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April 17, 2012 • Volume 9 / Number 8

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NEWS

Targeted Nanoparticle Tested in Patients with Cancer

Artist's rendering of BIND-014. Illustration by Gaël McGill, Digizyme, Inc.

The first trial to test a targeted nanoparticle capable of controlling a drug's release is now under way in humans. By packaging molecules of the chemotherapy drug docetaxel in nanoparticles, researchers aim to deliver a higher dose of the drug directly to tumors and to reduce the toxicity to patients. 

In animal studies performed before the trial, the nanoparticle delivered a greater amount of the drug to tumor cells than could be achieved with the unpackaged (or free) drug. In addition, the nanoparticle did not show any more toxicity than docetaxel on its own.

Researchers from the Massachusetts Institute of Technology (MIT), Brigham and Women's Hospital, Harvard Medical School, BIND Biosciences, Inc., and their colleagues reported the development of the nanoparticle, called BIND-014, in the April 4 Science Translational Medicine. Read more > >

IN DEPTH

UPDATES

  • Legislative Update

    • Latest State Cancer Legislative Database Update Now Available
  • CDC Update

    • Calls to Tobacco Quitline Hit Record High after Launch of National Ad Campaign
  • Notes

    • Free Telephone Workshop Series for Cancer Survivors Begins April 24
    • Public Comment Sought on Draft Statement on Ovarian Cancer Screening
    • Apply to Visiting Scholars Program at Frederick National Laboratory by May 11
    • Applications for Oncology Fellowships Due May 31
    • NCI Requests Targets for Monoclonal Antibody Production and Characterization


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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Featured Article


Read more articles in the Technology Series here.

Targeted Nanoparticle Tested in Patients with Cancer

Artist's rendering of BIND-014. (Illustration by Gaël McGill, Digizyme, Inc.) Artist's rendering of BIND-014. (Illustration by Gaël McGill, Digizyme, Inc.)

The first trial to test a targeted nanoparticle capable of controlling a drug's release is now under way in humans. By packaging molecules of the chemotherapy drug docetaxel in nanoparticles, researchers aim to deliver a higher dose of the drug directly to tumors and to reduce the toxicity to patients. 

In animal studies performed before the trial, the nanoparticle delivered a greater amount of the drug to tumor cells than could be achieved with the unpackaged (or free) drug. In addition, the nanoparticle did not show any more toxicity than docetaxel on its own.

Researchers from the Massachusetts Institute of Technology (MIT), Brigham and Women's Hospital, Harvard Medical School, BIND Biosciences, Inc., and their colleagues reported the development of the nanoparticle, called BIND-014, in the April 4 Science Translational Medicine.

"Normally, when you give cancer drugs they go through the whole body, and they cause really bad side effects. And only a certain amount goes to the tumor," said Dr. Robert Langer of MIT, one of the senior authors of the study. "This trial has given us an initial indication that this nanoparticle approach is safer and much more efficacious."

Preclinical Promise

In a mouse xenograft model studied before the trial, the amount of docetaxel delivered to tumors was seven times higher in mice infused with the nanoparticle compared with mice that received unpackaged docetaxel. In addition, the researchers saw a greater reduction in tumor mass in mice that received the targeted nanoparticle compared with mice that received a nontargeted version of the nanoparticle. The reduction in tumor mass seen with the targeted nanoparticle was even greater when compared with free docetaxel. Side effects were no worse with the nanoparticles than with the unpackaged chemotherapy drug.

In other animal studies, the researchers found that docetaxel packaged in nanoparticles circulated in the bloodstream much longer than the unpackaged drug, and the drug remained safely encapsulated inside its shell while in the bloodstream. Also, BIND-014 did not accumulate in the liver, an unwanted occurrence that is almost always seen with other nanoparticles.

Based on these promising results in animals, the researchers have launched the phase I clinical trial to find the maximum tolerated dose in people with solid tumors that have not responded to a range of other chemotherapies. Although the trial is ongoing, the researchers reported initial clinical results in the Science Translational Medicine paper and provided additional data for the first 17 patients in a poster presented April 4 at the American Association for Cancer Research annual meeting.

Early data from the trial show that BIND-014 exhibits antitumor activity and is generally well-tolerated. Of note, tumors shrank in a patient with metastatic bile duct cancer and a patient with tonsillar cancer. Both responses occurred at doses substantially lower than those given for unpackaged docetaxel, which is consistent with the preclinical finding that BIND-014 can accumulate in tumors more effectively. Another patient with cervical cancer had a durable reduction in tumor size for more than 6 months and currently remains on the treatment.

New Process

To create a nanoparticle that could safely carry docetaxel through the bloodstream and deliver the drug directly to tumors, the researchers developed a new process for designing nanoparticles. Typically, researchers have created a prototype nanoparticle and then tried to modify its characteristics by, for instance, attaching molecules known as ligands for tumor cell binding, explained Dr. Omid Farokhzad of Harvard Medical School, another senior author of the study.

Early data from the trial shows that BIND-014 exhibits promising antitumor activity and is generally well-tolerated.

The problem with this process, said Dr. Farokhzad, is an inherent lack of reproducibility for small changes in design. "You're going to get batch-to-batch variability, and with that variability we could not create nanoparticles that differed from each other very narrowly, to find the one nanoparticle that had exactly the right pharmacologic and pharmaceutical parameters we were looking for."

