NEWSLETTER OF THE NCI DIVISION OF CANCER PREVENTION

1

The core mission of the

Division of Cancer

Prevention (DCP) is

to conduct and support research to

improve the health of

the public by decreasing the incidence, mortality, and morbidity of cancer. Throughout

medical history, many of the improvements

in health have derived from advances in public health science and prevention. DCP continues in that tradition. Each component of

our Division is an integrated part of the

whole, starting with basic discoveries in

nutrition, chemoprevention, and molecular

markers. The goal is application to prevention, early detection, and survivorship; and

the most efficient and definitive test of the

true worth of the applications at the population level is the large scale clinical trial. 

We have championed definitive testing of

discoveries from a broad range of disciplines

such as epidemiology, molecular biology,

medical oncology, and clinical diagnostics in

definitive prevention and screening trials.

The Breast Cancer Prevention Trial represented the first time in history that a medical

intervention was definitively shown to

decrease the incidence of a common cancer.

In that sense, our Division has already written an important chapter in medical history.

And much more history remains to be written by us. Efforts continue for a number of

very high profile diseases that afflict

Americans: cancers of the colon, lung,

prostate, breast, ovary, cervix, and others.

Our efforts are important to the public,

which places strong emphasis on primary

prevention of cancer. Some of our pioneering

studies are described in this issue of the

PreventionPOST. They are palpable evidence

of what our dedicated staff can accomplish

and of what the future can hold. ■

From the Top B ARRY KRAMER

Deputy Director, DCP

ur business in DCP is prevention—cancer prevention to be exact. When we think of

prevention, we think about ways of frustrating cancer, of putting obstacles in its

path. But how do we know what works and what doesn’t work? That’s where the

clinical trials of DCP come into play. Clinical trials allow for rigorous scientific evaluation

of medical interventions, including chemopreventive agents, screening modalities, and cancer treatment regimens. Because DCP is an extramural division, we administer a plethora of

trials, some small and others quite large. Clinical trials are among the most important cancer prevention research being conducted in the world today. 

DCP’s trials often focus on primary prevention, i.e., strategies for reducing the incidence

of disease. Chemoprevention – administration of a pharmaceutical agent to reduce cancer

risk – is a major focus. One of DCP’s historically important endeavors, the Breast Cancer

Prevention Trial (BCPT), examined whether daily administration of 20 milligrams (mg) of

tamoxifen (brand name, Novaldex®) for 5 years reduced breast cancer incidence in women

at high risk of the disease. BCPT began in 1992 and randomized, in a double-blinded mancontinued on page 2

IN THIS ISSUE

From the Top 1

The Trials of DCP 1 

History of Cancer Prevention 2

Project Teams 3

Individual Spotlight 5 

Cancer Prevention Fellowship Program 6 

Prevention POST Credits 7 

Special Thanks 7

DCP Winter Bash! 8

Effects of the COX-2 Inhibitor 

Celecoxib in Patients with Familial

AdenomatousPolyposis: 

Anatomy of a Prevention Trial 10

DCP Websites 10

Transitions 11

The NCI Office of 

Management Analysis 12

Administrative Resource Center 13

Endpoints 16

June 2000

V O L UME 2/ISSUE 1

NEWSLETTER OF THE NCI DIVISION

OF CANCER PREVENTION

PreventionPOST

The Trials of DCP

P AMELA MARCUS

O
The first half of the Twentieth Century was a

time of remarkable progress in medicine and in

statistics. The discovery of antibiotics effective

against syphilis, puerperal sepsis, pneumonia,

malaria, and tuberculosis changed the way

medicine was practiced and improved the

health of many communities. During this same

period, the methods used to assess the efficacy of medical interventions evolved from relatively simple deterministic models to the probabilistic models so familiar today. Inferences

from clinical studies on single-arm series of

patients were enhanced by the use of historical

controls and by efforts to

make controls as similar as

possible to treated cases.

Randomization came into vogue

relatively late in this era. Two small

(and null) randomized trials, in 1931 and

1943, went virtually unnoticed. But in 1948, a

successful trial of streptomycin for pulmonary

tuberculosis was published in the British Medical

Journal by the Medical Research Council (MRC).

Austin Bradford (Tony) Hill (see photo page 3)

was Director of the Statistical Research Unit of

the MRC at the time, as well as Professor of

Statistics and Epidemiology at

the London School of Hygiene

and Tropical Medicine, a position

recently vacated by Hill’s mentor,

Major Greenwood (see photo left).

These two pioneers of statistics and epidemiologic methodology laid down the foundation for what is now considered a scientific paradigm: the randomized clinical trial. 

Greenwood trained as a physician and

undertook a research career under the tutelage of Leonard Hill (Austin Bradford Hill’s

HISTORY OF CANCER PREVENTION

Pioneers of Progress: Major Greenwood, Austin

Bradford Hill, and the Development of the

Randomized Clinical Trial (1900-1950)

DOUGLAS L. WEED

continued on page 3

Major Greenwood

(Courtesy of the National

Library of Medicine)

2 PreventionPost JUNE 2000

ner, over 13,000 women to either tamoxifen or placebo. In

mid-1998, investigators reported a significant 49% decrease

in breast cancer incidence for the group taking tamoxifen,

and in October of that year, the Food and Drug

Administration (FDA) approved tamoxifen for prevention

of breast cancer in high-risk women. Tamoxifen remains the

only drug approved by the FDA for reduction of risk of

breast cancer in high-risk women. 

Another pharmaceutical, raloxifene (brand name,

Evista®), currently is challenging tamoxifen in the Study of

Tamoxifen and Raloxifene (STAR). Raloxifene is a potentially promising breast cancer chemopreventive agent, having been observed to reduce breast cancer incidence by 76%

in a clinical trial designed to assess its usefulness in the prevention and treatment of osteoporosis. STAR opened enrollment in May, 1999 and will randomize, in a double-blinded

manner, around 22,000 post-menopausal women to either

20 mg of tamoxifen daily or 60 mg of raloxifene daily for 5

years. In addition to assessing whether raloxifene does as

good a job as tamoxifen at reducing breast cancer incidence, a major focus of STAR is to compare the long-term

safety of the agents. Tamoxifen is known to, and raloxifene

may possibly, increase risk of deep vein thromboses and

pulmonary embolisms (blood clots); both side effects can be

fatal. Tamoxifen also is known to increase the risk of

endometrial cancer. 

Prostate cancer chemoprevention also is under study in

DCP. The Prostate Cancer Prevention Trial (PCPT) is currently examining whether finasteride (brand name, Proscar®)

can reduce prostate cancer incidence. Finasteride was

approved by the FDA in 1993 for the treatment of benign

prostatic hyperplasia (BPH), and although never previously

used to prevent cancer, the drug reduces levels of dihydrotestosterone, a male hormone believed to be involved in

prostate cancer development. PCPT began in 1993, closed

enrollment in 1996, and randomized 18,882 healthy men

aged 55 and older to receive either 5 mg of finasteride or

placebo daily for 7 years in a double-blinded manner. The

PCPT is in full swing right now, with the first enrollees

scheduled to finish their drug regimens in October of this

year. Final results are expected towards the end of 2003 or

in early 2004.

Another trial of prostate cancer prevention is in its startup phase. The Selenium and Vitamin E Clinical Trial

(SELECT) will randomize 32,400 healthy middle-aged and

elderly men to one of four daily supplement regimens.

SELECT will use a factorial design, with participants receiving one of the following regimens: 200 micrograms (μg) of

selenium, 400 mg of vitamin E, 200 μg of selenium and 400

mg of vitamin E, or only placebo. Both selenium and vitamin E have shown promise as chemopreventive agents for

prostate cancer in clinical trials designed to assess the effects

of those agents on other cancers. A Request for

Applications (RFA) was issued in 1999; study center applications were due this past February. SELECT is expected to

randomize its first participant in the fall of 2000. 

