Men undergoing androgen deprivation therapy (ADT) lose muscle and strength and can also develop osteoporosis and other musculoskeletal problems. Findings from a small randomized trial published November 30 in the Journal of Clinical Oncology showed that a 12-week program that combined resistance and aerobic exercise was successful in improving strength, endurance, and quality of life in a group of men receiving ADT. Compared with 28 men receiving usual care, the 29 men in the exercise program increased their lean muscle mass, muscle strength, endurance, and balance, and reported better mental function and less fatigue and nausea. The exercise program had no effect on prostate-specific antigen (PSA) values, indicating “that combined resistance and aerobic exercise can safely be undertaken in patients with prostate cancer” receiving ADT, concluded the authors, led by Dr. Daniel A. Galvão from Edith Cowan University in Australia.
Results from a phase III clinical trial conducted in Germany suggest that the standard initial treatment for patients with slow developing (or indolent) types of B-cell lymphoma should be changed.
The trial's lead investigator, Dr. Mathias Rummel of the University Hospital in Giessen, Germany, reported that patients treated with a combination of rituximab (Rituxan) and bendamustine (Treanda) lived significantly longer without their disease progressing and were less likely to experience major toxicities than patients treated with the standard first-line treatment, a four-drug chemotherapy regimen plus the monoclonal antibody rituximab called R-CHOP. Read more > >
Declines continue. When it comes to cancer rates, those two words are always encouraging. In fact, they were the headline attached to most news stories last week reporting the release of the 2009 Report to the Nation on the Status of Cancer. Understanding that this is not just a single year's trend, as the report made clear, but that many cancer rates have been on the decline for more than a decade, is particularly encouraging. Read more > >
The president of the American Cancer Society shares his thoughts about past accomplishments and future efforts in cancer research Read more > >
- Fred Hutchinson Cancer Research Center to Operate NCI's CIS Contact Center
- Application Deadlines Approach for Interagency Oncology Task Force Fellowships
- President's Cancer Panel Examines Race and Cancer Burden
A MESSAGE TO READERS
NCI Cancer Bulletin Publication Break
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The NCI Cancer Bulletin is produced by the National Cancer Institute (NCI), which was established in 1937. Through basic, clinical, and population-based biomedical research and training, NCI conducts and supports research that will lead to a future in which we can identify the environmental and genetic causes of cancer, prevent cancer before it starts, identify cancers that do develop at the earliest stage, eliminate cancers through innovative treatment interventions, and biologically control those cancers that we cannot eliminate so they become manageable, chronic diseases.
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Trial Suggests New First-line Treatment Option for Slow-growing Lymphomas
Results from a phase III clinical trial conducted in Germany suggest that the standard initial treatment for patients with slow developing (or indolent) types of B-cell lymphoma should be changed.
The trial’s lead investigator, Dr. Mathias Rummel of the University Hospital in Giessen, Germany, reported that patients treated with a combination of rituximab (Rituxan) and bendamustine (Treanda) lived significantly longer without their disease progressing and were less likely to experience major toxicities than patients treated with the standard first-line treatment, a four-drug chemotherapy regimen plus the monoclonal antibody rituximab called R-CHOP. Patients who received rituximab and bendamustine were also more likely to see a nearly complete disappearance of their disease (complete response) compared with the standard first-line treatment.
The findings were presented December 5 at the American Society of Hematology annual meeting in New Orleans.
A majority of the 549 patients in the trial had follicular lymphoma; most of the remaining patients had either indolent lymphoma or mantle cell lymphoma. The latter is a more aggressive lymphoma that is also typically treated with the R-CHOP regimen, Dr. Rummel explained. Trial participants had substantial tumor growth, complications from their disease, or a large tumor burden. “So [these were] patients in need of treatment, with defined indications for treatment,” he said during a press briefing.
Among the 513 patients who were evaluated, the overall response rate—that is, the percentage of patients who experienced at least some tumor shrinkage following treatment—was very high in both groups, 92.7 percent in the bendamustine plus rituximab arm versus 91.3 percent in the R-CHOP arm.
However, in the longer-term, the two-drug regimen offered superior outcomes over R-CHOP. Median progression-free survival was 54.9 months versus 34.8 months, respectively, while the complete response rate was 39.6 percent versus 30 percent. Patients treated with bendamustine plus rituximab also had significantly lower rates of infections and of dangerous drops in white blood cells (WBC), and as a result they were much less likely to require treatment with granulocyte colony-stimulating factor to increase WBC production.
The trial was conducted primarily to see if the two-drug regimen was less toxic and equally as effective as R-CHOP, Dr. Rummel noted. “In the end,” he continued, “we…demonstrated a clear statistically significant superiority of the better tolerated regimen.”
Although he stressed that it can be important to have confirmatory results from another clinical trial, Dr. Richard Van Etten, director of the Tufts Medical Center Cancer Center, concurred with Dr. Rummel that these findings could alter the standard of care.
Some caution is warranted until longer-term data on toxicity are available, noted Dr. Anas Younes, a lymphoma researcher at the University of Texas M.D. Anderson Cancer Center, who made his comment in response to a reporter’s question via Twitter.
Also, there are no overall survival data yet to report. But because these are slow-developing cancers deemed incurable, that may not matter in terms of defining the standard of care, explained Dr. Richard Little of NCI’s Division of Cancer Treatment and Diagnosis. “It’s very difficult in this disease to base standard-of-care decisions on overall survival,” he said. “Most of the primary endpoint data that drives standard of care is based on progression-free survival, with significant attention paid to the treatment’s toxicity.” As a result, many clinicians may now favor the bendamustine-plus-rituximab regimen over R-CHOP in patients who require cytotoxic therapy, he said.
Dr. Rummel also stressed that the dose of bendamustine used in the trial is lower than what is indicated on the drug’s label for use in lymphoma patients in the United States. The lower dose is critical in this case, he said, because it helps to avoid unnecessary toxicities without apparently compromising effectiveness.
Several proposals have been submitted to NCI for early stage clinical trials using bendamustine and rituximab in combination with other novel agents in patients with follicular lymphoma, Dr. Little noted, in the hope of further improving efficacy and reducing toxicity.