To address this problem, the researchers created a library of more than 100 novel self-assembling nanoparticles. These nanoparticles start out as a long string of molecules, each with different functions—for example, holding and releasing the chemotherapy drug, hiding the nanoparticle from the immune system, or binding to tumor cells.

Small changes can be made to any of the molecules in the string before self-assembly, creating subtle variations that can be screened for the desired properties of a drug-delivery vehicle. When the desired properties are added to the string, they are dropped into a water-solvent solution containing the chemotherapy drugs to create a precisely designed nanoparticle.

Since some of the molecules in the string are repelled by water and some can mix with water, the nanoparticle folds in on itself and around the drug in a predictable, reproducible fashion, creating the final product. "We can now create nanoparticles with narrowly different biophysicochemical properties in a highly reproducible way. They will look the same every time, and we can test for the best nanoparticles in this library," said Dr. Farokhzad.

"We had done a lot of self-assembly work in our lab, so to us it was a natural approach to take for making nanoparticles, though the key here was the combination of self-assembly and use of this approach to make highly reproducible libraries of nanoparticles," added Dr. Langer.

A Firm Foundation

The initial work on the library was funded by a Centers of Cancer Nanotechnology Excellence grant from NCI's Alliance for Nanotechnology in Cancer. Hoping to rapidly advance their work to the clinic, in 2007 the researchers applied for and received an NCI Small Business Innovation Research grant to form BIND Biosciences, Inc., an independent company.

The scientists from BIND went on to screen their entire library in vitro to measure the rates of drug release and to test the stability of the nanoparticles. The most promising nanoparticles advanced to pharmacokinetic studies in rats. The researchers selected BIND-014 for further testing and manufacturing. (BIND-014 targets a protein called prostate-specific membrane antigen, which is found on the surface of prostate cancer cells and on the blood vessels feeding most other types of solid tumors.)

"This collaboration shows what can happen when you take nanotechnology forward and develop a really robust platform and product candidate, and get it into the clinic," said Dr. Jeffrey Hrkach, senior vice president, Pharmaceutical Sciences at BIND Biosciences and lead author of the study.

"Hopefully, nanomedicines like this will lead to more manageable and more effective chemotherapies," said Dr. Piotr Grodzinski, director of NCI's Office of Cancer Nanotechnology Research, which operates the Alliance for Nanotechnology in Cancer. "Perhaps we can even revisit drugs that failed in clinical trials in the past because they were too toxic, if nanoparticles allow us to deliver these drugs in a safer way."

Sharon Reynolds

Cancer Research Highlights

Many Patients with Cancer Need Better Treatments for Pain

Inadequate pain treatment in patients with cancer remains a significant problem and appears to be more frequent among minorities, according to a new study. The findings were published online April 16 in the Journal of Clinical Oncology.

Dr. Michael Fisch of the University of Texas MD Anderson Cancer Center and his colleagues surveyed more than 3,000 patients with invasive forms of breast, prostate, lung, and colorectal cancer who were likely to have pain. The patients were treated at academic medical centers and community-based hospitals.

More than two-thirds of patients reported pain or requiring analgesics for pain control at their initial oncology appointment. Based on reported pain levels and the type and/or dose of prescribed pain medication, the researchers found that one-third of these patients received inadequate treatment for their pain.

Approximately 40 percent of patients who experienced moderate to severe pain did not receive the proper pain medication, and 20 percent of patients with severe pain received no pain medication. In surveys done after follow-up visits with their oncologists 4 to 5 weeks later, patients reported little improvement in pain management. One month is a fairly short follow-up period, the authors acknowledged, as effective pain management usually requires monitoring and adjustments.

Minority patients were nearly twice as likely as white patients to receive inadequate pain treatment, the researchers found. The disparity in adequate pain treatment among minority groups could be due to multiple factors, they wrote, including communication problems and patient trust issues, as well as “system issues,” such as drug availability.

In addition, patients with earlier stages of cancer reported inadequate pain management at different time points after diagnosis. This indicates not only that patients with early-stage cancers need better pain management, but that the medical profession should better characterize pain symptoms and identify pain sources, noted Dr. Worta McCaskill-Stevens of NCI’s Division of Cancer Prevention (DCP) and a co-author of the study.

“This study is a stepping stone to better evaluation of pain,” she said, noting that doctors adhere more closely to other treatment guidelines than to pain management guidelines.

“Only one in six responding medical oncologists [in the study] reported frequent referrals to specialists in either pain or palliative care,” wrote Drs. Martin Stockler and Nicholas Wilcken in an accompanying editorial. “Clearly more work is needed, perhaps in medical school, but certainly in residency and fellowship programs.”

This is an issue that goes beyond physicians, noted Dr. Ann O’Mara, head of palliative care research in DCPand a co-author of the study. Nurses and other health care staff should also receive more training in this area, she advised.

Further reading: “Survey of Oncologists Suggests Lack of Progress in Cancer Pain Management

More Chemotherapy May Help after Initial Treatment for Childhood Leukemia Fails

A small percentage of children diagnosed with acute lymphoblastic leukemia (ALL) responds poorly to initial chemotherapy. When this initial treatment, called induction therapy, fails to induce a complete clinical remission, most leukemia experts would recommend an allogeneic stem cell transplant. However, a new study suggests that at least some of these children may do better if they receive additional chemotherapy rather than a stem cell transplant.

