National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
March 24, 2009 • Volume 6 / Number 6

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NEWS

Prostate-specific antigen is a substance produced by the prostate. It can be detected in the blood of adult men and may be found in higher levels in men who have prostate cancer and other prostate conditions.

No Definitive Answers from Initial Results of Prostate Screening Trials

Regular screening for prostate cancer with the prostate-specific antigen (PSA) test did not reduce deaths from the disease after 7 years of follow up, according to the long-awaited results from two large randomized trials, one conducted in the United States and the other in Europe. Read more > >

COMMENTARY

Director's Update: Making Connections between Stem Cells and Cancer

The striking similarities between stem cells in normal tissue that are responsible for continuously replacing adult tissues and a very small subset of cells found in growing tumors have sparked considerable interest in the research community. As a result, there is perhaps no better time for cancer biologists to draw on the considerable knowledge of our colleagues in embryology and developmental biology to explore questions about the initiation and progression of cancer—and potentially to understand how it develops resistance to therapies and how it metastasizes. Read more > >

A Conversation With...Dr. Jorge Gomez

The director of NCI's Office of Latin American Cancer Program Development discusses the office's plans and goals Read more > >

IN DEPTH

UPDATES

  • Notes

    • In Memoriam: Former NCI Director Dr. Carl Baker
    • CTCAE 4.0 Posted for Public Review
    • Free Telephone Workshop Series for Cancer Survivors
    • Registration Open for Neuropathic Cancer Pain Symposium
    • NCI Hosts International Art Exchange Exhibit
    • Robotic Surgery Featured in BenchMarks

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.

For more information about cancer, call 1-800-4-CANCER or visit http://www.cancer.gov.

NCI Cancer Bulletin staff can be reached at ncicancerbulletin@mail.nih.gov.

Featured Article

No Definitive Answers from Initial Results of Prostate Screening Trials

Prostate-specific antigen is a substance produced by the prostate. It can be detected in the blood of adult men and may be found in higher levels in men who have prostate cancer and other prostate conditions. Prostate-specific antigen is a substance produced by the prostate. It can be detected in the blood of adult men and may be found in higher levels in men who have prostate cancer and other prostate conditions.

Regular screening for prostate cancer with the prostate-specific antigen (PSA) test did not reduce deaths from the disease after 7 years of follow up, according to the long-awaited results from two large randomized trials, one conducted in the United States and the other in Europe.

After 9 years of follow up, however, the European trial found that PSA screening every few years did produce a small mortality benefit. The 10-year follow-up from the American trial is not yet complete, although investigators said the results to date are consistent with the 7-year follow-up data.

The findings, from the NCI-led Prostate, Lung, Colorectal and Ovarian (PLCO) Screening Trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial, were published online in the New England Journal of Medicine on March 18.

In both studies many more men were diagnosed with prostate cancer in the active screening arms than in the control groups, which PLCO leaders said confirms long-standing concerns that PSA screening often leads to “overdiagnosis” and overtreatment of cancers that would never have been life-threatening.

“There’s no question that there are men who are getting the side effects [of treatment] without getting any of the benefit,” said PLCO co-author Dr. Edward Gelmann of the Herbert Irving Comprehensive Cancer Center in New York, during a press briefing on the results.

The findings, he continued, support recommendations issued last August by the U.S. Preventive Services Task Force against routine PSA screening of men aged 75 and older, who are likely to have a life expectancy of less than 10 years. For younger men, he continued, the findings offer a good foundation for doctors and patients to make individualized decisions based on factors such as PSA results and the risks and benefits of biopsy and treatment.

The prostate component of the PLCO trial randomized nearly 77,000 men to annual screening with a PSA test for 6 years and digital rectal exam (DRE) for 4 years, or to the usual care of their physicians, which included PSA screening in more participants than the study leaders had expected. Mortality due to prostate cancer was uncommon and effectively the same in both groups at 7 and 10 years of follow up.

NIH Challenge Grant: Biomarkers and the PLCO Biorepository

Under an NIH Challenge Grant available as a result of the American Recovery and Reinvestment Act, NCI is soliciting applications for funding to use available biospecimens from the PLCO Screening Trial for prospective studies focused on the discovery and validation of cancer early detection biomarkers (RFA 03-CA-109).

According to Dr. Christine Berg, the PLCO biorepository is ideally suited for use in nested, case-control biomarker discovery and validation studies. “This is an excellent example of NIH using new funds to leverage an unparalleled resource that we’ve already developed,” she said.

Deadline for applications is April 27. For more information, contact Dr. Berg at bergc@mail.nih.gov.

That doesn’t mean that with longer follow-up a mortality benefit might not be seen, said Dr. Christine D. Berg, the trial’s lead investigator. Prostate cancers among men in the “usual care” group tended to have higher Gleason scores (between 8 and 10), an important predictor of disease aggressiveness. “So, there may be a survival difference that emerges after more than 10 years, but it would be a small difference,” she said.

At 9 years of follow-up, the ERSPC showed a 20 percent reduction in mortality among men aged 55 to 69 (at enrollment into the study) who underwent PSA screening every 4 years. Much like what was seen in PLCO, the mortality rates between men in the screening and control arms were nearly identical for the first 7 years. It was around that time in ERSPC, however, when the rates began to diverge.

The trials’ discrepant results could be attributed to several key differences in their designs, said PLCO co-author Dr. Gerald Andriole of the Washington University School of Medicine. Not only was ERSPC significantly larger (182,000 participants) and did it use a different screening interval than the PLCO, but most centers involved in the study also had a lower PSA cutoff to refer participants for clinical follow up (3 ng/ml versus 4 ng/ml).

