Giving radiation therapy in fewer but larger doses may be an alternative to standard radiation therapy for some women with early-stage breast cancer. A trial testing this approach, called hypofractionated radiation therapy, has found that the regimen tested did not increase long-term toxicities and resulted in rates of survival and local recurrence similar to those seen with standard radiation therapy. The study results, published in the February 11 New England Journal of Medicine, had the longest follow-up results of any study to date of hypofractionated radiation therapy for breast cancer. Read more > >
by Drs. Bhadrasain Vikram, James Deye, and C. Norman Coleman
Radiation therapy has been used to treat cancer for over a century. A high enough dose of ionizing radiation will kill any living cell, and cancer cells are no exception. The objective of radiation therapy, therefore, is to deliver high enough doses of radiation to cancer cells while minimizing the dose to healthy cells that are also exposed.
We are not yet at a point where we can image individual cancer cells in cancer patients, but we can image macroscopic clusters of cancer cells ranging in size from a few millimeters to several centimeters. The radiation oncologist then strives to irradiate that cluster of cancer cells (the “target volume”) in a beam of high-dose radiation while minimizing the dose to healthy tissues (the “organs at risk”) outside the cluster. Read more > >
A MESSAGE TO READERSTraining Featured on Cancer.gov
This month the Cancer.gov homepage highlights training at NCI and through extramural sources. Read more about these opportunities by clicking in the banner or going to NCI Features: Training the Future Oncology Workforce.
Also, check out the NCI Cancer Bulletin special issue on training, published December 1, 2009, that includes important commentaries from key leaders about the future of the cancer research workforce.
- Initiative Aims to Reduce Unnecessary Radiation Exposure from Medical Imaging
- Rituximab Approved for Chronic Lymphocytic Leukemia
- FDA Announces Risk Management Program for Anemia Drugs
- NCI 2011 Budget Proposal Available Online
- NCAB Convenes Its First Meeting of 2010
- NCI Funds Eleven Centers for Cancer Systems Biology
- President’s Cancer Panel Concludes Series on Disparities and Cancer
Selected articles from past issues of the NCI Cancer Bulletin are available in Spanish.
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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Shorter Course of Radiation Effective and Safe for Some Women with Early-stage Breast Cancer
Giving radiation therapy in fewer but larger doses may be an alternative to standard radiation therapy for some women with early-stage breast cancer. A trial testing this approach, called hypofractionated radiation therapy, has found that the regimen tested did not increase long-term toxicities and resulted in rates of survival and local recurrence similar to those seen with standard radiation therapy. The study, published in the February 11 New England Journal of Medicine, had the longest follow-up results of any study to date of hypofractionated radiation therapy for breast cancer.
Breast-conserving surgery (BCS) plus adjuvant radiation therapy has been firmly established as a safe alternative to full mastectomy for most women with early-stage breast cancer. The radiation therapy part of that regimen is vital, as long-term data have shown that it greatly reduces the risk of tumor recurrence.
However, almost a third of women in North America do not get radiation therapy after BCS. “Although the use of breast-conserving surgery is increasing, the number of women who receive appropriate radiation therapy after breast-conserving surgery is actually decreasing,” said Dr. Timothy Whelan, professor of oncology at McMaster University in Ontario, Canada.
The reasons for this lack of adherence to treatment standards are numerous and complicated, but they include the fact that a standard course of radiation therapy requires 25 treatments spread out over 5 weeks, a significant added burden for many patients who have already undergone surgery and may be starting hormone therapy or chemotherapy. Because hypofractionated radiation therapy may be less burdensome than standard radiation therapy, some oncologists believe the finding could have an immediate impact on breast cancer care in the United States.
Renewing an Old Idea
“Back in the 1960s some treatment centers first tried hypofractionated radiation therapy, but the researchers didn’t decrease the total dose of radiation, so they saw an increase in toxicity,” said Dr. Whelan. “After that, there was a great reluctance to engage in hypofractionation.”
Starting in 1993, researchers coordinated by the Ontario Clinical Oncology Group randomly assigned 1,234 women with early-stage breast cancer that had not spread to nearby lymph nodes to receive either the international standard radiation dose—50 Gy of whole-breast radiation given in 25 fractions over 5 weeks—or a hypofractionated radiation schedule—42.5 Gy of whole-breast radiation given in 16 fractions over 3 weeks. Patients received hormone therapy, chemotherapy, or both as deemed necessary by their doctors.
Ten years after treatment, the incidence of local recurrence (recurrence in the same breast) was 7.5 percent in the standard radiation therapy group and 7.4 percent in the hypofractionated radiation group. The probability of survival at 10 years was also virtually identical: 84.4 percent in the standard radiation therapy group and 84.6 percent in the hypofractionated group.
Late toxic effects did increase over time, but with no significant differences observed between the groups. Ten years after treatment, 70.5 percent of women in the standard radiation therapy group had no skin problems associated with treatment, compared with 66.8 percent in the hypofractionated radiation group. Few cardiac-related deaths occurred in either group. And 71.3 percent of women in the standard radiation therapy group and 69.8 percent in the hypofractionated radiation group had excellent or good overall cosmetic outcomes, as measured by nurses associated with the trial. (See the related Cancer Research Highlight in this issue.)
“We made a tremendous effort to follow these women long term, because there were lots of concerns about increased toxicity with hypofractionation,” said Dr. Whelan. “We’ve fortunately been able to show that while there was some toxicity, it was equivalent to that seen with standard treatment.”
Careful Application Required
As radiation oncologists look to incorporate these results into their practice, Dr. Bhadrasain Vikram, chief of the Clinical Radiation Oncology Branch in NCI’s Division of Cancer Treatment and Diagnosis, cautioned that “it is important to understand that these results cannot be extrapolated beyond the women who were eligible for this study—that is, women who had negative surgical margins and did not need radiation to their axillary lymph nodes.”