Prevention also can be accomplished through the use of

mass screening programs. The goal of these programs is to

reduce the death toll from cancer by identifying cancerous

lesions earlier, at a time when tumors are asymptomatic and

Trials of DCP continued from page 1

continued on page 12
NEWSLETTER OF THE NCI DIVISION OF CANCER PREVENTION

3

As DCP’s matrix-based organization evolves, project

teams (a.k.a. “eggs”) are growing in number and

scope. Project team members join together to tackle

specific tasks in the Division. Projects suitable for team

work include the following: planning research initiatives,

coordinating workshops to address particular topics, and

addressing administrative issues important to the Division’s

mission. Project teams also provide a mechanism for DCP

staff to collaborate with outsiders who have an interest in

the Division’s activities. Staff from other NCI Divisions,

DCP advisory groups, representatives from other Federal

agencies, extramural researchers, and others are often invited to participate in project teams. 

If are you reading this article, you may know about the

DCP Newsletter Project Team, but what about the others?

(See list of project teams in side box.) 

EGGS Database

Creating a project team involves obtaining the sponsorship

of a Coordinating Unit member, recruiting members, and

submitting a proposal to the Coordinating Unit for

approval. The process includes completing the Project

Team/Capsule Concept Proposal form. Karen Johnson leads

a team with the task of developing EGGS, the project team

database. This database will manage information about

Division project teams. When it is completed, DCP staff will

be able to access the database to find out what’s happening

on the project teams. 

Selected Project Teams (Team Leaders)

Cancer Genome Anatomy Project - CGAP (Barbara Dunn)

EGGS Database (Karen Johnson)

Prevention of Languishing Studies (Jaye Viner and 

Rose Mary Padberg)

HPV Vaccine (Terri Cornelison)

Assessment of Spiral CT (John Gohagan)

DCP Newsletter (Doug Weed) 

Ovarian Cancer Prevention (Karen Johnson)

Molecular Targets for Dietary Prevention of Prostate Cancer 

(Carolyn Clifford)

Molecular Signatures of Infectious Agents (Sudhir Srivastava)

Single Nucleotide Polymorphisms (Iqbal Ali)

Non-scientific Staff (Felicia Carr)

Protocol Review Project (Lori Minasian)

Assessment of Spiral CT

DCP has formed a project team to evaluate the feasibility of

conducting a randomized clinical trial (RCT) of low-dose

spiral (helical) computed tomography (CT) as a screening

modality for lung cancer. Currently no lung cancer 

screening modality is recommended by any organization.

However, chest x-ray is being evaluated in the PLCO trial.

During the last decade, progress in diagnostic imaging

established high-resolution computed tomography (HRCT)

as the standard of practice for assessing lung abnormalities

observed on chest x-ray. Low-dose spiral CT as a technologProject Teams

JENNIFER FLACH

father). He learned mathematical statistics from Karl

Pearson at University College, London. His research

interests were broad by today’s standards, ranging from

vital statistics to experimental epidemiology (in which

epidemics were observed in mouse populations under

controlled conditions). He studied industrial accidents,

nutritional deficiencies, the physiologic effects of compressed air, and theoretical statistics. On the subject of

cancer, Greenwood wrote in a 1935 textbook that statistical

and epidemiological methods had reached no clear-cut

conclusion of general etiologic importance. He was convinced nevertheless that cancer prevention was a likely

reality. He described cancer mortality differences in different social

classes and for cancers of the “upper part of the alimentary canal.”

Greenwood proposed that some as-yet-unknown manipulable exposure

was responsible for the differences observed. We recognize today that

smoking may have been the culprit, as Greenwood’s student, Tony Hill,

would later study in a large cohort of British physicians, a

study he collaborated on with Richard Doll. Hill intended

to study medicine but gave it up after a long convalescence for tuberculosis acquired in World War I. He studied economics, then statistics (also under Karl Pearson)

and worked with Major Greenwood at the MRC. His

series of papers in Lancet (1937) were eventually published as one of the first textbooks of medical statistics. In

1948, and for several years following, Hill rode a remarkable

wave of interest in randomized trials, publishing papers on

their conduct, ethics, and statistical analysis. Hill’s contribution to the design and conduct of randomized clinical trials

was judged by some to be as valuable as the discovery of penicillin.

Today, the randomized trial remains our methodologic gold standard,

thanks in great measure to the remarkable work of Major Greenwood

(1880-1949) and Austin Bradford Hill (1897-1991). ■

Pioneers of Progress continued from page 2

Sir Austin Bradford Hill

continued on page 4
4 PreventionPost JUNE 2000

ical refinement of spiral CT utilizes the simultaneous

smooth, continuous movements of a rotating x-ray tube and

horizontally moving x-ray table to produce views of the

lung. This technology permits continuous rapid acquisition

of images of multiple thin sections of an entire chest in a

single breath hold, typically about 15 seconds. The Lancet

published the baseline results from the Early Lung Cancer

Action Project (ELCAP), a study that explores the ability of

low-dose spiral CT to detect lung cancer lesions. A randomized control trial is needed to assess the mortality impact of

lung cancer screening by spiral CT. The Spiral CT

Assessment Project Team includes members from the

EDRG, BRG and OD of the Division of Cancer Prevention.

Cancer Genome Anatomy Project (CGAP)

The CGAP Project Team is tapping into the resources of the

NIH Cancer Genome Anatomy Project. The CGAP is an

interdisciplinary initiative for the development of informatics and scientific tools needed to decode the molecular

anatomy of the cancer cell. The focus of the CGAP project

team is to investigate the differential expression of genes in

precancerous versus normal (or at-risk normal appearing)

tissue in human and animal models. Results of these investigations will provide insight into the mechanisms of carcinogensis and be used in the development of new chemopreventive agents. Barbara Dunn of the Basic Prevention Science

Research Group leads the team, which includes members

from a variety of DCP research groups as well as external

members involved in the CGAP. The team plans to implement pilot projects that will lead to larger research endeavors such as Program Announcements and Requests for

Applications.

HPV Vaccine 

The Human Papilloma Virus (HPV) Vaccine Project Team

was created to implement recommendations resulting from

a September 1998 meeting on cervical cancer and HPV vaccines. HPV is associated with the development of up to

95% of cervical cancers. Prophylactic vaccines for HPV

have shown feasibility in animal models, leading to investigations in humans. The team is reviewing the efficacy endpoints for therapeutic/preventive vaccines for HPV, working

with clinical trials cooperative groups to identify potential

study populations, working with researchers in DCEG to

plan a prevention trial of an HPV vaccine in Costa Rica,

and exploring collaborations with industry. DCTD, DCEG,

and FDA are also represented on the project team. Terri

Cornelison, Breast and Gynecologic Cancers Research

Group, is the team leader. 

Nonscientific Staff

The Nonscientific Staff Project Team was one of the earliest

project teams started in the Division. This team was created as

a way for nonscientific staff to be more involved in planning

and coordination of administrative support functions of the

Division, such as preparing travel, training new administrative

staff, and meeting planning. Felicia Carr, the team leader,

explained that the team wants to “be out there, to be helpful

to scientific staff.” In particular, the team offers its expertise to

research groups needing help in the reorganization.

Protocol Review

One of the primary functions of the Division of Cancer

Prevention is the scientific, regulatory, and administrative review

of clinical protocols and concepts it sponsors. In the past, the

Community Oncology and Prevention Trials Research Group

and the former Chemoprevention Branch conducted separate

protocol reviews. After DCP’s reorganization, the work of the

Chemprevention Branch was spread across several research

groups and it became apparent that a centralized review function was needed. In June of 1999, the Protocol Review Process

Project Team was formed to explore existing procedures for

reviewing clinical protocols and make recommendations for

coordinating and streamlining review efforts. Linda Parreco was

hired to head a centralized Protocol Information Office (PIO)

for DCP, in the Office of the Associate Director for Clinical

Research. She credits the Protocol Review Project Team for laying much of the groundwork for the creation of the PIO. “The

vision for the PIO was to create a single process whereby Phase

I-III clinical research concepts and protocols, regardless of funding sources, are reviewed in a centralized process,” said Linda.