In an accompanying commentary in NEJM, Dr. Michael J. Barry of Harvard Medical School wrote that even if the small mortality benefit seen in the ERSPC is real, it is “important to remember that the key question is not whether PSA screening is effective, it’s whether it does more good than harm.”

Proponents and skeptics of regular PSA screening alike have warned about the overdiagnosis and overtreatment of prostate cancers linked to PSA screening. Estimates of overdiagnosis have ranged from 20 to 80 percent in various studies. A modeling study published March 10 estimated that PSA-related overdiagnosis in the United States could be as high as 42 percent. In the PLCO trial the estimated risk of overdiagnosis at seven years was 22 percent, while in the ERSPC trial it was more than 70 percent, a difference that Dr. Barry said was most likely the result of the smaller difference between screening intensities in the two arms of the PLCO than in ERSPC.

The extent of overdiagnosis, stressed Dr. Andriole, should help to “temper those knee-jerk reactions” to immediately perform biopsies and pursue aggressive treatments.

Looking forward, Dr. Berg said she is hopeful that clinical decision models can be developed based on data from these two trials and other studies, and that new molecular biomarkers will be found that accurately identify aggressive cancers that need to be treated. NCI’s Early Detection Research Network is supporting research on a number of these markers.

Dr. Berg also stressed that the PLCO biorepository houses 2,000 tumor samples as well as blood samples, making it a valuable tool for continued biomarker discovery and validation. (See sidebar.)

Although there has been significant progress to date on the biomarker front, she said, “I think the pace of discovery and the rapidity with which we will get these answers will improve.”

—Carmen Phillips

Cancer Research Highlights

Three-Drug Regimen May Preserve the Voice Box in Larynx Cancer

Induction chemotherapy with a combination of three drugs significantly improved preservation of the larynx in patients with larynx and hypopharynx cancers compared to a commonly used two-drug regimen, French researchers reported. The larynx is commonly called the “voice box” because it is where sound is generated; its removal dramatically impairs speaking and swallowing. The findings were published online March 24 in the Journal of the National Cancer Institute.

The results come from a phase III randomized trial in which more than 200 patients with operable, locally advanced larynx or hypopharynx cancer were given an “induction chemotherapy” regimen—that is, treatment prior to “definitive” therapy with radiation or chemotherapy and radiation combined. Patients were assigned to either the three-drug combination of docetaxel, cisplatin, and 5-fluorouracil (TPF) or cisplatin and 5-fluoruracil (PF) alone for induction. In the trial, patients who responded to either induction chemotherapy regimen underwent subsequent radiation therapy, with or without chemotherapy; nonresponders underwent surgery.

At a median follow-up of 3 years, larynx preservation was 70.3 percent in patients assigned to the TPF regimen and 57.5 percent in patients assigned to PF. Patients in the TPF arm also had a better overall response rate than patients in the PF arm, 80.0 percent versus 59.2 percent, although there was no statistically significant difference in overall or disease-free survival. Side effects such as neutropenia and febrile neutropenia were worse in the TPF arm.

Although the trial has its limitations, explained Dr. Arlene Forastiere from the Sidney Kimmel Comprehensive Cancer Center, it adds to the evidence showing that the three-drug regimen is a more effective induction chemotherapy approach than the two-drug regimen. Among the limitations, she noted, was that the trial could not distinguish between patients with cancers of the larynx and hypopharynx. “This is important because the biology and natural history of these cancers is quite different despite their anatomic proximity,” she said.

Induction chemotherapy and simultaneous chemotherapy and radiation, called “concomitant chemoradiation,” have proven to be effective alternatives to surgery. Even with these results, Dr. Forastiere continued, it’s still not known whether induction chemotherapy is equivalent to, not as good as, or better than concomitant chemoradiation for preserving the larynx.

Obesity Worsens Survival after Pancreatic Cancer Surgery

Patients who are severely obese have a greater likelihood of lymph node metastases, disease recurrence, and decreased overall survival following pancreatic cancer surgery, reported a research team from the University of Texas M.D. Anderson Cancer Center. Published in the March 2009 Archives of Surgery, the single-institution study found that patients with a body-mass index (BMI) greater than 35 had a twofold greater risk of disease recurrence and death than patients with lower BMIs.

Noting that other studies have shown an association between similar BMI measurements and the risk of death from pancreatic cancer, Dr. Jason B. Fleming and colleagues said that the results of their new study “suggest that obesity is a host factor affecting tumor biology independent of the difficulties (patient- and treatment-related) involved in delivering oncologic care in obese patients.”

They looked at data from 285 consecutive patients who underwent surgery for pancreatic adenocarcinoma at M.D. Anderson between 1999 and 2006. Patients with a BMI greater than 35 had a median survival of 13.2 months, whereas patients with a BMI less than 23 had a median survival of 27.4 months. Nineteen of 20 patients with a BMI greater than 35 experienced disease recurrence at the last follow up, compared with 161 of the remaining 264 patients (95 percent versus 61 percent).

Patients with a BMI greater than 35 were less likely to receive radiation therapy before surgery than patients with lower BMIs, the team found, a complicating factor in assessing the risk of lymph node metastasis. Even so, after adjusting for that difference, there was a 12-fold greater incidence of lymph node metastasis in patients with a BMI greater than 35 compared with those with a lower BMI.

“To our knowledge,” they wrote, “the relationship between obesity and lymph node metastases observed in this study is the strongest reported in the literature to date, and it is supported by clinical and laboratory studies showing a relationship between obesity and cancer progression.”