The results also cannot be applied to partial-breast irradiation, he explained, which uses hypofractionation but still as an experimental technique being tested in clinical trials.
But for whole-breast radiation in women who fit the study criteria, “it’s very confirmatory data, showing this works,” said Dr. Julia White, chair of the Radiation Therapy Oncology Group’s breast committee and professor of radiation oncology at the Medical College of Wisconsin. “I think this will influence practice in the United States, in certain patients, and I think the women who would benefit the most are those for whom [a standard course of radiation therapy] is the most burdensome. Those are the women traveling a long way to get radiation and who might choose mastectomy.”
Cancer Research Highlights
Lower-dose Radiation Regimen for Breast Cancer Less Harmful to Quality of Life
In the United Kingdom, women who have early-stage breast cancer are often treated after surgery with hypofractionated radiation therapy, a lower-dose radiation regimen given in fewer but larger doses. According to a report published online February 5 in Lancet Oncology, this regimen is slightly less harmful to quality of life, including a woman’s body image, than the standard dosing regimen after 5 years of follow up.
Dr. Penelope Hopwood of the Institute of Cancer Research in the United Kingdom and her colleagues reviewed data from 2,208 women enrolled in the Standardisation of Breast Radiotherapy (START) trials A and B. In the START A trial, women were randomly assigned to receive the international standard regimen—adjuvant radiation of 50 Gy given in 25 fractions over 5 weeks—or one of two hypofractionated regimens: either 39 Gy or 41.5 Gy given in 13 fractions over 5 weeks. In the START B trial, women were randomly assigned to receive the standard regimen or an even shorter hypofractionated regimen of 40 Gy in 15 fractions over 3 weeks.
The studies included women who had mastectomies and women who had breast-conserving surgery (BCS), with 78 percent in trial A and 88 percent in trial B receiving BCS. Most of the women had medium-sized breasts, had undergone dissection in the lymph nodes of the armpit, and had not received radiation to the armpit. At 6-month intervals, participants completed questionnaires to report pain, swelling, stiffness, or sensitivity in the breast, shoulder, or arm, as well as skin problems and body image. They were also photographed so that researchers could objectively assess changes in their breast and skin appearance.
Women who received lower doses of radiation (i.e., 39 Gy or 40 Gy) had better skin appearance after 5 years than those who received either of the two higher doses (41.5 Gy or 50 Gy). Patients who received hypofractionated radiation reported a quality of life after 5 years that was similar to those who had received the standard regimen. There were some differences in specific symptoms that seemed to favor the hypofractionated treatment, but these were not statistically significant.
“These ratings by patients…strengthen evidence in favour of hypofractionated regimens, with a potential for fewer adverse effects on the normal breast tissues,” the authors wrote. They noted, however, that regardless of whether the women received hypofractionated or standard adjuvant radiation, 40 percent of women still reported moderate to severe concerns about body image after 5 years and nearly one-third had significant arm and shoulder pain, underlining the need for more research into patient-reported outcomes of quality of life following surgical and radiation treatment.
Chemo-switch Plus Sorafenib Regimen Shows Promise in Advanced Kidney Cancer
Findings from a small phase II clinical trial suggest that a three-drug treatment that includes the targeted agent sorafenib (Nexavar) and two different ways of delivering chemotherapy, dubbed a “chemo-switch” regimen, has potential as a treatment for advanced renal cell cancer (RCC). Patients who received the treatment regimen had progression-free survival (survival without tumor growth) and response rates comparable to what has historically been seen with other first-line treatment options for metastatic RCC, including sunitinib (Sutent). The results were published online February 15 in Lancet Oncology.
The researchers treated patients with traditional chemotherapy—the drug gemcitabine (Gemzar) delivered at the maximum-tolerated dose—followed by metronomic chemotherapy—frequent, low doses of chemotherapy—using capecitabine (Xeloda) along with sorafenib. Both metronomic chemotherapy and sorafenib inhibit tumor blood vessel formation. Some patients continued to receive sorafenib after chemotherapy was completed.
The 40 patients in the trial, led by Dr. Joaquim Bellmunt of University Hospital del Mar-IMIM in Barcelona, had yet to receive treatment for their disease and were not candidates for treatment with either IL-2 or interferon-α, immune-stimulating treatments that are commonly used in patients with metastatic RCC.
Half of the patients experienced a partial response (tumor shrinkage of 30 percent or more) during the trial, and 17 had stable disease. The median progression-free survival in these 40 patients was 11.1 months; it was 12 months in the 34 patients for whom complete efficacy data were available. Adverse events “were mild to moderate in severity,” the researchers wrote, although seven patients halted treatment altogether because of side effects.
Despite its limitations, such as small size and nonrandomized design, the study results suggest that the approach “is worthy of further pursuit” in future trials, said Dr. Ramaprasad Srinivasan of the Urologic Oncology Branch in NCI’s Center for Cancer Research. These are the strongest results seen with sorafenib as a first-line treatment in metastatic RCC, Dr. Srinivasan noted, and “are better than might have been expected with sorafenib alone.”
Scientists Map Gains, Losses of DNA in Thousands of Tumors
Researchers have conducted a large-scale analysis of thousands of tumors to identify a particular type of genetic alteration known as DNA copy number changes. These changes occur when regions of chromosomes are duplicated inappropriately or deleted during cancer development. The new study may provide the most comprehensive view to date of the types and extent of copy number changes across cancers.
A majority of the copy number changes found in one tumor type were found in several others as well, the researchers reported in the February 18 Nature. “We have known that many cancer-causing genetic events are the same across different types of cancer, and this study expands our understanding of this phenomenon,” said lead investigator Dr. Matthew Meyerson of the Dana-Farber Cancer Institute.
