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The NSABP is the oldest, largest, and
arguably best known breast and colorectal cancer research
group in the world. The group conducts large scale clinical
trials designed to improve the treatment and prevention
of both breast and bowel cancers. The organization,
established in 1958, and funded since that date by the
National Cancer Institute (NCI), has its headquarters
in Pittsburgh, Pennsylvania. The NSABP membership includes
nearly 200 nucleus institutions and an additional 300
satellite centers located throughout the United States,
Canada and Puerto Rico.
Many of these member institutions are
university hospitals or large comprehensive cancer centers
but the majority are community based institutions. This
allows patients to have access to state-of-the-art cancer
research studies without the burdens or costs of travel
to large hospitals. They are able to receive their care
closer to home with the support of family and friends.
More than 3,000 physicians, nurses and other medical
professionals in the member institutions and their satellites
conduct NSABP treatment and prevention studies.
Since 1971, more than 110,000 individuals
have enrolled in NSABP clinical trials. The NSABP has
played a vital role in improving and, indeed, in establishing
the standard treatments for breast cancer.
Over the past 30 years, the treatment of breast cancer
has improved dramatically and the results of NSABP trials
have been a major factor in those advances. The most
visible change has been in the surgical treatment of
breast cancer.
Dr. William Stewart Halsted was one
of the fathers of modern American surgery and the Chairman
of Surgery at Johns Hopkins University Hospital in the
late 1800’s. He is credited with the development
of the radical mastectomy, a deforming operation which
involves the removal of the entire breast, the underlying
chest wall muscles and all of the lymph nodes in the
armpit.
Dr. Halsted’s patients were of
the Victorian age and many felt that breast cancer was
akin to a venereal disease and delayed seeking care
until they had very large breast cancers. The radical
mastectomy was designed in part to treat such individuals
but was also in keeping with the postulates of tumor
biology of the day. At that time, cancer was thought
to be largely a local disease that spread in a local,
predictable, time dependent fashion. If such were true,
there was the potential with large operations to remove
all of the cancer cells and to cure the patient. Despite
patients presenting with smaller cancers, the radical
mastectomy remained the standard operation for breast
cancer for close to 100 years.
In the 1960’s, Dr. Bernard Fisher
and his brother, Dr. Edwin Fisher, a world renowned
breast cancer pathologist, conducted a series of experiments
in their laboratory at the University of Pittsburgh,
which challenged the Halstedian view of cancer spread.
In these animal experiments they were able to show that
tumor cells spread through the lymph nodes and the blood
circulation. They viewed breast cancer as a systemic
disease, not just a lump in the breast. If their findings
were correct, bigger operations, like the radical mastectomy,
would be no more effective than less extensive procedures.
This was a nice hypothesis that required proof.
Beginning in 1971, the NSABP entered
over 1,600 women in the clinical trial designed to test
the effectiveness of radical mastectomy compared to
the less extensive total mastectomy which limits the
surgical procedure to removal of the breast. The initial
results were published in 1975 and demonstrated that
the radical mastectomy treated women did no better than
those treated with total mastectomy. The impact was
an almost overnight elimination of the use of radical
mastectomy. The 25 year results published in the New
England Journal of Medicine in 2003, continued to demonstrate
the same findings.
These radical mastectomy results partially
confirmed the new tumor spread hypotheses. For the NSABP
the next step was to evaluate the effectiveness of lumpectomy,
the surgical removal of just the breast cancer lump
with a rim of normal breast tissue. Beginning in 1976,
over 2,100 women entered this study and were assigned
to receive either the modified radical mastectomy (total
mastectomy plus the removal of lymph nodes in the armpit),
or lumpectomy with and without breast radiation. Now,
over 20 years later, continued follow-up of these patients
shows that lumpectomy plus breast irradiation is as
effective as mastectomy. Today, the majority of women
who develop breast cancer have the option of choosing
lumpectomy with the knowledge that the results are as
good as mastectomy.
If breast cancer is a systemic disease,
a theory partially confirmed in the previous studies,
the next logical step would be to treat it systemically
using adjuvant therapy. Adjuvant therapy (therapy in
addition to surgery and radiation) can take many forms.
