AGING AND OLD AGE AS RISK FACTORS FOR MULTIPLE PRIMARY TUMORS

Release Date:  December 18, 1998

PA NUMBER:  PA-99-030

P.T.

National Institute on Aging
National Institute of Dental and Craniofacial Research

PURPOSE

The National Institute on Aging (NIA) and the National Institute of Dental and
Craniofacial Research (NIDCR) invite research grant applications for studies to
define the magnitude and nature of the problem of multiple primary tumors and
their association with advancing age and to develop biostatistical and etiologic
methodologies for assessment of multiple primary tumors, with special emphasis
in older-aged cancer patients.  This solicitation is intended to stimulate
research to build a knowledge base on occurrence of age-related multiple primary
tumors.  Current research on multiple primary tumors (i.e., one or more malignant
lesions in the same person that are not recurrences, extensions, or metastases
of a previous malignancy) does not address the high potential of older persons
diagnosed with cancer or who have had previous cancers to be at risk for second
primaries.  This Program Announcement (PA) encourages investigators to conduct
research in epidemiology, methodology of disease classification (i.e., nosology),
biostatistical methodology, gerontology, carcinogenesis, genetics, and
environmental causes emphasizing the high-risk potential for people previously
diagnosed with cancer to develop second primary tumors.

Advances and improvements in the early detection, diagnosis, and treatment of
cancer have increased survival of cancer patients, enabling them to live longer
and, possibly, develop a second primary tumor.  As survival rates improve, and
the population ages, the number of older patients with second primary cancers
will increase.  In many industrial nations, the existing high proportions of
elderly persons, increasing length of life, and shifts in the population age
structure toward an even greater number of older people combine to create the
need for greater attention to older cancer patients as an emerging target group
for evaluation of multiple primary tumors. Methodological issues in definition,
coding, statistics, and reporting must be addressed in approaching these studies.

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, Aging and Old Age as Risk Factors
for Multiple Tumors, is related to the priority areas of older adults, cancer,
and surveillance and data systems.  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 202-512-1800). 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

The mechanisms of support will be the investigator-initiated research project
grant (R01) and the exploratory/developmental grant (R21) mechanisms  The R21 is
used for pilot projects or feasibility studies to support creative and novel
research that may produce innovative advances in science.  Funds under the R21
mechanism 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
grant program.

RESEARCH OBJECTIVES

Background

Overall, persons in the age group 65 years and older account for 60% of all
incident tumors in the U.S.  As the U.S. population ages and progress is made in
early detection and improved treatment, the numbers of individuals living with
a diagnosis of one or more cancers continues to rise.  In 1998, it has been
estimated that 1,228,600 new cases of cancer will be diagnosed.  According to
National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results
(SEER) data, 14% of newly-diagnosed cancers are in individuals who already have
had a previous malignancy. This translates into 172,000 patients of whom 129,000
are 65 years or older. Yet, there is a dearth of data on multiple primary tumors
as they may occur in older persons. This is an important area for the integration
of aging and cancer research.

More than fifteen years ago, Lee and colleagues asserted that "multiple primary
malignant tumors have passed the stage of pathologic curiosity to become a
significant medical problem, particularly for the elderly." (1)  Having one tumor
offers no protection from acquiring a second malignancy for a person of any age.
Indeed, the presence or history of a malignancy is often associated with
increased susceptibility to another tumor.  Who are the current or former cancer
patients most likely to be "hit" by a second primary cancer?  What insights into
the etiology of cancer can be obtained from studies on older patients who have
developed multiple primary tumors?

The risk of multiple primary tumors in older persons may be related to host
factors, persistence of environmental exposures, increased sensitivity to
carcinogens, length of time of exposure to carcinogens, immune competence, or any
combination of these and other factors.  In recent years, the adverse effects of
cancer treatment such as radiation and drug therapies as they may induce multiple
primary tumors has received considerable attention. The specific focus for these
investigations is the potential carcinogenicity derived from treatment for  the
earlier tumor.  Intensive research has been carried out to evaluate the risk of
leukemias and lymphomas, and different tumors resulting from radiation therapy
and chemotherapy. (2, 3)  Investigators involved in breast cancer research
examine agents that might promote development of other primary tumors. (4)

Integrating aging and old age for research on risk factors for multiple tumors
offers a pathway to an increased understanding of all malignant lesions and
primary tumors occurring as single entities, synchronous cancers, and
metachronous cancers.

According to Berenbaum, consideration of multiple primary tumors in the past in
humans was believed to be an abnormal phenomenon. (5)  He suggested that it is
the comparative rarity of the occurrence of multiple tumors in humans that is
abnormal in the light of new knowledge derived from epidemiologic investigations. 
His observations suggest a fundamental question that could be contemplated in any
discussion of multiple tumors in general, and for older-aged patients in
particular.  A question that is also central to the development of this research
initiative: Why do only some cancer patients exposed to the same risk factors
develop additional tumors?

