National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
June 12, 2012 • Volume 9 / Number 12


Study Finds Small Increase in Cancer Risk after Childhood CT Scans

Young patient having a CT scan. A new study shows that radiation exposure from computed tomography (CT) scans in childhood results in very small but increased risks of leukemia and brain tumors in the first decade after exposure. The study, led by researchers from NCI and Newcastle University, is the first analysis of CT scans that looked at exposed patients directly instead of using models based on atomic bomb survivors or other populations accidentally exposed to large doses of radiation. Read more > >


Dr. Patricia Steeg A Conversation with Dr. Patricia Steeg on Redesigning Clinical Trials to Test Therapies that Could Prevent Cancer Metastasis

The head of the Women's Cancers Section in NCI's Laboratory of Molecular Pharmacology argues that the current system for clinical trials must be redesigned if there is to be a decline in breast cancer metastasis.



  • FDA Update

    • Pertuzumab Approved to Treat Some Metastatic Breast Cancers
  • Update

    • Cancer Control P.L.A.N.E.T. Portal Gets New Look
  • Notes

    • NCI's Barnett Kramer Named ASCO Fellow
    • NCI Advisory Boards, Director's Consumer Liaison Group to Meet End of June
    • Free Workshop for Cancer Survivors: Changing Roles and Responsibilities of Caregivers
    • Workshop to Focus on Integrating the "Omics" into Biology, Clinical Care
    • NCI's Tom Misteli Wins Flemming Award

Selected articles from past issues of the NCI Cancer Bulletin are available in Spanish.

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Featured Article

Study Finds Small Increase in Cancer Risk after Childhood CT Scans

Young patient having a CT scan. Although computed tomography is an important diagnostic technique, it should be performed only when necessary and with the lowest dose of radiation possible.

A new study shows that radiation exposure from computed tomography (CT) scans in childhood results in very small but increased risks of leukemia and brain tumors in the first decade after exposure. The study, led by researchers from NCI and Newcastle University in the United Kingdom, is the first analysis of CT scans that looked directly at exposed patients instead of using models based on atomic bomb survivors or other populations accidentally exposed to large doses of radiation.

The findings were published June 6 in The Lancet.

CT scans remain an invaluable diagnostic technique, and the absolute risks are small, the study authors emphasized. "If providing a CT scan is clinically justified, and performed using the appropriate dose, the benefits from the scan should far outweigh any of these small cancer risks," said Dr. Amy Berrington de González, a senior investigator in NCI's Radiation Epidemiology Branch and senior author of the new cohort study.

For the study, researchers led by Dr. Mark Pearce of Newcastle University's Institute of Health and Society used data collected between 1985 and 2002 from more than 175,000 patients in the United Kingdom who had at least one CT scan before the age of 22. The researchers reviewed records from radiology departments of hospitals within the U.K. National Health Service and cross-referenced them with the National Health Service Central Registry, which provides information on cancer incidence and mortality.

If providing a CT scan is clinically justified, and performed using the appropriate dose, the benefits from the scan should far outweigh any of these small cancer risks.

—Dr. Amy Berrington de González

The researchers focused on leukemia and brain tumors because bone marrow and the brain are particularly sensitive to radiation. Children are also more sensitive to radiation than adults because of their rapidly dividing cells and growing bodies.

Because different types of CT scans (for example, CT scans of the head or abdomen) deliver different and nonuniform radiation doses to the organs of the body, the researchers assessed the risk of leukemia and brain tumors in relation to estimated doses absorbed by the bone marrow and brain for each type of CT scan.

Other factors can affect the estimated absorbed dose, including a patient's age and sex. The year the CT scan was performed can also affect the estimated absorbed dose, because the radiation doses used in CT have fallen since the procedure was introduced to the clinic in the 1980s.

Taking all of these factors into account, the analyses suggested that, using current CT scanner settings, the cumulative dose from two to three head CT scans could roughly triple the risk of brain cancer, and the cumulative dose from five to ten head CT scans before the age of 15 could roughly triple the risk of leukemia.

FDA Proposes New Guidelines for Pediatric Imaging Devices

The Food and Drug Administration (FDA) is seeking public comment on a draft proposal encouraging manufacturers to consider the safety of children in the design of new x-ray imaging devices, which include CT scanners. The FDA will also host a public workshop on July 16 to bring together industry representatives, physicians, radiologic technologists, physicists, and patient advocates to discuss the draft guidance.

The researchers concluded that although these risks may seem large, the absolute risks remain very small: about one extra case of leukemia and one extra brain tumor would occur for every 10,000 head CT scans during the first decade after exposure, according to the estimates.

"This is a large public health problem but a very, very small individual problem," commented Dr. Thomas Slovis, editor of the journal Pediatric Radiology and chief of radiology at Children's Hospital of Michigan, who was not involved in the study. Though parents may worry about the potential harms to a child of radiation exposure, "there's [also] harm from not making a diagnosis," he explained. "If CT is the best test for an indication, it absolutely should be done.

"It's only when the use is inappropriate or unnecessary that there is a risk without benefit," he added. Over the last 10 years, the medical community has been reducing the unnecessary use of medical radiation in children and tailoring imaging protocols to require the absolute minimum amount of radiation possible, continued Dr. Slovis. 

One of the largest educational and advocacy efforts, the Alliance for Radiation Safety in Pediatric Imaging's Image Gently campaign, now has 70 medical organizations participating, explained Dr. Donald Frush, a member of the alliance's steering committee and professor of radiology and pediatrics at Duke University.

Whether they work directly in imaging or not, "people are much more aware of the issue of radiation dose now than they were 10 years ago," Dr. Frush said. "We're beginning to have a much greater and more enduring impact on our technologists and trainees—our residents and our fellows—about this as well."

This is a large public health problem but a very, very small individual problem.

—Dr. Thomas Slovis

In addition to education, he added, significant improvements in the CT machines and in scanning protocols have allowed for reductions in the radiation dose required for a scan.

Medical experts are working to ensure that CT is used only when it is the best test to answer a given clinical question—and to understand when tests that don't require radiation may be a better choice. For example, the recent Choosing Wisely campaign, led by the American Board of Internal Medicine Foundation, included a recommendation to consider ultrasound before CT to diagnose appendicitis in children.