In Talking about Prostate Cancer, Medical Language May Confuse Some Patients

Medical terms that physicians routinely use to discuss prostate cancer with patients, and that also appear in patient-education materials and research studies, are unfamiliar to many men with low literacy levels. This finding, reported in the Journal of Clinical Oncology on March 23, comes from interviews with more than 100 predominantly African American men at two low-income clinics in Virginia. The average patient was 58 years old and had a fifth-grade literacy level.

Fewer than half of the men understood the terms “erection” or “impotent,” and only 5 percent understood the term “incontinence”—words that are all commonly used to communicate the potential risks of prostate cancer treatments to patients. Many of the men were not familiar with basic aspects of human anatomy.

The researchers, led by Dr. Kerry Kilbridge of Massachusetts General Hospital, said that a limited understanding of prostate cancer terms and low literacy could be barriers to informed consent for treatment. In addition, the results of research studies, such as those assessing quality of life, may be inaccurate if participants lack an understanding of the questions.

The new findings could be used to improve communication about prostate cancer. The researchers created a table of synonymous colloquial terms for the common medical words used for prostate cancer. They urge caregivers not to assume that patients have a working knowledge of their internal anatomy and organ systems. “A safer place to start teaching prostate cancer is based on what a patient sees in the mirror,” they wrote.  

An accompanying commentary added, “Not only do we have to take heed in the language we use in communicating with patients in our clinical work, we must investigate rigorously whether the words contained in our study measures are actually understood by low-literacy populations.”

Rare Genetic Disorder Reveals How UV Exposure May Cause Melanoma

Much of what is known about how ultraviolet radiation (UV) causes skin cancer relates only to basal cell and squamous cell carcinoma. For melanoma, a less common but far more deadly form of the disease, there has been less evidence. New research suggests that UV-induced mutations in a gene called PTEN that normally suppresses tumors may play an important role in the formation of melanoma, according to findings published yesterday in the Proceedings of the National Academy of Sciences.

Researchers from NCI’s Center for Cancer Research and their collaborators at Brown University analyzed 59 melanoma samples taken from 8 patients with xeroderma pigmentosum (XP) who were seen at the NIH Clinical Center between 1971 and 2008. XP is a rare genetic disorder that compromises the ability of cells to repair DNA damage to the skin, putting these patients at a nearly 1,000-fold increased risk of melanoma, which progresses rapidly.

The researchers found that 56 percent of the XP melanomas analyzed harbored mutations in the PTEN gene. Of these mutations, 91 percent included DNA base substitutions of the type that usually result from UV damage, with between 1 and 4 changes per tumor. These mutations were also detected among melanomas in situ, those at the earliest stage of disease. Melanomas from the same person sometimes had different PTEN mutations, indicating that they arose independently.

The findings “provide a clear mechanistic framework for the role of UV in the induction of melanomas,” Dr. Kenneth Kraemer and colleagues wrote, “and a sound rationale for UV protective measures for melanoma prevention.”

Director's Update

Making Connections between Stem Cells and Cancer

Dr. John E. Niederhuber Dr. John E. Niederhuber

The striking similarities between stem cells in normal tissue that are responsible for continuously replacing adult tissues and a very small subset of cells found in growing tumors have sparked considerable interest in the research community. As a result, there is perhaps no better time for cancer biologists to draw on the considerable knowledge of our colleagues in embryology and developmental biology to explore questions about the initiation and progression of cancer—and potentially to understand how it develops resistance to therapies and how it metastasizes.

Indeed, future strategies for treating the disease may be informed by insights drawn from knowledge of embryonic stem cell biology and the intricate genetic processes that lead to the formation of organs. Against this backdrop, President Barack Obama’s Executive Order lifting restrictions on federal funding for research on embryonic stem cells will greatly impact cancer research in the years ahead.

There is a growing body of evidence that some tumors are driven by a small number of cells that have properties similar to embryonic stem cells. According to the cancer stem cell hypothesis, these rare cells are the only cells within a tumor that can self-renew and give rise to diverse progeny, much like stem cells in the embryonic setting and in adult tissues. These cells are therefore known as cancer stem cells or tumor-initiating cells. 

Unlike the bulk of tumor cells, tumor-initiating cells may be able to endure hostile environments by entering a state of dormancy. This hypothesis, if confirmed, could help explain why many patients with cancer unfortunately relapse after apparently successful treatments.

The elucidation of early events in the transformation of normal cells into malignant cells is essential if we are to advance research on cancer stem cells. Recent studies have revealed that the genetic signatures of some poorly defined high-grade tumors are similar to those of embryonic stem cells. In particular, genes associated with self renewal appear to be active in both the normal and the tumor stem cells. This tells us that the activation of an embryonic stem cell-like genetic program in certain adult cells may induce self-renewal characteristics and trigger a progression to tumor-initiating cells. 

We also know that normal human embryonic stem cells themselves can transform to become malignant cells. Thus, to define the genetic regulatory networks and cell signals that drive normal embryonic stem cells toward malignancy, it may be necessary to profile gene expression patterns of normal and transformed embryonic stem cells. Such experiments could provide clues to the most important regulatory genes that are altered in the events leading to cancer.

In theory, the availability of a larger spectrum of normal, stable human embryonic stem cell lines should make it easier to define such signatures and associate them with the earliest events in malignancy for human disease.

My own lab has been focused on identifying stem cells within the NCI 60 cell lines through the use of surface markers identified in the literature that are associated with tumor stem cells. In another project, we are investigating whether viruses that cause cancer need to infect the adult tissue stem cells in order to trigger a transformation of these cells. We hypothesize that if non-stem cells are infected, these cells would simply die and cancer would not develop. Stem cells, by contrast, live a long time and through their ability to self-renew would be able to perpetuate the genetic changes initiated by a virus. 

