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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 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.
As the NSABP moves into its 51st 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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