By learning from the past, experts hope to improve
clinical trials and increase the number of effective agents available for the
prevention of cancer.
Cancer prevention is designed to prevent, reverse or slow the
development of cancer among healthy people at average or high risk for the
disease. Over the past two decades, this growing field has been marked by
triumphant clinical trials that led to FDA approvals and, perhaps surprisingly,
unsuccessful trials that provided valuable information.
Although some may view these unsuccessful trials as failures, many
experts agree that the data drawn from such trials have proven invaluable,
shedding light on potentially harmful agents once thought to be useful in
cancer prevention and elucidating ways in which clinical trials can be improved
upon in the future.
“Our ultimate goal is to prevent or delay a cancer diagnosis long
enough so that an individual never gets the disease,” Howard Parnes,
MD, chief of the prostate and urologic cancer research group, division of
cancer prevention at the National Cancer Institute, told HemOnc
HemOnc Today spoke with several experts to learn more about
successful trials, lessons learned from unsuccessful trials, possible
improvements to trial design and the anticipated future of cancer prevention.
In 1998, the FDA approved the selective estrogen receptor modulator
tamoxifen for the prevention of breast cancer among women at high risk for the
disease. At that time, tamoxifen had already been FDA approved for the
treatment of breast cancer for almost 20 years. Approval for breast cancer risk
reduction was based on results of the Breast Cancer Prevention Trial (BCPT),
which began enrolling in 1992.
Howard Parnes, MD, of the NCI, was an investigator with the
PCPT and SELECT trials, both cancer chemoprevention trials.
Photo by Phillip Rosenburg
The trial was initiated by the National Surgical Adjuvant Breast and
Bowel Project and included 13,388 women aged 60 or older, women aged between 35
and 59 with a five-year predicted risk for breast cancer of at least 1.66%, or
those with a history of lobular carcinoma in situ. Patients were randomly
assigned placebo or tamoxifen 20 mg per day for five years.
Tamoxifen reduced the risk for invasive breast cancer by 49% and
noninvasive disease by 50%. The selective estrogen receptor modulator also
reduced the occurrence of ER–positive tumors by 69%. However, tamoxifen
was also associated with an increased incidence of endometrial cancer among
women aged 50 or older.
“We do use tamoxifen in high-risk women who are willing to accept
the minor or moderate risk of side effects with the benefit of a 50% reduction
in their risk for breast cancer,” said Powell Brown, MD, PhD,
professor of medicine at Baylor College of Medicine, associate director of
cancer prevention and director of the cancer prevention and population sciences
program at the Dan L. Duncan Cancer Center.
A second success in breast cancer prevention came in 2007 when the FDA
approved another selective estrogen receptor modulator, raloxifene, for the
prevention of invasive breast cancer in postmenopausal women with osteoporosis
or those at high risk for the disease.
Results of the Study of Tamoxifen and Raloxifene (STAR) trial
demonstrated that raloxifene was as effective as tamoxifen in reducing the risk
for breast cancer; both drugs reduced the risk by about 50%. However, compared
with tamoxifen, raloxifene was associated with a 36% reduction in uterine
cancers — although this was not statistically significant — and a 29%
reduction in blood clots.
Success in breast cancer chemoprevention trials can be attributed to the
beneficial properties of both tamoxifen and raloxifene; however, some experts
acknowledge the pretrial processes that played a role in those victories.
“In the case of tamoxifen, we had trials in the adjuvant setting
that demonstrated a decrease in the rate of breast cancer recurrence in the
same breast and also the occurrence of a new primary breast cancer in the
opposite breast. Those were randomized controlled trials, not observational
studies,” Barnett Kramer, MD, MPH, associate director for disease
prevention at the National Institutes of Health, told HemOnc
According to Kramer, conducting large-scale studies based on the results
of randomized human studies compared with observational data or bench research
provided a stronger background of evidence to justify both tamoxifen and
raloxifene in the large-scale setting.
Prostate cancer prevention has also seen its share of success with
studies like the Prostate Cancer Prevention Trial (PCPT) and the Reduction by
Dutasteride of Prostate Cancer Events (REDUCE) study, both of which showed a
reduction in the risk for disease with the use of a 5-alpha reductase
The PCPT, which was stopped early after reaching the primary endpoint,
included 18,882 men who were randomly assigned daily finasteride 5 mg or
placebo for seven years. Finasteride was associated with a 24.8% reduction in
prostate cancer; however, the drug was also associated with a small increase in
high-grade prostate cancer.