Reporting their findings in the April 12 New England Journal of Medicine, the researchers noted that doctors can cure 8 in 10 children newly diagnosed with ALL. But certain subgroups of patients tend to do worse than others. For instance, patients whose cancers do not go into complete clinical remission after 4 to 6 weeks of induction therapy are at high risk for poor outcomes.

To determine the optimal treatment for these patients, the researchers analyzed data on more than 44,000 children who participated in ALL clinical trials around the world. Of these children, 1,041 had cancers that responded poorly to induction therapy. Most of these patients went on to have a stem cell transplant, but some received only additional chemotherapy.

A subset of the children whose cancers did not respond to induction therapy unexpectedly showed better long-term survival with chemotherapy alone than with stem cell transplantation. These children were younger than age 6, had precursor B-cell ALL rather than T-cell ALL, and had no other high-risk clinical or genetic features.

More than 70 percent of the children in the subgroup that received additional chemotherapy rather than a stem cell transplant survived at least 10 years, which was more than twice the survival rate of the entire group of patients who did not respond to induction therapy.

“This study tells us that the failure of induction therapy should no longer be considered an automatic indication for a bone marrow transplant,” said co-author Dr. Ching-Hon Pui, chair of the St. Jude Children’s Research Hospital department of oncology. “[But]a 72 percent survival rate is still not acceptable, and we need to find better ways to treat these patients,” he added.

The study also demonstrates “the power of large collaborative efforts to discover important new insights into disease,” said Dr. Karen Rabin of Baylor College of Medicine, who wrote an accompanying editorial. The benefit of chemotherapy for these patients emerged only after 14 research groups on three continents combined their results.

For Older Patients with Leukemia, Low Doses of Gemtuzumab Improve Survival

In a randomized trial, patients aged 50 to 70 with previously untreated acute myeloid leukemia (AML) who received the targeted therapy gemtuzumab ozogamicin (Mylotarg) in addition to standard chemotherapy lived longer than patients who received standard chemotherapy alone. These results, published online in The Lancet on April 4, counter some earlier studies that indicated that the drug was ineffective and too toxic.

Gemtuzumab received accelerated approval for AML from the Food and Drug Administration (FDA) in 2000, but the confirmatory clinical trial required for full approval showed that the drug did not improve survival and increased toxicity, including the risk of treatment-related death. The manufacturer, Pfizer Inc., voluntarily withdrew the drug from the general market in 2010, though clinical trials have continued.

In the current trial, which was conducted by the Acute Leukemia French Association, the researchers used a lower dose given over 3 days during chemotherapy instead of a higher dose given over 2 days to reduce side effects. In the study, 139 patients received standard chemotherapy with the drugs daunorubicin and cytarabine, and 139 received standard chemotherapy plus gemtuzumab ozogamicin.

The addition of low, fractionated doses of gemtuzumab ozogamicin improved overall survival and event-free survival (time to relapse, death, or assessment that the disease is not responding to treatment). After 2 years of follow-up, event-free survival was 41 percent for the patients who received gemtuzumab ozogamicin and 17 percent in the control group. Overall survival 2 years after treatment was 53 percent in the gemtuzumab ozogamicin group and 42 percent in the control group.

Although patients in the gemtuzumab ozogamicin group were more likely to experience side effects, particularly more-persistent reductions in white blood cells and platelets, deaths during treatment did not differ significantly between the two groups. “The use of fractionated lower doses of gemtuzumab ozogamicin allows the safe delivery of higher cumulative doses and substantially improves outcomes in patients with acute myeloid leukemia,” wrote the authors.

“These results are quite important if confirmed [in additional trials],” commented Dr. Wyndham Wilson of NCI’s Center for Cancer Research, who was not involved in the research. Few advances have been made in the treatment of older patients with AML in recent years, he added, and effective new drugs are badly needed.

A Conversation With

A Conversation with Dr. Lowell Schnipper about Cancer Care and the Choosing Wisely Campaign

Nine professional medical societies, including the American Society of Clinical Oncology (ASCO), each recently released a list of the five most commonly performed medical tests and procedures within their specialties that are not supported by published evidence and contribute heavily to unnecessary health care spending in the United States. The release was part of the American Board of Internal Medicine (ABIM) Foundation's Choosing Wisely campaign.

Dr. Lowell Schnipper, of Harvard Medical School and chair of the ASCO Cost of Cancer Care Task Force, which spearheaded ASCO's contribution to the Choosing Wisely campaign, spoke with the NCI Cancer Bulletin about the top-five list and the larger effort behind it.

Dr. Lowell E. SchnipperDr. Lowell E. Schnipper

Why is the Choosing Wisely campaign important? Is the campaign just focused on saving money, or is it broader than that?

ABIM and the specialty societies are participating in this campaign because we believe that the best care is the right amount of care.

If you deliver the right amount of care in a milieu that is otherwise characterized by the delivery of too many interventions or therapies, you will definitely spend less on health care. Nobody would dispute that as a laudatory goal, particularly in a country where we are all concerned about health care and other expenditures. However, this campaign is really about quality of care, with the assumption that if evidence-based care is the norm, the lowest possible expense will follow.

In my specialty of breast cancer, for example, when we give more care than the clinical situation warrants, we invariably expose patients to the risk of new findings that have no disease-specific relevance and may have no clinical importance. This situation frequently elicits anxiety in the patient and stimulates physicians to do more scans, more x-rays, and, not uncommonly, invasive biopsies. That's what I call too much care, which can hurt patients instead of help them.