What is hampering these investigations—indeed, hampering all research into cancer stem cells—is the inability to clearly identify the adult epithelial stem cell. The availability of new embryonic stem cell lines in research would facilitate studies of the genetic program associated with the maturation, or differentiation, of a stem cell. This could lead to markers that would allow us to truly identify adult tissue stem cells for the first time.

Once that hurdle is passed, experiments such as those with the NCI 60 cell lines and the viral oncogenesis studies could proceed with the knowledge that the targeted cell is in fact a stem cell.

In the area of treatment, a central question is whether cancer stem cells can be made vulnerable to therapies by identifying and disrupting critical cell-signaling pathways. Promising work in this area has come recently from the laboratory of Dr. Mary J.C. Hendrix at the Northwestern University School of Medicine. Her team has identified an embryological signaling pathway that is improperly activated in metastatic melanoma and that could be targeted for the reprogramming of aggressive tumor cells.

This research, which was done using federally approved embryonic stem cell lines, confirms previous studies showing that the embryonic environment can reprogram cancer cells, in effect “taming” aggressive melanoma cells under experimental conditions. As a next step, Dr. Hendrix has shown that the microenvironment of embryonic stem cells therefore may be a previously unexplored therapeutic entity for controlling abnormally expressed embryonic factors in aggressive tumor cells.

Such unexpected connections and opportunities for therapies are likely to emerge as more researchers focus on the mechanisms of embryogenesis and developmental biology.

Dr. John E. Niederhuber
Director, National Cancer Institute

A Conversation With

A Conversation with…Dr. Jorge Gomez

Dr. Jorge Gomez is director of NCI’s Office of Latin American Cancer Program Development (OLACPD), which was formed in 2008 by NCI and NIH’s Fogarty International Center to advance cancer research and research capacity in partnership with Latin American countries. Last week, Dr. Gomez, other NCI staff, and U.S. scientists met with delegations from five Latin American nations for a 3-day workshop to develop pilot projects in breast cancer research in the region.

Dr. Jorge Gomez Dr. Jorge Gomez

What are the goals of OLACPD?
The goal is to develop a program to sponsor cancer research in Latin American countries in partnership with their governments and research institutions. OLACPD will also sponsor training and help build infrastructure for cancer research in the region. The majority of the investment NCI has made in the region in past years has been in the form of training grants through Fogarty or through other types of grants and subcontracts, so this is a new approach for our collaboration in Latin America.

It’s also the first time that we’re collaborating through formal agreements with the ministries of health in Latin America. These government agencies are assembling clinical research networks in their own countries, which will basically create a United States–Latin American cancer research network. The health ministries are providing some matching funds for this project, so NCI is not doing it alone. We’re also collaborating with their research institutions, which work closely with their government agencies.

Who attended the workshop and what was accomplished?
There were delegations from Argentina, Brazil, Chile, Mexico, and Uruguay, representatives from different NCI divisions, centers, and programs, and prominent U.S. scientists in breast cancer research, who provided their input and brainstormed about the research concepts that were being discussed.

The goal of the workshop was to lay the groundwork for one or two pilot research projects that will have an impact on breast cancer management in Latin American women. The research projects will be implemented in the five countries and potentially also within research institutions in the United States.

We want to address how we can all contribute to the overall knowledge of breast cancer. For example, what is the molecular classification of breast cancer in Latin American women compared with what is known right now about breast cancer subtypes in the United States and Europe? In Latin America, and in other parts of the world, they generally follow U.S. models. That may not be the best way of managing breast cancer treatment, recurrence, and follow-up care for Latin American women living in the region or those who reside in the United States.

What are the next steps for the pilot projects?
Based on the discussions at the workshop, we have identified two research concepts for molecular profiling and early detection that will be reviewed by the OLACPD steering committee in the next few months. Eventually, those or other research proposals will be transformed into clinical research protocols to be implemented in the five countries in partnership with the ministries of health and in close collaboration with NCI.

We expect this pilot clinical research network for breast cancer to be a model that we will use to look at other common cancers in Latin America, such as colon cancer and gastric cancer. We hope that we can support clinical research in the region in a way that can be the basis for studying other types of cancer in a more systematic and orderly way.

Special Report

Discovering the Secrets of Brain Tumors

Physicians decide how to treat brain cancer in part based on what a patient’s tumor looks like under the microscope. But while the microscope can help classify a tumor, it cannot always reveal the molecular changes that drive the disease. And in an era of molecularly targeted therapies, this is what physicians and patients increasingly want to know.

Molecular markers have been identified and even genomic tests have been developed for breast and other common cancers, but progress has been slower in brain cancer. Obtaining the tumor tissue needed for molecular studies is difficult, and hundreds, if not thousands, of samples are needed to capture the genetic diversity of brain cancer.

Nonetheless, there is reason for optimism. Some of the first genomic studies of cancer included surveys of brain tumors, and for the first time, several clinical trials are enrolling patients based on tumor markers, such as combined deletions on chromosomes 1 and 19.

A database being developed by NCI and its partners around the country could also help move the field toward more individualized care. The Glioma Molecular Diagnostic Initiative (GMDI) is collecting and integrating molecular, genetic, and clinical data on hundreds of patients with gliomas, the most common type of brain tumor.

Changing the System

The March 1 issue of Cancer Research includes one of the first publications using the study’s database. The researchers propose a new classification system for gliomas based on tumor gene activity. While the results are considered preliminary, they illustrate the promise of an approach that seeks to integrate different types of information from patients with the disease, the researchers said.

