CANCER PHARMACOLOGY AND TREATMENT IN OLDER PATIENTS

Release Date:  May 11, 1998

PA NUMBER:  PA-98-069

P.T.

National Institute on Aging
National Cancer Institute

PURPOSE

The National Institute on Aging (NIA) and the National Cancer
Institute (NCI) invite research grant applications to expand the
understanding of the pharmacology of antineoplastic agents in older
patients.  This research initiative specifically addresses the
disposition, efficacy, and effectiveness of anti-cancer agents in
older cancer patients.  The increased risk of the major cancers
with advancing age and their prominence in older-aged persons are
well known.  The information developed in the past three or more
decades in cancer pharmacology and geriatric pharmacology should be
integrated to provide extensive application of the combined
expertise to devise appropriate therapeutic strategies for cancer
patients 65 years and older.

Experts in aging and cancer can benefit from interdisciplinary
studies provided by the combined perspectives of the pharmacology
of aging and cancer pharmacology, comparing knowledge and
experience, and developing studies on unique aspects of aging on
pharmacokinetics (time course of absorption, distribution,
metabolism, and excretion of drugs from the body) and
pharmacodynamics (response of the human host to the drug). In
treating elderly cancer patients, special consideration also must
be given to the pathophysiological changes that occur with aging,
particularly the decline of organ systems and their decrease in
functional capacity.  Age-associated loss of efficiency is an
acknowledged issue.

The goal of this program announcement is to stimulate research to
improve treatment and care of older persons affected with cancer
with explicit attention to aging and old age and their effects on
anti-cancer therapy pharmacokinetics and pharmacodynamics.

HEALTHY PEOPLE 2000

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 PA, "Cancer Pharmacology and Treatment in Older
Patients", is related to the priority areas of chronic diseases and
disabling conditions and 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
202-512-8100).  These documents are also available on the World
Wide Web at:  http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic 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.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

Support of this program announcement is through the National
Institutes of Health (NIH) traditional investigator-initiated
research project grant (R01) mechanism and the
exploratory/developmental grant (R21) mechanism.  The R21 program
is used for pilot projects or feasibility studies to support
creative and novel research that may produce innovative advances in
science.  R21 awards are limited to $100,000 direct costs per year
(up to two years).  Continuation of projects developed under the
R21 mechanism is through the R01 mechanism.

RESEARCH OBJECTIVES

Background

Summary Data -- Cancer is a disease primarily associated with
aging.  NCI Surveillance, Epidemiology, and End Results (SEER)
Program indicates that more than 60% of all cancers diagnosed and
69% of all deaths due to cancer are in persons 65 years and older. 
From a site-specific perspective, SEER Program data report a median
age range of 66-74 years for seven major sites of cancer common to
both men and women  -- colon, leukemia, lung, pancreas, rectum,
stomach, and urinary bladder.  The median age for prostate cancer
is 71 years.  Breast and ovarian cancers, often regarded as
diseases of young women, have median ages just under age 65 (64 and
63 years, respectively).

The age group 65 years and older makes up approximately 13% of the
total U.S. population, one in seven persons.  This percentage is
expected to increase to more than 20% by 2030 when the anticipated 
"baby boom" expansion peaks -- one in five persons will be 65+. 
Although older persons bear the brunt of the cancer problem and the
number of aged individuals at high risk for a malignancy will
increase, data are sparse on evaluation and management of cancer in
the elderly.  No foundation of knowledge has been established to
respond to the many unanswered questions regarding the impact of
age-associated changes and intercurrent diseases on the course of
cancer in the elderly.

Numerous studies in gerontology and geriatric medicine indicate
that the prevalence of chronic diseases (e.g., arthritis, heart
disease, cerebrovascular disease, diabetes, hypertension) increase
with advancing age.  Thus, there is a broad range of chronic
illnesses and impairments present in older patients at the time of
their cancer diagnosis and some individuals acquire excessive
multiple pathology and age-related physical decline as they age,
while others experience minimum changes.  Moreover, the health
status of older persons is often affected by physiologic
alterations (i.e.,"geriatric conditions") that produce
vulnerabilities such as renal insufficiency, chronic obstructive
pulmonary disease, cardiovascular disease, cerebrovascular disease,
urinary incontinence, falls, decreased immune response to
infections, hearing impairment, under nutrition, and disability. 
Clinicians need to know how the drugs perform in older persons with
far less than ideal health and those with good to excellent health.