The campaign is also directed at patients. Patients will be encouraged to discuss their care with their doctors, ask them how wise is it to do a given procedure, and ask if there are downsides to a test or procedure.

ASCO's Five Key Opportunities to Improve Cancer Care

1. Avoid unnecessary anticancer therapy, including chemotherapy, in patients with advanced solid-tumor cancers who are unlikely to benefit, and instead focus on symptom relief and palliative care.

2. Don't perform PET, CT, and radionuclide bone scans in the staging of early prostate cancer at low risk for metastasis.

3. Don't perform PET, CT, and radionuclide bone scans in the staging of early breast cancer at low risk for metastasis.

4. Don't perform surveillance testing (biomarkers) or imaging (PET, CT, and radionuclide bone scans) for patients without symptoms who have been treated for breast cancer with curative intent.

5. Avoid administering white blood cell stimulating factors to patients who have a very low risk (less than 20 percent) for febrile neutropenia.

How were these five procedures and tests selected?

The task force—which included physicians, advocates, and representatives from the pharmaceutical industry—first came up with a list of suggestions for ASCO's top-five list. We discussed them by e-mail and in person. Once we arrived at a tentative list, we distributed it to the ASCO Clinical Practice Committee, which is composed of nearly 200 oncologists, if you include the leaders of the state clinical oncology societies. I don't remember getting very many negative responses to the suggestions we distributed, although some questions or reservations certainly were brought up.

The items we honed in on had to meet certain criteria. Specifically, we wanted the top five to be supported by a body of evidence in the form of studies in the literature and/or be the subject of expert guidelines, either generated by ASCO or a respected group such as the National Comprehensive Cancer Network.

Why do you think these procedures are overused?

I think the dominant reasons that cut through all of them is the anxiety that a cancer diagnosis presents, the importance of not missing something clinically important, and the reality of an advanced cancer that's already made a person very sick and the proximity of that person's death. I think these are more than enough to motivate and frighten anybody, patient or doctor, to turn over any stone that can reasonably be overturned.

You asked if there are financial factors that underlie overuse. I believe that most of us would concur that the economic milieu in which we practice medicine today does not neatly align the incentives for physicians, society, and the patient in a way that would contribute to delivery of the least costly care. There are also real tort concerns, which motivate overuse to protect one against malpractice allegations. But I reject the idea that this is driven by greed; physicians want to do the right thing for our patients

I have patients who have undergone surgery, radiation, and chemotherapy, who come in and report being well. But they'll say, "Well, how do you know I'm okay? Don't you need to check me out, do some scans, to make sure that I'm okay?"

It's counterintuitive to a patient, and it can be counterintuitive to a doctor, to tell them that finding metastatic disease doesn't help us help them survive longer. That's really what the data that support our top five list tell us…and it's a difficult concept for the patient to absorb. Some day, novel treatments may in fact aid us in extending survival of those with metastatic disease sufficiently to warrant continuous surveillance. We are not there yet, and when evidence supports our arrival at that point, our guidelines must change.

Is it important that the top five list came from the medical community?

I really do think that's important. One of ASCO's motivating factors for forming the Cost of Cancer Care Task Force was to be responsible citizens and stewards of the nation's heath care system.

We were fully aware that major changes in health care delivery were going to happen one way or another, because the rising costs of care are becoming unsustainable. And as uncomfortable as it can be to talk about some of these issues, we much prefer that professionals in the field develop management recommendations, rather than the government or insurance companies, because [these issues] require sophisticated clinical insights.

We feel that [the medical community] is best able to identify how to provide the best care, where we can most effectively reduce unnecessary procedures, and still come out with the best results for our patients.

Interviewed by Carmen Phillips

Special Report

Norwegian Study Estimates Overdiagnosis of Breast Cancer from Screening

Physician analyzing a mammogram film A study in Norway suggests that between 15 and 25 percent of invasive breast cancers were overdiagnosed with the institution of a national mammography screening program.

As many as 1 in 4 invasive breast cancers diagnosed in Norway through the country's widespread, population-based mammography screening program never would have caused the woman harm or required treatment, researchers reported in the April 3 Annals of Internal Medicine. The finding, based on an analysis of the country's breast screening program, adds to concerns about overdiagnosis in breast and other cancers.

Overdiagnosis refers to the detection of tumors that, if left alone, would not cause any symptoms of disease or death. Because doctors cannot reliably distinguish these tumors from potentially fatal cancers, most screening-detected invasive breast cancers are treated, often with surgery and postoperative therapy that includes radiation plus hormone therapy, chemotherapy, or both systemic therapies.

The new findings, together with previous studies, suggest that a substantial proportion of screened women are diagnosed with invasive cancers unnecessarily and are exposed to the toxic effects of treatments they don't need.

The investigators analyzed data from the Norwegian Breast Cancer Screening Program, which began as a pilot program in 1996 in four of Norway's 19 counties and was later expanded to include the remaining counties over a 9-year period. Specifically, they compared the number of breast cancers diagnosed in counties that had screening programs in place with the number of cases diagnosed in counties that did not have screening programs during the same period.