Multiple primary tumors may occur in the same tissue or organ as the previous
cancer (e.g., skin, colon, bilateral breast, urinary bladder, oral cavity,
oropharynx, or multiple foci of occult carcinoma in the prostate) or affect
different tissues and organs. Moreover, initiation and promotion of
carcinogenesis differ in mode of induction, mechanism of action, and how these
processes are affected by host factors (age, sex, genetic constitution, hormonal
status, and immunologic functions) or by extrinsic influences (diet, lifestyle
habits, occupation, etc.).

Hormone dependent tumors may form a syndrome of different combinations of
synchronous or metachronous tumors of breast, ovarian, and endometrial cancers.
(6, 7)  Multiple tumors are noted in significant excess in respiratory and upper
digestive tracts and are probably related to shared risk factors such as smoking
behavior and/or alcohol consumption. (8)  There is an increased risk in
developing additional primary melanomas following the initial development of a
melanoma. (9)  Independent malignant lesions are frequently found in stomach and
colon cancers. (10)  A pattern of increased risk of colon cancer following a
breast cancer has been described. (11, 12)  Alkylating agents have been
associated with the development of  multiple tumors, for example, in the
lymphomas and leukemias. (7) The list could continue depending on the index tumor
under observation and the anatomic system.

International Registries.  Contributions from the epidemiologic studies conducted
in tumor registries that cover whole countries (e.g., Sweden, Denmark, Finland)
and geographic regions (e.g., Japan, Italy, the Netherlands) have demonstrated
the different problems that are connected with multiple tumors with data from
their well-defined population groups. (3, 13-14)  Cancer patients are at higher
risk for subsequent neoplasms than the general population.  Patterns of etiologic
cluster, positive and negative associations of different tumors, length of
follow-up time, and risk of a new primary are being investigated.  Pathology-
based registries take advantage of autopsy data to show the manifested and latent
risk of multiple tumors. (15)  Our nation and other countries are experiencing
or will soon experience a large expansion of their elderly populations. 
Currently, as in the United States, approximately 13% of the respective
populations of Japan and the Netherlands is 65 years and older.  In Denmark,
France, Italy, Sweden, and the United Kingdom, the present percentages of the
population aged 65+ range from 14% to 18%.  By 2030, the proportion of the 65+
for the United States is predicted to reach 20%.  This figure will be surpassed
in the countries in Europe just mentioned and in Japan.

Working Groups. An international working group on multiple primary tumors in the
elderly, sponsored by the NIA and the NCI, met at the NIH in Bethesda in June,
1996, and examined issues regarding the occurrence of multiple primary tumors in
older patients.  The working group assisted in planning for research that would
increase prospects for generating information to address risk, etiology,
precursor lesions, and environmental exposures with a focus on older patients.
Their recommendations for research on multiple primary tumors in the elderly
included conducting methodologic, descriptive, and analytic epidemiologic studies
using population-based surveillance data.  Such studies are expected to produce
insights for follow-on studies in etiology, genetic susceptibility, and
carcinogenic mechanisms applicable to older persons.

In a meeting of advisers to the NIA Geriatrics Program, January, 1997, the study
of multiple primary tumors in older patients was among the priority
recommendations discussed for integrating aging and cancer research.  Targeted
attention to the older age group for multiple primary tumors is important for
understanding the predisposition to cancer in general and for early detection of
second primaries. (16)

Consistent with the recommendations of these working groups, this PA encourages
studies to: (a) define the magnitude of the problem of multiple primary tumors
associated with aging and old age to estimate which cancer patients are at excess
risk for multiple primary tumors; (b) develop biostatistical and etiologic
methodology for assessment of multiple tumors in older-aged cancer patients; (c)
develop insights about cancer etiology and mechanisms of risk identification; (d)
ascertain modifiable host and environmental factors; and (e) determine key shared
predisposing factors to development of multiple tumors.

Research Goals and Scope

This PA is intended to attract those investigators engaged in cancer research to
conduct studies on multiple primary tumors in older persons and encourage
research interest of investigators who already have background and experience in
conducting studies on multiple primary tumors to include a focus on aging and
aged cancer patients in comparison to younger patients.  Use of existing data to
document the magnitude of the multiple primary tumor problem for older patients,
generate hypotheses, develop study designs and methodology to respond to this
research initiative are expected.  Epidemiologic resources such as population
databases, special tumor registries (e.g., family cancer registries), twin
registries, databases on longevity, and tissue and data resources for cancer
research, and other tissue banks may be applied to the multiple tumor problems
in older patients.  Investigations and a follow-up on cancer cohorts over time
may include independent or add-on investigations to tumor registration.