It is not common to see reports in the medical oncology literature
on how elderly cancer patients tolerate chemotherapy or how
oncologists treat older cancer patients.  Patients in the large
multi-center cancer treatment trials that provide the fundamental
data for medical practice tend to be younger than 65 years. 
Overall, there is a low percentage of elderly patients entered into
these types of studies, though this may vary somewhat according to
a specific cancer site (e.g., men in their mid-seventies and older
are generally those most severely affected by prostate cancer). 
Thus, research questions addressed in the multi-center clinical
trials efforts are not generalizable to older patients with
concomitant diseases and poor physiological functioning.  These
age-associated problems have precluded their entry into such
studies. We face the dilemma that cancer treatment interventions
are not targeted for the age group enduring the most cancer.

As new therapies such as biologics and anti-angiogenic agents are
developed that are not cross resistant to standard chemotherapy and
involve less toxicity, the pharmacodynamics of these agents and
potential efficacy must be addressed in an elderly population.
Definitive answers to the many questions that arise about the
impact of aging on cancer therapy are urgently needed.

Geriatric Medicine and Oncology Working Group/President's Cancer
Panel Meeting

This research initiative consolidates the recommendations of the
NIA/NCI Working Group on Pharmacology in Aging and Cancer, held at
the NIH in December 1994.  Objectives of the meeting were to
identify ways to develop information on principles of drug therapy
for elderly cancer patients from existing databases and instigate
new studies that would build an adequate knowledge base in this
deficient scientific area.  Participants in the NIA/NCI Working
Group agreed that information exchange is essential.  They
concurred that the pharmacokinetics and pharmacodynamics of anti-
cancer agents may vary widely from person to person, and that
physiological condition rather than chronological age should be the
basis for therapeutic choice and dose administration. 
Recommendations for research focused on how advances made on the
fundamental principles of cancer and geriatric pharmacology may be
applied to the study of antitumor drugs in treatment of cancer in
the elderly.

Cancer pharmacology in aging patients was a major issue addressed
by President Clinton's Cancer Panel in a public forum at the
University of Michigan Turner Geriatrics Center in July, 1997.  The
meeting was attended by researchers, clinicians, patient advocates,
and others expert in cancer and gerontology.  The recommendation
was to examine the pharmacologic properties and toxicity of cancer
drugs given to older patients, as well as to individualize drug
therapy to address the diversity and changes in physiologic
functioning that occur in older age.

Consistent with the recommendations of the NIA/NCI Working Group
and the President's Cancer Panel, this initiative seeks to
stimulate research to advance cancer therapeutic objectives of
geriatric medicine and medical oncology and encourage investigators
in these clinical professions to work in tandem to improve the
treatment of the elderly.  The intent is optimize treatment of
older patients by decreasing the drug risk to the largest extent
possible while increasing its benefit, considering tumor type;
condition of the patient (i.e., health status of the patient prior
to cancer diagnosis); drug-disease interaction; drug-age
interaction; and drug-drug interaction.

Research Goals and Scope

The PA emphasizes research to improve the care and treatment of
older-aged patients through evaluation of tolerance and response to
standard, experimental, newly-designed anti-cancer agent regimens
independent of, and in conjunction with, multimodality
interventions in the context of geriatric pharmacology.  It
encourages the extramural research communities in cancer and
geriatric pharmacology to combine expertise and apply the knowledge
bases of both disciplines to research initiatives relevant to older
cancer patients.

Clinical studies relevant to this pharmacology initiative promote
two major areas of investigation:  (1) Studies to assess the age-
dependent differences that influence drug efficacy and adverse drug
effects used to treat the tumors that disproportionately affect the
elderly. This includes the parameters of drug absorption,
distribution, metabolism, and excretion as well as age-host and
drug interactions.  Alterations in immune function and cell cycle
kinetics may also affect the pharmacodynamics of the therapeutic
drugs. What influence does age have on these physiologic factors 
and the proposed therapeutic intervention? (2) Cancer site-specific
studies that confront and deal with the multiple health problems
inherent in older persons diagnosed with a malignancy.  How are
these conditions and their multiple pharmacy needs managed in the
context of cancer treatment planning?  What impact do co-existing
health problems have on clinical trial enrollment?