The results suggest that between 15 and 25 percent of invasive breast cancers were overdiagnosed with the implementation of a mammography screening program. After 10 years of biennial screening, the study authors estimated that for every 2,500 women invited to be screened, 6 to 10 women were overdiagnosed, 20 were diagnosed with breast cancer that required treatment, and 1 death from the disease was prevented.

The analysis did not include noninvasive tumors known as ductal carcinoma in situ (DCIS), even though most of these lesions are only detectable by mammography. The authors said DCIS should be analyzed separately because different analytic methods would be required. Inclusion of DCIS would have further increased the estimates of overdiagnosis, since a large proportion of these tumors would never become life-threatening cancers.

The authors also acknowledged that additional factors beyond screening might have affected breast cancer rates in the counties.

Nonetheless, the "overdiagnosis and unnecessary treatment of nonfatal cancer creates a substantial ethical and clinical dilemma and may cast doubt on whether mammography screening programs should exist," the authors wrote. Until doctors can reliably identify potentially fatal cancers that require early detection and treatment, "women eligible for screening need to be comprehensively informed about the risk for overdiagnosis," they concluded.

The authors of an accompanying editorial emphasized that women in the United States often start annual mammography screening at age 40, whereas Norwegian women start biennial screening at age 50. "Given more frequent screening over a longer time, overdiagnosis probably occurs more often in the United States than in Norway," they wrote.

Any amount of overdiagnosis is serious, however, and steps should be taken to address the issue, the editorialists continued. Most patient-education materials fail to mention overdiagnosis, and most women are unaware of its possibility. "We have an ethical responsibility to alert women to this phenomenon," they concluded.

"Overdiagnosis from cancer screening is one of the most pressing clinical issues in the field of cancer screening," said Dr. Barry Kramer, director of NCI's Division of Cancer Prevention and editor-in-chief of the NCI Physician Data Query (PDQ) Screening and Prevention Editorial Board.

"With increasingly sensitive screening tests for a variety of cancers, the problem is likely to increase," Dr. Kramer continued. "For that reason, NCI has identified studies to distinguish overdiagnosed cancers from life-threatening cancers as a high priority area of research."

Edward R. Winstead

A Closer Look

Using Imaging to Pinpoint Genetic Mutations in Brain Tumors

Illustration of a patient undergoing a magnetic resonance scan.A magnetic resonance scan of a brain tumor aims to detect a surrogate marker for IDH mutations (2-HG) in a patient with a suspected glioma. The spectra identified could assist in diagnosis, prognosis, and monitoring of the tumor.

Recent studies suggest that a noninvasive imaging technique can identify the presence of certain genetic mutations in gliomas, the most common type of brain tumor, by detecting a substance produced as a consequence of those mutations. If further studies validate the finding, oncologists may be able to use this approach to diagnose tumors carrying the mutations, distinguish different glioma subtypes,monitor tumor progression, and detect recurrences—all without repeated surgeries or biopsies.

The technique uses magnetic resonance spectroscopy (MRS) to detect 2-hydroxyglutarate (2-HG), a chemical that is scarce in normal tissues but accumulates in gliomas that harbor mutations in two related genes, IDH1 and IDH2. Until now, the only way to detect IDH mutations or 2-HG in a tumor was a biopsy and analysis of tissue samples. Taken together, the new work provides evidence that 2-HG could serve as a noninvasive biomarker of tumors with IDH mutations.

More than 70 percent of adults with invasive, lower-grade (grade II or III) gliomas carry IDH mutations. IDH mutations are uncommon in primary forms of glioblastoma, but they are found in many secondary glioblastomas, which arise from lower-grade gliomas. Glioblastoma is the most aggressive type of glioma.

Tumors with IDH mutations make an aberrant form of the enzyme isocitrate dehydrogenase (IDH), which plays an essential part in a metabolic pathway that cells use to generate energy. The mutations not only impair the enzyme's normal function but also give it the ability to make 2-HG.

MRS can be done at the same time and with the same magnetic resonance imaging (MRI) equipment medical centers use for diagnostic imaging. While MRI scans provide anatomical and structural information, MRS provides information on cellular activity by detecting metabolites in tissue, explained Dr. Ovidiu Andronesi, an instructor in radiology at Harvard Medical School and lead author of one of the recent studies.

Informative Mutations

Currently, a definitive diagnosis of glioma requires a biopsy and examination by a pathologist, who assigns a grade of I to IV to the tumor, with grade IV (glioblastoma) being the most aggressive. However, "two grade II tumors may look the same under the microscope, but one may be very slow-growing and another may kill the patient within 2 years," noted Dr. Howard Fine, chief of NIH's Neuro-Oncology Branch, who was not involved in the MRS studies. "We need to get to the point where we're [classifying tumors] on the basis of the genetics and the molecular biology," he said.

Thus, researchers were interested to find that patients with glioblastoma who have IDH mutations generally live longer than patients who lack the mutations. Several studies have also found that IDH mutations are associated with better outcomes in lower-grade gliomas, although this link is not as firmly established.

"Across [glioma] patients within the same tumor grade, there is a prognostic advantage to having an IDH mutation," said Dr. Susan Chang, director of Neuro-Oncology at the University of California, San Francisco (UCSF), who collaborated on a study led by UCSF radiology and biomedical imaging professor Dr. Sarah Nelson. If further studies confirm this advantage, assessing a tumor's 2-HG status with MRS could be used to divide patients into groups with similar prognoses for clinical trials of new therapies, Dr. Chang said.