“We see the PIO development process as a tangible growth

opportunity for the Division. It forces us to have a clear vision

of what research we want, what we want it to look like, and

how we will evaluate it,” she added. ■

continued on page 15

DCP home base: Executive Plaza 

Project Teams continued from page 3
NEWSLETTER OF THE NCI DIVISION OF CANCER PREVENTION

5

INDIVIDUAL SPOTLIGHT

The Individual Spotlight

goes to Karen Johnson,

newly appointed Chief

of the Breast and Gynecologic

Cancer Research Group, and

Sudhir Srivastava, newly

appointed Chief of the Cancer

Biomarkers Research Group. 

Karen Johnson is a medical

oncologist and Maryland

native. She received her first

diploma from Miss Welch’s

Jack and Jill Kindergarten,

Chestertown, Maryland, and

“was so pleased with that diploma that I kept trying to get

more”. She completed a Ph.D. in inorganic chemistry at the

University of Delaware, was a medical student at Jefferson

Medical College, Philadelphia, resident and oncology fellow at

Georgetown University Hospital, and received her M.P.H.

from The Johns Hopkins University. Dr. Johnson’s areas of

interest are breast and ovarian cancers.

Who were your most influential teachers? My parents. 

They were both school teachers, and they started my

instruction early.

What world event had a major effect on your life? The

assassination of John F. Kennedy, because it confirmed

fatalism.

How do you relax? Reading fiction and antiquing.

What is your favorite play? She Stoops to Conquer, by

Oliver Goldsmith (1728-1774), because it makes you laugh.

What is your favorite book? The End of the Pier, by

Martha Grimes. It is well constructed and poignant in

understanding life.

Who is your favorite author? Thomas Hardy.

What is your favorite sound? A child’s voice.

What is your favorite vegetable? Garden tomatoes.

What is your favorite sport? As a participant, tennis; 

as a spectator, ice skating.

What is your greatest accomplishment to date?

Just surviving, hopefully with grace; and not yet having

become an embarrassment to my young nieces aged 7 

to 15!

Sudhir Srivastava, who has been at the NCI since

1987, was born in Azamgarn, India, and immigrated to the United States in 1977, after obtaining a

Ph.D. at age 23 from Banaras Hindu University in biological science. In the U.S., he obtained two masters’

degrees: one in computer science from Virginia

Commonwealth University (VCU) and one in public

health from The Johns Hopkins University. Dr. Srivastava

taught in the Department of Physiology and Biophysics at

VCU for five years before his interest in prevention

research brought him to the NCI. Dr. Srivastava is the

youngest, non-clinical and first Asian-American elected to

the prestigious American Joint Committee on Cancer. His

specific research interest is

molecular detection and

screening of cancer.

What has had the most

effect on your work? Family

members afflicted with cancer. My cousin has gallbladder cancer, and my aunt had

cervical cancer.

What event had the most

effect on your life? My

mother’s death. I shared my

glories and agonies with her.

I was so inspired by her

strength and dignity through her own struggles that I was

able to carry on.

What is your best advice for young investigators in cancer

prevention medicine? Be persistent and dedicated to 

prevention research, as this is still an evolving field and

answers may not be apparent soon.

What are your favorite books, and why? Biographies of

President John F. Kennedy and Mahatma Gandhi (Mohan

Das Karam Chand Gandhi). Both are inspirational with

forward-looking ideas.

What is your favorite sound? Flowing river.

What is your favorite vegetable? Okra.

What do you hate the most? Waiting.

What place have you never been to that you would like

to visit? Africa. I would like to go on a Safari.

What is your proudest moment? Succeeding in my belief.

What is your greatest accomplishment to date? The successful launching of the Early Detection Research Network. ■

Congratulations!

TERRI L. CORNELISON

Karen Johnson

Sudhir Srivastava
6 PreventionPost JUNE 2000

At the Forefront of Training SUSAN WINER

The Cancer Prevention Fellowship Program (CPFP)

has been busy. In November, twenty-eight applicants

were interviewed for the Fellowship Program, Class

of 2000. This is a new record! Fifteen offers were extended

and 15 were accepted. During the three day interviewing

process, we invited three former Fellows to give a lecture as

part of the ongoing DCP Colloquia series: Karen Kafadar,

PhD (University of Colorado at Denver), Florence Houn,

MD, MPH (FDA), and Ann Coleman, PhD (University of

Arkansas for Medical Science).

The new class of Fellows includes:

Erik Augustson, PhD, University of Alabama; Alexis B.

Bakos, PhD, Johns Hopkins University School of Nursing;

Jagjit S. Gill, PhD, Mayo Graduate School; Elizabeth Jones,

MD, Clinical Center, NIH; La Creis Kidd, PhD, Johns

Hopkins University School of Public Health; Kerri

McGowan Lowrey, JD, Division of Cancer Control and

Population Sciences, NCI; Theodore Marcy, MD, University

of Vermont College of Medicine; Leah Mechanic, PhD,

University of North Carolina at Chapel Hill; Pauline

Mysliwiec, MD, Indian Health Service/Phoenix Indian

Medical Center; Dina Paltoo, PhD, Morgan State

University; Mark Parascandola, PhD, Clinical Center, NIH;

Heather Poetschke, PhD, University of Texas, MD

Anderson Cancer Center; Susan Steck, PhD, MPH,

University of North Carolina at Chapel Hill; Susan

Thomas, PhD, Indiana University; Janet Tooze, PhD,

University of Colorado Health Sciences Center; and Maja

Zecevic, PhD, University of Virginia Cancer Center. Nearly

all of these new Fellows will first be obtaining Masters of

Public Health (MPH) degrees at schools of public health

around the country.

Just completing their MPH’s are 8 second year Fellows who

will be joining us at the NCI in June. They will begin their

training by attending summer prevention courses and after

will include work with an approved NCI preceptor. These

fellows include: 

David Berrigan, PhD, MPH (exp.), University of California, 

Berkeley

Philip Castle, PhD, MPH (exp.) Johns Hopkins University 

Graça Dores, MD, MPH (exp.) University of Alabama at 

Brimingham

Mollie Howerton, PhD, MPH (exp.), Johns Hopkins 

University

Claudine Kavanaugh, PhD, MPH (exp.), Johns Hopkins 

University

Jackie Lavigne, PhD, MPH (exp.), Johns Hopkins 

University

Volker Mai, PhD, MPH (exp.), Harvard University

Pothur Srinivas, PhD, MPH (exp.), Johns Hopkins

University

Also joining this group are two new Fellows who previously

received their MPH’s: Elizabeth Jones, MD, PhD (exp.)

Johns Hopkins University and Susan Steck, PhD, MPH

University of North Carolina, Chapel Hill.

New Course in Grants and Grantswriting

In January, as part of the growth of the Fellowship

Program, a new course was offered, Grants and

Grantsmanship Workshop. This new course was created to

teach our Fellows the ins and outs of grant writing. For

those Fellows who plan to return to academia, grantsmanship is an important career development tool. Guest lecturers for the course were current NCI grantees Shine Chang,

PhD and Maureen Goode, PhD from the University of

Texas, M.D. Anderson Cancer Center and Ginger Krawiec,

MPA from the American Cancer Society headquarters in

Atlanta, Georgia. Also presenting at the course were Sherry

Mills, MD, MPH, Suresh Mohla, MD, PhD, and Lisa Begg,

PhD, all from the NCI. Each Fellow was asked to prepare a

2-page grant. Mac Stiles, DDS, PhD, MPH, of NIH’s Center

for Scientific Review, NIH, held a mock study section for

the grant applications. The course was a great success and

several of the Fellows suggested that a grant writing club be

formed. A volunteer writing club that meets twice a month

has been set up. Currently, 8 Fellows are in the club. Steve

Hursting is the mentor for this group.