The analysis included 3,100 tumors representing 26 types of cancer. More than 150 chromosome regions were found to be duplicated or missing in several cancers, including many regions that had not previously been linked to copy number changes. More work is needed to identify which DNA segments within these chromosome regions may be driving the cancer and which ones are merely present but do not contribute to the disease.
The most common copy number changes involved either relatively small segments of chromosomes (about 1.8 million units of DNA, or .03 percent of the human genome, in size) or much larger ones, the length of a chromosome arm or a whole chromosome. Certain families of genes were more commonly involved in copy number variations than others, including those that regulate cell death, such as the genes MCL1 and BCL2L1.
“We’re starting to see that copy number changes are going to be critically important for certain diseases,” said NCI Deputy Director Dr. Anna Barker. The results of large-scale genomic studies like this one are going to give researchers direction as they try to identify the changes that are most important in cancer, she added. To facilitate these efforts, the study authors have made their data available through the Web site Tumorscape.
Researchers Learn How a microRNA May Promote the Spread of Breast Cancer
A microRNA, a short RNA molecule that regulates the activity of genes, called miR-9 appears to be important in breast tumors’ ability to spread to other parts of the body and gather nutrients to survive and grow, according to a study published online February 21 in Nature Cell Biology.
Researchers from the laboratory of Dr. Robert Weinberg at the Whitehead Institute for Biomedical Research showed that, in breast cancer cell lines, miR-9 inhibits the expression of the protein E-cadherin, which helps cells adhere to one another and form tissues. The result, wrote Dr. Li Ma and colleagues, was that tumor cells underwent a transformation known as the epithelial-mesenchymal transition, or EMT, meaning they gained the ability to both migrate from their original location and invade other tissues. The researchers also found that the microRNA was activated by the well-known cancer-inducing gene MYC.
They confirmed these activity patterns in mouse models of breast cancer, showing that increasing levels of miR-9 in mice with breast tumors that normally do not spread led to large numbers of small lung tumors. Conversely, blocking miR-9 in mice carrying a breast tumor known to be particularly metastatic led to fewer metastases.
In addition to the metastasis findings, experiments in breast cancer cell lines and mouse models of breast cancer showed that miR-9 induced a cascade of events within tumor cells—including activation of the protein β-catenin—that led to the production of VEGF, a key driver of tumor blood vessel development. Tumors in mice implanted with breast cancer cells that expressed miR-9 had an abundance of blood vessels both within the tumor and at the tumor edges.
However, the research team found that blocking E-cadherin and activating β-catenin “seem to be necessary but not sufficient” for increasing VEGF activity, indicating that there are other miR-9 targets that are needed for this effect.
One such target may be α-catenin, suggested Drs. Yeesim Khew-Goodall and Gregory J. Goodall from the Center for Cancer Biology in Adelaide, Australia, in an accompanying commentary. The α-catenin protein is located near β-catenin inside cells, and α-catenin can block the β-catenin activity that leads to VEGF production.
The Australian researchers also noted that other studies have shown that miR-9 RNA is active in tumor samples from metastatic but not localized breast and liver cancers, indicating that the molecule may promote metastasis in multiple tumor types.
Guest Director's Update
Working within Radiation Oncology to Maximize Benefits and Minimize Harms
Radiation therapy has been used to treat cancer for over a century. A high enough dose of ionizing radiation will kill any living cell, and cancer cells are no exception. The objective of radiation therapy, therefore, is to deliver high enough doses of radiation to cancer cells while minimizing the dose to healthy cells that are also exposed.
We are not yet at a point where we can image individual cancer cells in cancer patients, but we can image macroscopic clusters of cancer cells ranging in size from a few millimeters to several centimeters. The radiation oncologist then strives to irradiate that cluster of cancer cells (the “target volume”) in a beam of high-dose radiation while minimizing the dose to healthy tissues (the “organs at risk”) outside the cluster. Invariably, due to the intertwining of tumor cells and normal tissues both at the margins but also within the center of the tumor, there is some radiation delivered to the organs at risk. This can lead to adverse effects, ranging from those appearing within hours or days (diarrhea during irradiation of a cancer located in the abdomen or pelvis, for instance) to those appearing decades later, such as tissue scarring and radiation-induced second cancers.
The radiation device industry has worked with researchers in the field to make it easier for radiation oncologists to “conform” the high-dose region to the target volume by introducing new technologies such as three-dimensional conformal radiation therapy, intensity-modulated radiation therapy, stereotactic radiation therapy, and proton radiation therapy. Several new devices have received 510(k) Clearances by the FDA on the basis that they are extensions of existing technology, and these devices are now used in routine clinical practice by radiation oncologists and reimbursed by insurers. However, as pointed out in a series of recent articles in The New York Times, the complexity of the new technology and the rapid pace at which it has entered practice may have created new avenues for error.
NCI is a research institution. Thus, it does not regulate technology or reimbursement. But given the importance of quality assurance for the conduct of NCI clinical trials, and recognizing radiation technology’s promise as well as potential pitfalls, more than 10 years ago the Radiation Research Program (RRP) and the Cancer Therapy Evaluation Program in NCI’s Division of Cancer Treatment and Diagnosis set about establishing an agile and continuously evolving infrastructure to: 1) protect patients volunteering in multi-institutional clinical trials sponsored by NCI who would receive advanced-technology radiation therapy as a part of their treatment; and 2) facilitate robust clinical trials to evaluate the benefits and harms of the new technology.
As a result, NCI not only supports research to develop and evaluate new radiation technology, we also support numerous clinical trials where the principal question is not specifically related to the radiation but the quality of radiation must be appropriately safeguarded so that it does not jeopardize the ability of the trial to test its hypothesis.