MRS could also be used to diagnose IDH-mutated gliomas before surgery and to distinguish them from nonmalignant brain lesions, such as those due to multiple sclerosis, said Dr. Elizabeth Maher, a neuro-oncologist who led a study at the University of Texas Southwestern Medical Center with physicist Dr. Changho Choi. Although the approach is still experimental, Dr. Maher said she has already used it to diagnose a low-grade glioma in the brain stem of a 20-year-old patient, helping the patient avoid a risky biopsy procedure.

Study Results

Researchers have used several MRS techniques to detect 2-HG, which can be difficult to distinguish from some common brain metabolites with established clinical MRS methods. Dr. Nelson and colleagues noninvasively detected and measured 2-HG in small tissue samples taken from recurrent gliomas in 52 patients originally diagnosed with grade II glioma. They found a strong correlation between the presence of 2-HG in tissue samples and the presence of IDH1 mutations in tumor tissue. (IDH1 mutations are much more common than IDH2 mutations.) They also correlated varying levels of 2-HG in IDH-mutated tumors of different grades with several histopathology parameters, including the density of tumor cells in a sample.

While the UCSF researchers used MRS to detect 2-HG ex vivo (outside the body), Dr. Andronesi's team showed that noninvasive MRS could also detect 2-HG unambiguously in vivo (in the body) in two glioma patients with IDH-mutated tumors. They did not detect 2-HG in four healthy volunteers or in four primary glioblastoma patients who lacked IDH mutations.

In a perspective article accompanying the two studies, Drs. Philippe Metellus and Dominique Figarella-Branger of the Hôpital de la Timone in Marseille, France, detailed the potential clinical applications of "these major findings." However, they wrote, "the MRS methodology used in these studies is not available in all clinical radiology settings. Also, in vivo proof-of-principle data will need to be reproduced in a larger cohort."

Physicians hope to use magnetic resonance spectroscopy to noninvasively detect tumor recurrence after surgery.

Those concerns were addressed at least in part by the UT Southwestern study and by a study led by Dr. Linda Liau, professor and vice chair in the Department of Neurosurgery at the University of California, Los Angeles. Both used in vivo MRS methods that could be done routinely in most hospitals and medical centers with relatively minor modifications of standard MRS techniques.

Dr. Liau's team showed that, in 24 of 27 patients with gliomas of various grades, in vivo MRS could detect the higher 2-HG levels found in tumors with IDH1 mutations. They also showed that 2-HG levels measured noninvasively by MRS in patients prior to surgery correlated with 2-HG levels measured in corresponding tumor samples with a laboratory technique known as liquid chromatography-mass spectroscopy (LC-MS).

And, in their study of 30 patients with grade II, III, or IV gliomas, Dr. Maher and colleagues showed that in vivo MRS detection of 2-HG correlated with mutations in IDH1 or IDH2 and with increased 2-HG levels measured in tumor samples by LC-MS. The team also estimated the concentrations of 2-HG in patient's tumors.

Taking It to the Next Level

The MRS methods used by each group have advantages and disadvantages, and most teams are still refining and optimizing their approaches. "The jury is still out on which is the best approach," Dr. Nelson said. "One would have to do a head-to-head comparison under similar circumstances in order to establish [which is best]."

As Dr. Andronesi noted, researchers now need to "establish the sensitivity and specificity of these methods—so-called validation…using genomics as the gold standard" for detecting IDH mutations. "It's important that validation is done not only in one center and by one group, but that other people can replicate [the findings]," he said.

In anticipation of testing possible clinical applications, researchers are working to show that in vivo MRS can be used not only to detect 2-HG but also to accurately measure the concentration of 2-HG in a tumor. "Showing [that] something is there is one thing," Dr. Nelson noted. "Being able to measure it to a plus or minus 10 percent accuracy, which you need to do in order to look at subtle changes, is something else."

If 2-HG levels are shown to reflect changes in tumor growth or progression, physicians could use MRS measurement of 2-HG levels to monitor responses to therapy, or to detect early signs of tumor progression in patients with IDH-mutated gliomas. "Eventually, about 80 percent of low-grade tumors will transform into the highest-grade tumors, and we have no way of picking that up [on an MRI] before there's an outgrowth of a big tumor," Dr. Maher said.

Similarly, physicians hope to use MRS to noninvasively detect tumor recurrence after surgery. Doing so is "one of the biggest challenges that face oncologists today," Dr. Nelson noted, because changes on a standard MRI that suggest a recurrence may also be due to effects of treatment.

"In the broader scheme of things, it may be that 2-HG is not the only important metabolite," Dr. Liau said. Her group as well as Dr. Maher's and Dr. Nelson's are using in vivo MRS to study changes in a range of metabolites in gliomas. Such information could be used to establish "molecular fingerprints" of tumor grade and disease progression and to understand more about the basic biology of why gliomas form and develop.

Elia Ben-Ari

Related reading: "Newly Discovered Mutation Found in More Brain Tumors"

Featured Clinical Trial

Testing Vascular Disruption Combined with Chemotherapy for Advanced Solid Tumors

Name of the Trial
Phase I/II Trial of Crolibulin (EPC2407) Plus Cisplatin in Adults with Solid Tumors with a Focus on Anaplastic Thyroid Cancer (NCI-11-C-0027). See the protocol summary.