Cancer Research Highlights
Bone Drugs Linked to Fewer Cases of Breast Cancer
A new analysis from the Women’s Health Initiative (WHI) study has found that the use of drugs called bisphosphonates, which are taken to improve bone health, was associated with a nearly 33 percent reduction in the incidence of invasive breast cancer compared with women who did not take the drugs. Although preliminary, the findings raise the possibility that this commonly used class of drugs may have a role in preventing breast cancer, researchers said at the 2009 CTRC-AACR San Antonio Breast Cancer Symposium.
Bisphosphonates are taken primarily for the treatment of osteoporosis but can also treat bone-density problems in patients with cancer-related conditions. Laboratory studies have suggested that these agents may also have anticancer effects, providing a possible biological explanation for the association.
To find the association, Dr. Rowan Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and his colleagues analyzed data on 151,000 women in the observational component of the WHI. Of the 2,216 women who were using bisphosphonates when they entered the study, 64 developed breast cancer, and most of those cancers (50) were estrogen-receptor positive.
The results translate into 32 percent fewer cases of invasive breast cancer among users of oral bisphosphonates—primarily alendronate (Fosamax)—compared with nonusers. A second study presented in San Antonio found a nearly 30 percent reduction of postmenopausal breast cancers among women in Israel who used bisphosphonates for at least a year compared with nonusers.
Since neither study was a randomized controlled trial, the results should be considered hypothesis-generating and are by no means proof, noted Dr. Leslie Ford of NCI’s Division of Cancer Prevention and the institute’s WHI liaison. “One issue is that women who take bisphosphonates often have low bone density because they are in a low estrogen environment,” she said, “so these women would be at a lower risk for breast cancer than women who did not get bisphosphonates.” This could be an alternative explanation for the result.
An ongoing clinical trial is looking at the role of bisphosphonates in the adjuvant treatment of breast cancer. If the results indicate that women taking the drugs have a lower rate of cancer in the opposite (contralateral) breast than women not taking bisphosphonates, this would “be a very intriguing finding and would make the current observations even stronger,” said Dr. Ford. Nonetheless, randomized controlled trials in the preventative setting would be needed for this to become the standard of care, she added.
Bisphosphonates have been linked to osteonecrosis of the jaw, and the FDA issued a warning about musculoskeletal side effects of these drugs in January 2008. A year later, the FDA’s Dr. Diane Wysowski warned of an increased risk of esophageal cancer and death in patients taking oral bisphosphonates.
U.S. Cancer Cases and Deaths Continued to Decline in 2006
The overall rate of new cancer cases diagnosed (incidence) and deaths from cancer (mortality) continued to decline significantly in the United States through 2006, due largely to lower lung, prostate, and colorectal cancer rates in men and lower breast and colorectal cancer rates in women. New diagnoses for all cancers decreased, on average, almost 1 percent per year between 1999 and 2006. Cancer deaths decreased 1.6 percent per year between 2001 and 2006. Researchers from NCI, CDC, American Cancer Society, and North American Association of Central Cancer Registries reported these findings in the Annual Report to the Nation on the Status of Cancer (1976-2006), published online December 7 in Cancer.
This year’s report featured a special section on colorectal cancer (CRC) trends. Over the most recent data collection period, new cases of CRC fell 3.0 percent per year in men and 2.2 percent in women, while deaths from CRC fell 3.9 percent per year in men and 3.4 percent in women. Using data from NCI’s SEER Program and the CDC’s National Center for Health Statistics, the researchers used a microsimulation model, MISCAN-Colon, from NCI’s Cancer Intervention and Surveillance Modeling Network (CISNET) consortium to estimate the impact of historical changes in modifiable risk factors (obesity, smoking, and diet), screening, and treatment on past CRC incidence and mortality trends and to project future mortality trends through 2020.
Of the 26 percent reduction in CRC mortality from 1975 to 2000, estimates from MISCAN-Colon modeling indicated that slightly more than half was due to increased screening (especially of older adults using the fecal occult blood test, sigmoidoscopy, and colonoscopy), more than a third was due to improvements in risk factors, and the remaining reduction can be attributed to better treatment. The model predicted a “36 percent overall decline in CRC mortality from 2000 to 2020 if current trends in risk factors, screening, and treatment continue,” and, with accelerated cancer control efforts, “an overall mortality reduction of 50 percent by 2020 is possible,” the authors wrote.
“The continued decline in overall cancer rates documents the success we have had with our aggressive efforts to reduce risk in large populations, to provide for early detection, and to develop new therapies that have been successfully applied in this past decade,” said NCI Director Dr. John E. Niederhuber in a statement. “Yet we cannot be content with this steady reduction in incidence and mortality. We must, in fact, accelerate our efforts to get individualized diagnoses and treatments to all Americans and our belief is that our research efforts and our vision are moving us rapidly in that direction.”
Nilotinib Effective and Safe in Initial Treatment of Chronic Leukemia
Preliminary results from a phase III trial testing nilotinib (Tasigna) against imatinib mesylate (Gleevec) as first-line treatment for chronic-phase chronic myelogenous leukemia (CML) indicate that nilotinib is effective and safe as initial treatment for this disease. The findings were presented December 8 at the 2009 American Society of Hematology annual meeting.
Imatinib has been a model for cancer drug developers because it specifically targets a mutant protein called BCR-ABL. Unfortunately, many patients eventually develop resistance to the drug, and this has led to the development of second-generation targeted therapies such as nilotinib and dasatinib (Sprycel) to treat imatinib-resistant CML.
An international group of researchers, led by Dr. Giuseppe Saglio of the University of Turin in Italy, enrolled 846 patients into the ENESTnd trial. Participants were randomly assigned to receive 300 mg of nilotinib twice daily, 400 mg of nilotinib twice daily, or 400 mg of imatinib once a day.
At 12 months of follow-up, patients receiving either dose of nilotinib had fewer white blood cells expressing the mutant BCR-ABL protein and were more likely to have no leukemia cells detected by laboratory techniques (a complete cytogenetic response) compared with patients receiving imatinib. Patients receiving nilotinib were also less likely to have their disease progress to an advanced stage.
