National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
January 12, 2010 • Volume 7 / Number 1


Physicians Urged to Consider Active Surveillance in Prostate Cancer

The most explicit call to date for expanding the use of active surveillance in the treatment of prostate cancer was made last week by the National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of leading cancer centers. Updated guidelines from the group urge clinicians to offer active surveillance to their patients with prostate cancers that are at low risk of progressing to life-threatening disease. Read more > >


Andrea Denicoff (left) and Dr. Jeffrey Abrams (right)

Guest Director's Update: Targeting Barriers, including Insurance Coverage, to Improve Clinical Trial Participation

by Andrea Denicoff and Dr. Jeffrey Abrams

Lack of health insurance coverage for the routine cost of care for patients taking part in clinical trials—including doctor visits, hospital stays, clinical laboratory tests, and other expenses—is a major barrier to participation. Read more > >

Guest Commentary by Brenda Nevidjon: Health Care Changes—How Cancer Care Initiatives Can Help

The president of the Oncology Nursing Society describes initiatives in oncology nursing that may be a model of the health care system Read more > >

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  • CDC Update

    • HPV Vaccine Added to Adult Immunization Schedule
  • Notes

    • In Memoriam: NCI's Dr. James W. Jacobson
    • NCI Sponsors Symposium on Glycomics in Cancer Detection and Diagnosis
    • NCI Symposium Addresses Biospecimen Quality in Cancer Research
    • NCI's Recovery Act Web Site Showcases Funded Researchers

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

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Featured Article

Physicians Urged to Consider Active Surveillance in Prostate Cancer

The most explicit call to date for expanding the use of active surveillance in the treatment of prostate cancer was made last week by the National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of leading cancer centers. Updated guidelines from an NCCN panel urge clinicians to offer active surveillance to their patients whose prostate cancers are at low risk of progressing to life-threatening disease.

Active surveillance—in the past also called “watchful waiting” and “expectant management”—refers to a strategy of forgoing immediate treatment after a diagnosis of prostate cancer in favor of regularly scheduled testing and clinical exams to closely monitor the disease. Active surveillance can include prostate-specific antigen (PSA) testing, digital rectal exams (DRE), and prostate biopsies. If, at some point, there are indications that the disease is progressing—such as significant growth in the tumor or a rapid increase in PSA level or higher tumor grade on biopsy—definitive treatments such as surgery or radiation therapy can be pursued.

Of the more than 192,000 estimated prostate cancer cases diagnosed in 2009, about half may fall in the low-risk category, explained Dr. Bhupinder Mann from NCI’s Division of Cancer Treatment and Diagnosis.

How the NCCN Guidelines Define Low Risk

Low risk

Expected survival:

  • Less than 10 years


  • Tumor stage: T1-T2a
  • Tumor grade: Gleason score 2-6
  • PSA level: < 10 ng/mL

Patients should get:

  • PSA as often as every 6 months
  • DRE as often as every 12 months
Very low risk

Expected survival:

  • Up to 20 years


  • Tumor stage: T1-T2a
  • Tumor grade: Gleason score ≤6
  • PSA level < 10 ng/mL
  • < 3 positive biopsy cores, ≤ 50% cancer in each core

Patients should get:

  • PSA as often as every 6 months
  • DRE as often as every 12 months

Under the updated guidelines (available online with free registration), active surveillance should be recommended to men with low-risk prostate cancer who have a life expectancy of less than 10 years. Men with low-risk cancers have a relatively low PSA level and their tumors are small, confined to one side of the prostate, and have a low tumor grade, or Gleason score (see sidebar). The guidelines also established a new category of very-low risk, or clinically insignificant prostate cancer. In men with a life expectancy of up to 20 years who fall into this new category, the guidelines recommend advising only active surveillance as the preferred management approach.

“The entire [prostate cancer] treatment committee is concerned about the overdiagnosis and overtreatment of prostate cancer,” explained the panel’s chair Dr. James L. Mohler from the Roswell Park Cancer Institute. The impetus for the update, Dr. Mohler continued, was the publication last year of results from two large clinical trials of prostate cancer screening that showed there was significant overdiagnosis and overtreatment of cancers that likely would have never been a cause for concern.

“Most men find out that they have prostate cancer and what do they want? They want it gone,” Dr. Mohler said. “There are too many men suffering the side effects of treatment, and society is bearing the costs of those treatments. And too much of it is unnecessary.”