A chemotherapy trial conducted by the NSABP in the early
1970’s, was the first to demonstrate that chemotherapy
delivered after surgery can improve the survival of
women with early stage breast cancers.
Hormonal therapies are an additional
type of adjuvant treatment that are effective in breast
cancers that contain certain proteins called hormone
receptors. NSABP trials were among the first to demonstrate
that the oral hormonal therapy, tamoxifen, could reduce
the risk of breast cancer recurrence and improve survival.
Tamoxifen has been the most commonly prescribed breast
cancer drug in the world and this had a major impact
on reducing the number of deaths due to breast cancer.
Current NSABP studies are evaluating aromatase inhibitors,
a new hormonal therapy, that appear to be better than
tamoxifen and have fewer side effects.
Newer targeted treatments for breast
cancer which are neither chemotherapies nor hormonal
therapies are also under evaluation. In November of
2005, the New England Journal of Medicine reported the
results of an NSABP trial which demonstrated that Herceptin,
a monoclonal antibody, an entirely new and exciting
biologic agent, directed at a specific protein found
in an aggressive form of breast cancer proved to be
a hugely beneficial treatment. This study sets the stage
for an entirely new direction in the treatment of breast
cancer. Trials with other promising agents in this family
of drugs are in development at the Pittsburgh headquarters.
Since 1992, the NSABP has been actively
involved in breast cancer prevention studies. In the
first large scale breast cancer prevention study ever
conducted, the NSABP’s P-1 trial demonstrated
that tamoxifen given to healthy women at an increased
risk for the future development of breast cancer, can
reduce the incidence of the disease by close to 50%.
These results presented in 1998, were a huge first step
and established the principle that breast cancer is
a preventable disease. The second step is now completed.
Raloxifene, a drug long used in the prevention and treatment
of osteoporosis, is thought to have the anti-cancer
properties of tamoxifen while producing fewer side effects.
The Study of Tamoxifen and Raloxifene
(STAR) opened in 1999, entered over 19,000 healthy post-menopausal
women and was closed to entry in 2004. The initial results
of this trial were announced in April 2006. The third
breast cancer prevention trial is already under development
and will be initiated in the Fall 2006. The search continues
for an even more effective and safer drug to prevent
breast cancer.
The NSABP conducts important correlative
studies in conjunction with its adjuvant trials and
these have been responsible for defining many of the
standard diagnostic and prognostic tools that are used
today in women with breast cancer. Recently, using the
NSABP Tissue Bank, which has been described by the NCI
as a "national treasure”, the NSABP Foundation,
in collaboration with industry, developed a 21-Gene
Assay called Oncotype DX, that is used in node negative
receptor positive breast cancer patients to more precisely
identify those with an excellent prognosis who can be
treated with only a hormonal therapy, and those with
a poorer prognosis who could obtain substantial benefit
from the addition of chemotherapy to their hormonal
treatments. Similar efforts to more precisely target
those individuals requiring specific adjuvant therapies
are already underway in colon cancer.
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The NSABP began its research program
in colorectal cancer in 1977, and since that time has
randomized almost 15,000 patients into large Phase III
trials. The data from these trials have had a significant
influence on the treatment of colorectal cancer and,
indeed, a trial initiated in 1987 established the standard
of care for chemotherapy following surgical removal
of the primary tumor in colon cancer patients. A review
of the findings after ten years of follow-up of these
patients still shows a substantial survival advantage
in favor of 5-FU and leucovorin, a regimen still used
today as a standard of care. Because of the positive
result from this early trial, 5-FU and leucovorin have
become the control arm for subsequent NSABP trials assessing
adjuvant therapy in patients with colon cancer. A study
that accrued nearly 2,500 patients was reported at the
2005 meeting of ASCO, the largest international oncology
meeting in the world. The study demonstrated the value
of adding a third drug (oxaliplatin) to the standard
of 5-FU and leucovorin, which produced a significant
improvement in disease-free survival.