NCI’s contribution to quality cancer care extends well beyond the 1 to 2 percent of the patients receiving radiation therapy in the United States as a part of an NCI-sponsored clinical trial. As noted in The New York Times series, our policies, procedures, and lessons learned have in some cases been adopted or adapted by other institutions and organizations interested in improving quality and protecting patients. These include credentialing of individuals and facilities, quality monitoring and mentoring, training tools, and analyses of patient outcomes. Additional information about the NCI-supported infrastructure can be obtained from the RRP and the following links:
- The NCI Advanced Technology Consortium and the Radiological Physics Center
- The Current Status and Future Potential of Advanced Technologies in Radiation Oncology: Part 1, Part 2, Commentary 1, Commentary 2
Looking to the future, the infrastructure created by NCI can serve as an important resource—perhaps even the foundation—for quality improvement programs envisioned by other federal and state agencies, professional societies, institutions, and individuals. We are working closely with our colleagues in the cancer Biomedical Informatics Grid (caBIG) to make that possible, as well as with colleagues at the FDA, Veterans Health Administration, Agency for Healthcare Research and Quality, and professional organizations such as the American Association of Physicists in Medicine and American Society for Therapeutic Radiology and Oncology. Already, approximately 20 percent of radiation oncology facilities in the United States are capable of digital data exchange through this infrastructure.
Furthermore, thanks to the harmonization efforts of the last decade and outreach to industry, it is possible to link most of the remaining facilities to this infrastructure for digital data transfer, collection, and analyses. Therefore, although this NCI infrastructure was created to facilitate multi-institutional prospective treatment efficacy trials, it could also facilitate other kinds of studies, including observational or cohort studies for comparative effectiveness research and post-marketing surveillance of new drugs and devices.
Finally, it could also serve as a demonstration project for a “learning health care system,” wherein each new patient will be precisely matched to similar patients in the vast national and even global database to help physicians select the best personalized treatment strategy that will result in the best possible outcome for their patients.
Dr. Bhadrasain Vikram
Branch Chief and Deputy Associate Director
Radiation Research Program, NCI Division of Cancer Treatment and Diagnosis
Dr. James Deye
Radiation Research Program, NCI Division of Cancer Treatment and Diagnosis
Dr. C. Norman Coleman
Radiation Research Program, NCI Division of Cancer Treatment and Diagnosis
Personalizing Biomarkers for Cancer
Demonstrating a new use for DNA-sequencing technology, researchers at the Johns Hopkins Kimmel Cancer Center have developed individualized biological markers for patients with cancer. The biomarkers, which can be detected in blood, could potentially help doctors manage the disease in patients.
In a pilot study, the researchers used next-generation DNA sequencing tools to identify genetic changes called chromosome rearrangements. The changes, which occur when chromosome regions are swapped or merged inappropriately, were then used to create genetic fingerprints for individual tumors.
To test potential clinical applications, the researchers first identified rearrangements in the tumors of two patients with colorectal cancer. They then showed that blood tests could pick up these same changes in DNA shed into the circulatory system by tumors, allowing them to track levels of abnormal tumor DNA as a biomarker over time.
In one case, the patient’s biomarker levels dropped substantially after a tumor was removed, before rising again later. The levels declined once more after subsequent chemotherapy and a second surgery, though not to zero. This was likely because of a small lesion that remained in the patient’s liver, the researchers said.
“This study is a proof of principle, and it demonstrates that the approach worked well for these particular patients,” said lead investigator Dr. Victor Velculescu, who co-directs the cancer biology program at Johns Hopkins. The strategy represents one of the first applications of next-generation, whole-genome sequencing that could be clinically useful for patients, he said.
A report on the method, called Personalized Analysis of Rearranged Ends (PARE), will appear in the February 24 issue of Science Translational Medicine.
“This is an exquisitely thoughtful and useful application of DNA sequencing technology,” said Dr. Stephen Chanock, who directs the Laboratory of Translational Genomics in NCI’s Division of Cancer Epidemiology and Genetics and who wrote an editorial accompanying the study.
In addition to marking the tumor for forensic purposes, the strategy could reveal insights into the biology of tumors. “What this method allows us to do very nicely is to quickly identify sets of markers, and we can see how they change during the disease,” Dr. Chanock continued. “The presence or absence of these markers may reveal insights into the life cycle of a tumor.”
Because some rearrangements may disappear and others may emerge over time, it will be important to test sets of markers rather than individual rearrangements, Dr. Chanock noted. This would reduce the chances that a patient might be found incorrectly to have no cancer when in fact the disease had simply gone undetected.
The Johns Hopkins team did not set out to develop personalized biomarkers when the project began. They sequenced the genomes of six colorectal and breast tumors, hoping to find recurring chromosome rearrangements like those that are hallmarks of cancers of the blood. But they found none. Instead, the sequencing revealed that each tumor had these rearrangements and each one was different—on average, nine per tumor.
Right away the researchers realized that rearrangements were promising biomarkers. Not only were the changes specific to the tumors, but these were large, dramatic events in the genome. They would be easier to detect than point mutations, where a single letter of DNA is altered.
“This study is an exciting step forward in terms of how we might develop and use these types of biomarkers in patients,” said NCI Deputy Director Dr. Anna Barker. “While there is a lot more work to do, it opens up some new windows for investigation.” If the biomarkers are reproducible and highly sensitive, they could help address a range of clinical needs, such as improving the detection of residual disease following surgery, she added.
Dr. Velculescu and coauthor Dr. Luis Diaz, an assistant professor of oncology at the Kimmel Cancer Center, presented the findings last week at the annual meeting of the American Association for the Advancement of Science. They said the approach could be made broadly available to patients in several years if costs could be brought down and the findings were confirmed. The cost was about $5,000 per patient, primarily for DNA sequencing. But the cost of next-generation sequencing has declined sharply and is expected to keep falling, they noted.