Side effects and rates of drug discontinuation due to side effects were similar between the groups. Nilotinib is known to potentially cause problems with heart rhythm and function, but no severe cardiac side effects have been observed to date in the ENESTnd trial, Dr. Saglio reported. Although the investigators cautioned that the trial is still ongoing, the presenters suggested that nilotinib may eventually replace imatinib as the standard first-line therapy for CML.
Androgen Deprivation Therapy Linked to Cardiovascular Disease, Diabetes
Studies have indicated that older men receiving androgen deprivation therapy (ADT) for the treatment of prostate cancer may be at increased risk of cardiovascular disease and diabetes. A new study suggests that ADT can increase the risk of these side effects among all men undergoing this treatment.
To conduct the study, Dr. Nancy L. Keating of Harvard Medical School and her colleagues performed an observational study of 37,443 men treated with ADT through the Veterans Health Administration. The results appeared online December 7 in the Journal of the National Cancer Institute.
“Although the risks associated with androgen deprivation therapy remain incompletely defined, the potential for harm from this treatment underscores the importance of better understanding its benefits,” the researchers concluded.
Of the 37,443 men, 39 percent received some form of ADT as part of their treatment. The majority of these men underwent treatment with a gonadotropin-releasing hormone (GnRH) agonist, a type of drug that blocks the body’s production of testosterone. Only 0.8 percent underwent bilateral orchiectomy (removal of the testicles), 3.3 percent received oral antiandrogen monotherapy (treatment with a drug that blocks testosterone from binding to prostate cancer cells), and 4.9 percent received a combined androgen blockade (the combination of an antiandrogen monotherapy drug and a GnRH agonist). Patients with pre-existing cardiovascular disease or diabetes were excluded from the analyses, and factors such as cholesterol levels and statin use were taken into account.
Treatment with a GnRH agonist was associated with an increased risk of diabetes, coronary heart disease (CHD), heart attack, sudden cardiac death, and stroke. Combined androgen blockade was associated with an increased risk of CHD, and orchiectomy was associated with an increased risk of CHD and heart attack. Oral antiandrogen monotherapy alone, however, was not associated with an increased risk of any of the studied outcomes.
ADT has been shown to extend survival for men with locally advanced prostate cancer, but its benefits for men with less advanced disease are not clear, explained Dr. Peter C. Albertsen in an accompanying editorial. Despite this lack of clarity, its use in men with less advanced cancer has been increasing.
Antioxidant Supplement May Prevent Return of Precancerous Colorectal Growths
Long-term results from a clinical trial conducted in Italy suggest that an antioxidant compound may play a role in preventing colorectal cancer. In the trial, participants were randomly assigned to take a placebo or a selenium-based antioxidant compound supplement for 5 years following the removal of precancerous growths in the colon called metachronous adenomas. Participants who took the supplement had a statistically significantly reduced risk of adenoma recurrence compared with participants who took the placebo. The results were reported at the American Association for Cancer Research Frontiers in Cancer Prevention Research conference in Houston.
The reduction in risk extended out 13 years after participants had stopped taking the supplement, reported Dr. Luigina Bonelli of the National Institute for Cancer Research in Genoa, Italy, and colleagues.
There were 411 participants in the trial, and data on survival and the results of at least one total colonoscopy were available for 311 patients. The supplement used in the trial, manufactured by Pharma Nord, was a combination of selenomethionine, zinc, vitamin C, and relatively high doses of vitamins A and E.
Overall, participants who took the supplement had a 41 percent reduced risk of developing adenomas over the long term. Adenomas returned in 4.2 percent of patients in the supplement arm compared with 7.2 percent in the placebo arm. The reduction was especially pronounced in patients who had previously had advanced adenomas removed, which for this report included 111 participants in the antioxidant arm and 109 in the placebo arm. Among these participants, those who took the supplement had a nearly 90 percent reduction in the risk of developing advanced adenomas compared with those who took the placebo.
Regarding the clinical implications for these findings, Dr. Bonelli said: “We need further information to better target the treatment.” Participants with prior advanced adenomas did appear to obtain the greatest benefit, she added, and there was little to no toxicity associated with the supplement.
The findings, while promising, have to be interpreted with some caution, noted Dr. Asad Umar, chief of the Gastrointestinal and Other Cancers Research Group in NCI’s Division of Cancer Prevention. “Other data from observational and clinical trials examining the effect of selenium on colorectal cancer have yielded mixed results,” showing either a decreased risk or no effect, he said. Selenium also appeared to have no effect in prevention trials for skin and prostate cancer, he added.
Modeling a Future without Cancer
Declines continue. When it comes to cancer rates, those two words are always encouraging. In fact, they were the headline attached to most news stories last week reporting the release of the 2009 Report to the Nation on the Status of Cancer. Understanding that this is not just a single year’s trend, as the report made clear, but that many cancer rates have been on the decline for more than a decade, is particularly encouraging.
While progress against cancer—lower rates of new cancer cases and of cancer deaths—is welcome news at any time, I daresay none of us at NCI considers modest but steady progress to be sufficient. We must continue every effort to develop new understandings and comprehensive solutions to complex diseases. Yet, the report also makes a convincing case that we must work even harder to fully employ today’s best methods of treatment and cancer risk reduction.
This year’s report includes a special feature, which uses incidence and mortality modeling projections to show that colorectal cancer mortality could fall by as much as 50 percent by 2020 if many more Americans have regular colorectal cancer exams, exercise more, eat more healthily, and stop smoking, among other things. The potential benefit is stunning when you consider that it’s estimated that colorectal cancer will take nearly 50,000 lives in the United States in 2009. Clearly, community-based programs of NCI and its partner agencies must even more strongly promote screening, improved nutrition, and smoking cessation.
In colorectal cancer, even applying today’s adjuvant chemotherapy regimens to more patients could have a major impact. In their modeling efforts for the report, researchers assessed data on use of, and disease-free survival rates associated with, four chemotherapy regimens used to treat advanced colorectal cancer during different historical time periods. Just increasing conventional colorectal cancer treatment rates over time—from 8 percent of patients in 2005, to between 45 percent and 83 percent of patients by 2020—would have a significant impact on colorectal cancer mortality.