"If you do an unnecessary CT examination," said Dr. Frush, "it's an unjustifiable radiation exposure."

Sharon Reynolds

Further reading: "The Downside of Diagnostic Imaging"

More information: Computed Tomography (CT): Questions and Answers and Radiation Risks and Pediatric CT: A Guide for Health Care Providers

Cancer Research Highlights

For Some Breast Cancers, New Drug May Be Treatment Option

Results from an international clinical trial suggest that women with metastatic, HER2-positive breast cancer that is no longer responding to the targeted therapy trastuzumab (Herceptin) may soon have a new treatment option.
Women who received the investigational drug trastuzumab emtansine (T-DM1) lived more than 3 months longer without their tumors progressing than women who received the chemotherapy drug capecitabine (Xeloda) and the targeted drug lapatinib (Tykerb). With one exception, T-DM1 also had far fewer serious side effects than the capecitabine-lapatinib combination, the trial’s leaders reported last week at the American Society of Clinical Oncology annual meeting.

 “T-DM1 should offer an important therapeutic option in the treatment of HER2-positive breast cancer,” said the study’s lead investigator, Dr. Kimberly Blackwell of the Duke Cancer Institute at Duke University.

The drug’s manufacturer, Genentech, stated it will seek approval from the Food and Drug Administration this year for use of T-DM1 in women with metastatic breast cancer.

T-DM1 is an antibody-drug conjugate composed of the monoclonal antibody trastuzumab, which targets the HER2 receptor on breast cancer cells, chemically linked to the chemotherapy drug DM1.

The median progression-free survival in women treated with T-DM1 was 9.6 months, compared with 6.4 months in women treated with capecitabine and lapatinib, Dr. Blackwell reported. The results were based on an interim analysis of the trial’s data. Overall survival was similar in the two treatment groups, but at the time of the analysis there was a statistical trend toward improved overall survival, with more than 65 percent of patients in the T-DM1 treatment group still alive after 2 years compared with more than 47 percent of patients in the capecitabine-lapatinib control group.

Although more women taking T-DM1 had a potentially dangerous drop in platelet levels (thrombocytopenia), other side effects such as vomiting, diarrhea, and hand-foot syndrome were much more likely in women in the control group. The thrombocytopenia was effectively managed with dose reductions, Dr. Blackwell noted, and more women in the control group had to have their dose reduced because of side effects.

“T-DM1 really works in this population,” said Dr. Louis Weiner of the Georgetown Lombardi Comprehensive Cancer Center during the plenary session. Additional research is needed to better understand how best to use it in combination with other available treatments, Dr. Weiner continued.

Preoperative Chemotherapy, Radiation Improve Survival in Esophageal Cancer

Patients with esophageal cancer who received chemotherapy and radiation before surgery survived, on average, nearly twice as long as patients treated with surgery alone. The findings, from a large randomized trial of neoadjuvant chemoradiotherapy for the disease, were published May 31 in the New England Journal of Medicine.

Patients treated with carboplatin and paclitaxel chemotherapy plus radiation prior to surgery had a median overall survival of nearly 50 months, compared with 24 months for patients treated with surgery alone.

Dr. Pieter van Hagen of Erasmus University Medical Center and his colleagues enrolled 368 patients who had cancer of the esophagus or of the junction between the stomach and the esophagus that had not spread to other organs. Trial participants were mostly men, and the median age was 60. Patients benefited from preoperative therapy regardless of whether they had adenocarcinoma, the most prevalent form of esophageal cancer in the United States, or squamous cell carcinoma, the most prevalent form of the disease worldwide.

Previous trials to test the superiority of preoperative chemotherapy and radiation in esophageal cancer failed to enroll enough patients to reach definitive conclusions. “The successful completion of this trial is an impressive effort, and the results should be considered high-level evidence in favor of this preoperative regimen,” commented Dr. Jack Welch, head of gastrointestinal therapeutics for NCI’s Cancer Therapy Evaluation Program, who was not involved in the study.

Patients randomly assigned to the chemoradiotherapy arm of the study received five courses of chemotherapy with carboplatin and paclitaxel plus concurrent external-beam radiation therapy, followed by surgery, usually within 4 to 6 weeks of completing preoperative treatment. This preoperative regimen has been widely adopted in the United States within the past year and has also been adopted as a standard therapy in some trials being conducted by NCI-supported cooperative groups, Dr. Welch said. For example, a phase III trial is testing a combination of neoadjuvant chemoradiotherapy with the targeted agent trastuzumab in patients whose tumors express the HER2 biomarker, explained Dr. Welch.

In another study, patients initially treated with chemotherapy based either on the Dutch study regimen or an alternative regimen are being assessed with PET scans; those who do not respond are switched to the other therapy, which is then combined with radiation. In both studies, researchers are trying to tailor the chemoradiation regimen used in Dr. van Hagen’s study to obtain the best possible result for individual patients, Dr. Welch said.

For Some Skin Cancers, Targeted Drug Hits the Mark

In January, the Food and Drug Administration approved a drug called vismodegib (Erivedge) for treating advanced cases of basal cell carcinoma (BCC). The vast majority of BCCs, the most common form of skin cancer, can be treated surgically, but patients with locally advanced or metastatic disease have had no effective treatments until this year.

Final results from the trial that led to the approval of vismodegib appeared in the New England Journal of Medicine on June 7. A companion report describes how vismodegib, which is taken as a pill, prevented and shrank tumors in people with basal cell nevus syndrome (BCNS), an inherited condition that can cause a person to develop hundreds to thousands of BCCs.

“It is a landmark day for patients with basal cell carcinoma and all those involved in their care—the greatest advance in therapy yet seen for this disease,” noted Dr. John T. Lear of University of Manchester in an accompanying editorial. But continuous administration of the drug can cause “considerable and frequent” side effects, including muscle cramps, hair loss, and loss of the sense of taste. 

These side effects led some patients to stop taking the drug, he noted. One-quarter of the patients experienced serious adverse events, and seven died. "The relationship between the study drug and the deaths is unknown," the researchers wrote.