“Over the last five years or so, subsequent analyses have shown
that this increase was due, at least in part, to better detection of high-grade
disease,” said Parnes, a researcher on the PCPT. “We now know that
finasteride increases both overall detection of prostate cancer and the
detection of high-grade prostate cancer. Therefore, the initial study results,
reported in The New England Journal of Medicine in 2003, underestimated
the benefits and overestimated the harms of finasteride.”
The findings of the PCPT were supported and strengthened by the recent
data from the REDUCE trial, which demonstrated a similar reduction in prostate
cancer prevalence with no significant incidence in high-grade disease.
REDUCE included men with PSA between 2.5 ng/mL and 10 ng/mL (aged 50 to
59) or between 3.0 ng/mL and 10 ng/mL (aged 60 to 75) at initial screening. All
men had one negative prostate biopsy within six months prior to study entry.
Participants were randomly assigned dutasteride or placebo; 10 core biopsies
were performed at two and four years.
Dutasteride was associated with a 23% reduction in the risk for prostate
cancer, and there was no overall increase in the prevalence of high-grade
“For now, our successes have been with targeting pathways: the
hormonal pathway in the case of breast cancer and the hormonal pathway in the
case of prostate cancer,” Kramer said. “The more general gunshot
approach with vitamins and minerals to date has not proven successful, at least
not in a relatively well-nourished population such as the United States.”
To date, cancer prevention studies of vitamins and micronutrients have
not only proven unsuccessful in the United States but also have shed light on
previously unknown toxicities associated with supplements and the people
potentially at highest risk. Although studies like CARET, SELECT, ATBC and the
Physicians’ Health Study II did not meet their primary endpoints, many
experts agree that the universal messages they conveyed are important: Vitamins
and minerals may not be as innocuous as once believed and prevention trials
must be based on the strongest evidence.
“The bar should be high, which means that when you’re dealing
with healthy people you should be very meticulous, not only looking for
evidence of benefit but also looking for evidence of harm. The most efficient
way to do that is through randomized controlled trials,” Kramer said.
Randomized, controlled trials of vitamins and micronutrients were
largely based on observational and epidemiologic data, however. According to
William N. William, MD, assistant professor in the department of
thoracic/head and neck medical oncology at The University of Texas M.D.
Anderson Cancer Center, such observational and epidemiologic studies are not
adequately designed to look at whether or not certain vitamins should be given
for prevention. When planning large, prospective, definitive studies, it is
always best to have good epidemiologic data supported by strong biological
rationale, which is obtained through extensive preclinical testing. William
also acknowledges, however, that when some of the studies were designed years
ago, there was a lack of good preclinical models to test prevention drugs.
The SELECT trial, which examined the use of 400 IU vitamin E and 200 mcg
selenium for the prevention of prostate cancer, demonstrated that these agents
given either alone or in combination did not prevent prostate cancer. Instead,
vitamin E was associated with a small increase in prostate cancer and selenium
with a small increase in diabetes. “These were most likely chance
associations rather than a true cause and effect relationship given that these
trends were not statistically significant and, even more importantly, were not
observed in men who received both selenium and vitamin E,” Parnes said.
“The rationale for SELECT was based not only on epidemiological
observations and laboratory studies, but on secondary analyses of randomized,
clinical trials such as ATBC,” said Parnes, also a researcher on SELECT.
“It is important to remember that we did the trial precisely because we
did not know if it would work; that is the reason for doing clinical
Brown agreed. He noted the importance of recognizing that there is no
area of medicine or drug development that has 100% success, which results in a
lower number of successful phase-1 trials of cancer drugs. Experts should,
however, recognize that there is not enough knowledge to select
‘homeruns’ every time, he said.
Although SELECT was not a “positive” trial, according to
Parnes, “putting nutritional supplements to the test in randomized
clinical trials provides an important public health service, considering the
huge number of people who take these agents every day, despite a paucity of
evidence regarding both efficacy and toxicity.”
Like SELECT, the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer
Prevention Trial tested vitamin E and beta-carotene in a population of 29,133
male smokers in Finland to determine whether either supplement had anticancer
Vitamin E had no effect on lung cancer incidence or overall mortality,
but beta-carotene was associated with an 18% increase in lung cancer incidence
and an 8% increase in overall mortality. The effects of beta-carotene were
stronger among men with a modest alcohol intake and those who smoked at least
20 cigarettes per day. However, vitamin E was associated with 32% fewer
prostate cancer cases and 41% fewer deaths from prostate cancer. This secondary
finding led directly to the inclusion of vitamin E in SELECT.