Janet Newburgh shows

Charisee Lamar 

and Pam Mink a typical

delivery of grant 

appications at CSR.

Christian Abnet, Steve

Hursting, Rachel

Stolzenberg-Solomon,

Beth Dixon, Heng Xie,

Lisa Colbert and

Christine Sweeney

examine examine 

applications as 

Dr. Newburgh explains

the assignment.

C ANCER PREVENTION FELLOWSHIP PROGRAM 
DCP Newsletter Project Team

EDITORIAL GROUP:

Doug Weed (Editor-in-Chief), 

Pamela Marcus, Judy Smith, Dee Sullivan

GRAPHIC ARTS GROUP:

Terri Cornelison, Jennifer Flach

DISTRIBUTION & INTERNET GROUP:

Ron Lubet, Michelle Nestorio, Susan Winer

CONTRACT & LIAISON GROUP:

Don Henson, Pamela Marcus

Special thanks go to Cancer Prevention Fellow Graça Dores, MD, MPH

(exp.), our resident cartoonist. Dr. Dores was the Director, Special

Hematology/Oncology Laboratory at the Memorial Hospital in

Providence, Rhode Island before her acceptance into the NCI Fellowship

Program. Graça went to the University of Alabama in Birmingham for her

MPH. She will be relocating to the DC area to begin the second year of

her Fellowship at the NCI.

Also, very special thanks go to Linda Bremmerman and Eric Graves

for their enthusiasm and tireless effort in producing the first edition 

of PreventionPOST. Please welcome the newest member of the team,

Judy Smith, RN, MSN, AOCN. Judy is part of the Lung and Upper

Aerodigestive Cancer Research Group.

SPECIAL THANKS

NEWSLETTER OF THE NCI DIVISION OF CANCER PREVENTION

7

As part of the course, Fellows visited the Center for

Scientific Review (CSR). Dr. Janet Newburgh, Referral Officer,

Center for Scientific Review, gave the Fellows a first-class tour

of the facilities from the receiving dock at the back door of the

building to the room that codes and assigns each and every

submitted grant. The Center for Scientific Review receives all

NIH grant applications, and then codes and distributes each

grant to the appropriate Institute and Division.

Summer Curriculum

In July, we start our summer short courses in cancer prevention. This year several changes have taken place. First, we

have a new name for this activity: the NCI Summer

Curriculum in Cancer Prevention. We also have divided the

course into 2 parts. The first part, Principles and Practice in

Cancer Prevention and Control, will be held from July 5 to

August 4. The second part, Molecular Prevention, will be held

from August 7 to August 11. Also, we have new topics and

new lecturers. In addition, we have added a special feature 

to this summer activity—the First Annual Advances in Cancer

Prevention Lecture. This summer’s speaker is Bernard Levin,

MD, from The University of Texas, M.D. Anderson Cancer

Center. This lecture will be held in the Lister Hill 

auditorium (NIH main campus), on Thursday August 3rd at

3:00 p.m. All are invited to attend.

Our widely popular summer course attracts a variety of

attendees. Every summer the NCI’s Office of International

Affairs sponsors a number of interested clinicians and

researchers from developing countries. These attendees come

primarily from Asia, Eastern Europe, South America, and

Africa. Our 2nd year Fellows and other interested people

complete the audience. If you would like to attend all or any

part of these courses, please contact our office at 301-496-

8640 and we will happily to assist you. 

Interview with a former Fellow

In November, 1999, one of our graduates,

Diana Jeffery, PhD, joined the NCI as a

Health Scientist Administrator/ Program

Director in the Division of Cancer Control

and Population and Sciences. She will

administer 30-40 grants, mainly R01s.

Diana was a Fellow from 1986-88, back

when the Fellowship Program was referred

to as the Cancer Control Science

Associates Program. The program is now called the Cancer

Prevention Fellowship Program.

When you left the NCI, where did you go?

I left the Program and went to the Department of

Epidemiology and Biostatistics, Memorial Sloan Kettering

Cancer Center in New York. Then in 1989, I went to the

Nursing Research Center, Vanderbilt University School of

Nursing as an Assistant Professor and Assistant Director. 

At the same time I was the Associate Director of Nursing,

Nursing Research, Veterans Hospital in Nashville,

Tennessee. In 1995, I joined the Hawaii State Health

Department in the Epidemiology Department. Taking on 

the duties of a Clinical Psychologist in 1998, I worked at

the Kapiolani Women’s Center in Honolulu.

The group looks at the

shelves soon to contain

applications assigned to

an institute for review.

Diana Jeffery

continued on page 9
8 PreventionPost JUNE 2000

Peter Greenwald, Mary Lou Carter, Barbara Redding and Susan Winer.

From trail mix to fresh asparagus to tiny toast, there

was something for everyone at this year’s DCP winter

party. Held on the afternoon of Friday, January 21st

at the home of DCP’s very own Dave Levin, more than 60

DCP’ers stopped by to munch, mingle, and catch up with

their colleagues. The Biometry Research Group, charged

with organizing the party, did a fantastic job, due in particular to the hard work of Vance Berger, Christine Donati,

Richard Fagerstrom, Jenny Gaegler, Grant Izmirlian, Dave

Levin, and Pam Marcus.

In between the socializing, guests enjoyed a wide variety

of snacks. On the menu were nutritious finger foods,

including plenty of those fruits and veggies to help everyone

reach that 5-a-day goal! Cheeses were available, as were

tasty dips, pasta salads, and hot apple cider. For those looking to cheat on their diets, cookies and chips also could be

found. It was a party, after all!

Live entertainment was provided by DCP’s Grant

Izmirlian and his friend Russell Sledge. Grant, on the sax,

and Russell, on the bass, jammed on jazz classics, including

“Blue in Green,” a Miles Davis classic, and “Donna Lee,”

made famous by Charlie Parker. After Russell’s departure,

Grant switched over to the piano, entertaining guests with

his rendition of Scott Joplin’s Maple Leaf Rag and Bach’s

Goldberg Variations. 

Door prizes also were a part of this year’s DCP party.

Harriet Greenwald, in a very fair and high-tech manner,

pulled names from a glass fish bowl. Barbara Dunn of the

Basic Prevention Science Research Group won a gift certificate to Giant, and Gary Kelloff of the Chemopreventive

Agent Development Group won a potpourri mat. The other

prizes—a chocolate rose and a gift certificate to Fresh Fields

—went to Don Corle and Jenny Gaegler, both of Biometry.

Questions were raised regarding the preponderance of winners from the research group responsible for organizing the

party, but Biometry statisticians, as to be expected, were

quick to attribute it to chance. ■

DCP Winter Bash!

P AMELA MARCUS

Barry Kramer, Peter Greenwald, Karen Johnson, Richard Fagerstrom,

and Phil Prorok share a laugh while munching and drinking cider.

Carolyn Clifford and

Leslie Ford chat.

Temugen Wallace enjoys fresh

steamed asparagus.

Socializing in the sun room, from left to right: Linda Gray, Judy Binstock, Ned

Englund, Gloria Rasband, Mukesh Verma, Andrew Hruszkewycz, Vance Berger,

Peter Greenwald.
NEWSLETTER OF THE NCI DIVISION OF CANCER PREVENTION

9

Winter Bash!

What brought you back to the NCI?

I was not particularly happy with managed care and decided to look around and I saw the opening advertised in the

American Psychological Association’s magazine, the

Monitor. This is just what I wanted to do; I sent in my

application, interviewed, and got the job.

What changes have you noticed in the 

Fellowship Program?