We often talk about a highly personalized approach to cancer research, patient diagnosis, and the development of biomarkers and targeted therapies, all tied to the unique cancer burdens of individuals. As this report strongly highlights, by applying some very straightforward actions that we know are effective today, and using them efficiently, we can make perhaps an equally large dent in the cancer burden. This will truly complement the benefit over the coming decade likely to be derived from targeted chemotherapy agents currently in the research and development pipeline.
For proof of that point, one needs look no further than lung cancer. Many have hypothesized that if we immediately got every smoker in America to quit, the overall death rate in the United States due to tobacco-related cancer could be cut in half.
There is one other area in which I have become convinced we have a great chance to dramatically impact cancer incidence and mortality: infectious agents. Current evidence indicates that as many as one in five cancers have an infectious cause. My belief is that with an increased effort, research addressing how viruses or bacteria can impact cancer causation may continue to give us significant opportunities to reduce incidence and mortality.
In fact, more than a dozen viruses already have been associated with various types of cancer. Researchers are still learning how a cell that is infected with a virus becomes a cancer cell. Hepatitis B and C have been linked to liver cancer conclusively and there are several cancers, including cervical cancer, that are associated with the human papillomavirus (HPV). Additionally, Helicobacter pylori has been linked to stomach cancer and several viruses have been associated with leukemia, lymphoma, and Kaposi sarcoma. Scientists are currently examining potential connections between some viruses and brain, colon, breast, and prostate cancer, although no definitive associations have been established yet for these diseases.
Identifying, treating, and even possibly preventing cancers caused by infectious agents such as retroviruses are ongoing challenges, because each virus causes cancer through a different process and some viruses cause cancer indirectly. Each day we are gaining a better understanding of the relationship between infection, immunity, and genetics. With this new understanding, we are beginning to develop new therapies and novel vaccines that target viruses, which could help lower the number of cancers that are associated with infections.
One of our great areas of promise in addressing the cancer burden comes from the intense study of the genetic and epigenetic alterations associated with the initiation and progression of cancer. The Cancer Genome Atlas (TCGA) project, a joint effort of NCI and the National Human Genome Research Institute, has been an extremely successful pilot that continues to unveil the genetic alterations, translocations, and mutations of a growing list of cancers. Using this comprehensive dataset may also provide unique insights into telltale signs of infectious agents.
During this past decade we have clearly broadened and deepened the tools that we have available to fight cancer. By effectively using these tools in the coming decade, we have an excellent opportunity to truly accelerate the rate of decline for many types of cancer. We are entering the second decade of the 21st century with a strong hope of reaching the goal of making many cancers chronic diseases, at worst, and memories of a bygone era, at best.
Dr. John E. Niederhuber
Director, National Cancer Institute
Moving Toward a World with Less Cancer and More Birthdays
The American Cancer Society held its 96th annual meeting last month in Los Angeles, where the Society’s national volunteer and staff leaders gathered to conduct our annual business and to discuss ways that we can position ourselves for optimal delivery on our mission to save more lives from cancer.
This year, in addition to handling our required governance business, we had an extremely informative general session centered around the historic power and influence of women throughout the history of the American Cancer Society. From our legendary Women’s Field Army to today’s “mommy bloggers,” women have helped deliver our mission in their role as the primary health care decision-makers in nearly all U.S. households. We examined how women are using their passion and power to transform the world around them and why, as we become a more constituent-focused organization, they are a critical market for the Society as it moves forward.
We culminated our meeting on the evening of Thursday, November 19, by bestowing our highest award, the Medal of Honor, on three distinguished scientists, Drs. Edward Harlow, Arnold Levine, and Marvin Zelen, and famed cancer survivor Lance Armstrong. However, a personal highlight was on Thursday afternoon, when I was inaugurated as the national volunteer President of the Society. The key to our ongoing success is the vital core of dedicated volunteers at the heart of the Society, who are relentless in their dedication to see an end to cancer. To that end, I am extremely humbled and pleased to represent the Society as its 2009–2010 President.
Our American Cancer Society enjoys unparalleled trust and confidence from the American public when it comes to cancer information and the ability to recommend what is the right thing for the country when it comes to health care reform. We have achieved that trust and confidence by bringing excellence to cancer prevention, treatment, research, and advocacy. Our American Cancer Society is respected because of its actions over the years: deliberate, cautious, in many ways predictable, science-based, and a voice for all cancer patients regardless of age, gender, race, ethnicity, sexual orientation, or political affiliation, because cancer respects no boundaries.
In my inaugural address I drew attention to the awesome task confronting our American Cancer Society in the coming year, to ensure that the integrity of, and trust and confidence in, our Society shall not be diminished. As we have worked to improve cancer prevention and the delivery of cancer care, we have learned much about the complicated process of trying to assimilate identified problems with health care delivery into the reality of health care reform. Our task in continuing this work is immense but our resolve steadfast. As we move forward, we recognize that the solutions to issues surrounding cancer prevention, treatment, research, and advocacy must be as uniquely American as is the public that provides our support.
As a global grassroots force of more than 3 million volunteers, the American Cancer Society fights for every birthday threatened by every cancer in every community. We save lives by helping people stay well through preventing cancer or detecting it early; helping people get well by being there for them during and after a cancer diagnosis; by finding cures through investment in groundbreaking discovery; by fighting back and rallying lawmakers to pass laws that will defeat cancer; and rallying communities worldwide to join the fight.
As the nation’s largest non-governmental investor in cancer research, contributing about $3.4 billion, we turn what we know about cancer into what we do. As a result, about 11 million people in America who have had cancer and countless more who have avoided it will be celebrating birthdays this year. To learn more about us or to get help, call us any time, day or night, at 1-800-227-2345 or visit http://www.cancer.org.
Dr. Alan G. Thorson
President, American Cancer Society
Adapting the Science of Supplements and Cancer Prevention
Numerous studies suggest that avoiding excess weight, exercising regularly, and eating a diet heavy on fruits and vegetables decreases the risk of many diseases, including cancer. But as the expanding obesity epidemic has shown, there are major obstacles to getting broad swaths of people to adopt such a healthful lifestyle. So, for many years, cancer researchers have investigated whether specific nutrients—those that epidemiologic and animal model studies have suggested could sway cancer’s course—could decrease cancer risk.