Results from the CARET study confirmed the findings from the ATBC,
demonstrating a 12% increase in the risk for lung cancer and an 8% increase in
death from any cause among participants assigned to beta-carotene.
“I consider CARET, in one sense, a triumph of evidence-based
medicine because we got a surprise: We found that smokers may actually be at
increased risk for lung cancer with what was thought previously to be an
innocuous intervention,” Kramer said. “It turns out beta carotene
probably does convey harm.”
Vitamins E and C were studied in the Physician’s Health Study II, a
randomized clinical trial designed to assess the effect of these agents on
prostate and total cancer incidence. The recently published results revealed no
evidence of benefit for these vitamins in the study population of middle-aged
or older men.
“The mistake and haste we’ve seen with some of these studies
is taking drugs that were not tested very well in smaller settings and jumping
into phase-3 studies. That’s where we need to use a little pause,”
said Edward Kim, MD, assistant professor of thoracic/head & neck
medical oncology at The University of Texas M.D. Anderson Cancer Center.
According to experts like Kim, there are several ways in which cancer
prevention trials can improve. The first step is to examine prevention
strategies in an optimized patient population.
“In many of the studies we conduct, whether in prevention or
therapeutics, we don’t see a big difference or meaningful improvement with
the newer drugs because there are a good number of patients in the study that
don’t derive as good of a benefit, but there is a certain population that
does,” he said.
Other experts like William, who co-authored a paper with Kim that was
published in Nature this year, agreed that patients at very high
risk for cancer should be targeted for clinical trials. Doing so would maximize
trial design by lowering the number of patients necessary for enrollment, which
in turn would shorten trial time. In addition, including patients who will
respond the best to any given treatment or intervention and excluding those who
are at highest risk for adverse events may improve trial outcomes.
“In essence, what we’re trying to do is personalize cancer
chemoprevention in the same way cancer chemotherapy is being personalized
today,” William said.
In addition to personalized prevention, Kim said that it is crucial to
identify a biomarker as an intermediate endpoint. Because invasive cancer takes
time to develop and become clinically evident, identifying a sensitive marker
to serve as an intermediate endpoint would result in a reduction of required
However, using lessons of the past and learning more about the nature of
different cancers may be one of the most invaluable strategies. According to
Kramer, learning more about molecular pathways will make experts smarter,
though the time when those insights could lead to successes are hard to
Although the future of cancer prevention is uncertain, researchers
continue to examine a multitude of interventions for the prevention of cancer.
Despite the lack of luck with vitamins and micronutrients, most agree that they
may have a role in the future of cancer prevention. However, molecularly
targeted agents and the use of combined agents may be the most promising.
“Cancer has a very complicated biology and using narrowly targeted
single agents is probably not going to be the major path to success,”
Parnes said. “If you have a target that is both necessary and sufficient,
such as BCR-ABL translocation in CML, it’s a different story. But solid
tumors are genetically more complicated than that, so it seems likely that
combinations of agents will need to be developed to maximize the potential of
According to Kim, treatment and prevention have lined up side by side.
“We’re finding more drugs for treatment that are safer and easier to
take that have lower side effect profiles and demonstrated activity, which is
helping with prevention.”
And though the road to prevention has been marked with more failures
than successes, many experts agree that the future of cancer prevention is
“Cancer prevention has been effective. We’re going to need to
educate the population that in the future, cancer prevention interventions may
not be applied broadly to the population but may be best applied to the highest
risk group,” Brown said.
For more information:
- Alpha-tocopherol, beta-carotene cancer prevention trial. National
Cancer Institute website. www.cancer.gov
- Andriole. #LBA1. Presented at: American Urologic Association Annual
Meeting; April 25-30, 2009; Chicago.
- Beta-carotene supplements confirmed as harmful to those at risk for
lung cancer. National Cancer Institute website.
- Cancer prevention. National Cancer Institute website.
- Fisher. J Natl Cancer Inst. 1998;90:1371-1388.
- Gaziano. JAMA. 2009;301:52-62.
- Hampton. JAMA. 2005;294:29-31.
- Lippman. Cancer Res. 2002;62:5119-5125.
- Lippman. JAMA. 2009;301:39-51.
- Study of tamoxifen and raloxifene (STAR) trial. National Cancer
Institute website. www.cancer.gov/STAR
- Tamoxifen: Questions and answers. National Cancer Institute
- William. Nature. 2009;doi:10.1038/nrd2663
- William. Cancer prevention in the 21st century. Presented at: 9th
Annual Oncology Update: Advances and Controversies; January 17-21, 2009; Park