Modified dosing schedules may limit the side effects and are being investigated, noted Dr. Aleksandar Sekulic of the Mayo Clinic, who led the BCC study. In the phase II trial, 30 percent of patients with metastatic disease had a partial response, and 43 percent of patients with locally advanced disease had a complete or partial response. The study included 104 patients.

The BCNS study was a randomized trial involving 41 patients. Patients who received vismodegib developed, on average, two new BCCs that warranted surgery per year, compared with 29 new BCCs among those who received a placebo. However, more than half of the patients taking vismodegib discontinued treatment because of side effects. Once patients stopped taking the drug, tumors began to slowly reappear.

“We still feel that this medicine is a life-changing therapy for these patients,” said Dr. Jean Tang of Stanford University, the first author of the study. “But patients cannot take the drug every day.” Her team has initiated a second trial to investigate the best way to give the drug.

The drug is designed to block signals that drive the growth of cancer cells though the Hedgehog signaling pathway. This pathway is silent in adult tissues, except in certain parts of the body, such as hair follicles. By shutting down the pathway in normal cells, the drug may cause hair loss and other side effects.

Although unpleasant, the side effects are an indication that the drug is hitting its target, noted Dr. Sekulic. These studies are “an important step forward,” he continued, adding that “the vast majority of BCCs can be prevented with good sun protection.”

Further reading: “For People with Rare Skin Cancer Syndrome, Drug Brings Relief and Hope” and “Drug to Treat Basal Cell Skin Cancer Approved after Priority Review

Study Suggests New Treatment Option for Some Lymphomas

Updated findings from a large European clinical trial indicate that patients with some types of lymphoma could initially be treated with the chemotherapy drug bendamustine (Treanda) and the targeted agent rituximab (Rituxan). The majority of patients in the trial had follicular lymphoma, and the remainder had either mantle cell or indolent (slow-growing) lymphoma.

Findings from the trial, which involved 514 newly diagnosed patients, were reported last week by lead investigator Dr. Mathias J. Rummel of the University Hospital Giessen in Germany at the American Society of Clinical Oncology annual meeting.

After a median follow-up of nearly 4 years, patients who received the two-drug combination lived more than twice as long without their disease progressing (69.5 months versus 31.2 months) as patients who received the standard first-line treatment, rituximab and a chemotherapy regimen called CHOP, or R-CHOP.

Despite the improvement in progression-free survival in patients treated with bendamustine and rituximab, overall survival did not differ between the two patient groups. As a result, some researchers may hesitate to promote the drug combination as the new standard of care for all patients with these lymphomas, according to Dr. Wyndham Wilson, head of the Lymphoma Therapeutics Section in NCI’s Center for Cancer Research, who was not involved in the study.

Although there was a higher incidence of mild skin reactions in patients who received bendamustine and rituximab, other major side effects were far less common, including neuropathy and the dangerous drops in white blood cell count known as neutropenia. Only 4 percent of patients who received bendamustine and rituximab required treatment with granulocyte colony-stimulating factor to counter neutropenia compared with 20 percent of patients who received R-CHOP.

Dr. Rummel cited several reasons why the bendamustine-containing combination did not lead to improved overall survival: First, almost half of the patients whose cancer progressed after R-CHOP crossed over to treatment with bendamustine and rituximab. Second, these types of lymphoma grow slowly and tend to have better long-term survival, so patients would need to be followed for a longer time before a difference in overall survival might be seen.

Bendamustine, which was developed in Germany and has been used in Europe for decades to treat blood cancers, is approved in the United States for the treatment of indolent lymphoma, but only for cancers that have progressed following treatment with a regimen that includes rituximab. Bendamustine is also approved for the treatment of chronic lymphocytic leukemia.

Study Shows First Effective Drug for Cancer Patients with Peripheral Neuropathy

Results of a phase III trial (CALGB-170601) show that duloxetine (Cymbalta) effectively treats painful peripheral neuropathy caused by certain types of chemotherapy. The results, from the first randomized clinical trial to show an effective treatment for chemotherapy-induced peripheral neuropathy (CIPN), were presented last week at the American Society of Clinical Oncology annual meeting.

CIPN causes chronic pain, tingling, and numbness—mainly in the hands and feet—that can interfere with a patient’s ability to perform everyday activities and to receive needed doses of chemotherapy. CIPN affects 20 to 30 percent of cancer patients treated with taxane and platinum-based chemotherapy drugs, which can damage nerve cells. CIPN may continue for months or even years after treatment is stopped and may worsen over time.

Dr. Ellen Lavoie Smith of the University of Michigan and her colleagues studied 181 people 18 years old or older who had previously reported high levels of pain from peripheral neuropathy caused by prior treatment with paclitaxel or oxaliplatin. They found that almost 60 percent of patients taking daily duloxetine for 6 weeks reported a decrease in pain, compared with nearly 40 percent of patients taking a placebo. Pain levels increased in 11 percent of duloxetine-treated patients and in 28 percent of those who took the placebo.

The most commonly reported side effect was fatigue, which was significantly higher in patients taking duloxetine than in patients taking the placebo.

“This study is the first to demonstrate statistically significant improvements in established neuropathic pain compared to placebo,” said Dr. Joanna Brell of NCI’s Division of Cancer Prevention. “While duloxetine is approved by the Food and Drug Administration for painful neuropathy caused by diabetes, there are no such treatments for CIPN.” Duloxetine is also approved to treat depression.

Also in the News: Even Low Doses of Radiation in Childhood May Raise Breast Cancer Risk

More childhood cancer survivors who received radiation to the chest as part of cancer treatment may be at risk of breast cancer later in life than previously thought, according to data presented at the American Society of Clinical Oncology annual meeting.

Dr. Chaya Moskowitz of Memorial Sloan-Kettering Cancer Center presented data from more than 1,200 women participating in the Childhood Cancer Survivor Study who received radiation to the chest as children, adolescents, or young adults. She and her colleagues found that nearly one-quarter of the women who received 20 gray (Gy), a unit of absorbed dose, of radiation or more developed breast cancer by age 50, with about half of those developing the disease before age 40. In addition, 7 percent of women who received lower doses of radiation—10 to 19 Gy—developed breast cancer by the age of 40. In contrast, a 20-year-old woman in the general population has a less than 2 percent chance of developing breast cancer by age 50.

