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. Sandra Zink at the address
noted below.


Application for Public Health Service cooperative agreements must be
submitted on form PHS 398 (rev. 9/91).  Application kits are available
from most institutional business offices, and may be obtained from the
Division of Research Grants, National Institutes of Health, 5333
Westbard Avenue, Bethesda, MD 20892, telephone (301) 496-7441.

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 2a of the face page of the application

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 legible 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:

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

Applications must be received by August 26, 1992.  If an application is
received after that date, it will be returned. Also, the DRG will not
accept any application in response to this announcement that is the
same as one currently being considered by any other NIH review group or
awarding unit.

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 (rev.

The applicant organizations for the Operations and Statistical Center
may propose a consortium arrangement for operations of the Center if
necessary.  The Operations and Statistical Center and the Radiotherapy
Centers will constitute a single Cooperative Group to conduct the
clinical trials. The PI of the Operations and Statistical Center will
serve as the Chairperson of the Cooperative Group.

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


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 to the applicant by the NCI, but may be submitted as
investigator-initiated research grants. Questions concerning the
responsiveness of proposed research to the RFA should be directed to
program staff.

If the number of applications submitted 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 will be by the National Cancer Advisory Board.

Review Criteria

Review criteria for the Operations and Statistical Center include:  (1)
the leadership ability of the PI and documented experience in dealing
with the problems of cooperative clinical research; (2) proposed
methodology for the conduct of the clinical trials to attain the
research objectives; (3) ability of the Operations and Statistical
Center staff to monitor clinical trials for quality assurance; (4)
adequacy of statistical support necessary for the design, monitoring,
analysis, and reporting of the 3DCRT cooperative multi-center clinical
trials; and (5) capability to design and develop a database documenting
dose and irradiated volume with normal tissue response.

For the Radiation Center applicants, review criteria include: (1)
documented experience in the development and conduct of clinical trials
at their institution; (2) documented evidence that their institution
has the potential to accrue the necessary patients through patterns of
referral, previous experience, and accession; (3) proposed methodology
for the conduct of the clinical trials; (4) availability of appropriate
facilities, treatment planning capabilities, appropriate staff, and
appropriate hardware to treat patients and perform clinical trials in
a 3DCRT environment; and (5) adequacy of provisions for the protection
of human subjects.

The review group will critically evaluate the submitted budgets and
will recommend an appropriate budget and period of support for each
approved application.


The earliest feasible start date for the initial awards will be April
1, 1993.  Awards will be made solely on the basis of peer review and
only the most meritorious will be considered, contingent upon the
availability of funds.  Although this program is provided for in the
financial plans of the NCI, the award of cooperative agreements
pursuant to this RFA is contingent upon the availability of funds for
this purpose.


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

For technical information:

Dr. Sandra Zink
Program Director
Radiation Research Program
National Cancer Institute
Executive Plaza North, Suite 800
Bethesda, MD  20892
Telephone:  (301) 496-9360
FAX:  (301) 480-5785

For business information:

Ms. Barbara Fisher
Grants Management Specialist
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 242
6120 Executive Blvd.
Rockville, MD  20852
Telephone:  (301) 496-7800, Ext. 29
FAX:  (301) 496-8601


This program is described in the Catalog of Federal Domestic Assistance
No. 93.395, Cancer Treatment Research.  Awards are made under the
authorization of Public Health Service Act, Title IV, Sections 301, 410
and 411, Part A (Public Law 78-410, as amended by Public Law 99-158, 42
USC 241 and 285 (a.)) and administered under the 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.  Leibel, SA, GE Hanks, S Kramer, Int J Rad Oncol Biol Phys <10>, pp
401-409 (1984).

2.  Smith, WGJM, PA Helle, WLJ van Putten, AJ Wijnmaalen, JJ
Seldenrath, BHP van der Werf-Messing, Int. J Rad Oncol Biol Phys <18>,
pp 23-29 (1990).

3.  Special Supplement, Int J Rad Oncol Biol Phys, <21, No. 1>, May 15,


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