“Unlike the standard classification system for gliomas, we came up with a system that is based purely on biology,” said lead investigator Dr. Howard A. Fine, chief of NCI’s Neuro-Oncology Branch in the Center for Cancer Research. “The results confirm and extend the findings of smaller glioma classification studies published previously,” he added.

Collectively, these studies show that there are subtypes of brain tumors defined not by their appearance under the microscope, but rather by the molecular pathways that are altered in tumors, said Dr. Mark Gilbert, professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center, who was not involved in the research.

“These studies all have the same goal,” Dr. Gilbert continued. “For a hundred years we’ve made treatment decisions on the basis of looking at brain tumor tissue under the microscope. Yet we know that two patients can have very different outcomes even though their tumors look identical, so it would be helpful if we could figure out the pathways that made the cancers different.” 

Clinical Genomics

Created to help attain that goal, GMDI has enrolled more than 800 patients with gliomas at 14 institutions around the country. A tumor sample collected during surgery for each patient is sent to NCI for molecular analysis. Clinical information on each patient is then linked to molecular and genetic descriptions of the tumor in a public database called REMBRANDT (Repository of Molecular Brain Neoplasia Data).

“We have built the largest cancer clinical genomics database for any tumor type, let alone an uncommon type such as glioma,” said Dr. Fine. In the Cancer Research study, the researchers used 159 gliomas from GMDI to develop an algorithm that assigns gliomas to six subtypes under two groups, glioblastomas and oligodendrogliomas. They validated the algorithm in three additional data sets, totaling nearly 700 gliomas.

The results confirm what physicians have always known—that some patients will do better than others for reasons that may not be understood, said Dr. Michael Prados, director of translational research in neuro-oncology at the University of California, San Francisco Comprehensive Cancer Center. He also leads a consortium that provided some of the annotated tumor samples used in the analysis.

“If we really want to change the outcomes for patients, then we need therapies that address changes in particular pathways,” added Dr. Prados. “We don’t have those therapies now, so the challenge going forward is: How will we use this information to make a difference in patients therapeutically?”

Exploring the Biology

As a next step, Dr. Fine’s group is characterizing the biology of the tumors to inform the development of new therapies. Until very recently, most patients with brain cancer received the same toxic drugs. But with a growing pipeline of molecularly targeted cancer drugs, physicians can start to evaluate these agents rationally in clinical trials.

Given that the most common subtypes may include only about 10 percent of all tumors, the selection of patients for these trials will be critical. A drug may perform poorly in a trial of unselected patients, and therefore could be discarded, even though it may be very effective for a specific subset of patients.

“For prognostic purposes, for drug development, and for the design of future clinical trials, we really need to be able to group brain tumors according to their underlying biology,” said Dr. Fine.

The genome surveys published last year and a recent follow-up report about relatively common mutations in brain tumors have set the stage for more individualized approaches to the disease. And while much more work remains to be done, everyone in the field seems to be moving in the same direction.

“Information is power, and these studies are all expanding the knowledge base,” said Dr. Prados. “This will let us develop therapies for patients in a more specific way.”

—Edward R. Winstead

Spotlight

Treatment Approach Using Radiofrequency Waves Heats Up

It began with chemotherapy-induced sleeplessness and some pie pans. At one point hot dogs were involved. It inspired residents of two small communities 1,300 miles apart, and eventually landed in the labs of two major academic medical centers. And, sadly, just 5 weeks ago, the man who began it all died of treatment complications after a nearly 7-year battle with B-cell leukemia.

The story of retired radio engineer and executive John Kanzius and the radiofrequency (RF) generator that he dreamed would one day be part of a highly effective cancer treatment captivated readers of Discover magazine and viewers of “60 Minutes.” Now his invention is maneuvering through the steps needed to demonstrate readiness for clinical testing in humans.

“Realistically, we still have hoops to jump through and things to prove,” said Dr. Steven A. Curley from the University of Texas M.D. Anderson Cancer Center, who, along with Dr. David Geller from the University of Pittsburgh Medical Center, has been part of this project since its earliest days. “But I’ll continue to work on this and move it forward because I think it has great promise.”

An image of pancreatic cancer cells treated with gold nanoparticles. The cells on the left received 2 minutes of external radiofrequency (RF) field treatment resulting in unstable nuclei and pitting. The cells on the right received no RF treatment and their nuclei and organelles remain intact. (Image courtesy of Dr. Stephen Curley) An image of pancreatic cancer cells treated with gold nanoparticles. The cells on the left received 2 minutes of external radiofrequency (RF) field treatment resulting in unstable nuclei and intracellular damage. The cells on the right received no RF treatment and their nuclei and organelles remain intact. (Image courtesy of Dr. Stephen Curley)

A Trojan Horse…on Fire

RF, Kanzius realized one restless night, is an ideal way to attack cancer cells from outside the body. At low levels, it doesn’t harm healthy tissue, but in a matter of minutes it can heat up metal in the RF field to nearly 130 degrees Fahrenheit. So, figured Kanzius, why not use RF waves to heat up metal nanoparticles that have found their way into cancer cells?

At his summer home in Sanibel, FL, he used pie pans to create his first RF device. In the garage of his long-time home in Erie, PA, Kanzius tested the device on America’s favorite ballpark snack. He would eventually use his own money to build a more sophisticated RF generator that Dr. Geller, and later Dr. Curley, went on to use in cancer cell line and animal model studies.

In these studies, nanoparticles are introduced and exposed to low-level RF waves for just a few minutes. The intense heat generated in the infiltrated cells “denatures proteins, disrupts lipid bilayers, and results in irreparable damage to intracellular structures and organelles,” Dr. Curley and his colleagues at M.D. Anderson explained in their most recent paper.

While the preclinical work has proven successful, there is still much to be done, stressed Dr. Geller.