Much has been learned from this work, researchers in the field say, but, as is the case with treatment, each new discovery points to new areas of focus and other potential avenues of progress.
With promising bioactive compounds in the pipeline, many prevention researchers are focused on figuring out not just whether something like sulforaphane, a natural compound found in broccoli and broccoli sprouts, can kill cancer cells in a test tube or animal model—which it does, quite well—but how, at the molecular level, it accomplishes this task, whether there are some cancer cells that are more likely to respond to it, and whether there are ways of discerning early on that the intervention is having its intended effect.
Prevention: A Complex Matter
A number of supplements have been tested in large prevention trials, including vitamins A, C, and E; selenium; beta-carotene; and folic acid. At least one trial has demonstrated a reduction in cancer deaths with a combination of supplements, while several others found no reduction or even a small increased risk.
“There was suggestive evidence in humans” to support the large clinical trials conducted to date, said Dr. Peter Greenwald, director of NCI’s Division of Cancer Prevention (DCP). Millions of people are taking supplements in the belief that they can improve their health, including preventing cancer, he continued, so getting data from randomized clinical trials—the gold standard of biomedical research—is critical.
But given the complexity of cancer, acknowledged Dr. Alan Kristal, a long-time cancer prevention researcher at the Fred Hutchinson Cancer Research Center, it raises questions about whether “high doses of micronutrients are going to have an impact on cancer risk.”
And Dr. John Milner, chief of DCP’s Nutritional Science Research Group, says that, in the pursuit of nutrition-based cancer prevention, it’s more than just the complexity of cancer that has been underestimated. “In many ways, the lesson is that food and what we need to live is a lot more complex than we’ve ever thought,” Dr. Milner said.
It’s that complexity that researchers are increasingly tackling more directly.
At Ohio State University, Dr. Gary Stoner and his colleagues have been studying the cancer prevention potential of black raspberries for the last decade. Much of their work has focused on a powdered form of the entire berry, which eliminates the water that makes up 85 to 90 percent of the berry’s weight.
The researchers began with laboratory and animal model studies, and when these studies demonstrated that the berry powder had prevention potential, they transitioned to small human trials. Some promising results have been seen in early stage human trials for esophageal, oral, and colorectal cancer prevention. A small skin cancer prevention trial is on the immediate horizon.
In the case of oral cancer, the Ohio State team worked with collaborators from the University of Kentucky to produce a berry powder-infused gel that is applied to precancerous oral lesions. Treatment for 6 weeks shrunk the lesions by as much as 50 percent and decreased the activity of genes related to cell growth and proliferation. Based on the results, NCI is funding a phase II, placebo-controlled trial of the gel.
“You can establish that something might work in a much smaller trial with a lot less money,” Dr. Stoner said. “You can get a good idea if it will inhibit proliferation in a trial of 20 patients.”
Small human trials, explained Dr. Kristal, can “integrate what’s known about the carcinogenesis process and see whether we can manipulate that process with micronutrients or bioactive compounds.” Even then, he stressed, they have to be carefully designed to ensure that they produce meaningful results that can potentially inform further studies and larger trials.
At UCLA’s Jonsson Comprehensive Cancer Center, for instance, Dr. William Aronson is leading a phase II clinical trial of fish oil supplements, which are a plentiful source of omega-3 polyunsaturated fatty acids. The trial is randomly assigning men with prostate cancer who are scheduled to have their prostates removed to a low-fat diet with fish oil supplements or a standard Western diet for 4 to 8 weeks.
By analyzing tissue and blood samples taken before and after surgery, the researchers aim to determine whether the low-fat diet and fish oil combination alters the levels of certain serum and tissue proteins that may be associated with prostate cancer progression. “Such biomarkers may indicate that the intervention is working and will be an essential component of long-term human dietary intervention trials,” Dr. Aronson explained.
Even here there are challenges, noted Dr. Kristal, because once potential biomarkers are discovered, it then has to be demonstrated that a change in a biomarker alters the course of the disease.
Both short-term trials and analyses of tissue samples from the large trials that have already been conducted may also help to address another critical issue: variability in response. “Any time you do a study, even with drugs, you don’t get 100 percent effectiveness. You only get some people who respond,” said Dr. Milner. “That’s what happens with many nutrients as well.”
All of this work, stressed Dr. Greenwald, is moving in the right direction to get these nutritional interventions into phase II and III trials. “If you have studies that clearly show an effect on biological endpoints that we think are related to cancer risk, a mechanism, and human data, that’s very useful information,” he said.
Moving Forward to Phase III Trials
While more early stage trials are on the horizon, those in the field agree that there will probably be somewhat fewer large phase III trials. One such trial, the VITamin D and omegA-3 triaL, dubbed VITAL, is set to begin enrolling the first of 20,000 planned participants in January 2010. The NCI-supported trial will test whether regular use of vitamin D and fish oil supplements, taken either alone or in combination, reduces overall cancer risk (as well as the risk of heart disease and stroke) in women aged 65 and older and men aged 60 and older.
“There is a narrow window of opportunity for doing a trial of this nature,” said the study’s principal investigator, Dr. JoAnn Manson, from Brigham and Women’s Hospital and Harvard Medical School. Only in the last 2 years, Dr. Manson believes, “has the strength of the evidence for vitamin D and fish oil reached that threshold” to support launching a trial of this size. In addition, she argued, if researchers wait too long, “so many people could be taking [these supplements] that the trial will no longer be feasible.”
Sales data on supplements support her concern. According to The Nielsen Company, sales of vitamins and supplements for June 2008 to June 2009 were up 5 percent over the previous year, totaling $1.5 billion. Vitamin D and fish oil are two of the biggest sellers.
VITAL researchers will analyze blood samples from a subset of participants to see if baseline levels of markers like 25-hydroxy vitamin D, the primary form of vitamin D circulating in the blood, and omega-3s correlate with reduced disease risk. And because the trial has a specific focus on recruiting a large number of minority participants, the researchers can analyze whether factors like participants’ race or ethnic background influenced the response to the supplements and whether supplement consumption can reduce health disparities by race.