The Johns Hopkins group has expanded their study to identify other common cancers that are amenable to this strategy. It will also be important to establish how early in the development of cancer the markers are detectable.
The researchers are hopeful that this approach might help distinguish patients who are at risk of relapse and need additional therapy from those who could be safely spared more treatment. Such questions will need to be addressed in prospective clinical trials.
“In terms of next steps, it will be important to show that the new strategy is not just novel but also useful in real clinical situations,” noted Dr. Sridhar Ramaswamy, an assistant professor of medicine at the Massachusetts General Hospital and Harvard Medical School, who directs a laboratory focused on translational cancer genomics.
“The million-dollar question when you have a patient who has undergone treatment for cancer is does the person have incipient disease,” said Dr. Ramaswamy. “Circulating tumor cells are one way to pick up microscopic cancers that are not readily apparent, and this is potentially a different way.”
What’s exciting about the strategy, he added, is that the researchers are using the powerful new genetic tools to go after individualized mutations in tumors. The tools are more commonly used to identify recurrent genetic changes shared among many patients.
Thousands of Genomes
The genomes of thousands of patients with cancer will be sequenced over the next few years. As the data from large-scale projects such as The Cancer Genome Atlas and the Pediatric Cancer Genome Project become available, researchers will increasingly focus on translating the results into knowledge and clinical tools, Dr. Barker predicted.
“The community is really starting to think about new ways to detect genomic changes in tumors and about how to use the changes as biomarkers,” she said. “All of these studies are building an invaluable cancer genomics knowledge base, and this will move us toward improving the care of patients with cancer.”
—Edward R. Winstead
A Closer Look
This is the third article in a series of stories related to cancer survivorship. Look for the symbol on the left in an upcoming issue for the next article in the series.
Chemotherapy-induced Peripheral Neuropathy
It usually starts in the hands and/or feet and creeps up the arms and legs. Sometimes it feels like a tingling or numbness. Other times, it’s more of a shooting and/or burning pain or sensitivity to temperature. It can include sharp, stabbing pain, and it can make it difficult to perform normal day-to-day tasks like buttoning a shirt, sorting coins in a purse, or walking. An estimated 30 to 40 percent of cancer patients treated with chemotherapy experience these symptoms, a condition called chemotherapy-induced peripheral neuropathy (CIPN).
CIPN is one of the most common reasons that cancer patients stop their treatment early. (See sidebar for a list of drugs that can cause CIPN.) For some people, the symptoms can be mitigated by lowering the dose of chemotherapy or temporarily stopping it, which diminishes the pain within a few weeks. But, for other patients, the symptoms last beyond their chemotherapy for months, years, or even indefinitely.
“Peripheral neuropathy can be an incredibly debilitating side effect,” explained Dr. Ann O’Mara, head of NCI’s Palliative Care Program in the Division of Cancer Prevention. “We can’t predict who will come down with it or to what degree they will get it. So there are a lot of questions around this issue, in terms of preventing and treating it.”
Outside of clinical trials, CIPN symptoms are commonly managed in a manner similar to other types of nerve pain—that is, with a combination of physical therapy, complementary therapies such as massage and acupuncture, and medications that can include steroids, antidepressants, anti-epileptic drugs, and opioids for severe pain. But these therapies have not demonstrated true efficacy for CIPN, and virtually all of the drugs to treat peripheral neuropathy carry side effects of their own.
Life with Neuropathy
Cynthia Chauhan is a patient advocate who is very active in the cancer community. She participates with several boards and committees that advise NCI-sponsored clinical trial groups, including the North Central Cancer Treatment Group and the Southwest Oncology Group, and she is co-chair of the Patient Advocate Working Group for the Translational Breast Cancer Research Consortium. She is also very familiar with the burden of peripheral neuropathy and the shortcomings of current treatments.
A two-time cancer survivor, Ms. Chauhan lives with peripheral neuropathy that arose spontaneously—called idiopathic neuropathy—nearly 15 years ago. Her symptoms include shooting pains, fiery numbness, and tingling in her hands and feet, as well as a lack of sensitivity to temperatures. Her mother developed chronic CIPN during her treatment for stage IV ovarian cancer and, because of the pain, has terrible difficulty sleeping. “But without the drugs that caused her neuropathy, she would not have survived,” Ms. Chauhan said. “So she uses that knowledge to balance the negative aspects.
“I’m an optimist by nature,” Ms. Chauhan continued. “I like to focus on what I have, rather than what I don’t have, and I can still walk and use my hands—I’m an artist, so my hands are important to me. That I can still use them is very positive.”
She has tried several medications for her neuropathy, and all of the systemic drugs caused unbearable side effects. Today she manages her pain with Lidoderm patches and the practice of guided imagery and meditation, which she says function mostly as distractions for the pain. “Nothing ever stops it. It’s a 24-7 issue with me. I know that drugs work for some people, and if you can find effective medications under the care of a really knowledgeable physician, that’s great,” she said. “But more basic and translational research is critical for those of us who are living with the condition.”
Understanding the Pain
NCI’s Symptom Management and Health-related Quality of Life Steering Committee, of which Ms. Chauhan is a member, met in Rockville, MD, last year to discuss these issues. This steering committee is one of several that advise NCI as it works to improve the efficiency of clinical trials so that proposed treatment hypotheses can be translated more quickly into new screening, treatment, and prevention options for patients.
What actually causes CIPN, on the cellular and tissue level, is still largely a matter of speculation. There is evidence that nerves can become sensitized because the concentration of salts in the fluid surrounding them changes, or because the channels that use these salts to trigger nerve impulses become dysfunctional. These or other changes may actually damage the structure of nerves. (See image above.)
Because the underlying etiology may vary according to the chemotherapy agent and from patient to patient, more research with animal models is needed, in addition to clinical trials, to try to define the causes of CIPN and identify means to prevent or alleviate it, said Dr. Charles Loprinzi, the Regis Professor of Breast Cancer Research at the Mayo Clinic in Rochester, MN, who chaired the steering committee meeting.