To address the goal of advancing optimum therapy for older cancer
patients, selected areas for studies are listed.  Grant
applications are not limited to these specific areas.  The list is
neither all-inclusive nor exclusive, nor is it in order of priority
interests.  Additional research aims that maximize the potential
for positive therapeutic effects and minimize toxicity in elderly
patients will be considered.

o Studies on how anti-cancer agent effects are modified by aging
processes with attention to dosage, adverse reactions, drug-drug
interaction, drug-age interaction, changes in body composition,
organ, and immune function, and the older person's own use of
medications (prescribed and over the counter).

o Prospective studies that emphasize the entry of older-aged
patients into cancer treatment protocols that will evaluate the
independent effects of age-related factors.  These studies may
involve chemotherapy, biologic therapy, surgery, radiation therapy,
and multimodality treatment interventions.

o Phase IV trials (standard therapy outcome) may be developed to
address ways to improve therapeutic management of older cancer
patients.

o Pharmacokinetics and pharmacodynamics modeling of selected anti-
cancer agents and patient response applied to chemotherapy and
biologic therapy questions pertinent to elderly patients.

o Age-associated toxicity effects.
 --Mucositis, cardiotoxicity, nephrotoxicity, myelotoxicity, and
neurotoxicity.

o Age-associated pharmacodynamic effects.
--Mechanisms of antitumor drug resistance and repair
--Markers of angiogenesis and related events
--Immune responsiveness.

o Explore differences in the pharmacokinetics and pharmacodynamics
of chemotherapeutic and biologic antitumor agents between older and
younger patients and the potential mechanisms for these
differences.

o Studies that characterize the inadmissible elderly patients to
research protocols (e.g., physical incapacity from other medical
conditions; family/patient decisions; memory loss; depression;
cognitive function; lack of social support or transportation) that
include data on treatment administered in the clinical setting
outside the protocol involvement.

o Development of methods to evaluate performance status of older
patients regarding preexisting diseases or conditions (renal
problems, cardiac history, severity of hypertension, immune
suppression, etc.) as prognostic indicators for drug sensitivity
and dose intensity.

o Development of leads and hypotheses for research on cancer
pharmacology in older patients from extant databases are permitted
under this research solicitation.  Selected questions of clinical
trials and survey data could be informative as a basis for the
research proposed by the investigator(s).  Drawing conclusions,
however, from the information on the subsets of older-aged patients
in the clinical trials databases because of patient selection bias
is cautioned.

DEFINITIONS--Often, the terms "old", "aged", or "elderly" are
defined using the chronological age of 65 as a point of
demarcation.  This age cutoff is arbitrary and historically
associated with entitlements and eligibility for various programs. 
While the research encouraged by this PA does not restrict
applicants to this age boundary, it is expected that study patients
will be those who are in the age group in which cancer primarily
occurs as previously described.

Methods should be proposed by the applicant that express
physiologic age of the study patients. Parameters describing the
older patient could be measurement of organ function such as
creatinine clearance or hepatic clearance of a marker substance. 
Applicants are expected to identify what is meant by "aged", "old",
or "elderly" in the context of the research.  Age comparisons with
younger persons are appropriate and may be included.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of the NIH that women and members of minority
groups and their sub-populations must be included in all NIH
supported biomedical and behavioral research projects involving
human subjects, unless a clear and compelling rationale and
justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the
research.  This policy results from the NIH Revitalization Act of
1993 (Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects
should read the "NIH Guidelines For Inclusion of Women and
Minorities as Subjects in Clinical Research," which have been
published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and in the NIH Guide for Grants and Contracts, Volume
23, Number 11, March 18, 1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may provide additional
information concerning the policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.  Application kits
are available at most institutional offices of sponsored research,
or may be obtained from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701
Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301-710-0267, email: grantsinfo@nih.gov. Applications are also
available on the World Wide Web at: 
http://www.nih.gov/grants/funding/phs398/phs398.html

The program announcement title and number must be typed on line 2
of the face page of the application form and the YES box must be
marked.