Advances may not come as fast as some might like, but they are happening, said Dr. Aronson. “I think we’re going to make very significant progress over the next 5 years and we’re going to gain important information that we can incorporate into larger trials.”
A Closer Look
Putting Circulating Tumor Cells to the Test
Doctors have known for 140 years that tumor cells can escape into the blood of patients with cancer, and it has taken almost as long to find ways to capture these circulating tumor cells, or CTCs. But at least a dozen experimental tools for isolating the cells have emerged recently, creating new possibilities for using CTCs to understand how cancers spread and also to improve the care of patients.
To clarify the changing landscape and foster collaborations, NCI recently convened a meeting of cancer biologists, clinicians, and technologists—the people who develop the tools for capturing these elusive cells. More than 500 participants came to the NIH campus in September to hear presentations on cutting-edge technologies and exchange ideas about where the field needs to go.
The focus of the meeting was translational science—moving technologies from the lab to the clinic—and many presenters said that CTCs could play an important role in medicine. Doctors, they said, may one day be able to select treatments for patients and then monitor the effectiveness of those treatments simply by drawing and analyzing blood. In short, testing CTCs could be a kind of “liquid biopsy.” There was also considerable interest in using the cells to learn about the metastases that cause most cancer deaths.
“Everybody understands how important research on these cells is; first and foremost, for patients, but also for other reasons, such as health economics,” said Dr. Howard Scher of Memorial Sloan-Kettering Cancer Center, who presented at the meeting. “If doctors can use CTCs to tell patients that a drug is not going to work ahead of time, then you’ve spared the patients toxicity and allowed them to move on to something else.”
But Dr. Scher cautioned that discovering and capturing these cells is only the first step. For CTCs to be used as biological markers for cancer, the prognostic value of these cells first needs to be validated, he continued, noting that the FDA has a path for biomarker development that has several stages similar to clinical trials for drugs.
FDA officials were at the meeting and gave presentations on the regulatory aspects of developing these new technologies, which are critical for moving the tools into the clinic, noted Dr. Avraham Rasooly of NCI’s Division of Cancer Treatment and Diagnosis and the FDA Center for Devices and Radiological Health, who was one of the organizers.
The agency has cleared a technology called CellSearch for capturing and counting CTCs in patients with metastatic breast, prostate, and colorectal cancers as a prognostic tool. CTC counts above certain thresholds (five or more per sample in breast and prostate cancer; three or more per sample in colorectal cancer) are associated with a poor prognosis and may be an indication the disease is progressing.
Many of the experimental tools in development are designed to go beyond prognosis and into the realm of personalized medicine. And for good reason: With a growing number of targeted cancer medicines, doctors want to know the genetic subtype of a patient’s tumor, and this information could, in theory, come from CTCs.
“The future of targeted therapies in cancer is completely dependent on a patient’s genetic profile, and you also need to be able to do serial monitoring of patients over time,” Dr. Daniel Haber of Massachusetts General Hospital (MGH) said at the meeting. “When a patient stops responding to therapy, you need to know why and the principal mechanism of resistance.”
His group, co-led by Dr. Mehmet Toner, a biomedical engineer at MGH, has developed the CTC-Chip, a microfluidic device that can capture CTCs from blood. (See movie above.) The team has shown, in principle, that they could use CTCs from the blood of patients with lung cancer to detect mutations in the gene EGFR, which are biomarkers for whether a patient is likely to respond to a certain type of therapy.
In another study, the group is asking whether CTCs can be detected in men with prostate cancer before the disease spreads. Currently, there is no way to identify patients at risk of relapse. The trial includes men whose cancers have not yet spread; their blood will be drawn before and after surgery, and then sampled periodically as the trial proceeds.
“If we could use CTCs to predict which patients are going to relapse, then doctors could consider additional treatments beyond surgery for those patients,” said Dr. Sunitha Nagrath, one of the investigators.
In the Clinic
At the Lombardi Comprehensive Cancer Center at Georgetown University, Dr. Minetta Liu uses the CellSearch test in conjunction with routine imaging in her clinical practice. In a recent study of women with metastatic breast cancer, she and her colleagues found a strong correlation between CTC counts and radiographic evidence of the disease progressing. Their findings provide further evidence that counting CTCs in blood can predict the effectiveness of systemic treatments.
“We are all clearly interested in these cells, and patients are always eager for additional information about their health,” said Dr. Liu.
Being able to assess a treatment’s effectiveness from a simple blood draw could limit the number of time-consuming radiology studies a patient would have to undergo, she continued, while also providing additional reassurance about the effectiveness of a particular treatment regimen. Similarly, testing CTCs could prompt doctors to change treatments earlier than would be suggested by an imaging study alone.
This is important, Dr. Liu stressed, because for women with metastatic breast cancer the focus of treatment is to preserve an individual’s quality of life. “In the absence of a cure, the ability to maximize treatment benefit and minimize toxicity and discomfort are of the greatest importance,” she said.
Some patients may benefit from new therapies as their tumors evolve over time. A trial has just been launched to see whether CTCs can be used to identify women with metastatic breast cancer who are candidates for trastuzumab (Herceptin), even if previous tests did not suggest that they should receive the drug. Women whose tumors have abnormal levels of the protein HER2 are candidates for the drug.
“This trial represents a shift in the current thinking about how to manage metastatic disease,” said the lead investigator, Dr. Massimo Cristofanilli of the University of Texas M.D. Anderson Cancer Center. Using a modified version of the CellSearch system, the study will not just count CTCs but try to use them as biomarkers to inform therapy by assessing HER2 expression in them, added Dr. Cristofanilli, who will soon join the Fox Chase Cancer Center.
“We may be able to offer what is very effective treatment to patients who wouldn’t receive Herceptin because the primary tumor was HER2-negative,” noted Dr. Jeffrey Smerage of the University of Michigan, another investigator in the trial.