To that point, a study published last September estimated that, since 1986, as many as 1 million men have received definitive treatment for a prostate cancer (diagnosed as a result of PSA screening) that would have never threatened their lives. Despite the concerns about overtreatment and the call to expand active surveillance, Dr. Mohler stressed that it’s still an individual decision that patients must make in consultation with their physicians.

Although there are clear benefits to active surveillance in the appropriate patients, the guidelines panel noted that choosing this treatment approach is not a simple process or decision. In addition to the need for frequent exams and tests, from a disease perspective, waiting to see if the cancer progresses could eventually mean having to treat a more aggressive tumor, with a lower likelihood of cure and a greater risk of serious side effects.

The risk of such progression, Drs. Mann and Mohler agreed, is low. According to Dr. Mohler, the risk of a significant tumor grade increase is around 5 percent, and the risk of an increase in PSA is between 16 and 25 percent.

No data have been published from randomized clinical trials directly comparing active surveillance to immediate, definitive treatment. But based on the available evidence, Dr. Mann said, “In low-risk patients, active surveillance with delayed curative intervention is an acceptable strategy.” That contention is supported by two recently published studies (here and here) which both reported equivalent long-term cancer mortality outcomes in men who opted for active surveillance compared with those who received immediate, definitive treatment. (See the cancer research highlight in this issue on a comparative effectiveness study released last week.)

Dr. Paul Godley, a medical oncologist at the University of North Carolina Lineberger Comprehensive Cancer Center, said the recommendations are overdue. However, he noted, there are still questions about active surveillance that need to be worked out, including the appropriate trigger for transitioning to definitive treatment. “I think that will still be fairly subjective based on what the patient and his physician are comfortable with,” he said.

There’s also the matter of how clinicians will react to the updated recommendations, given that immediate, definitive treatment appears to be a fairly ingrained practice. An online poll conducted January 2009 via the New England Journal of Medicine, for instance, presented a case example of a 63-year-old man with low-risk prostate cancer. Among the respondents from the United States (not all of whom were clinicians), approximately 70 percent chose either radiation therapy or surgery over active surveillance as the preferred management option.

It is unclear, Dr. Godley said, whether the recommendation “will make the trend lines change a whole lot.” But, he continued, “it may make some physicians more comfortable with doing active surveillance themselves or referring patients to a group that is using it in their low-risk patients.”

Carmen Phillips

Cancer Research Highlights

Study Weighs Comparative Effectiveness of Low-risk Prostate Cancer Treatments

When it comes to the treatment of low-risk prostate cancer, a new comparative effectiveness study has concluded that the various approaches—including active surveillance, surgery, and radiation therapy—result in similar overall survival and tumor recurrence rates. However, compared with the immediate treatment options, active surveillance yields both a comparable net health benefit and more quality-adjusted life years for men age 65 and older, according to the economic model used in this study.

Researchers at the Institute for Clinical and Economic Review, which is based at the Massachusetts General Hospital’s Institute for Technology Assessment, examined the published evidence on different approaches being used to manage low-risk prostate cancer and the results of a simulation model that can project the long-term effects of each approach for large populations. Their review also included a comparison of the relative economic cost of each approach. The literature review and analysis were aided by an evidence review group of nearly 50 members that included top prostate cancer specialists from across the country, patient advocates, and representatives from medical device, pharmaceutical, and health insurance companies.

Their task was complicated, the reviewers acknowledged, by a lack of published trials that compared the different options head-to-head, as well as other factors. In addition to traditional open surgery (or radical prostatectomy), they assessed the clinical and cost effectiveness of robotic and traditional laparoscopic prostatectomy, as well as of brachytherapy and intensity-modulated radiation therapy. Because of the limited published data on proton beam radiation therapy, a treatment for localized prostate cancer that has gained popularity, the reviewers called it “premature” to offer any “judgments about its relative benefit or inferiority to other options.”

Lenalidomide Helps Delay Progression of Multiple Myeloma

Initial results from a phase III trial testing lenalidomide (Revlimid) as a component of multiple myeloma treatment indicate as much as a 58 percent reduction in the risk of disease progression for patients who used the drug, according to a news release issued by NCI. The trial was stopped early because the independent data and safety monitoring committee overseeing the trial found that the study demonstrated a longer time before the cancer progressed following autologous blood stem cell transplantation for those patients receiving the study drug than those receiving a placebo.

Lenalidomide was developed as a more potent yet safer version of thalidomide, and it has been approved by the FDA to treat myelodysplastic syndromes. The drug has also been used as a first-line induction therapy for multiple myeloma, a cancer that begins in plasma cells. Following induction therapy, myeloma patients typically receive autologous stem cell transplantation, which, if successful, may be followed by use of another drug as maintenance therapy to prevent disease recurrence or progression.