Submit the signed, original, single-sided application, along with
five exact, single-sided copies and five collated sets of appendix
materials to:

CENTER FOR SCIENTIFIC REVIEW (formerly Division of Research Grants)
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established Public
Health Service referral guidelines.  Applications that are complete
will be evaluated for scientific and technical merit by an
appropriate peer review group convened in accordance with NIH peer
review procedures.  As part of the initial merit review, all
applications will receive a written critique and undergo a process
in which only those applications deemed to have the highest
scientific merit, generally the top half of applications under
review, will be discussed, assigned a priority score, and receive
a second level review by the appropriate national advisory council
or board.

Review Criteria

The goals of NIH-supported research are to advance our
understanding of biological systems, improve the control of
disease, and enhance health.  The reviewers will comment on the
following aspects of the application in their written critiques in
order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals.  Each of these
criteria will be addressed and considered by the reviewers in
assigning the overall score weighting them as appropriate for each
application.  Note that the application does not need to be strong
in all categories to be judged likely to have a major scientific
impact and thus deserve a high priority score.  For example, an
investigator may propose to carry out important work that by its
nature is not innovative but is essential to move a field forward.

o  Significance:  Does this study address an important problem?  If
the aims of the application are achieved, how will scientific
knowledge be advanced?  What will be the effect of these studies on
the concepts or methods that drive this field?

o  Approach:  Are the conceptual framework, design, methods, and
analyses adequately developed, well-integrated, and appropriate to
the aims of the project?  Does the applicant acknowledge potential
problem areas and consider alternative tactics?

o  Innovation:  Does the project employ novel concepts, approaches
or method? Are the aims original and innovative?  Does the project
challenge existing paradigms or develop new methodologies or
technologies?

o  Investigator:  Is the investigator appropriately trained and
well suited to carry out this work?  Is the work proposed
appropriate to the experience level of the principal investigator
and other researchers (if any)?

o  Environment:  Does the scientific environment in which the work
will be done contribute to the probability of success?  Do the
proposed experiments take advantage of unique features of the
scientific environment or employ useful collaborative arrangements?
Is there evidence of institutional support?

The initial review group will also examine: the appropriateness of
proposed project budget and duration; the adequacy of plans to
include both genders and minorities and their subgroups as
appropriate for the scientific goals of the research, and plans for
the recruitment and retention of subjects; the provisions for the
protection of human and animal subjects; and the safety of the
research environment.

AWARD CRITERIA

Applications will compete for available funds with all other
approved applications.  The following will be considered in making
funding decisions:

o  Quality of the proposed project as determined by peer review
o  Availability of funds
o  Program priority

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Rosemary Yancik, Ph.D.
Geriatrics Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 3E327 MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-5278
FAX:  (301) 402-1784
Email:  YancikR@exmur.nia.nih.gov

Ms. Diane Bronzert
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Suite 734, MSC 7432
Bethesda, MD  20892-7432
Telephone:  (301) 496-8866
FAX:  (301) 480-4663
Email:  Bronzertd@ctep.nci.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Cynthia Riddick
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  RiddickC@exmur.nia.nih.gov

Ms. Sara Stone
Grants and Contracts Management Office
National Cancer Institute
6120 Executive Boulevard, Suite 243, MSC 7432
Bethesda, MD  20892
Telephone:  (301) 496-7800, ext. 266
FAX:  (301) 496-8601
Email:  StoneS@GAB.nci.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.866, Aging Research and 93.395, Cancer Treatment
Research.  Awards are made under authorization of the Public Health
Service Act, Title IV, Part A (Public Law 78-410), as amended by
Public Law 99-158, 42 USC 241 and 285) and administered under PHS
grants policies and Federal Regulations 42 CFR 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.

The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all
tobacco products.  In addition, Public Law 103-227, the Pro-
Children Act of 1994, prohibits smoking in certain facilities (or
in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early
childhood development services are provided to children.  This is
consistent with the PHS mission to protect and advance the physical
and mental health of the American people.

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