Dr. Ann Gramza Dr. Ann Gramza

Principal Investigator
Dr. Ann W. Gramza, NCI Center for Cancer Research

Why This Trial Is Important
Malignant solid tumors must establish a constant supply of blood in order to grow beyond 1 to 2 mm in diameter. They accomplish this by secreting proteins and chemicals that signal nearby blood vessels to grow offshoots into the tumor in a process called tumor angiogenesis. But these new blood vessels differ from normal blood vessels. They tend to be immature, with poorly developed vessel walls that leak readily, and grow in a disorganized, haphazard manner throughout the tumor, in contrast to the strict organization of normal vasculature.

Numerous drugs and biological agents have been developed to interfere with tumor angiogenesis. These angiogenesis inhibitors typically work by blocking the activity of growth factors secreted by the tumor that spur the formation of new blood vessels or signaling pathways in blood vessel endothelial cells that are targets for the secreted growth factors.

However, a new class of drugs, called vascular disrupting agents, is also being developed to target the tumor blood supply. In contrast to angiogenesis inhibitors, which prevent the formation of new blood vessels to a tumor, vascular disrupting agents attack a tumor's established blood supply. In animal studies, this approach caused cancer cells within the core of tumors to die rapidly from a lack of nutrients.

These studies also revealed that tumors treated with vascular disrupting agents tended to maintain viable cancer cells around their periphery, where the cells may be able to obtain sufficient nutrients from the surrounding tissue. This observation has led to a strategy of pairing vascular disrupting agents with conventional chemotherapy drugs. Researchers believe that combining these treatments will cause synergistic effects because, although vascular disrupting agents seem to kill cells in the core of a tumor effectively, conventional chemotherapy drugs are much better at killing cancer cells around a tumor's periphery.

NCI researchers are studying the potential of the vascular disrupting agent crolibulin (EPC2407 and MX-116407) in combination with the chemotherapy drug cisplatin to treat advanced cancers. A previous animal study of the combination showed that crolibulin markedly enhanced the anticancer activity of cisplatin.

In this phase I/II trial, doctors will first assess the safety and tolerability of intravenous crolibulin and cisplatin in patients with advanced solid tumors that have not responded to previous treatment and establish the maximum tolerated dose for the combination. In the second part of the trial, patients with anaplastic thyroid cancer will be randomly assigned to receive crolibulin and cisplatin at the maximum tolerated dose established in the first part of the study or cisplatin alone. Doctors will look for differences in progression-free survival and response rates, as well as assess the effects of treatment on certain molecular markers.

"Anaplastic thyroid cancer is very aggressive and is among the most deadly and rapidly destructive of all solid tumors," said Dr. Gramza. "Patients with this disease have no effective treatment options and most die within months of their diagnosis. Effective therapies for this uniformly fatal malignancy are urgently needed, and there is evidence that combinations such as crolibulin and cisplatin may potentially benefit these patients."  

For More Information
See the lists of eligibility criteria and trial contact information or call the NCI Clinical Trials Referral Office at 1-888-NCI-1937. The call is toll free and confidential.

An archive of "Featured Clinical Trial" columns is available at http://www.cancer.gov/clinicaltrials/featured.

Legislative Update

Latest State Cancer Legislative Database Update Now Available

NCI's State Cancer Legislative Database (SCLD), a program that maintains a database of state cancer-related health policies, has posted the latest edition of the SCLD Update on its website. The issue includes a summary of new measures enacted in the fourth quarter of 2011.

The issue also features a special report that reviews the nearly 250 cancer-control measures passed by the states in 2011, as well as a table on legislative activity related to state tobacco settlements.

In addition to the latest edition of the SCLD Update, the SCLD program recently posted a fact sheet on state excise taxes on cigarettes, chewing tobacco, and snuff. All 50 states and the District of Columbia tax the sale of cigarettes, and the nationwide average during 2011 was approximately $1.46 per pack. Forty-nine states and the District of Columbia tax the sale of chewing tobacco and snuff; Pennsylvania is the only state that does not.

Map of the United States indicating excise tax rates per pack of cigarettes ranging from $0.60 or less to more than $2.00.

CDC Update

Calls to Tobacco Quitline Hit Record High after Launch of National Ad Campaign

Smokefree.gov and 1-800-QUIT-NOW tile

Two weeks after the Centers for Disease Control and Prevention (CDC) launched the Tips from Former Smokers campaign, calls to the national tobacco quitline number 1-800-QUIT-NOW more than doubled, and visits to smokefree.gov more than quadrupled.

The number of calls rose from 14,437 between March 12 and March 18 to a record 34,413 between March 26 and April 1, the CDC reported. The ads were launched March 19 and will run for at least 12 weeks in a variety of national media platforms, including television, radio, billboards, online, theaters, magazines, and newspapers.

Previous experience from state and local media campaigns promoting quitlines shows that at least five to six smokers try to quit on their own for every one person who calls a quitline.

The campaign features compelling stories of former smokers living with smoking-related diseases and disabilities and the toll smoking-related illnesses take on smokers and their loved ones. The ads focus on smoking-related lung and throat cancers, heart attack, stroke, asthma, and Buerger's disease, a rare condition affecting arteries and veins in the arms and legs.

The campaign also features suggestions from former smokers and reasons why people have quit. The ads are tagged with 1-800-QUIT-NOW, a toll-free number to access support for quitting, or smokefree.gov, which provides free quitting information.