At Stanford University, researchers are asking whether the analysis of CTCs can match patients and drugs early in treatment. The team will profile certain genes in CTCs using blood drawn from men with prostate cancer before and after they receive an experimental drug. As the trial progresses, it will be clear who the responders are, and the researchers will then look for associations with CTC gene profiles.
“We’re trying to find out which genes are being expressed in the CTCs and whether they might help us choose a therapy,” said Dr. Stefanie Jeffrey, a breast cancer surgeon at Stanford and a lead investigator of the study. “Hopefully, we’ll be able to find out from the profile before patients are even on the drug whether they are likely to respond.”
The trial is using a device called the MagSweeper to capture CTCs for analysis. As with so many of the technologies, Dr. Jeffrey developed the tool with a multidisciplinary team that included engineers and genome scientists. Some of their preliminary studies have suggested that not all CTCs are alike and that some may have characteristics of stem cells.
“I think we’ll learn that this is a lot more complex than we initially thought based on our paradigm of cancer cells being shed by a tumor,” Dr. Jeffrey said. “The field is just now burgeoning, and we still have a great deal to learn.”
Dr. Thomas Ashworth, the Australian physician who observed CTCs in a patient with cancer in 1869, could not have foreseen where his discovery would lead.
“What’s most exciting is that the technology is reaching a point where we can ask some questions, and trials are actually being done in multiple diseases,” said Dr. Scher. The most important question, he added, may be: “How will testing CTCs help us make medical decisions?”
—Edward R. Winstead
Featured Clinical Trial
Defining Optimal Therapy for Metastatic and Recurrent Cervical Cancer
Name of the Trial
Phase III Randomized Study of Paclitaxel in Combination with Cisplatin or Topotecan Hydrochloride with Versus without Bevacizumab in Patients with Stage IVB, Recurrent, or Persistent Carcinoma of the Cervix (GOG-0240). See the protocol summary.
Dr. Krishnansu Tewari, Gynecologic Oncology Group
Why This Trial Is Important
Treatment options are limited for women with metastatic or recurrent cervical cancer. Currently, treatment of these women often includes chemotherapy with the drug cisplatin. Unfortunately, only up to one third of patients with metastatic and recurrent disease will respond to cisplatin-based chemotherapy, and these responses are short-lived, on the order of months. Additionally, because cisplatin-based chemotherapy (in combination with radiation therapy) is also used to treat patients with earlier-stage disease, recurrent cervical cancer may be resistant to additional treatment with platinum drugs. Therefore, doctors are trying to find alternative, non-platinum combinations for advanced disease that are able to shrink tumors and help patients live longer. Previous clinical trials have offered some promising leads, indicating that patients may benefit from treatment with the drugs paclitaxel and topotecan, as well as biological agents that target tumor angiogenesis.
A recent phase III trial of four cisplatin-based chemotherapy combinations in patients with advanced cervical cancer showed a trend toward better survival when cisplatin was combined with paclitaxel. The trial was stopped early, however, because none of the regimens appeared likely to provide a statistically meaningful benefit over the others, reinforcing the need for a non-platinum-based option. Topotecan combined with cisplatin has also demonstrated benefit in patients with advanced disease, but researchers suspect much of this benefit may be due to the effects of topotecan alone. These observations provide a rationale for pairing paclitaxel and topotecan, and a small pilot study demonstrated that the combination is safe and clinically active.
Antiangiogenesis therapy using the biological agent bevacizumab is also being investigated in women with advanced cervical cancer. Results of a phase II trial of bevacizumab alone, in women with persistent (refractory) or recurrent disease, showed the drug to be well tolerated and active.
In this phase III trial, women with metastatic, recurrent, or persistent cervical cancer that cannot be treated with surgery and/or radiation therapy will be randomly assigned to one of four treatment groups: paclitaxel plus cisplatin, paclitaxel plus topotecan, or either of these combinations with the addition of bevacizumab. Doctors will compare overall survival and the frequency and severity of side effects in patients treated with these regimens.
“Women with such advanced cervical cancer unfortunately have very few treatment options,” said Dr. Tewari. “So, it’s critical for them to explore clinical trials. This is the first randomized phase III study of a targeted agent in metastatic or recurrent cervical cancer, and it is the only U.S. phase III trial exploring the use of non-platinum combination chemotherapy in this patient population.”
Cancer Center Profile
St. Jude Children's Research Hospital Comprehensive Cancer Center
Director: Dr. Michael B. Kastan • 262 Danny Thomas Place, Memphis, TN 38105
Phone: 901-595-3300 • Web site: http://www.stjude.org
St. Jude Children’s Research Hospital was established by the late entertainer Danny Thomas to provide treatment for children affected by catastrophic diseases, regardless of their race, religion, or ability to pay. Beyond their treatment, he wanted to build a hospital that would find cures and ways to prevent their diseases. In the late 1950s, Mr. Thomas and more than 100 others who had joined his cause formed the American Lebanese Syrian Associated Charities (ALSAC), the fundraising organization for St. Jude, and the hospital opened its doors in 1962. At that time, the 10-year event-free survival rate for the most common form of childhood cancer, acute lymphoblastic leukemia, was just 4 percent.
St. Jude has grown immensely since then. Today it employs a staff of more than 3,300 and has a daily operation budget of $1.4 million. The hospital occupies 2.5 million square feet of clinical, research, and administrative space, and about 5,700 active patients are seen at St. Jude yearly, most of them treated on a continuing outpatient basis as part of ongoing research programs. Patients are referred by doctors from all 50 states, as well as other countries. Clinical and research efforts still focus on cancer, but also include acquired and inherited immunodeficiencies, sickle cell disease, infectious diseases, and genetic disorders in children.
In 1977 St. Jude received its first NCI Cancer Center Support Grant. The hospital has been continually funded by NCI every year since then. It received special designation in 2008 as a Comprehensive Cancer Center, due to the combined disciplines of basic, clinical, and population-based research, and today it is the only NCI-designated comprehensive cancer center that focuses solely on pediatric cancers.
Among its list of achievements, the hospital boasts a faculty with renowned clinical and research staff, including recipients of the Nobel Prize and Albert Lasker Basic Medical Research Award. And because of research at St. Jude, the survival rates for numerous pediatric cancers have vastly improved; today the 10-year event-free survival rate for patients at St. Jude who are treated for acute lymphoblastic leukemia is more than 90 percent.