In this clinical trial (CALGB-100104), between 100 and 110 days after successful treatment with melphalan and transplantation of the patient’s own stem cells, which were harvested prior to chemotherapy, 460 patients who had no progressive disease were randomly assigned to receive lenalidomide or a placebo and took the drug until their disease began to progress. Most of the patients who received lenalidomide showed no evidence of progressive disease, while progression occurred in half of those taking a placebo within 778 days. Because of the trial’s early termination, there is no proof yet of an overall survival benefit.

“This study answers the important question for multiple myeloma patients regarding maintenance lenalidomide therapy starting at 100 days following transplant,” said the trial’s principal investigator Dr. Philip L. McCarthy, Jr., of Roswell Park Cancer Institute and the Cancer and Leukemia Group B. “We now know that prolonged maintenance therapy with lenalidomide when compared to placebo will delay disease progression.”

The Eastern Cooperative Oncology Group and the Blood and Marrow Transplant Clinical Trials Network also participated in this research.

Genetic Study of Lymphoma Tumors Points to Possible Therapies

A genetic study of lymphoma tumors has revealed the importance of a signaling pathway long suspected of playing a role in certain forms of the disease. DNA mutations were found in two components of the B-cell receptor signaling pathway in a subset of patients with diffuse large B-cell lymphomas (DLBCL). In additional experiments, the researchers showed that drugs could kill these lymphoma cells by blocking signals from this pathway.

Reporting their findings January 7 in Nature, Dr. Louis Staudt of NCI’s Center for Cancer Research and his colleagues estimate that the mutations are present in approximately one-fifth of the activated B-cell-like (ABC) subtype of DLBCL. Although the mutations are rare or nonexistent in the other subtypes, they appear to be important in the development of the disease for those patients who harbor the mutations.

The mutations affect two components of the B-cell receptor—the proteins CD79B and CD79A. DLBCL originates in B cells, which are part of the body’s immune system. When normal B cells encounter a foreign substance, proteins on the cell surface called B-cell receptors activate a cascade of signals that help the cell to survive and proliferate. In tumors with the mutations, the researchers observed “chronic active” B-cell receptor signaling, in which the tumor cells spontaneously activated this pathway.

“We have found mutations that affect a key signaling pathway in certain lymphoma tumors, and these mutations represent a genetic smoking gun that reveals the importance of this pathway in this type of cancer,” said Dr. Staudt. The findings suggest that future clinical trials of agents targeting this pathway should focus on patients with ABC DLBCL, he added.

In laboratory experiments, several compounds selectively killed lymphoma cells with chronic active B-cell receptor signaling, including dasatinib (Sprycel), which is approved for treating chronic myelogenous leukemia. The drug turned off the signaling pathway by inhibiting a component of it, and, as a result, the mutant cells died, the researchers said.

“This is a fascinating and elegant paper,” wrote immunologist Dr. Klaus Rajewsky of Harvard Medical School in an e-mail message. “A role for the B-cell receptor in lymphoma development, progression, and maintenance has long been suspected, and it will be interesting to see whether other signaling cascades downstream of this receptor contribute to these processes in other contexts.”

Vaccine Kills Residual Leukemia Cells in Patients Treated with Imatinib

In an early phase clinical trial testing a therapeutic vaccine in patients with chronic myeloid leukemia (CML) who were taking the drug imatinib (Gleevec), no cancer cells could be detected in 7 out of 19 participants for a median period of 22 months. The trial results were published in the January 1 Clinical Cancer Research.

Although imatinib has greatly improved survival for patients with CML, in most cases it does not entirely eradicate cancer cells in the body. Residual cancer cells can eventually cause a relapse.

The experimental vaccine was constructed from a CML cell line engineered to express a protein called granulocyte-macrophage colony-stimulating factor (GM-CSF), which helps draw immune cells to the site of the vaccination. These immune cells then encounter proteins (called antigens) found on the surface of the engineered CML cells. The researchers, led by Dr. B. Douglas Smith of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, hoped that, after encountering the antigens, the immune cells would be able to locate and kill CML cells elsewhere in the body.

Nineteen patients with chronic-phase CML enrolled in the trial; all of them had been taking imatinib (for a median of 37 months) but still had measurable tumor cells in the body. Patients continued to take imatinib during the trial. All patients received four vaccinations spaced 3 weeks apart. Side effects were mostly mild, although three patients experienced painful reactions at their injection sites.