Current guidelines for childhood cancer survivors generally recommend early screening—with breast MRI— only for patients who received 20 Gy of radiation or more; the guidelines do not recommend earlier screening for women who received lower doses.

Also in the Journals: Global Cancer Burden Expected to Shift 

Researchers from the International Agency for Research on Cancer (IARC) estimate that 16 percent, or around 2 million, of the 12.7 million new cancer cases diagnosed in 2008 were caused by infectious agents (viruses, bacteria, and parasites). Existing public health efforts to prevent infection “could have a substantial effect on the future burden of cancer worldwide,” the authors concluded. Their analysis was published May 9 in Lancet Oncology.

A second study suggests that “any reductions in infection-related cancers will be offset by an increasing number of new cases that are more associated with reproductive, dietary, and hormonal factors,” including breast, colorectal, and prostate cancers. Using a variety of data on cancer patterns and health and economic measures, the researchers calculated that in 2030 there would be 22.2 million new cases of cancer, up 75 percent from 2008. Their findings were published June 1 in Lancet Oncology.

For more information about global cancer research, visit NCI’s Center for Global Health.

A Conversation With

A Conversation with Dr. Patricia Steeg on Redesigning Clinical Trials to Test Therapies that Could Prevent Cancer Metastasis

Dr. Patricia SteegDr. Patricia Steeg
In a perspective published May 30 in Nature, Dr. Patricia Steeg argues that the current system for clinical trials must be redesigned if there is to be a decline in breast cancer metastasis, which is the leading cause of death from the disease. Dr. Steeg, who heads the Women's Cancers Section in NCI's Laboratory of Molecular Pharmacology, recently spoke with the NCI Cancer Bulletin about the challenges in developing treatments that prevent metastasis and her proposal for a new clinical trial design to test such therapies.

How big a problem is metastatic breast cancer, and would your proposal apply to other cancers besides breast cancer?

This year, nearly 40,000 women will die of breast cancer, and metastatic disease is the largest contributor to these deaths. Although the annual number of breast cancer deaths is declining, it's not declining by much.

The proposal I've put forth should apply to a number of different cancers, particularly those where the majority of patients are diagnosed before they have full-blown metastatic disease, or if they have limited, treatable metastatic disease. One could imagine applying this to prostate, bladder, and colon cancers.

Why is treating metastatic cancer so challenging? Are there any effective, approved treatments?

First off, metastasis research is tough to do. There is no in vitro, or lab bench, model for metastasis, so you have to use animals and the experiments are long and complex. Most of our animal model data show that we can prevent the formation of metastases. Taking those preclinical findings and validating them in a clinical trial is, currently, just about impossible.

We have a few adjuvant treatments in breast cancer that can partially prevent metastasis when given early after the initial surgery and radiation therapy. These include cytotoxic chemotherapies, which kill cells; estrogen receptor antagonists; and some molecularly targeted therapies, like the HER2 inhibitor trastuzumab [Herceptin]. 

But nothing cures in the metastatic setting, and up to 30 percent of women with early breast cancer will suffer distant recurrence and ultimately die of their disease, so there's a lot of room for improvement.

How do cancer metastases differ biologically from the original tumor?

When you compare metastases to the patient's primary tumor, many gene and protein expression patterns can be the same, but others differ. In addition, there are more mutations in a metastatic tumor than in the primary tumor, and one metastasis may have mutations that another metastasis in the same patient does not. So, our old approach of just looking at the patient's primary tumor may not give us all of the information, or the best information, that we need for "precision medicine," or personalized medicine.

What makes current clinical trials poorly designed to test drugs that could prevent metastasis?

My lab and others have identified a number of compounds that will prevent the formation of metastases in mice. These compounds are not inherently cytotoxic—they don't kill tumor cells. Nor were they designed to be synergistic with traditional chemotherapy drugs. But those are the two criteria by which most compounds [are judged] in clinical trials.

Phase I and phase II clinical trials are done in patients with advanced, refractory metastatic cancer—patients who have had many therapies, and these therapies have failed them. In the phase II trials, we ask, does the drug shrink the metastases? And then, if it does, the compound will keep progressing through the clinical trial process, and it will be tested against the current standard of care in a phase III trial to see if it will produce responses in patients with metastatic disease.

But a drug that prevents metastasis may not shrink a large, refractory metastatic tumor. It has a different mechanism of action that is not being picked up by the clinical trial system. That is why I've proposed that we take a detour in that path of clinical trials, either before or just after phase II trials, to do what I call phase II randomized metastasis-prevention trials.

How should such trials be designed?

After we see that a drug is safe, we have a hint of activity, and we know that it can be combined with the standard of care, let's try looking for metastasis prevention. Let's take patients who either have no detectable metastases but are at high risk of disease progression, or patients who have a limited numbers of metastases and have been treated with standard therapy. Those patients would receive the standard of care and be randomly assigned to receive the placebo or the potential metastasis preventive in a clinical trial.

For patients who don't have metastases, the most important endpoint would be time to development of the first metastasis. For patients who do have metastases and have been treated, the endpoint would be time to development of a new metastasis. I think that this would give these drugs a fair chance to show metastasis-preventive activity. If the endpoint is only shrinkage of an existing, bulky metastatic lesion, these drugs are going to fail.

What will it take to change the process and implement your proposal?

This is doable; it's just going to take collaboration. Part of the reason I wrote this perspective is to get a conversation going. Oncologists are going to have to work closely with the molecular biologists, who can tell them what compounds to test and in what circumstances. And they're going to have to work very closely with the FDA [Food and Drug Administration] and get guidance on the appropriate trial design. Then they're going to have to work closely with patients and advocates, so that patients understand that this is a new paradigm—it's untested but it holds promise—and will work with us to get these trials moving.

Beyond publishing the perspective in Nature, how are you working with others to implement these ideas?

I'm part of an ad hoc group of government and academic researchers who have been meeting monthly to discuss new trial designs, new approaches, and new drugs for brain metastases of breast cancer. I've heard many of the concepts that I've laid out in this editorial in these conversations.