“It’s one thing to kill cancer cells in a test tube, or even an animal,” he said. “It’s another to kill a tumor in a human and make a cancer disappear.”

Reaching the Target

The work completed thus far demonstrates the rapid progression from a concept of blistering malignant cells with RF waves toward precisely focusing RF waves on cancer cells by using nanoparticles with targeting agents attached to them. The initial work by Dr. Curley's team involved single-walled carbon nanotubes unadorned by a targeting molecule, given to Dr. Curley by a patient he was treating at the time—Dr. Richard Smalley, a Nobel Prize winner for nanotechnology research who died in 2005.

Both Dr. Curley’s and Dr. Geller’s groups are now using gold spherical nanoparticles. In their most recently published work, Dr. Curley’s group attached the EGFR-targeted monoclonal antibody cetuximab (Erbitux) to the gold nanoparticles.

Introducing these gold nanoparticles into cell lines of pancreatic and colorectal cancer, which both overexpress EGFR, and exposing them for just a minute to an RF field killed nearly 100 percent of the cancer cells, the M.D. Anderson team reported.

“We probably wouldn’t use cetuximab in humans,” Dr. Curley noted. “EGFR is highly expressed in many normal tissues, and we would get significant uptake in normal tissue in the RF field.”

Dr. Geller’s team has shown that they can use RF to heat up liver tumors in a rat model. They used “naked” gold nanoparticles in the experiments, however, that were injected directly into the tumors. Both Drs. Curley and Geller are still working to find molecules that are highly specific to cancer cells.

“For each cancer, we’re going to have to come up with unique strategies,” Dr. Geller explained. “What works for liver cancer may not work for breast or prostate cancer.”

The Path Forward

Tackling cancer in this way, said Dr. Piotr Grodzinski, program director for the NCI Alliance for Nanotechnology in Cancer, is “generally an attractive idea.” Other researchers, in fact, have developed similar approaches, he added, “with their own twists.”

Texas-based Nanospectra Biosciences, for example, has received FDA approval for a phase I study in patients with unresectable head and neck cancer using a device that emits near-infrared light to heat up gold nanoparticles in tumors. And the German company MagForce developed a device that employs an alternating magnetic field to heat up magnetized nanoparticles; the device is being tested in phase I and II trials in Europe for several cancers.

Other investigators, added Dr. Nicholas Panaro, a senior scientist in NCI’s Nanotechnology Characterization Laboratory, are studying different targeting molecules—DNA fragments called aptamers, and diabodies, which are antibody fragments—to see if they can more effectively deliver nanoparticles only to cancer cells.

Meanwhile, Therm Med, the company established by Kanzius to help commercialize his device, is in the process of scaling it up so that it can be used for large animal and eventually human studies. Drs. Geller and Curley believe that with continued progress and funding they can launch initial human trials in the next few years.

“John was a one of a kind,” said Dr. Geller. “We certainly hope to continue the research because that’s what he wanted us to do.”

—Carmen Phillips

A Closer Look

Survivorship
This is the first article in a new series of stories related to cancer survivorship. Look for the symbol on the left in an upcoming issue for the next article in the series.

Delving Into Possible Mechanisms for Chemobrain

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After undergoing surgery, chemotherapy, and radiation therapy for stage II breast cancer, Lori (who asked to be identified only by her first name) was looking forward to getting back to her normal, busy life as a working mother of two.

This image of the human brain uses colors and shapes to show neurological differences between two people. The blurred front portion of the brain is associated with complex thought. (Image courtesy of Arthur Toga, University of California, Los Angeles) This image of the human brain uses colors and shapes to show neurological differences between two people. The blurred front portion of the brain is associated with complex thought. (Image courtesy of Arthur Toga, University of California, Los Angeles)

But within weeks of returning full-time to her job as a city planner, she knew something was wrong. “I couldn’t work, I couldn’t think,” she said. Before, multitasking had been second nature, but now it exhausted her. At home, she found that trying to do things like plan dinner for her family was more than she could cope with.

“My brain feels so heavy and tired...I can feel everything slowing down, getting cloudy,” she said.

Lori has the classic symptoms of chemobrain: cognitive changes associated with cancer or cancer treatment, most often experienced as difficulties with concentration, memory, multi-tasking, and planning ability. These changes usually first become apparent during chemotherapy (hence the name) and, in around 20 percent of survivors, persist well after treatment has ended.

A More Complicated Explanation

Although chemobrain was first identified and named by breast cancer survivors, research now suggests that the same constellation of symptoms also affects survivors of other cancers. Early studies of patients’ cognitive functioning after chemotherapy estimated that the number of survivors with chemotherapy-associated cognitive changes ranged from 17 percent to 75 percent.

When researchers began to measure cancer patients’ cognitive functioning both before and after chemotherapy, however, they were surprised to find that before undergoing chemotherapy, 20 to 30 percent of patients had lower cognitive performance than would be expected based on their age and education. Subsequent studies have consistently shown similar findings.

“This suggests that aspects of cancer biology may influence cognitive functioning, or that there are as-yet-unidentified shared risk factors for mild cognitive changes and the development of cancer,” said Dr. Tim Ahles, who studies chemobrain at Memorial Sloan-Kettering Cancer Center.

“It’s more complicated than chemotherapy,” added Dr. Ahles. “Almost no one who is treated for cancer receives only chemotherapy. Other aspects of treatment may be equally important to understanding changes in cognitive functioning.”

Increased Vulnerability

Evidence from animal and imaging studies suggests, for example, that the drug tamoxifen, widely used to treat hormone-receptor-positive breast cancer, may disrupt cognitive and other brain functions. In addition, some studies have found that hormonal agents such as goserelin and leuprolide may cause adverse cognitive effects in men who have prostate cancer.