"Although they may be tough to watch, the ads show people living with real, painful consequences from smoking," said CDC Director Dr. Thomas R. Frieden. "For every one person who dies from tobacco, 20 are disabled or disfigured or have a disease that is unpleasant, painful, [and/or] expensive. There is sound evidence that supports these ads—and, based on the increase in calls to 1-800-QUIT-NOW, we're on our way to helping more smokers quit."

Smoking remains the leading cause of preventable death and disease in the United States, killing more than 443,000 Americans each year. Cigarette smoking costs the nation $96 billion in direct medical costs and $97 billion in lost productivity each year.  In addition, more than 8 million Americans are living with smoking-related diseases, including cancer, and every day more than 1,000 youths younger than 18 become daily smokers

Nearly 70 percent of smokers say they want to quit, and about half make a serious attempt to quit each year. The Tips from Former Smokers campaign can provide motivation, information, and resources to help.

Graph showing the number of calls to 1-800-QUIT-NOW between March 1 and April 8

Notes

Free Telephone Workshop Series for Cancer Survivors Begins April 24

Richard Dickens, Dr. David Spiegel, Dr. Lorenzo Cohen Richard Dickens, Dr. David Spiegel, and Dr. Lorenzo Cohen

The tenth annual Cancer Survivorship Series "Living With, Through, and Beyond Cancer" will hold the first of four workshops on April 24, from 1:30 to 2:30 p.m. ET. This free series offers cancer survivors, their families, friends, and health care professionals practical information to help them cope with concerns and issues that arise after treatment ends.

Part I of the series is titled "Using Mind/Body Techniques to Cope with the Stress of Survivorship." Workshop speakers include Richard Dickens of CancerCare, Dr. Lorenzo Cohen of the University of Texas MD Anderson Cancer Center, and Dr. David Spiegel of Stanford University School of Medicine.

Participants can listen online or by telephone. To register, visit the CancerCare website.

The remaining three workshops will be held from 1:30 to 2:30 p.m. ET on the following dates:

These workshops are presented by CancerCare, in collaboration with NCI, LIVESTRONG, the American Cancer Society, the Intercultural Cancer Council, Living Beyond Breast Cancer, and the National Coalition for Cancer Survivorship.

Public Comment Sought on Draft Statement on Ovarian Cancer Screening

The U.S. Preventive Services Task Force (USPSTF) issued a draft statement reaffirming its recommendation against routine screening for ovarian cancer in women who are at average risk of the disease. The draft Reaffirmation Recommendation Statement is available for comment until May 8 at 5:00 p.m. ET.

Based on an evidence review published April 10, the USPSTF concluded that routine screening with transvaginal ultrasound and testing for the serum tumor marker CA-125 does not help to reduce deaths from ovarian cancer. "There is at least moderate certainty that the harms of screening for ovarian cancer outweigh the benefits," the draft states.

Instructions on how to submit comments are available online.

See also: "Ovarian Cancer Screening Method Fails to Reduce Deaths from the Disease"

Apply to Visiting Scholars Program at Frederick National Laboratory by May 11

The Frederick National Laboratory for Cancer Research, until recently known as NCI-Frederick, is accepting applications to its new Visiting Scholars Program. The program is a unique opportunity for researchers to work on important cancer and AIDS projects with teams of scientists at the only national laboratory in the United States devoted exclusively to biomedical research.

In 2012, visiting scholars will have the opportunity to work on challenges related to affinity reagents, proteomics, advanced preclinical research, and virus genomics. Applicants may also propose their own research focus that supports the Frederick National Laboratory's mission, research programs, and capabilities.

Program coordinators invite early career and established investigators within or outside the cancer research community to submit an Expression of Interest form by May 11. More information about eligibility and how to apply is available online

Applications for Oncology Fellowships Due May 31

IOTF tile

The Interagency Oncology Task Force (IOTF), a joint initiative between NCI and the Food and Drug Administration (FDA), recently announced fellowship training opportunities for Ph.D.s, M.D.s, and M.D./Ph.D.s (or their equivalents).  

The IOTF Joint Fellowship Program trains scientists in cancer research and research-related regulatory review to develop skills needed to bridge the two distinct processes. Fellows will learn to build awareness of regulatory requirements into the early stages of medical product development and will devise strategies to improve planning throughout the research and regulatory review phases.

"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 the 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.

Fellowships are available in Oncology Product Research/Review. Applications are due May 31 for fellowships that begin in September 2012. More information about the fellowships and eligibility requirements is available online .

NCI Requests Targets for Monoclonal Antibody Production and Characterization

The Antibody Characterization Program in NCI's Office of Cancer Clinical Proteomics Research provides researchers with reagents and other critical resources that support protein/peptide measurements and analysis. In an effort to provide well-characterized monoclonal antibodies to the scientific community, the program requests cancer-related protein targets for affinity production and distribution. Submissions will be accepted through July 9.

Submissions will be reviewed and considered for merit based on their justification and contribution to existing NCI-funded projects. Priority will be given to projects that apply the antibodies to proteomics research.

Successful applicants can expect to be notified on or before August 30. All materials (such as proteins/peptides) must be ready and available when a target is submitted. For more information and the application form, please go to NCI's Antibodies Data Portal.

Please address questions to Dr. Tara Hiltke at hiltket@mail.nih.gov or 301-451-8511.