It's extraordinarily productive when preclinical molecular biologists can get feedback from a wide variety of clinicians. [That feedback] shapes our work when we go back to the bench and design the next experiment. The clinicians hear about our mouse results and take them with the appropriate grain of salt, but seriously consider them. And we have to do our mouse experiments in a way that can be translated into a clinical trial. It's a valuable two-way conversation.

For this proposal to spread and be accepted, the FDA is going to have to issue some guidance. I don't think a drug company is going to spend money, or that clinicians are going to risk part of their careers, to bring something forward until there is a path to approval.

Here sits the preclinical research that says drug X and drug Y will meaningfully prevent metastasis. But these drugs are failing in the clinical trial system, and they are never getting to the patient in the appropriate setting. [As a result], the drug company loses the investment in drug development, the research scientist loses a clinical hypothesis, and the patients continue to lose their lives.

Interviewed by Elia Ben-Ari

FDA Issues Draft Guidance to Speed Approval of Drugs for Aggressive, Early-Stage Breast Cancer

On May 21, the Food and Drug Administration (FDA) released draft guidance aimed at speeding the approval of drugs that could prevent breast cancer recurrence when given early in the course of disease, before surgery. Dr. Richard Pazdur of the FDA and Dr. Tatiana Prowell of Johns Hopkins University and the FDA commented on the proposed guidelines in the May 30 New England Journal of Medicine.

The draft guidance proposes that new drugs be tested before lumpectomy or mastectomy in patients who have a high risk of distant disease recurrence and death with existing therapies. These clinical trials would use pathologic complete response—the absence of signs of residual disease in biopsied lymph nodes or breast tissue—as their primary endpoint. Following accelerated approval, researchers would have to demonstrate an improvement in disease-free survival or overall survival for a drug to retain FDA approval.

The draft guidance is open for written comments and suggestions until July 30.

Special Report

Expanding the Playing Field: Immune-Based Therapy Shows Potential for Lung, Other Cancers

Results from two early-phase clinical trials presented last week at the American Society of Clinical Oncology annual meeting provide further evidence that priming the immune system to attack tumors has potential as a treatment for certain cancers. The findings were also published June 2 in the New England Journal of Medicine (NEJM, here and here).

The promise of immunotherapy is something that actually cuts across some of those boundaries and may change every single treatment paradigm that we're currently developing.

—Dr. Ross Camidge

Although preliminary, the results are notable because, in both trials, the treatments produced substantial tumor shrinkage in some patients with non-small cell lung cancer, which has been extremely resistant to immune-based therapies thus far, the trial leaders explained. And in many of these patients, the tumor responses were maintained for a year or more.

"I think it's one of the most exciting things I've seen in recent years," said Dr. D. Ross Camidge, a lung cancer researcher at the University of Colorado Denver, who was not involved in either study. "A lot of the progress we've made recently has been about identifying molecular subtypes of lung cancer and having very specific targeted treatments. The promise of immunotherapy is something that actually cuts across some of those boundaries and may change every single treatment paradigm that we're currently developing."

Both studies tested investigational drugs that target molecules known as "checkpoint" molecules, which help restrain immune responses so they don't harm the body. Tumors can co-opt these checkpoint molecules, weakening the immune system's ability to eradicate the tumors.

Tumor shrinkage was also seen in patients with melanoma and kidney cancer. Previous studies have shown that these cancers can respond to immunotherapy, and the Food and Drug Administration (FDA) has approved immunotherapies for patients with these tumors. In addition, one of 17 patients with ovarian cancer who received one of the investigational drugs also had a tumor response.

Unleashing the Immune Response

The two drugs tested in the trials are monoclonal antibodies, one of which targets a receptor protein known as PD-1 on the surface of activated T cells. The other drug targets a binding partner (ligand) of PD-1, called PD-L1, which is expressed at higher than normal levels on many tumors and on cells in the tumor microenvironment in response to inflammatory stimuli.

Both agents are being developed by Bristol-Myers Squibb, which was the primary funder of both trials.

Last year the FDA approved the first checkpoint molecule inhibitor, ipilimumab (Yervoy) to treat advanced melanoma. Ipilimumab, however, targets a different checkpoint molecule, CTLA-4, on the surface of activated T cells.

Patients in the trials also had stomach, breast, colorectal, castration-resistant prostate, or pancreatic tumors that grew despite multiple prior treatments. Nearly 300 patients were enrolled in the trial testing the PD-1 targeted agent, and slightly more than 200 were enrolled in the trial testing the PD-L1 targeted agent. Both trials tested escalating doses of the drugs, starting with a low dose. If no significant side effects were seen, the researchers incrementally increased the doses for patients who enrolled later.

The results are intriguing not only because of the number of the responses but also because of their durability, noted Dr. Suzanne Topalian of the Johns Hopkins University School of Medicine, who led the trial testing the PD-1 targeted agent. Among 31 patients who responded to the PD-1 targeted agent and were followed for at least one year, 20 had responses that persisted for at least a year.

Patient Response Rates by Cancer Type

 Anti-PD-1 TrialAnti-PD-L1 Trial
Melanoma26 of 94 patients9 of 52 patients
Kidney9 of 332 of 17
Lung14 of 765 of 49
Ovariann/a1 of 17

The most common side effects of treatment included fatigue, rash, and diarrhea. Other less-common side effects, such as fever, were consistent with the activation of the immune system. Five percent of patients in the trial targeting PD-1, and 6 percent in the trial targeting PD-L1 trial, stopped receiving treatment because of severe side effects, and three patients who received the PD-1 targeted drug died of uncontrolled lung inflammation, called pneumonitis, caused by the treatment.

"The pneumonitis is a safety concern," said Dr. Camidge. And finding a method to predict which patients are most likely to benefit from these agents will be essential to justify both the risks and expected costs of any licensed immune therapy, he added.

In an attempt to address this issue, Dr. Topalian and her colleagues examined tumor samples collected before treatment from a subset of patients in the anti-PD-1 trial. They found that about one-third of the patients whose tumors expressed PD-L1 had measurable tumor responses, whereas no responses were observed in patients whose tumors did not express the protein. Much more work is needed, she stressed, before PD-L1 could be considered a predictive biomarker of response to treatment.