The NSABP has also contributed to the
advancement of adjuvant therapy for patients with rectal
cancer. A controlled clinical trial demonstrated a significant
improvement in local tumor control when pelvic radiation
therapy was given in addition to postoperative chemotherapy.
This is an important finding since uncontrolled tumor
in the pelvis can produce severe pain, infections, and
interference with function of the urinary bladder. Another
clinical trial demonstrated that radiation and chemotherapy
can be safely given preoperatively for patients with
rectal cancer, and that the achievement of a complete
tumor response correlates with improved long term outcome.
The NSABP is presently conducting a
study to determine if the addition of anti-angiogenesis
therapy with bevacizumab, a new genetically engineered
monoclonal antibody that “starves” the tumor
by interrupting the blood supply, will increase the
effectiveness of chemotherapy treatments currently used
to treat patients with colon cancer in the surgical
adjuvant setting.
In rectal cancer, the NSABP is conducting
a clinical trial to improve the effectiveness and convenience
of preoperative chemotherapy when combined with radiation
for operable rectal cancer. The oral agent capecitabine
is being evaluated to determine if it can be substituted
for continuous infusion 5-FU, a cumbersome treatment
that requires central venous catheters and ambulatory
infusion pumps. It will also determine whether the addition
of oxaliplatin to the chemotherapy regimen will further
improve local tumor control. Hopefully, fewer patients
will require radical surgical resection of the rectum
with establishment of a permanent colostomy when treated
with the newer regimens. The NSABP will also collaborate
with another cooperative group to determine the value
of bevacizumab combined with chemotherapy following
rectal cancer surgery to prevent tumor relapse.
The goal of these trials is to conduct
definitive Phase III multidisciplinary surgical adjuvant
studies to improve the long-term survival of patients
with cancer of the colon or rectum.
The NSABP is also committed to help
tailor treatments for individual patients through study
of molecular tumor markers. In collaboration with Genomic
Health, Inc., a molecular assay (RT-PCR) has been applied
to paraffin-embedded tumor specimens from patients participating
in NSABP colon cancer adjuvant therapy clinical trials
over the years. Preliminary results indicate the possibility
of selecting which colon cancer patients truly need
postoperative chemotherapy following removal of their
colon cancer, and which are very likely cured with surgery
alone. If confirmed by other studies in progress, these
results will spare many patients now receiving adjuvant
chemotherapy the risk and side effects associated with
these treatments. Other tumor marker studies are addressing
which patients have an excellent chance of cure when
treated with standard 5-FU and leucovorin chemotherapy,
and which would be best served by incorporation of newer
systemic agents. The overall goal of these studies is
to identify which patients require further treatment
following surgery and which regimen would be most effective
for each patient.
Of great importance to all cancer patients,
is the improvement of the quality of their lives and
to that end, the NSABP was one of the first research
groups to establish quality of life studies as an integral
part of our major Phase III trials. The NCI and others
have long looked to the NSABP for leadership in this
vital area of research. In the area of rectal cancer,
our goal is to improve the efficacy and decrease the
toxicity of the pre-operative chemotherapy and radiation
therapy treatment required of these patients. The primary
goal is to increase the number of patients who can undergo
sphincter-sparing surgery, thereby avoiding the need
for a colostomy. In moving toward our ultimate goal
of cure and our immediate goal of long-term survival,
we must seriously consider the quality of life that
new treatment measures can provide.
Over the last several years, accrual
to our Phase III breast and colorectal trials has increased
significantly. Indeed, when comparing our most recent
5 year grant period with the previous 5 years, there
was a 100% increase in the number of patients accrued
to our studies, and the number of accruals per institution
increased 161%. During this period, we reduced the number
of sites by instituting several requirements resulting
in greater efficiency, higher accruals, increased data
integrity, and lower costs. Accruals continue to increase
and in Fiscal Year 2006, we expect to enroll 6,000 patients.
As the NSABP moves into its 48th year, we are positioned
to maintain our leadership in cancer research. Our goal
remains the same: to identify targeted treatment and
prevention regimes; ultimately, leading to cure and
prevention strategies in breast and bowel cancer.
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