A lot of changes have been made. In the beginning, only

MDs could get an MPH degree and Fellows had a GS rating. You had to have your PhD for two years before applying to the Program. There were 3 people in the class and we

had 6 months of intense classroom instruction. When the

course was completed, we were heavily recruited by all of

the Divisions. I did site visits, went to grant reviews, and

had homework every night. Our program leader, Dr. David

Poskanzer, was in charge of the training and the branch and

almost all of our lecturers were from NCI.

What do you see in the future for cancer prevention?

I would like to see more behavioral work and more research

done on survivors, especially in under-served populations

including the elderly. The quality of care for the elderly with

cancer is a special concern, as is public policy and the HMOs.

Recruitment

The Cancer Prevention Fellowship Program has recently

begun a major recruitment effort for the Fellowship

Program. In early March, Susan Winer set up a booth at the

Johns Hopkins University School of Public Health’s

Marketplace 2000 Career Fair. Former Hopkins graduates

Rita Misra, PhD, MPH and Christine Sweeney, PhD, MPH,

helped to answer questions. Our current Hopkins students

also stopped by. Later in the month, Susan set up a recruitment exhibit for the Fellowship Program at the Prevention

2000 meeting held in Atlanta. Over 500 people attended the

meeting. The NCI has a large display booth that is on display at many of the large research meetings. Our brochures

and information on the Fellowship Program are prominently displayed.

About the Fellows

Many of our Fellows continue their careers by joining the

NIH. Joining the NCI recently are Karen Woodson, PhD,

MPH and Luke Ratnasinghe, PhD, MPH in the Division of

Clinical Sciences. Samir Sauma, PhD, MPH is now working

in the Office of Science Opportunity, Office of the Director.

Maria T. Canto, DDS, MPH recently joined the National

Institute of Dental and Craniofacial Research.

Congratulations and best wishes for their continued success!

Special congratulations go to three former Fellows,

Rosalind Breslow, PhD, MPH; Pamela Marcus, MS, PhD;

and Stephen D. Hursting, PhD, MPH, who presented at the

Plenary Session of the American Society of Preventive

Oncology meeting, held in Bethesda, MD, on March 5

through 7. Their papers were among the top 5 abstracts

submitted. Also presenting an abstract was current Fellow,

Rachel Stolzenberg-Solomon, PhD. Her abstract was selected as one of the top 16 submitted. The poster sessions were

well represented by both current and former Fellows.

Current Fellows Lisa Colbert, PhD, MPH and Kathy

Radimer, PhD, MPH had posters, as did two former

Fellows, Sharada Shankar, PhD, MPH and Ann Coleman,

PhD. who received an Honorable mention in the Best Poster

award. In addition to presenting at the Plenary Session,

Steve Hursting also had a poster on display.

At the 1999 ASPO meeting in Houston, TX, two of the

five plenary talks were from former Fellows, Karen

Woodson, PhD, MPH and Steve Hursting, PhD, MPH.

Dr. Hursting, the Deputy Director of the Cancer Prevention

Fellowship Program, was also a plenary speaker at the 1998

ASPO meeting.

All in all, our Fellows have done a terrific job at the

ASPO meetings!

Congratulations go to Kevin and Kimberly Knopf on the

birth of their second child, a daughter, Sarah Bingham.

Sarah is welcomed to the family by her brother, Nathaniel.

Did you know that Christian Abnet, PhD, MPH, has a

license to perform marriages? When asked what his motivation was for applying for the license, Christian said that he

did it to be able to legally perform a friend’s wedding. ■

Dave Levin shows Ping Hu the merits

of his kitchen appliances.

Victor Kipnis, Rose Mary Padberg, Shannon Brandon, 

and Barry Portnoy enjoy the fine fare and good company.

Cancer Prevention Fellowhsip Program continued from page 7
Want to learn about the research activities in DCP?

Then check out its website! The DCP Homepage

(http://dcp.nci.nih.gov) contains links to key division

activities, function statements, e-mail addresses, Division

reports, and other useful information. A chart of the new

organizational structure is even available. Designed as an

image map, the chart actually simplifies finding websites. 

A click on the name of any organ based or foundation

research group will bring up its site. Practically everything

you want to know about DCP is on the Website.

PreventionPost is even available. 

The DCP site is maintained by our Webmaster, Dr.

David Levin of the Biometry Research Group, who can

update pages from his personal computer. Initiated four

years ago, the DCP website was one of the first developed 

at NCI. At that time (we were part of DCPC) each Branch

assumed responsibility for maintaining its section of the

web. Dr. Susan Rossi helped develop many of the original

homepages, including those for PLCO.

As the NCI moved forward with its web development,

additional options for maintaining web pages became available. The current DCP website is a combination of pages

maintained directly by individual research groups, by Dr.

Levin, by Mr. Eric Graves of our Administrative Resource

Center (ARC), by NCI contractors, and others. An effort is

currently underway to coordinate all DCP pages to insure

that they contain up-to-date information and conform to

NCI web standards. The Early Detection Research Network

(EDRN) has already adopted NCI standards for its site. 

The web pages bring a wealth of information. They contain, for example, information about our research activities

and links to key sites. Literature searches can be done

through DCP’s library website. Articles from on-line journals

can be downloaded or books located in the library.

Prevention research initiatives can be found on the

Chemopreventive Agent Development Research Group’s

(CADRG) website. Through its site, Biometry can download

programs to consumer audiences including statistical routines

and data bases. The site developed by the ARC serves as a

bulletin board. Questions about travel, procurement, personnel or other topics can be submitted through the site. The

questions and answers are posted for all to see. Some sites

even have photographs of staff, which adds a personal touch.

There are multiple links to sites critical for DCP staff.

The DCP Library, for example, has links to the Library of

1 0 PreventionPost JUNE 2000

DCP Websites

DONALD E. HENSON

continued on page 11

continued on page 14

The headline in the January 17, 2000 Science section

of the New York Times read “Serendipity And Hope

In Our War on Cancer.” The major impetus for the

article was COX-2, a possible pharmaceutical agent for 

cancer prevention/treatment, and a recently completed Phase

II/III clinical trial of the drug. This trial, which was funded

and heavily developed by the Division of Cancer Prevention,

examined the efficacy of the COX-2 inhibitor Celecoxib on

regression of existing polyps in individuals with familial 

adenomatous polyposis (FAP). The trial led to FDA approval

of Celecoxib for individuals with FAP and directly reflects

major efforts by the Gastrointestinal and Other Cancers

Research Group (GOCRG) and the Chemoprevention Agent

Development Research Group (CADRG). In totality, it is a

collaborative effort based on interactions between GOCRG,

CADRG, clinicians at M.D. Anderson (Houston, TX) and

St. Marks (London, UK), and G. D. Searle, a pharmaceutical

firm. As with any trial, this trial practically dictated the need

for one or two primary spokespersons; nevertheless, the

Celecoxib trial actually represents the efforts, knowledge,

and eccentricities of a far wider range of individuals including the COX-2 developmental people at Searle, clinical and

preclinical people at DCP, the clinicians at the two primary

sites and finally, and perhaps most importantly, the patients

who enrolled in the trial. 

What the Trial Showed

Seventy-seven patients with FAP, a genetic syndrome associated with germ line mutations in the APC gene, were randomized to receive placebo or Celecoxib for six months.