The Comprehensive Cancer Center at St. Jude includes several cross-disciplinary, multi-departmental programs dedicated to specific diseases (Hematological Malignancies and Neurobiology and Brain Tumor), conceptual themes (Signal Transduction and Molecular Oncology), or novel therapeutic approaches (Developmental Therapeutics for Solid Malignancies). The cancer center also includes a new Cancer Prevention and Control Program, which builds on the institution’s commitment to long-term follow-up of patients in the After Completion of Therapy Clinic.
Cancer Center faculty members conduct a broad spectrum of research, including basic science research, investigation of disease pathogenesis and drug resistance, translational research, behavioral and quality-of-life research, and therapeutic trials. These research programs depend upon shared resources that are supported by the NCI Cancer Center Grant at St. Jude, including animal resources, biostatistics, cell and tissue imaging, cytogenetics, flow cytometry and cell sorting, the Hartwell Center for Bioinformatics and Biotechnology, pharmacokinetics, protein production, vector development and production, transgenenic and gene-knockout research models, and a Molecular Clinical Trials Core Facility.
The center emphasizes interdisciplinary research aimed at understanding, preventing, and treating childhood cancers. Most of the more than 400 children who are treated for cancer each year are enrolled in disease-specific, frontline protocols, and they are followed long-term to track their outcomes as they enter adulthood.
The cancer center at St. Jude is the home site for several ongoing national cancer studies, including the Pediatric Preclinical Testing Program, the Childhood Cancer Survivors Study, and the Pediatric Brain Tumor Consortium, all of which are funded by NCI.
Other Notable Programs
St. Jude recently completed an extensive expansion program that bolstered the hospital’s research and treatment efforts, including the nation’s only on-site pediatric research center facility that produces highly specialized treatments and vaccines; an expanded Department of Immunology; and a new Department of Chemical Biology and Therapeutics for the discovery of new drugs.
Also, the Chili’s Care Center at St. Jude integrates patient care with research on evolving computerized tomography (CT) and magnetic resonance (MR) technology for radiation therapy, while a state-of-the-art cyclotron enables St. Jude researchers to undertake many new positron emission tomography (PET) radiochemistry studies. These imaging techniques help researchers and clinicians evaluate new therapeutic approaches quickly to determine those that are most likely to be successful.
Fred Hutchinson Cancer Research Center to Operate NCI's CIS Contact Center
On December 2, NCI selected the organization that will operate its Cancer Information Service (CIS) Contact Center. The program will be located at Fred Hutchinson Cancer Research Center in Seattle, WA, and will serve the United States, Puerto Rico, U.S. Virgin Islands, and the U.S.-associated Pacific Territories.
The contact center provides information to the public via the toll-free telephone number 1-800-4-CANCER, e-mail in English and Spanish, and LiveHelp instant messaging on NCI’s Web site. The CIS is the federal government’s source for the latest, most accurate cancer information for the public, patients and their families, and health professionals. For more than 30 years it has been providing up-to-date science-based information in easy-to-understand language. The center also provides smoking cessation counseling through NCI’s Smoking Quitline, 1-877-44U-QUIT. The contact center handles over 100,000 inquiries annually and has responded to over 10 million callers since its inception in 1976.
Application Deadlines Approach for Interagency Oncology Task Force Fellowships
The Interagency Oncology Task Force (IOTF), a joint initiative between NCI and the FDA, has announced fellowship training opportunities for Ph.D.s, M.D.s, and M.D./Ph.D.s or their equivalents in cancer-related scientific research and research-related regulatory review.
The IOTF Joint Fellowship Program trains a core of scientists in cancer research and research-related regulatory review to develop skill sets that bridge the two distinct processes. During the program, fellows will:
- Build awareness of regulatory requirements into the early stages of medical product development
- Devise strategies to improve planning throughout the research and regulatory review phases
- Learn how to bring state-of-the-art knowledge and technology to bear on the design, conduct, and review of clinical trials
“We believe that physicians and scientists who are highly trained in the regulatory process, and who also have an understanding of the inner workings of NCI and FDA, will be able to facilitate and speed the development and approval process for drugs, especially for chemotherapy,” said Dr. Jonathan Wiest, director of NCI’s Center for Cancer Training.
Fellowship programs are available for various career levels and vary in length between 1 and 4 years. View each program’s Web page for more information:
Clinical Oncology Product Research/Review for Oncology Fellows
Application deadline: January 31, 2010
Earliest start date: July, 2010
Clinical Oncology Product Research/Review for Board Certified (BC) Oncologists
Application deadline: January 31, 2010
Earliest start date: July, 2010
Oncology Product Research/Review Fellows
Application deadline: May 30, 2010
Earliest start date: September, 2010
Cancer Prevention Fellows
Application deadline: September 1, 2010
Earliest start date: July, 2011
The IOTF was established to enhance and accelerate the overall process of developing new cancer diagnostics and therapeutics and speed their delivery to patients. More information about the program fellowships can be found at http://iotftraining.nci.nih.gov.
President's Cancer Panel Examines Race and Cancer Burden
The President’s Cancer Panel held the third meeting of its 2009–2010 series, “America’s Demographic and Cultural Transformation: Implications for the Cancer Enterprise,” on December 9 in Wilmington, DE. The panel heard testimony on differences in cancer burden, type, and causes across various races and ethnic groups. Speakers noted that racial categories were based on political constructs rather than biological fact and cited as evidence molecular differences in cancer that do not follow racial boundaries. Lack of access to care, inconsistent delivery of care, language barriers, and socioeconomic disparities were cited as major factors contributing to the unequal cancer burden. Speakers suggested the current approach to medicine based on racial categories negatively impacts patient health; speakers recommended moving towards a personalized approach to medicine based on the patient’s individual history and risk factors, rather than on risk factors associated with a patient’s race.
The panel will consider speaker recommendations in writing their 2009–2010 report to the President. The panel will hear additional testimony on the effects of the changing U.S. population on cancer care and research at their final meeting of the series in Miami, FL, on February 2, 2010.