Studies using functional magnetic resonance imaging have identified structural brain abnormalities in patients treated with chemotherapy. In a study using positron emission tomography imaging, breast cancer survivors who had received chemotherapy in the previous 5 to 10 years used more of their brains to perform a short-term memory task than control subjects who had never received chemotherapy, a sign that their brains are having to work harder to complete the task. 

Findings from a preliminary study by Dr. Ahles and his colleagues at Dartmouth Medical School suggest that a form, or allele, of the APOE gene called ε4, which is associated with increased risk for Alzheimer’s disease, may be a genetic marker for increased vulnerability to chemobrain. In this study of 80 long-term survivors of breast cancer and lymphoma, participants with at least one ε4 allele had significantly lower scores on standard tests of visual memory and spatial ability and a tendency toward lower scores on psychomotor functioning than subjects who did not carry this allele.

Dr. Ahles and his team are currently analyzing the data from a larger study, looking at the role of genetic polymorphisms in the development of cancer-related cognitive changes. They are also investigating the hypothesis that patients whose cells have a reduced ability to repair the DNA damage caused by chemotherapy are at higher risk for chemobrain.

Dr. Patricia Ganz and her colleagues at UCLA’s Jonsson Comprehensive Cancer Center suspect that uncontrolled inflammation may be a cause of chemobrain. “Many of the patients in our breast cancer survivorship program who have cognitive complaints also have fatigue, sleep disturbance, or depression,” she said. “Our hypothesis is that polymorphisms in genes that regulate the immune system render some patients more vulnerable to this constellation of symptoms.”

Many cancer treatments, including surgery, radiation, chemotherapy, and immunotherapy, can increase inflammation, Dr. Ganz added, which may not resolve after treatment ends. “We have found that post-treatment fatigue is associated with specific single nucleotide polymorphisms in genes that code for interleukin-1 and interleukin-6, two cell-signaling molecules associated with both inflammation and cancer-related fatigue,” she explained. “Our research is examining whether disruption in immune regulation is also involved in the development of cognitive complaints.”

Treatment Studies

Research on treatments for chemobrain is still in its very early stages. Dr. Ganz is beginning a pilot study of rehabilitation strategies for affected breast cancer survivors. Some evidence suggests that medications that stimulate the central nervous system may moderate adverse cognitive effects.

Lori has obtained some improvement by taking the stimulant Adderall (dextroamphetamine and amphetamine). She also finds that exercise and getting a good night’s sleep help her feel more clear headed.

The most challenging aspect of chemobrain, she said, is its invisibility. “I look fine, so people think I’m well. But my brain still isn’t well.”

Dr. Julia Rowland, who directs NCI’s Office of Cancer Survivorship, is encouraged that this new body of research is bringing needed attention to and better scientific understanding of the cognitive problems that affect many survivors during and after treatment. “The very real challenges caused by cancer-related difficulties with memory and thinking have been poorly understood and are often dismissed when reported by survivors,” said Dr. Rowland. “Findings from these studies should empower survivors to ask their medical providers what can be done to help them improve their cognitive health, especially after treatment ends.”

Eleanor Mayfield

Featured Clinical Trial

Helping Survivors of Childhood Cancer Quit Smoking

Name of the Trial
Efficacy of Tobacco Quitline for Childhood Cancer Survivors (XPD07-140).  See the protocol summary.

Dr. Robert Klesges Dr. Robert Klesges

Principal Investigator
Dr. Robert C. Klesges, St. Jude Children’s Research Hospital

Why This Trial Is Important
Advances in treatment over the past 30 years have dramatically increased the survival rates for childhood cancers, and many children diagnosed with cancer now survive their disease well into adulthood. Unfortunately, treatments for childhood cancers often cause long-term health problems, leaving survivors more susceptible to cardiovascular, pulmonary, and other illnesses (including second cancers) than people in the general population.  

Studies have shown that childhood cancer survivors are almost as likely to smoke as everyone else. Smoking greatly increases the risk of illness for these survivors, as it does for any smoker, but the effects of smoking combined with possible late-onset (delayed) adverse effects of cancer treatment make childhood cancer survivors a high-risk population. Therefore, it is vitally important for these survivors to refrain from smoking if they haven’t started or to quit smoking if they have. Telephone “quitlines” have proven beneficial in helping smokers to quit and may be an effective tool for helping childhood cancer survivors who want to stop smoking.

In this study, adult survivors of childhood cancer who smoke and want to quit will be randomly assigned to one of two quitline-based strategies: counselor-initiated quitline consultations or self-paced quitline consultations. With the counselor-initiated strategy, smokers who enroll in the study will be called at predetermined intervals for six telephone sessions. Additionally, they will be given nicotine-replacement therapy for 8 weeks (provided this is not medically contraindicated). Smokers assigned to the self-paced quitline consultations will initiate up to six counseling sessions themselves and will receive a 2-week starter kit of nicotine-replacement therapy. 

“We know that adults who have survived childhood cancer and who smoke are at great risk of harm and need help to quit,” said Dr. Klesges. “People who enroll in this study will get an intervention that has proven effective in previous studies, regardless of their assigned strategy. The help is free and specifically tailored to the needs of survivors of childhood cancer.”

For More Information
See the lists of entry criteria and trial contact information or call the St. Jude study quitline at 1-877-4-SJ-QUIT. The toll-free call is confidential.