FAP individuals typically develop hundreds of adenomas in

the colon beginning in their mid to late teens. Thus, each

participant in the study had multiple existing polyps at the

initiation of the study. The study endpoints included determining the effects of Celecoxib on number and size of identified polyps and an overall assessment of its efficacy based

on blinded review of videotaped endoscopies by a panel of

five experts. Celecoxib caused a dose-dependent reduction

in total polyp number, with an approximate 30% reduction

for the highest dose. Furthermore, the expert panel assessed

a significant improvement in overall disease for individuals

receiving the highest dose of Celecoxib, as compared with a

Effects of the COX-2 Inhibitor Celecoxib in Patients with Familial Adenomatous Polyposis:

Anatomy of A Prevention Trial

R ON LUBET
NEWSLETTER OF THE NCI DIVISION OF CANCER PREVENTION

1 1

Congress, NCI Event Calendar, National Center for Health

Statistics, NIH Library, and many others. The website for

CADRG contains a list of funding announcements and staff

publications. The EDRN website has links to all major NCI

research programs, such as the Cancer Genetics Network

and the Cancer Genome Anatomy Project. The website also

lists tissue and technology resources available to the extramural community through the EDRN. A list of publications

by EDRN investigators is included. A link to a dietary

assessment calibration/validation register is also available

through the DCP website. The registry contains a search

engine for publications and studies in the field of nutrition.

Often, it is easier to use links to find websites than take the

time with search engines to find addresses. 

Plans are to make our website even more useful to DCP,

the NCI, and the public. Our site will play a key role in

DCP’s research programs especially through secure sites.

Investigators will submit research results directly through

these sites enabling data to be posted rapidly. The EDRN 

is establishing a secure site for transmitting patient data,

announcing prepublication results, and providing internal

reports. Much work remains to be done on the web, but 

the efforts of the DCP staff are very apparent. ■

DCP Websites continued from page 10

We would like you to join us in welcoming new staff to DCP:

Vance Berger, PhD.

Mathematical Statistician

Biometry Research Group

From the Federal Drug

Administration

Kathleen Foster, RN

Nurse Specialist

Breast & Gynecologic Cancer

Research Group

From the Lombardi Cancer Center,

Georgetown University

Nicholee (Nikki) Herman

Administrative Officer, ARC

From FDA

Ping Hu, ScD

Mathematical Statistician

Biometry Research Group

From the Center for 

Statistical Services

Brown University

DEE SULLIVAN

Grant Izmirlian, PhD

Mathematical Statistician

Biometry Research Group

From the Epidemiology,

Demographics & Biometry Program,

NIA

Tanyan Bailey

Secretary

Nutrition Science Research Group

Thea Kalebic, MD, PhD

Special Expert

Biomarkers Research Group

From the Cancer Diagnostic Program,

NCI

Linda Parreco, RN MS

Clinical Trials Nurse Specialist

Office of the Associate Director for

Clinical Research

Judith Smith, RN, MSN, AOCN

Clinical Trials Nurse Specialist

Lung and Upper Aerodigestive

Cancer Research Group

From the Radiation Oncology Branch,

NCI

Simon Rosenfeld, PhD

Mathematical Statistician

Biometry Research Group

Eva Szabo, MD

Medical Officer

Lung and Upper Aerodigestive

Cancer Research Group

From the Cell & Cancer Biology

Branch, NCI

Departures:

Everyone at DCP sends good wishes to Lori Minasian and Julia

Lawrence who recently left DCP.

Lori, the former Chief of

Community Oncology, joined the

staff at Georgetown University.

Julia was a Medical Officer in the

Breast and Gynecological

Oncology Research Group and is

beginning a new chapter in her

professional and personal life in

New Orleans. 

TRANSITIONS
1 2 PreventionPost JUNE 2000

The Office of Management Analysis (OMA) is the principal staff resource for management analysis at the NCI. The

OMA provides several administrative related products and

services that can be tailored to the needs of individual customers. These services include workload studies that provide

a snapshot of resource utilization for managers; internal

OMB forms; survey development and review; and records

management services.

During 1999, the OMA surveyed Principal Investigators

and extramural scientists to assess their satisfaction with

administrative services; streamlined the OMB information

collection process; and cultivated more efficient use of office

space for scientific research by doubling

shipments of records to the National

Archives Records Center.

The OMA staff is located in EPS 330

and is ready to provide the highest quality

products, services, and solutions to the

NCI scientific staff. The Chief of OMA is

Marilyn G. Jackson.

Information on NCI’s administrative policies can be found

on the OMA Website at http://www.nci.nih.gov/oma/index.htm,

or call (301) 496-6985 to speak to a staff member. ■

PROFILE

The NCI Office of Management Analysis

KAREN HARDY

Marilyn G. Jackson

more amenable to treatment and cure. The Prostate, Lung,

Colorectal, and Ovarian Cancer Screening Trial (PLCO) is

examining, as its name implies, the usefulness of screening

modalities for each of four cancer sites: digital rectal exam

(DRE) and the prostate-specific antigen (PSA) blood test for

the prostate; chest x-ray for the lung; flexible sigmoidoscopy for the colorectum; and transvaginal ultrasound

and the CA-125 blood test for the ovaries. PLCO randomized its first participant in 1993; enrollment will cease in

2001, after recruitment of about 150,000 participants.

Individuals randomized to the intervention arm receive all

applicable tests (prostate modalities are only given to men

and ovarian modalities are only given to women), while

individuals randomized to the control arm are asked to follow their normal health care routine. PLCO participants

will be followed for at least 13 years. Completion is currently slated for 2014, but interim analyses, which may produce final results at an earlier date, will begin within a year

or two. 

Sometimes trials are conducted to help us identify the

best way to manage disease or prevent more serious disease.

The ASCUS/LSIL Triage Study (ALTS) is one such trial.

ALTS is assessing how best to proceed after either of two

mild abnormalities, ASCUS (atypical squamous cells of

undetermined significance) or LSIL (low-grade squamous

interepithelial lesions), is found on routine cervical cancer

screens (Pap smears). At present, it is unclear how best to

proceed when ASCUS or LSIL is diagnosed, because these

lesions may resolve without treatment. Nevertheless, aggressive treatment using colposcopy is frequent in the United

States because physicians cannot tell which ASCUS and

LSIL lesions will regress spontaneously, which are associated with an underlying high grade lesion, and which may

progress to high grade lesions. ALTS began enrollment in

1996 and finished in late 1998, randomizing about 5,000

women with ASCUS or LSIL to one of three management

strategies: immediate colposcopy (cervical examination,

biopsy and necessary treatment), conservative management

(coloposcopy only if repeated cytology indicated a highgrade lesion), or human papilllomavirus (HPV) triage (management based in part on the results of a test for HPV, the

virus believed to cause most cervical cancers). In the HPV

triage arm, colposcopy was performed if cytology indicated

a more severe abnormality or DNA from HPV subtypes

associated with cervical cancer was present; otherwise,

watchful waiting was employed. This arm was designed to

assess whether an individual’s HPV status is useful in determining whether colposcopy is necessary. Early results, published in this year’s March 1 issue of JNCI, indicate that

most women with LSIL are HPV positive. This confirms the

etiologic association of HPV and LSIL, but suggests that

viral testing is of limited use for triage of LSIL. The role of

HPV testing in the management of women with ASCUS

continues, with findings expected within the year.

Although the larger trials often receive the most attention,

they are far from being the only prevention trials in DCP.

Smaller studies of prevention, including chemoprevention, risk

factor elimination, early detection, and disease management,

are numerous. Trials in DCP have addressed smoking cessation

methods, for example; others have tested pharmaceutical interventions to prevent recurrences and second primary tumors in

cancer patients. Pilot studies - smaller, preliminary versions of

proposed or approved studies - have been conducted to identify and correct problems before the principal study is underway. Chemoprevention trials also occur on a smaller scale,

testing agents that show promise in animal or basic science

research. Prevention of less common cancers is represented,

too – DCP administers trials of pediatric cancer, head and neck

cancer, and bladder cancer, to name a few. Precursor or earlystage lesions, including leukoplakia, colorectal adenomas, and

prostate-intraepithelial neoplasia, also have been studied. ■

Trials of DCP continued from page 2
NEWSLETTER OF THE NCI DIVISION OF CANCER PREVENTION

1 3

Some of you have probably heard the DCP ARC staff

talking about “Comprehensive Administrators” and

a new model for providing administrative services to

your program. The DCP ARC Staff would like for you to

know what they are striving to accomplish.