An Important Pathway

The trials' impact on immunotherapy research could be substantial, suggested Dr. Antoni Ribas, of UCLA's Jonsson Comprehensive Cancer Center, in an accompanying editorial in NEJM.

"These initial observations suggest that antibodies blocking PD-1 and PD-L1 are likely to provide a new benchmark for antitumor activity in immunotherapy," Dr. Ribas wrote.

An illustration showing how inhibiting the activity of PD-1 and PD-L1 can unleash the immune system to attack tumor cells. Image courtesy of the New England Journal of Medicine ©2012 Like CTLA-4, the target of the recently approved immunotherapy drug for melanoma, PD-1 and PD-L1 are part of an important molecular pathway that serve primarily to keep immune responses in check. Inhibiting the activity of these molecules can unleash the immune system to attack tumor cells. Image courtesy of the New England Journal of Medicine ©2012

Additional phase II trials of the PD-1 targeted agent are under way, and phase III trials involving patients with melanoma, non-small cell lung cancer, and kidney cancer are being planned. PD-1 pathway targeted agents are also top priority agents for clinical trials that will be conducted by researchers in NCI's Immunotherapy Clinical Trials Network.

"We've come to this point where we really understand the importance of these inhibitory pathways, which are holding the immune system back from recognizing cancer," said Dr. Topalian. "By blocking these pathways, we can then drive the immune system to recognize and destroy cancer cells.

"We feel that these findings, in addition to the findings reported in the past 2 years with ipilimumab, have established immunotherapy as a treatment for cancer," she added.

Carmen Phillips and Jennifer Crawford

Featured Clinical Trial

Adjuvant Everolimus for Resected Kidney Cancer

Name of the Trial
Phase III Randomized Study of Everolimus versus Placebo in Patients with Renal Cell Carcinoma Who Have Undergone Nephrectomy or Partial Nephrectomy (SWOG-S0931). See the protocol summary.

Dr. Christopher RyanDr. Christopher Ryan

Principal Investigator
Dr. Christopher Ryan, Southwest Oncology Group

Why This Trial Is Important
Renal cell carcinoma is the most common type of kidney cancer diagnosed in adults. People diagnosed with localized renal cell carcinoma are usually treated with surgery to remove the affected kidney (nephrectomy) or just the portion of the affected kidney that contains the tumor (partial nephrectomy). For many patients, tumor resection leads to long-term survival and likely cure. However, about 30 percent of patients treated with potentially curative resection have their cancer recur and ultimately succumb to metastatic disease.

Current standard practice is to monitor patients for recurrence after nephrectomy but not to treat them with postsurgical, or adjuvant, therapy. Over the past several years, however, a number of new drugs and biological agents have helped delay disease progression, improve survival, or both in patients with advanced or metastatic renal cell carcinoma.

Everolimus (Afinitor) is a targeted drug that blocks the activity of a protein called mTOR, which normally helps control cell growth, proliferation, and survival. Alterations in the signaling pathway that includes mTOR are common in cancer. Research has shown that treatment with everolimus can block tumor cell proliferation and tumor angiogenesis, which is the growth of new blood vessels to a tumor.

In 2009, everolimus was approved by the Food and Drug Administration (FDA) to treat metastatic kidney cancer that has progressed after treatment with either sorafenib or sunitinib. The FDA approved those two targeted agents earlier for the treatment of unresectable or metastatic renal cell carcinoma. Now, doctors would like to know if these new targeted therapies will also be effective adjuvant treatments for patients with resected kidney cancer. Sorafenib and sunitinib are being compared in a phase III adjuvant study conducted by the Eastern Cooperative Oncology Group.   

In this clinical trial, patients who have undergone partial or complete nephrectomy will be randomly assigned to take everolimus tablets or matching placebo tablets daily for 54 weeks. Doctors will follow the patients for 10 years to determine recurrence-free survival and overall survival. They will also study tissue and blood samples to determine how everolimus affects certain molecular biomarkers important in the biology of renal cell carcinoma.

"Patients with resected kidney cancer continue to have a significant risk of recurrence, and for now, there are no effective adjuvant therapies available to them," said Dr. Ryan. "Recent studies have established mTOR inhibition as a clinically relevant strategy for advanced renal cancer, so there is a good rationale for studying its potential in the adjuvant setting.

"For patients to participate in this study, they must be able to start their assigned study treatment within 84 days of surgery, so it's critically important that urologists who are performing the surgeries on these patients are aware of the trial and refer patients within that timeframe," he explained.

For More Information
See the lists of entry criteria and trial contact information or call the NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The toll-free call is confidential.

An archive of "Featured Clinical Trial" columns is available at

Community Update

Charting a Course to Genome-Guided Cancer Medicine

"It is not difficult to foresee a time when a person's individual genome can be sequenced for as little as $100, putting genetic studies in the realm of a routine laboratory test."

—Drs. Vincent J. DeVita and Steven A. Rosenberg
"Two Hundred Years of Cancer Research," New England Journal of Medicine

If the cost of sequencing DNA continues to decline, patients with cancer could have their tumors profiled as part of routine care. But how this might actually work is far from clear.

To begin developing some answers, NCI's Cancer Diagnosis Program (CDP) held a workshop last month in Bethesda, MD. More than 200 participants shared their ideas about the challenges involved in trying to bring new DNA sequencing technologies into the clinic.

These tools, known as next-generation DNA sequencers, can decode a relatively large amount of DNA in a short period of time (days or weeks). Although the accuracy of these tools is still being assessed, the instruments are increasingly affordable for clinical labs.

"We know that next-generation sequencing will be used in the clinic," said co-organizer Dr. Barbara Conley, associate director of CDP. "So this workshop focused on the barriers to making this happen and how we could address them."

The meeting included experts on all aspects of cancer care—pathologists, oncologists, laboratory scientists, statisticians, bioinformaticians, and drug and device manufacturers. A representative from the Food and Drug Administration and patient advocates also gave presentations.

Clinically Meaningful Mutations
Next-generation sequencing is being used at some medical centers, and some private companies are exploring its potential as well. Genetic information can help diagnose a patient's cancer or match patients with drugs that target specific molecular changes within their tumors.

A theme of the meeting was the need for a database that doctors could use when making decisions about a patient's treatment. It would include "clinically actionable information," such as genetic markers that identify candidates for a particular treatment.