Analytical phases of projects proposed are encouraged to develop hypotheses
leading to research on the causes and natural history of the second cancer (e.g.,
pathogenesis; generation of biochemical and molecular biological assays to
predict second cancer risk; use of paraffin embedded tissue blocks to follow up
on biopsies over time; use of specimens from tissue network resources).

Targeted areas of research relevant to this PA are identified below.  These are
not exclusive and related issues designated by the applicant will be considered

o Innovative research projects to advance the methodology on assessment and
reporting of multiple tumor risk.

o  Intricacies of coding multiple primary tumors, sequencing multiple tumors, and
distinguishing recurrence from a new primary.  International variability in
reporting multiple primaries, the accuracy and reliability of reporting for all
ages at diagnosis, and the effect of population movement in and out of the
reporting catchment areas are of interest.

o  Definition and enumeration of multiple primary tumors in older persons as
compared to younger persons.  Do risks change and if so, why?

o Special technical, analytical, and study design considerations for
investigating multiple primaries in older patients (e.g., appropriate reference
population, the likelihood of a previous tumor experience prior to the index
tumor, which rates -- excess, absolute, or relative -- to use in comparing older
and younger patients, truncated periods of observation and censoring).

o  Validation of new and/or current methodologies to demonstrate the present and
future magnitude of the multiple primary tumor problem by age at diagnosis.

o  Investigations of individual differences in host susceptibility regarding
diagnosis of multiple tumors according to age.

o  Determination of key shared predisposing and/or protective factors to
different cancers that are common to and disproportionately high in older-aged
persons (e.g., breast, ovarian, colon, bladder, stomach, pancreas, lung,
lymphomas, leukemias, oral, oropharynx, and prostate).

o  Identification of syndromes (e.g., pairs, trios, etc. of similar or dissimilar
tumors occurring in older patients). Ascertainment of how often two tumors co-
occur in patients as they age.

o  Epidemiologic studies of age-related familial, genetic, and environmental
factors that may influence the risk of multiple primary tumors and duration of
cancer survival.

o  Ancillary studies conducted with existing databases that relate to aging,
race, and ethnic similarities and differences.

o  Studies that assess risk potential for treatment-induced multiple primary
tumors (i.e., anti-cancer agents, radiation).

Definitions. The age threshold of 65+ referred to in this PA and the words
"aging", "old age" and "elderly" do not restrict research to this subsegment of
the population.  While this research initiative advocates emphasis on multiple
primary tumors directed toward the target age group of 65 years and older,
comparative aging studies may be included. It is also recognized that within this
age group further distinctions may be made regarding the "young-old" (65-74), the
"older-old" (75-84) and the "oldest-old" (85+) and/or other age-specific
categories could be appropriate to the solicitation (e.g., five-year age groups).

Criteria for diagnosis of multiple primary tumors are based upon the
classification generally agreed upon derived from the early work of Warren S and
Gates O "Multiple primary malignant tumors.  A survey of the literature and a
statistical study." (17), and Moertel CG "Multiple primary malignant neoplasms. 
Their incidence and significance" (18). A concise summary of the criteria
(presented below) was described by Krausz T, Azzopardi JG, and Wright NA.
"Criteria for diagnosis of second cancer." (8).

Multiple primary malignant neoplasms of the same tissue or organ.
-- Multicentric lesions of the same organ.
-- Multicentric lesions of a paired organ.
-- Multicentric lesions of the same tissue in contiguous organs.

Multiple primary malignant neoplasms of different tissues or organs.
Multiple primary malignant neoplasms in a given organ (tissue) system plus a
lesion of an unrelated organ.

Multiple tumors are also classified chronologically.
-- Synchronous (simultaneous) -- two or more tumors are present at the same time.
-- Metachronous (interval) -- first tumor is followed by a second at a later
date.

Coding of multiple tumors is an important concern. Data sources for coding
multiple tumors may vary between the United States and other countries and
between registries in the same countries.  Investigators responsible for tumor
registries are aware of varying procedures.  All coding discrepancies should be
described and procedures for resolution presented in the applicant's grant
application.

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. These documents may also be obtained from the World
Wide Web at
http://www.nih.gov/grants/guide/notice-files/not94-105.html

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. This
policy applies to all initial (Type 1) applications submitted for receipt dates
after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at the following URL address:
http://www.nih.gov/grants/guide/notice-files/not98-024.html

NOTE:  Applications received in response to this program announcement are
expected to focus on scientific issues related to aging and to aging-related
aspects of certain major tumors that occur primarily in adults and older persons. 
In describing the study design proposed, investigators may cite a focus on aging
or on aging-related aspects of cancer as the justification for why children will
be excluded.  In this regard, applicants may use Justification 1, the tumors to
be studied are not relevant to children.