What is a Comprehensive Administrator?

The goal of the ARC is to provide high quality administrative services to the Division of Cancer Prevention, to

advance the research mission of the DCP. To help accomplish this goal, a new model for administrative employees

has been conceived: the Comprehensive Administrator. 

Currently, the ARC is composed of Administrative

Officers, a Personnel Management Specialist, a Personnel

Assistant, and Administrative Technicians. In using the

Comprehensive Administrator model, the ARC will no

longer have staff designated to a specific function [e.g.

administration, personnel, purchasing]. Administrative services will be provided by a Comprehensive Administrator

and a Comprehensive Administrative Assistant, who will

address all of your needs and requests. In other words, you

will be able to come to one team of administrators to handle all of your administrative needs: personnel, travel, space,

budget, and so on.

This structure will increase the flexibility of the ARC staff,

permitting a greater focus on the success of the DCP mission. 

Pardon the Restructuring

To transform the staff into Comprehensive Administrators,

the ARC developed a training plan to cross-train staff in the

necessary areas. Administrative Officers are being trained in

personnel areas, Personnel Management Specialists are

trained in administrative areas, and support staff are crosstraining each other in the necessary systems and disciplines.

This training will enable the staff to assume a wider variety

of duties in order to be fully functional as Comprehensive

Administrators. 

The ARC is also planning to add a Program Analyst 

to the team. The Analyst will provide essential budgetary,

personnel, and systems data to the team, permitting 

the Comprehensive Administrators to focus on service

delivery issues.

When the Comprehensive Administrators complete their

training, it may be necessary to reassign some of the division’s groups from the existing Administrative Officers.

Your needs will be a critical part of any plan, and the ARC

will consult you before any changes are put in place. You

will also be notified well in advance of any changes.

How Can I Help With the Transition?

So glad you asked! Since the ARC’s goal is to provide the

best possible administrative services, they are developing an

assessment tool to see what is currently done well, what

needs improvement, and how DCP’s needs are changing.

While the assessment tool is under development, it is probable that some of you will be contacted for one-on-one interviews to help refine the instrument. Once a working assessment tool is in place, the ARC will be contacting each of you.

Your help in completing the assessment tool is critical–your

input will plot our future course. Please give a small portion

of your valuable time so the ARC can collect a substantial

body of meaningful data. If you only complete two assessments this year, make it this one and the 2000 Census!

Changes and Challenges

While there are some substantial changes projected for the

ARC Staff, the goal is to provide you with a seamless transition. Some challenges are ahead, the most imminent being

the renovation and move within the Executive Plaza North

building. Please be patient while these changes are taking

place. You are valued customers, and the ARC will continue

to improve its service to you! ■

The Comprehensive Administrator Model–A Vision 

To Provide You With Better Service JOY OSBORNE

ADMINISTRATIVE RESOURCE CENTER

DOUBLE BLIND CONTROL

Illustration : Graça Dores
1 4 PreventionPost JUNE 2000

worsening of disease over six months in patients on placebo. This efficacy was achieved at doses where there were no

differences in side effects between Celecoxib and placebo.

Background for the Trial

SCIENTIFIC

The trial is the result of an interesting combination of animal data, epidemiology studies, molecular targeting, drug

discovery, and anecdotal clinical data. Scientists first

observed that NSAIDS inhibit colon carcinogenesis in

rodents in the mid to late 1970s. Preclinical data in the

1980s and 1990s, much from our own division, further supported this observation by demonstrating both the efficacy

of many different NSAIDS, as well as efficacy of NSAIDS at

later stages in the carcinogenic process. During the same

time period, a number of epidemiologic studies demonstrated that regular NSAID use was associated with a significant

and similar reduction in colon adenomas, colon cancers,

and colon cancer related deaths in a general at-risk population. In fact, this data, along with data showing that surgical removal of adenomas profoundly reduces colon cancer

risk, is perhaps the most striking data demonstrating that

reduction of a preinvasive lesion (colon adenomas) profoundly affects cancer incidence. The initial anecdotal data

demonstrating the efficacy of NSAIDS (Sulindac) in patients

with FAP was reported by Dr. William Wadell at the

University of Colorado in 1983. 

The major drawback associated with the non-specific

NSAIDS employed in the preclinical or epidemiologic studies is the significant amount of side effects, including stomach ulceration, which results in tens of thousands of emergency room visits and thousands of deaths per year. When

most of these preclinical and epidemiologic observations

were made, there was one known form of the enzyme

cyclooxygenase, an enzyme that helps to metabolize arachidonic acid into prostaglandins. In 1990 it was determined

that there were two forms of cyclooxygenase. The first,

called COX-1, is expressed constitutively in many cells

including the stomach; the second, COX-2, is expressed

highly in inflammatory cells. The ability to develop specific

agents that inhibit COX-2 and reduce inflammation, without effecting COX-1 and resulting in decreased side effects,

had great economic potential. In fact, in a period of less

than ten years, work progressed from recognition of COX2, through development of highly specific inhibitors of

COX-2, to the development of two COX-2 agents that are

now on the market for arthritis and pain: Celecoxib (Searle)

and Refecoxib (Merck). This provides an extraordinary

example of the ability of pharmaceutical companies to

develop highly specific inhibitors quickly and to bring them

to market using smaller trials. Although these drugs were

developed for arthritis and pain, it was found that many

human tumors expressed the COX-2 isozyme. That gave

immediate impetus to study its use in prevention and treatment of cancer. Results of the first small animal cancer trials

with these agents were published in 1996. These studies

used both a classic, chemically-induced tumor model as well

as a knockout APC transgenic mouse and demonstrated

striking decreases in intestinal tumors in rodents treated

with COX-2 inhibitors.

NCI/Industry Collaboration

Development of partnerships between NCI and industry

that will foster collaboration and potentially result in financial sponsorship of prevention trial is not trivial. One of the

major concerns for industry is the possibility that a prevention trial will take ten or more years to complete, while a

therapy trial takes one to two years. As of the mid 1990s, 

a number of drug companies were developing COX-2

inhibitors. The Chemoprevention Branch, under the direction of Dr. Gary Kelloff, had ongoing interactions with 

several pharmaceutical companies. The company with the

greatest interest in a COX-2 inhibitor was Searle. Phil

Needleman, one of the pioneers in COX research, and 

John Alexander both had a potential COX-2 selective

inhibitor and an interest in the possibilities of prevention

studies. The addition of two individuals who were highly

committed to the development and completion of the trial,

Ernest Hawk and Gary Gordon, significantly enhanced

these efforts. Ernest Hawk, whose primary interest is in 

GI cancers, was in DCP’s Chemoprevention Branch, and

Gary Gordon, a researcher from Johns Hopkins, joined

Searle. This NCI/industry interaction certainly facilitated

completion of a small-scale prevention trial, and was particularly helpful in the instance of novel drugs. An important

aspect of accomplishing the study was the use of a trial

design that would give a strong indication of efficacy within

a few years, a major objective for all further Phase II trials.

It is probably one of the more striking examples of using

genetically-defined cohorts in a prevention trial.

Implications for Patients with FAP

The FDA determined that the results of the clinical trial, in

conjunction with data in Minmice (the mouse genetic equivalent of FAP) that showed striking efficacy of Celecoxib, warranted the recommendation that Celecoxib be given for adults

with FAP to complement their standard care, which consists

of prophylactic surgery and endoscopic surveillance. What is

the potential use of this agent for individuals with FAP? The

vast numbers of adenomas associated with FAP result in

repeated surgeries for affected individuals. Furthermore, FAP

patients will ultimately develop invasive cancer as well. The

use of an effective agent in this context may 1) facilitate endoscopic exams by reducing adenoma numbers, 2) delay or preCOX-2 Inhibitor continued from page 10

continued on page 15
NEWSLETTER OF THE NCI DIVISION OF CANCER PREVENTION

1 5

vent GI surgery, 3) delay or prevent disease emergence in adolescents, and 4) reduce or delay duodenal neoplasia.