“We need a multi-pronged approach,” he explained. “If we can better understand what causes CIPN in animals and which antidotes might be helpful for preventing and treating it, that doesn’t necessarily mean that [the antidotes] will be exactly the same in humans, but it will allow us the opportunity to screen promising compounds. Ones that successfully alleviate the symptom profiles in animals can be advanced to clinical trials in humans.”
Getting the Right Measures
“I’ve been very lucky not to develop this before now, actually…It’s likely just a side effect of the chemotherapy treatment that I’ve been receiving for the past 10 weeks (Taxol). And that’s why we’re taking a break from chemo this week,” Dr. Susan Niebur wrote in 2007 of her experience with peripheral neuropathy on her blog Toddler Planet, where she documents her experience as a mother and survivor of inflammatory breast cancer.
“Hopefully the week off will allow my system some time to recover and the pain to diminish. Already, my legs are responding more to me (no more wheelchair!) and I can feel my left foot. My right foot and leg, up to the knee, is still tingling and painful to the touch, but I hope that will also resolve in the next few days.” More than 2 years after finishing her chemotherapy, Dr. Niebur still has some residual neuropathy in her right foot and occasionally in her hand, but she wrote in an e-mail that it’s primarily a numbness now, “and a bother more than anything else.”
Patient-reported outcomes (PROs) during and after chemotherapy, such as those Dr. Niebur described, will be an important part of future research on CIPN. A tool that was developed by NCI and that is routinely used to record adverse effects from cancer treatment in clinical trials, the CTCAE, “is not adequate to help us fully understand this condition,” said Dr. Loprinzi. “As opposed to having a health care provider summarize the symptoms of a patient, it is much preferred to have patients more directly record their symptoms.”
PROs commonly include substantially more detailed and accurate information for a variety of symptoms. The steering committee identified several tools, including a 20-item patient questionnaire called the EORTC-QLQ-CIPN20, which appear to better capture this level of information.
Clinical Research Ahead
Several new agents have shown positive effects in pilot studies in patients with CIPN or neuropathy related to diabetes or HIV, and the steering committee has recommended that some of the more promising of these be pursued in larger placebo-controlled randomized clinical trials. Some of these trials are already enrolling patients, while others are still in the planning stages. More information about these trials can be found on NCI’s Web site.
For treating the pain associated with CIPN, agents that appear promising include the antidepressants duloxetine (see Featured Clinical Trial in this issue) and venlafaxine, which are both serotonin/norepinephrine-reuptake inhibitors. Another promising agent is a topical compound of the muscle-relaxant baclofen, the antidepressant amitriptyline, and the analgesic ketamine.
For preventing the onset of CIPN, the committee recommended further clinical testing of intravenous calcium and magnesium, which reduced CIPN symptoms by approximately half compared with a placebo in one trial involving patients receiving oxaliplatin; a peptide called glutathione, which is thought to bind to heavy metals and has shown promise in small trials in patients who are treated with platinum chemotherapies; acetyl-L-carnitine, a substance that was effective in animal models and in patients with diabetes and HIV; and the antioxidant alpha-lipoic acid.
Pharmacogenomic studies will also, it is hoped, help guide the identification of patients who are more or less likely to develop CIPN. One such study is being planned at the Mayo Clinic to determine how a variation in genes that control taxane and carboplatin metabolism may affect a person’s risk of getting CIPN.
“I’m a relatively conservative person, in terms of how I practice medicine and research,” said Dr. Loprinzi. “But I’m excited about this area. We’re just starting to tap it. Over the next few years, as study results become apparent, I’m reasonably confident that one or two, or possibly more, of these agents will be shown to be beneficial for patients.”
Featured Clinical Trial
Treating Pain from Chemotherapy-induced Peripheral Neuropathy
Name of the Trial
Phase III Randomized Study of Duloxetine Hydrochloride in Cancer Patients with Painful Chemotherapy-Induced Peripheral Neuropathy (CALGB-170601). See the protocol summary.
Dr. Ellen Smith and Dr. Richard Schilsky, Cancer and Leukemia Group B
Why This Trial Is Important
Chemotherapy has been a mainstay of cancer treatment for more than 50 years. Despite advances in chemotherapy drugs and their administration, however, many patients still experience distressing side effects related to treatment.
One chemotherapy-induced side effect that reduces the quality of life for many patients treated with drugs such as paclitaxel (Taxol) or oxaliplatin (Eloxatin) is peripheral neuropathy. This side effect develops when anticancer drugs damage nerve cells of the peripheral nervous system (the nerves beyond the brain and spinal cord). Patients with peripheral neuropathy may experience pain, tingling, numbness, or other uncomfortable sensations, usually beginning in their feet and/or hands. These feelings may get worse over time and affect more parts of the body (ankles, legs, arms).
The drug duloxetine (Cymbalta) has been shown to relieve pain associated with peripheral neuropathy caused by diabetes. Duloxetine helps maintain levels of the neurotransmitters serotonin and norepinephrine in the central nervous system (which includes the nerves in the brain and spinal cord). These neurotransmitters help prevent painful sensations from reaching the brain. Scientists want to know if duloxetine can also effectively treat pain from chemotherapy-induced peripheral neuropathy.
In this trial, patients with painful peripheral neuropathy caused by prior treatment with paclitaxel or oxaliplatin will be randomly assigned to receive either duloxetine or placebo pills for 6 weeks. All patients will then have a week without treatment (called a washout period), followed by a 6-week crossover period in which patients who received duloxetine initially will be given the placebo while those initially assigned to placebo will be given duloxetine. Neither the patients nor their health care providers will know who is receiving duloxetine or the placebo at any given time until after the study is over. Patients will complete pain and quality-of-life questionnaires weekly throughout the study.