At the moment, however, no such database exists. This may be the most significant challenge for managing and reporting genetic information, noted Dr. Jane Gibson of the University of Central Florida College of Medicine.

Discussions are under way at NCI about how best to address the need for a repository, an NCI official noted at the meeting.

Every Genome Is Different

Even with the costs of DNA sequencing dropping, clinical labs have limited resources. Rather than sequencing genomes or exomes (the protein-coding regions of genes), clinical labs could begin by sequencing panels of genes associated with cancer, several participants said.

You want the Reader's Digest version of the results so that a clinician can make sense of them. But you also want the research behind those results.

—Stephen Lincoln

Tumor DNA would need to be sequenced about 500 times to achieve the sensitivity needed for clinical decision-making, noted Dr. Maureen Cronin, an industry consultant. In comparison, many published genomes have been sequenced about 30 times, but this is "barely sufficient for tumor DNA," she added.

"Every patient's genome is different," said Dr. Elaine Mardis, co-director of the Genome Institute at Washington University. "And, ultimately, one wants to know exactly what these differences are."

There was no clear agreement about what a complete molecular workup of a tumor would look like. But whatever form the report to clinicians takes, it would be important not to overwhelm them with sequencing data, a few participants said.

"You want the Reader's Digest version of the results so that a clinician can make sense of them," said Stephen Lincoln of Complete Genomics. "But you also want the research behind those results."

The role of the DNA sequencing and analysis team, Dr. Mardis noted, is to offer evidence to the oncologist. "We're not in a position to tell the oncologist what to do or to advocate one therapy over another," she said. "We're just trying to help out." 

Choosing a Technology

Participants at the meeting reported using various next-generation sequencing tools, or platforms. These technologies are updated frequently, which has made it impractical to establish technological standards for clinical DNA sequencing.

Another challenge participants mentioned was the fact that not all cells within a tumor contain the same mutations. Furthermore, different amounts of tumor may be required for analysis depending on the type of tumor and the experiment.

"The elephant in the room here is which platform has the right mix of simplicity, cost efficiency, and high-quality data," said Dr. John Iafrate of Massachusetts General Hospital.

Perhaps even more important than the platform, some participants noted, is the ability to make sense of all the data generated. "The centerpiece of any clinical next-generation sequencing program would be bioinformatics," Dr. Gibson stressed.

What the field needs are "tools that can allow us to digest and present the data to clinicians so that they can ask meaningful and intelligent questions," said Dr. John Quackenbush of the Dana-Farber Cancer Institute.

Dr. Mardis, who has written about the cost of data analysis, added: "I fear that too much is being made across the board about the cost of sequencing when, really, the impactful and expensive activity in all [of] this is the analysis of the data."

The centerpiece of any clinical next-generation sequencing program would be bioinformatics.

—Dr. Gibson

When DNA sequencing becomes routine has less to do with the cost of the technology than with the perceived value of the results to the community, some participants said.

"It's not the cost that's going to drive this, it's the value [to patients and clinicians]," said Dr. Richard Press of the Knight Cancer Institute at Oregon Health and Science University. And for clinical labs, coverage for services by insurers will be critical, he added.

"When our data are considered to be clinically useful, there won't be any more complaints about the cost," added Dr. Iafrate. He cautioned, however, that the current costs of sequencing can be tens of thousands of dollars, and insurance might not cover the expense.

"You're trying to help a patient," Dr. Iafrate went on. "But if you don't find anything actionable in the results, and the patient gets a bill for $5,000, that is a problem."

Sharing Is Important

A recurring question at the workshop was: What should the level of evidence be for reporting a mutation to a clinician? One person suggested that the field eventually will need to have information from tens of thousands of patients in a well-annotated database, as well as definitions of clinically actionable variants. 

Everyone seemed to agree that, whatever happens, it will be important to share data. Data sharing will be necessary in cases in which different doctors treat the same patient years apart, as well as to create the most informative, useful database.

"Everyone believes we have a powerful opportunity to bring these tools into the clinic," said co-organizer Dr. Mickey Williams, of the Molecular Characterization and Clinical Assay Development Laboratory at the NCI Frederick National Laboratory for Cancer Research. "But we want to make sure that it happens in a thoughtful way."

Edward R. Winstead

Breast Cancer Genomes and Treatment Decisions

A major challenge in clinical DNA sequencing is the detection of rare mutations that contribute to cancer. And, as new research suggests, identifying rare mutations that drive tumors can be important for making clinical decisions.

In one of the largest such studies to date, researchers at Washington University School of Medicine in St. Louis sequenced the genomes of 77 women with breast cancer. Each tumor genome had a unique collection of mutations that affected a variety of genes; only a handful of genes were mutated frequently, the researchers reported in Nature on June 10.

"What we learn from sequencing is that the combinations of mutations for each patient are different," said Dr. Elaine Mardis, the study's senior author. An analysis of the sequencing results and patient medical records showed that tumors with mutations in certain pathways tended to respond similarly to a class of drugs.

These results suggest that a comprehensive analysis of each patient's genome should be done so that all mutations are known before selecting a treatment, Dr. Mardis noted. The researchers are planning a new trial in which treatment decisions would be based on the genomic signatures of breast tumors.

FDA Update

Pertuzumab Approved to Treat Some Metastatic Breast Cancers

The Food and Drug Administration (FDA) has approved pertuzumab (Perjeta) to treat women with HER2-positive breast cancer that has spread to other parts of the body. Pertuzumab is approved for use in combination with trastuzumab (Herceptin), another anti-HER2 therapy, and the chemotherapy drug docetaxel (Taxotere) to treat women who have not received previous anti-HER2 therapy or chemotherapy.

Pertuzumab is a monoclonal antibody that is believed to work by targeting a different part of the HER protein than trastuzumab.

Production issues may affect the long-term supply of the drug, so the FDA has limited its approval to supplies that have not been affected by those issues. Genentech, the drug’s manufacturer, said that the company is committed to taking steps to resolve these production issues in a timely manner.