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

Notes

In Memoriam: Former NCI Director Dr. Carl Baker

Dr. Carl Baker Dr. Carl Baker

Dr. Carl G. Baker, who served as NCI director from 1970 to 1972, died February 11 at the age of 88. He was head of the institute when the National Cancer Act of 1971 was passed, and during his 3 years as director NCI’s annual budget nearly tripled.

Dr. Baker received his undergraduate and medical degrees from the University of Louisville and a master’s degree in biochemistry from the University of California, Berkeley. He served as a Navy physician during World War II.

After a 23-year career at NIH, Dr. Baker left the institute in 1972 and became president of Hazelton Laboratories, a biotechnology research company. He subsequently was a senior official with the Health Resources Administration, and in 1976, he became medical director of the Ludwig Institute for Cancer Research, an international medical group in Zurich, Switzerland. He retired in 1982 but continued to serve on advisory panels and as a consultant for several years.

Dr. Baker reached the rank of rear admiral in the U.S. Public Health Service and received its Meritorious Service Medal. He served on the editorial boards of two cancer journals and was a director of the American Association for Cancer Research, director-at-large of the American Cancer Society, and a secretary of the American Chemical Society’s Division of Biological Chemistry.

CTCAE 4.0 Posted for Public Review

NCI’s Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 is widely accepted throughout the oncology research community as the standard grading scale for defining protocol parameters such as maximum tolerated dose, dose modification, and comparison of safety profiles between interventions.

NCI’s Cancer Therapy Evaluation Program and Center for Bioinformatics have revised CTCAE version 3.0 to address terminology agreement with the Medical Dictionary for Regulatory Activities (MedDRA) terminology, integration with caBIG data systems, and long-term governance of CTCAE. A draft of CTCAE version 4.0 is available for public review at http://ctep.cancer.gov/ under “CTEP Highlights” through April 10. The site includes further information about the revision and instructions for submitting comments. Questions should be addressed to ctcae4@bah.com.

Free Telephone Workshop Series for Cancer Survivors

The seventh annual telephone workshop series, “Living With, Through, and Beyond Cancer,” begins April 14. This three-part 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.

The program is supported by NCI, CancerCare, the Lance Armstrong Foundation, the Intercultural Cancer Council, Living Beyond Breast Cancer, and the National Coalition for Cancer Survivorship.

The workshops are free; no telephone charges apply. To register, visit the CancerCare Web site at www.cancercare.org/TEW. All workshops will take place on Tuesdays from 1:30 p.m. to 2:30 p.m. EDT on the following dates:

  • Part I: “Managing the Stress of Survivorship,” April 14
  • Part II: “The Importance of Nutrition and Physical Activity,” May 19
  • Part III: “Survivors Too–Family, Friends, and Loved Ones: Managing the Fatigue of Caregiving,” June 23

The workshops are also archived and available as podcasts on the CancerCare Web site.

Registration Open for Neuropathic Cancer Pain Symposium

Artwork for NCI's Neuropathic Cancer Pain Symposium

NCI and the NIH Pain Consortium will host a Neuropathic Cancer Pain Symposium on April 27 in Bethesda, MD. The symposium will bring together a multidisciplinary group of researchers, clinicians, and patient advocates to build upon the knowledge and understanding of the role pain and pain management have in cancer care. Attendees will address the knowledge gap in the area of neuropathic pain associated with the underlying disease and cancer therapy. The symposium will feature plenary sessions, panel discussions, and opportunities for networking. For more information and to register visit the meeting Web site.

NCI Hosts International Art Exchange Exhibit

A 7-year-old leukemia patient from Istanbul, Turkey, drew this image. The artist explained, 'This is the picture of the 23rd of April. I danced with my classmates. I will never forget that day.' A 7-year-old leukemia patient from Istanbul, Turkey, drew this image. The artist explained, "This is the picture of the 23rd of April. I danced with my classmates. I will never forget that day."

On February 12, NCI’s Office of International Affairs (OIA) hosted the launch of an international art exchange exhibit, a collaborative effort between Tracy’s Kids Pediatric Art Therapy Program, NCI, and the Middle East Cancer Consortium (MECC). The exhibit highlights artwork by pediatric cancer patients and their family members at cancer centers in the United States, Jordan, Israel, Egypt, and Turkey.

Tracy’s Kids is a nonprofit organization affiliated with Georgetown University Medical Center’s Lombardi Comprehensive Cancer Center. MECC was begun in 1996 with NCI assistance, and its members include Cyprus, Egypt, Israel, Jordan, the Palestinian Authority, and Turkey. Attendees came from across the NCI community, the Lombardi Comprehensive Cancer Center, and local advocacy groups. The keynote speakers were Ms. Ruth Hoffman, executive director of Candlelighters Childhood Cancer Foundation, and her daughter, Naomi Bartley, a pediatric cancer survivor.

The artwork is on display at the NIH Visitor Information Center on the NIH campus until April 20. For more information, contact Ms. Isabel Otero at isotero@mail.nih.gov or 301-435-4434.

Robotic Surgery Featured in BenchMarks

The surgical suite where doctors are using a surgical robot called the 'da Vinci' to help remove the prostate and lymphnodes. This surgical technique has the potential for fewer side effects. (Image courtesy of Dr. Peter Pinto of NCI's Urologic Oncology Branch) The surgical suite where doctors are using a surgical robot called the "da Vinci" to help remove the prostate and lymphnodes. This surgical technique has the potential for fewer side effects. (Image courtesy of Dr. Peter Pinto of NCI's Urologic Oncology Branch)

In the latest issue of NCI’s BenchMarks, readers will learn about robot-assisted surgery for cancer, and specifically robotic prostatectomy. The issue includes two videos, one of a surgeon performing a radical prostatectomy and the second of a robot-assisted radical prostatectomy.