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.
4/98) 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 301-435-0714, email:
grantsinfo@nih.gov. Applications are also available on the World Wide Web at
http://www.nih.gov/grants/forms.htm

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
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.  In the
written comments, reviewers will be asked to discuss the following aspects of the
application 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 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 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 methods?
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.
Cancer Section, 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

Ann L. Sandberg, Ph.D.
Neoplastic Diseases Program
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-24A
Bethesda, MD  20892
Telephone:  (301) 594-2419
FAX:  (301) 480-8318
Email:  ann.sandberg@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. Bonnie Smith
Division of Extramural Affairs
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-38
Bethesda, MD  20892
Telephone:  (301) 594-4805
FAX:  (301) 594-8301
Email:  SmithB@de45.nidr.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.866, Aging Research; No. 93.394, Cancer Detection and Diagnosis Research; No.
93.395, Cancer Treatment Research; and No. 93.399, Cancer Control 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.

References

1.  Lee TK, Myers RT, Scharyj M, Marshall RB.  Multiple primary malignant tumors
(MPMT): study of 68 autopsy cases (1963-1980).  J Am Geriatr Soc. 1982;30
(12):744-53.

2.  Boice JD, Day NE, Andersen NE, et al.  Second cancers following radiation
treatment of cervical cancer.  An international collaboration among cancer
registries.  JNCI.  1985;74(5):955-75.

3.  Storm HH, Andersson M, Boice JD Jr, Blettner M, Stovall M, Mouridsen HT,
Dombernowsky P, Rose C, Jacobsen A, Pederson M.  Adjuvant radiotherapy and risk
of contralateral breast cancer.  JNCI. 1992;84(16):1245-1250.

4.  Rutqvist LE, Cedermark B, Glas U, et al.  Contralateral primary tumors in
breast cancer patients in a randomized trial of adjuvant tamoxifen therapy. 
JNCI.  1991;83(18):1299-1306.

5.  Berenbaum I.  Two-stage carcinogenesis and multiple cancers. In: Stoll BA.
Risk Factors and Multiple Cancer.  New York: John Wiley and Sons Ltd.; 1984:3-12.

6.  Barber HR.  Cancers of breast, uterus, and ovary.  In: Stoll BA. Risk Factors
and Multiple Cancer.  New York: John Wiley and Sons Ltd.; 1984:315-30.

7.  Schottenfeld D. Multiple primary tumors.  In: Schottenfeld D,  Fraumeni JF.
Cancer Epidemiology and Prevention. New York: Oxford University Press, Inc.;
1996:1370-1387

8.  Krausz T, Azzopardi JG, Wright NA.  Criteria for diagnosis of second cancer. 
In: Stoll BA. Risk Factors and Multiple Cancer.  New York: John Wiley and Sons
Ltd.; 1984:227-59.

9.  Bellet RE, Vaisman I, Mastrangelo MJ, Lustbader E.  Multiple primary
malignancies in patients with cutaneous melanoma.  Cancer.  1977; 40:1974-81.

10.  Janssen CW Jr, Lie RT, Marstmann-Moe H, Matre R.  Who gets a second primary
cancer after gastric surgery?  Eur J Surg Oncol.  1990;16:195-99.
11. Adami HO, Bergvist L, Krusemo U, Persson I.  Breast cancer as a risk factor
for other primary malignant diseases.  A nationwide cohort study.  JNCI. 
1984;73:1049-55.

12.  Schwartz AG, Ragheb NE, Swanson GM, Satariano WA.  Racial and age
differences in multiple primary cancers after breast cancer: a population-based
analysis.  Breast Cancer Research and Treatment.  1989;14:245-54.

13. Adami HO, Bergstrom R, Hansen J.  Age at first primary as a determinant of
the incidence of bilateral breast cancer.  Cancer.  1985;55:643-7.

14.  Teppo L, Pukkala E, Saxen E.  Multiple cancer - an epidemiologic exercise
in Finland.  JNCI. 1985; 75(2):207-17.

15.  Silvestri F, Bussani R, Cosatti C, Bosatra A.  High relative risk of a
second pulmonary cancer in patients affected by laryngeal cancer: differences by
specific site of occurrence and lung cancer histotype.  Laryngoscope. 
1994;104:222-5.

16.  Yancik R.  Integration of aging and cancer research in geriatric medicine. 
Journal of Gerontology: Medical Sciences, 1997, 52A(6):M329-M332.

17.  Warren S, Gates O.  Multiple primary malignant tumors.  A survey of the
literature and a statistical study.  Am J Cancer. 1932; 16:1358.

18.  Moertel CG.  Multiple primary malignant neoplasms. Their incidence and
significance.  Recent Results in Cancer Research. 1966:7.


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