The approval was based on the results of a phase III clinical trial in which 808 women with HER2-positive metastatic breast cancer were randomly assigned to receive either pertuzumab, trastuzumab, and docetaxel or trastuzumab, docetaxel, and a placebo. The median progression-free survival of the women receiving pertuzumab was more than 6 months longer than those treated with the placebo (18.5 months versus 12.4 months).

The most common side effects observed in patients receiving the pertuzumab combination were diarrhea, hair loss, a decrease in infection-fighting white blood cells, nausea, fatigue, rash, and peripheral neuropathy.

The drug’s approval includes a Boxed Warning alerting patients and health care professionals to potential risks of birth defects and fetal death. Pregnancy status must be verified prior to the start of treatment.

The FDA approved pertuzumab under its priority review program, which provides for an expedited 6-month review of agents that may offer major advances in treatment. Update

Cancer Control P.L.A.N.E.T. Portal Gets New Look

Screenshot of the redesigned Cancer Control P.L.A.N.E.T. website

NCI has redesigned its Cancer Control P.L.A.N.E.T. web portal. The website—which provides information and tools for health professionals involved in cancer control—has a new look and feel, as well as a new topic area, more planning and evaluation resources, and additional intervention program criteria to help translate research into action.

The updated site is designed to make it easier for cancer control planners, program staff, and researchers to find the information and tools they need to design, implement, and evaluate evidence-based cancer control programs.

New features on the site include

  • Obesity Topics: Links to obesity resources, including statistics, programs, research synthesis, and planning tools;
  • RE-AIM: Resources for those wanting to apply the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework for evaluating health promotion and chronic disease programs; and
  • Research-Tested Intervention Programs (RTIPs): Obesity intervention programs and added RE-AIM scores.


NCI's Barnett Kramer Named ASCO Fellow

Dr. Barnett Kramer Dr. Barnett Kramer

Dr. Barnett Kramer, director of NCI's Division of Cancer Prevention, was made a Fellow of the American Society of Clinical Oncology (ASCO) at the group's annual meeting earlier this month. The award is given each year to honor ASCO's most active volunteers and to encourage others to volunteer. The award was previously called the ASCO Statesman Award.

Dr. Kramer chaired ASCO's Cancer Prevention Committee from 2006 to 2007 and served on ASCO's Health Services Committee. He has extensive experience in cancer treatment studies, primary prevention studies, and clinical screening trials of lung, ovarian, breast, and prostate cancers. He was a clinical professor in the department of medicine at the Uniformed Services University of the Health Sciences in Bethesda, MD, and was the chair of the NIH Continuing Medical Education Committee.

 Since 1994, he has served as editor-in-chief of the Journal of the National Cancer Institute. He also chairs the Physician Data Query (PDQ) Editorial Board on Screening and Prevention and is a member of the PDQ Treatment Editorial Board.

NCI Advisory Boards, Director's Consumer Liaison Group to Meet End of June

The National Cancer Advisory Board will meet June 25–26 in Bethesda, MD. The agenda will be posted shortly before the meeting, and an archived videocast will be posted a few days after the meeting. Videocasts of past meetings are available here.

Also meeting on June 25–26 is the Board of Scientific Advisors (BSA). The BSA provides scientific advice on scientific program policy, progress and the direction of NCI's extramural research programs, as well as concept review of NCI's extramural program initiatives. The agenda will be available shortly before the meeting and a videocast will be available online.

In addition to the board meetings, NCI's Director's Consumer Liaison Group (DCLG) will meet June 27–28 in Bethesda, MD. DCLG members provide informed, nonscientific perspectives to the NCI director on promoting research outcomes that are in the best interest of cancer patients.The agenda is available online, and the meeting is open to the public. Please register by e-mailing or by calling 301-435-7788.

Free Workshop for Cancer Survivors: Changing Roles and Responsibilities of Caregivers

Drs. Stewart Fleishman and Barbara Given Drs. Stewart Fleishman and Barbara Given

The tenth annual Cancer Survivorship Series, "Living With, Through, and Beyond Cancer," will hold the third of four workshops this year on June 19 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 III of the series, "Changing Roles and Responsibilities for Caregivers," will feature Suzanne Martz-Dones of Mount Sinai Hospital, Dr. Barbara A. Given of the Michigan State University College of Nursing, and Dr. Stewart B. Fleishman of Continuum Cancer Centers of New York: Beth Israel & St. Luke's-Roosevelt.

Participants can listen online or by telephone. To register, visit the workshop web page.

If you missed the first two workshops in the series, recordings are available online.

The final workshop in the series, "Managing Post-Treatment Neuropathy," will be held July 17 from 1:30 to 2:30 p.m. ET.

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.

Workshop to Focus on Integrating the "Omics" into Biology, Clinical Care

A workshop about the integration of different types of "omics" data in biology and medicine will take place June 19–20 on the NIH campus. The meeting will focus on integrating data from such fields as genomics, proteomics, and glycomics to better understand biological processes and improve clinical practice. Discussants will consider how best to use the myriad of data available from a single biological sample.

The workshop will be hosted jointly by the Proteomics Centers Program of the National Heart, Lung, and Blood Institute; NCI's Office of Cancer Clinical Proteomics Research; and the International Forum of Proteomics. It will be held 8:00 a.m. to 5:00 p.m. ET June 19 and 8:00 a.m. to 3:00 p.m. ET June 20 in the Building 60 Lecture Hall on the NIH campus. 

Registration for this free workshop is now closed, but the workshop will be videocast. Please e-mail Sonia Calcagno ( with questions.

NCI's Tom Misteli Wins Flemming Award

Dr. Tom Misteli Dr. Tom Misteli

Dr. Tom Misteli, a senior investigator in NCI's Laboratory of Receptor Biology and Gene Expression, received an Arthur S. Flemming Award on June 4.

For their exceptional contribution to the federal government, twelve recipients are honored annually by George Washington University and the Flemming Commission, in cooperation with the National Academy of Public Administration.

Dr. Misteli was selected for his work in cancer cell biology, including developing imaging methods to visualize the genome in living cells. This work has led to advances in the fundamental understanding of how genomes function, and it also has practical applications in biomedicine.

Dr. Misteli has used his methodologies to characterize molecular mechanisms involved in cancer progression, discover mechanisms of human aging, and invent a diagnostic strategy for detecting cancer.