Mechanisms Large-Mechanisms Small

Celecoxib is a highly selective COX-2 inhibitor and a superb

example of molecular targeting. There is little doubt that its

effect on arthritis is related to alterations in prostaglandin levels that result in profound alterations in the inflammatory

reaction. How COX-2 influences tumor cells may be less obvious. Is the apoptosis observed in many tumor cells following

COX-2 treatment directly related to alterations in

prostaglandins and arachidonic acid metabolism (ceramide) or

are there other effects, such as direct effects on PPAR receptor? Must COX-2 be observed in tumor epithelial cells of specific organs to be a candidate for a study? Or does its presence

in stroma, infiltrating macrophages, or even new vascular cells

connote a sufficient target? The latter might imply that COX2 is a relatively effective anti-angiogenic agent about which

there is already significant clinical data. We have found

Celecoxib to be effective in a UV skin model where COX-2 is

highly expressed in tumor epithelial cells, in mouse intestinal

adenomas (Min) where it appears to be expressed in the stroma and macrophages, and in mouse bladder cancer where it

appears to be expressed primarily in endothelial cells.

What Is To Be Done

Based on the data collected in the FAP trial, a number of

additional studies could be performed in these patients: 1)

suppression or delay of multiple adenomas in adolescents

with FAP; 2) confirmation of effects in longer term trials;

and 3) potential studies combining COX-2 with other effective agents (e.g., DFMO) to enhance efficacy. Furthermore,

since mutations in the APC gene are associated not only

with the FAP syndrome but also with most sporadic colon

polyps and colon cancers, prevention trials in this area seem

obvious. The striking animal data and COX-2 staining in

human actinic keratoses and bladder tumors also makes

these trials obvious. COX-2 is over-expressed in many

human cancers including lung, esophagus, breast, and pancreas and therefore may be a logical agent to be tested in

prevention trials. If the anti-antigenic theory is correct, the

opportunities seem limitless for COX-2. In the end only

intelligent and timely clinical trials will determine its efficacy. Is its usefulness limited to FAP or is it useful for the

colon or perhaps the entire GI tract? Is it more generally

applicable, perhaps the ultimate cancer panacea? One way

or the other, the COX-2 inhibitors have had a promising

start and there is certainly more to come. ■

COX-2 Inhibitor continued from page 14

Prevention of Languishing Studies (POLS)

NCI medical officers are acutely aware that clinical trials

languish for any of a number of reasons, including: cohort

and agent unavailability, staff issues, regulatory hurdles,

legal negotiations, and pharmaceutical industry priorities.

The POLS Project Team was formed to identify salient 

features of languishing Phase II and III clinical trials and it

presented an interim report to the Coordinating Unit (CU) 

in March 2000. The team concluded that in the majority 

of cases, poor accrual and failure to acquire agents is 

common in languishing studies. Although less common, 

staff issues (at the NCI and/or study sites) may be associated

with study delays. 

In an effort to increase efficiency of trial execution,

POLS created schedules based on completed or current

studies to serve as performance measures for DCP-contracted and CCOP clinical trials. POLS intends to use these measures to identify studies at risk for falling short of completion, optimize potential for rescuing high risk studies, and

reduce obstacles for other Division studies. The team

recruited a working group for the second phase of this

effort, assisting studies behind schedule. The working group

will set up a preliminary internal review to identify interventions that the NCI might initiate or suggest to the investigators, then monitor efficacy of these interventions. “The

Division is hopeful that early intervention for studies at risk

for delayed or failed execution will translate into fewer

wasted resources or missed opportunities to answer important scientific questions in clinical trials for cancer prevention,” said Jaye Viner, team co-leader. Rose Mary Padberg is

the other co-leader. Members of NCI contracts branch and

the DCP support contractor, CCS Associates, also participate on the team.

Single Nucleotide Polymorphism (SNP)

The SNP project team is exploring the functional significance of genetic polymorphisms in terms of both gene-gene

and gene-environment interactions. “The SNPs analysis of

relevant genes will be used as a molecular tool to explore

the genetic basis of cancer susceptibility and/or drug

response in clinical trials,” explained Iqbal Ali, the team

leader. Currently, the team is developing a study that will

identify and evaluate SNPs in patients at increased risk for

colon cancer due to Familial Adenomatous Polyposis who

respond to a certain chemopreventive agent.

The project team is the nucleus of a matrix-based organization. The number, type, and composition of project teams

tell a lot about the values, priorities, and goals of an organization. As DCP fills the blank “eggs” on the organization

chart, we will see what our project teams say about us. ■

Project Teams continued from page 4
1 6 PreventionPost JUNE 2000

PreventionPOST

Newsletter of the Division of Cancer Prevention

National Cancer Institute

Executive Plaza South, Suite T-41

6130 Executive Boulevard, MSC-7105

Bethesda, Maryland 20892-7105

My family congregates at North

Carolina’s Outer

Banks every

other summer

for a week of

freshly caught

shrimp at vacation

prices and ocean swimming.

Traditionally, our first activity is to

jump in the surf. Later, we walk the

beach from pier to pier. Along the way

we marvel at the size and splendor of

new cottages perched on giant wooden

posts and wonder how many years it

will be before the sea obliterates their

protective dunes and swallows them

whole. Two very different forces are at

work: the slow but steady erosion of

wind and tide-bound surf, and second,

the mighty storms that can steal ten

feet of dune in an afternoon.

Remarkably similar forces endanger

the methods and theories of biomedical science. Ask any historian or

philosopher of science. They will tell

you about the slow but steady evolution of scientific thought, the erosion

of ignorance if you will, as our understanding of disease mechanisms, etiology, and prevention gradually increases

with each published paper or technical

report. They will also tell you about

the occasional upheaval in thought, the

scientific revolution, that transforms

theories and methods in a historic

instant. Physical sciences were the first

carefully studied examples of this

view—the paradigm view—most often

associated with Thomas Kuhn, a

philosopher-historian. But earlier

thinkers, such as Ludwig Fleck, wrote

about the same phenomena in medical

science. Today, this view is very popular and there are many examples of

revolutionary discoveries and paradigm

shifts: X-rays, DNA, and the causal

effects of tobacco, to name a few.

Methodologic examples abound: applying quantitation to medicine and, as

you may have guessed, the method featured in this issue of PreventionPOST:

the randomized clinical trial, dominating scientific methodology in medicine

for the past fifty years.

The paradigm view of biomedical

science, in which periods of evolution

are punctuated by occasional revolutions, implies that whatever we think

we know today—whether theory of

cancer causation or method of evaluation—will eventually be overthrown,

altered significantly, revolutionized.

Someday, someone’s brain will light up

like Tom Terrific’s and, in an instant, a

sizable chunk of what we think we

know will become obsolete.

If all of this sounds a bit abstract

and a little too much like the science

fiction novels that make summertime

beach reading a joy, consider the fact

that nearly everyone accepts the randomized clinical trial as the strongest

possible way to test a hypothesis.

Randomized trials sit at the top of

everyone’s list of evidentiary hierarchies. After all, what could possibly be

better than the results of a randomized

controlled clinical trial? What could

possibly be a stronger, more valid, way

to test the efficacy of interventions?

I don’t have an answer and I don’t

know when someone will. But if I

were a gambling man, I’d bet that

eventually the rise and fall of the randomized trial paradigm will be taught

in courses on the history of medicine

and public health. Then again, if I

were a gambling man, I’d go to

Atlantic City for my summer vacation

and get free shrimp. ■

ENDPOINTS

The Rise and Fall of the Clinical Trial Paradigm

DOUGLAS L. WEED

Editor-in-Chief