“Neuropathic pain is different and often harder to treat than other types of pain,” said Dr. Smith. “There is a lot less known about the effects of various drugs on neuropathic pain.
“To date, several medications have been discovered to be helpful, but none has been able to fully alleviate the pain associated with chemotherapy-induced neuropathy,” she continued. “So we will likely need to develop an approach employing several drugs that work in different ways in hopes of creating a synergistic effect. Duloxetine may have a place in such an approach.”
Preventing Cancer by Taking Steps to Reduce Childhood Obesity
Last month the Department of Health and Human Services (HHS), Surgeon General Dr. Regina Benjamin, and First Lady Michelle Obama announced a new national effort to prevent childhood obesity and called for a focus on healthy choices, particularly better nutrition and increased physical activity.
On February 9, Mrs. Obama launched the Let’s Move campaign to promote both policy change and individual behavior change to prevent obesity. The campaign includes four core areas: healthy choices, healthier schools, physical activity, and accessible and affordable healthy food. Let’s Move public service announcements and comments from Mrs. Obama are available on the campaign’s YouTube channel.
This initiative comes at a time when obesity among Americans, and especially American children, is on the rise. Between 1980 and 2004, the prevalence of obesity more than doubled among adults and tripled among children and adolescents. Today, nearly one-third of all children in the United States are overweight or obese.
Obesity is a well-established risk factor for chronic diseases, including heart disease, diabetes, and cancer. Research indicates that obesity and physical inactivity may account for 25 to 30 percent of several major cancers, including those of the colon, breast (postmenopausal), endometrium, kidney, and esophagus. But there is also evidence that regular physical activity may lower the risk of colon and breast cancers.
Preventing and reducing obesity is an important cancer prevention strategy, said Dr. Rachel Ballard-Barbash, associate director of the Applied Research Program in NCI’s Division of Cancer Control and Population Sciences. “Research suggests that obesity at multiple periods throughout life may increase cancer risk and worsen prognosis,” she said. “Further, evidence suggests that if overweight or obesity persists from childhood through teenage years, the risk of obesity during adulthood is greater. We also know that efforts to prevent obesity in children must involve their families and communities. Therefore, obesity prevention efforts, such as the Let’s Move campaign, may be important not just to help control childhood obesity, but it may also reduce cancer-related morbidity and mortality in the United States.”
Given these associations, NCI investigators continue to work closely with colleagues across NIH and HHS to support research aimed at reducing childhood obesity. NCI is a member of the National Collaborative on Childhood Obesity Research (NCCOR), a joint effort by the CDC, NIH, Robert Wood Johnson Foundation, and U.S. Department of Agriculture, and recently issued program announcements of funding available for obesity policy research, including an announcement specifically addressing school nutrition and physical activity policies.
This research will evaluate how policies influence school nutrition and physical activity environments and students’ behavior in these areas, and it will also examine the policy implementation process and how school policies may affect the home and community environments with regard to nutrition, physical activity, and body weight.
“Policies to combat obesity are being implemented across the Unites States, yet few are being evaluated rigorously,” said Dr. Ballard-Barbash. “These two program announcements will fund urgently needed research on the impact of these policies on diet, physical activity, and weight-related behaviors.”
Dr. Ballard-Barbash, who serves as an NIH representative on the HHS Interagency Working Group on Obesity Research, recognizes a critical role for this research in supporting the goals of the Let’s Move campaign. “The initiative addresses childhood obesity by focusing on tools for families and providing supportive school and community environments,” she said. “The recent NCI funding announcements align perfectly by sponsoring research that will empower families and communities to create healthy environments.”
—Holly Aprea Gibbons
Initiative Aims to Reduce Unnecessary Radiation Exposure from Medical Imaging
On February 8, the FDA announced a new initiative to reduce unnecessary radiation exposure from three widely used types of medical imaging: computed tomography (CT), nuclear medicine studies (including positron emission tomography, or PET), and fluoroscopy.
Recently, researchers have raised concerns that overuse of CT and other diagnostic procedures that use ionizing radiation, as well as a lack of oversight of the amount of radiation used in these tests, may contribute to an unnecessary cancer risk in the general population.
“The amount of radiation Americans are exposed to from medical imaging has increased dramatically over the past 20 years,” said Dr. Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health, in a press release announcing the initiative. “The goal of FDA’s initiative is to support the benefits associated with medical imaging while minimizing the risks.”
The initiative will promote the safe use of medical imaging devices (including optimizing the radiation dose used during each procedure), support informed decision making (including appropriately justifying the use of procedures involving radiation exposure), and increase patients’ awareness of their exposure to radiation.
The FDA will begin by issuing targeted requirements for manufacturers of CT and fluoroscopic devices to incorporate new safeguards into the design of the machines, develop safer technologies, and provide appropriate training to support safe use by practitioners. The agency will solicit input on the details of these requirements at a public meeting being held on March 30 and 31.
Rituximab Approved for Chronic Lymphocytic Leukemia
The FDA has approved the use of rituximab (Rituxan) to treat patients with chronic lymphocytic leukemia (CLL). The approval covers the drug’s use with the chemotherapy drugs fludarabine and cyclophosphamide in patients who have yet to undergo treatment for CLL or whose disease is not responding to other approved treatments. Rituximab is a monoclonal antibody that targets a specific antigen, CD20, on cancer cells. By binding to the antigen, the drug triggers an immune response in the body against cells that express CD20.
The agency’s approval is based on the results of two clinical trials which showed that, in either treatment setting, the combination of rituximab and the two chemotherapy drugs led to statistically significant improvements in patient survival without tumor growth, known as progression-free survival. Complete response rates—that is, no visible signs of cancer—in both trials were approximately doubled in patients who received rituximab, fludarabine, and cyclophosphamide compared with those who received only fludarabine and cyclophosphamide. However, the incidence of several serious side effects was also significantly higher in patients who received all three drugs.
This is the third drug approved for treating patients with CLL since 2008, the FDA noted in a statement. In March 2008, the FDA approved bendamustine (Treanda) for the initial treatment of patients with CLL, and in October 2009 ofatumumab (Arzerra) was approved for patients with CLL whose disease is no longer responding to treatment.
FDA Announces Risk Management Program for Anemia Drugs
Under a new FDA requirement, health care providers who prescribe anti-anemia drugs called erythropoiesis-stimulating agents, or ESAs, to cancer patients must enroll in a risk management program. The program requires that health care providers be trained on the drugs’ appropriate use in cancer patients and document that they discussed with each patient the drugs’ risks, benefits, and FDA-approved uses. Providers must also give patients a medication guide that explains the risks and benefits of ESAs.
The new requirements are part of a Risk Evaluation and Mitigation Strategy (REMS) program to be implemented by the drugs’ manufacturer, Amgen Inc., under an agreement with the FDA. ESAs include epoetin alfa (Procrit/Epogen) and darbepoetin alfa (Aranesp).
The change is the latest in a series of regulatory actions taken by the FDA in response to data from studies involving patients with cancer, which found that the drugs were associated with increased mortality risk and accelerated tumor growth.
The agency understands that the requirements “will create new responsibilities for busy health care providers,” said Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research (CDER), during a press briefing on the new program. But in patients with cancer, Dr. Pazdur continued, the risk-benefit balance of treatment with ESAs can be “delicate.” In fact, because of the potential risks associated with their use, the drugs are no longer indicated for patients receiving chemotherapy in whom the expected outcome is cure. The risk management program, he stressed, will help patients “make the best possible choice given their particular situation.”
Clinicians who wish to prescribe the drugs to cancer patients must complete an Amgen-administered training and certification program called APPRISE. Health care providers who are not enrolled in APPRISE will be barred from prescribing the drugs for cancer patients.
Individual hospitals must also enroll in the APPRISE program and establish a system for ensuring that providers in the hospital who prescribe ESAs are enrolled and comply with the program. Providers and hospitals can start enrolling in APPRISE beginning on March 24 and have up to 1 year to enroll and become certified. Re-enrollment is required every 3 years.
The REMS program for ESAs is “breaking new ground for the FDA,” explained Dr. Patricia Keegan, director of CDER’s Division of Biologic Oncology Products. The agency has never required a single REMS that covers multiple agents, she noted, or that covered only a single indication for an approved drug that has multiple indications. ESAs are also approved to manage anemia related to the treatment of kidney disease and HIV.
NCI 2011 Budget Proposal Available Online
NCI recently released The Nation's Investment in Cancer Research, an annual report intended to inform the President about the progress and opportunities in our continuing efforts against cancer and to justify the administration’s budget request to Congress for additional funding for the nation’s battle against cancer. This plan and budget outlines NCI's vision for the future and the collective judgment of NCI staff, its advisory groups, and representatives of the cancer research and advocacy community. The report, “Connecting the Nation’s Cancer Community,” describes how NCI is using unexpected new financial resources from the American Recovery and Reinvestment Act and a steady stream of scientific and technological advances to make strides in cancer risk reduction, early detection, patient care, and survivorship.
NCAB Convenes Its First Meeting of 2010
The National Cancer Advisory Board’s (NCAB) first meeting of the year was held in Bethesda, MD, on February 18, after being postponed by the record-making snowstorms that shut federal government offices the week before. In addition to NCI Director Dr. John Niederhuber’s update on the NCI budget, NCAB members heard presentations on a variety of topics, including NCI’s Cancer Human Biobank, opportunities to collaborate with Walter Reed National Military Medical Center and Suburban Hospital, data from the most recent Annual Report to the Nation, and an update on NCI’s Community Cancer Centers Program. The agenda and a videocast of the meeting are now available.
NCI Funds Eleven Centers for Cancer Systems Biology
On February 18, NCI renewed its commitment to the study of cancer systems biology by awarding grants to 11 institutions to become part of its Integrative Cancer Biology Program (ICBP), which the institute launched in 2004 as NCI’s primary effort in this emerging field. Each institution will establish a Center for Cancer Systems Biology (CCSB), which will use integrative and multidisciplinary approaches to study cancer as a systemic disease. New technologies such as genomics, proteomics, and molecular imaging will be used to investigate, design, and validate computational and mathematical cancer models. These predictive models will simulate all stages of cancer and provide key insights into the spectrum of cancer progression, from tumor initiation through growth and metastasis.
In addition, the CCSBs will serve as training and outreach centers to inform other scientists in the cancer research community about integrative cancer biology. Further information on the success of the program thus far and the future of the ICBP can be found on the ICBP Web site.
President’s Cancer Panel Concludes Series on Disparities and Cancer
The President’s Cancer Panel held its fourth and final meeting of the 2009–2010 series, “America’s Demographic and Cultural Transformation: Implications for the Cancer Enterprise,” on February 2 in Miami, FL. The panel heard testimony on the disparity in cancer rates experienced across and within populations. Speakers discussed lack of health insurance, high poverty rates, geographic isolation, and cultural factors as major contributors to such disparities.
Additionally, speakers noted the tremendous genetic and behavioral heterogeneity that exists within racial/ethnic groups and the implicit bias that may permeate cross-cultural provider-patient relationships. The panel learned of NCI’s efforts to enhance research on cancer health disparities and cancer education and outreach to underserved communities. Speakers recommended cultivating a workforce of minority researchers and clinicians and partnerships between researchers and communities. The panel will summarize findings and recommendations from the 2009–2010 series in its annual report to President Obama.