After a median of 33 months of follow-up, 74 percent of the patients had a major molecular response (a major reduction in the number of CML cells in the bloodstream), and 37 percent had a complete molecular response (no CML cells detectable). CML cells remained undetectable in several patients at the time of publication (between 20 and 44 months after vaccination).

The researchers are planning a follow-up trial to determine if the benefits of immunotherapy persist after patients stop taking imatinib.

Cancer Cells Use Stored Fats to Fuel Aggressive Growth and Spread

An enzyme that is best known for breaking down stored fats in cells may be co-opted by cancer cells so that they can become more aggressive, Scripps Research Institute investigators have reported. Blocking the activity of the enzyme, MAGL, in cell lines of several aggressive cancers and in mouse models derived from the cell lines significantly tempered cell migration and tumor growth, Dr. Daniel Nomura and colleagues reported January 8 in Cell.

In the same mice in which MAGL levels were reduced, the research team found that a high-fat diet could kick start tumor growth. This latter finding, they wrote, “has provocative implications for the crosstalk between obesity and tumorigenesis.”

To conduct the study, the researchers first analyzed the expression of certain types of enzymes in cell lines of aggressive and non-aggressive melanoma, breast, and ovarian cancer. They found that MAGL levels were significantly elevated in the aggressive cell lines. They also found that when they increased MAGL levels in the non-aggressive cancer cell lines, the cancer cells became more aggressive.

MAGL promotes this aggressive posture in cancer cells, the researchers discovered, by unleashing free fatty acids (FFAs), which are integral components of cell membranes and other molecules in cells. The increased production of FFAs, in turn, stimulates the activity of a communication network of signaling lipids known to enhance the growth of tumors and movement of cancer cells. In the mice with inhibited MAGL expression fed a high-fat diet that led to increased tumor growth, the researchers noted, the tumors had significantly elevated levels of FFAs.

The study’s findings provoke “many exciting new questions,” wrote Drs. Jessica Yecies and Brendan Manning from the Harvard School of Public Health in an accompanying editorial. Among them is whether MAGL levels could “be used as a biomarker to predict the influence of dietary fats and obesity on tumor progression.”

Guest Director's Update

Targeting Barriers, including Insurance Coverage, to Improve Clinical Trial Participation

Lack of health insurance coverage for the routine cost of care for patients taking part in clinical trials—including doctor visits, hospital stays, clinical laboratory tests, and other expenses—is a major barrier to participation. Some insurance companies have chosen to deny coverage for the routine medical care a patient would receive whether or not he or she is participating in a clinical trial, thereby creating an out-of-pocket expense burden for patients who want to participate in a research study.

Andrea Denicoff (left) and Dr. Jeffrey Abrams (right)Andrea Denicoff (left) and Dr. Jeffrey Abrams (right)

Recognizing the threat that this burden poses to the individual care of patients, clinical trial participation, and in turn the improvement and advancement of cancer treatment, a number of state legislatures have worked with their regional insurance federations to draft laws or agreements that ensure standard care coverage, even when provided in a clinical trial, will not be denied.

The state legislatures of Texas, Oregon, and New Mexico recently passed laws that require this level of improved health care coverage for their residents. And in Nebraska, a voluntary agreement for insurance coverage was signed with the Nebraska Insurance Federation on November 6. Three Nebraska institutions in NCI’s Community Cancer Centers Program—Saint Francis Medical Center, Saint Elizabeth’s Regional Medical Center, and Good Samaritan Hospital—worked closely with many in the cancer advocacy community to help craft this agreement with insurers that will enable them to better serve their patients.

SCLD and Insurance Laws

To learn more about laws mandating insurance coverage for cancer patients in clinical trials, as well as laws pertaining to numerous other oncology issues, such as tobacco, care for specific cancer types, and cancer health disparities, go to NCI's State Cancer Legislative Database online.

Over half of states have added a routine health insurance provision for patients who are enrolled in clinical trials, as there is currently no federal legislation mandating such coverage. But that could soon change.

A clinical trials amendment was included in the health care reform bill passed late last month in the Senate. Senators Sherrod Brown (D-OH) and Kay Bailey Hutchison (R-TX) negotiated an agreement to include their amendment requiring insurers to cover routine care costs associated with clinical trials in the Senate health reform legislation (H.R. 3590). The provision covers cancer and other life-threatening diseases or conditions and applies to clinical trials funded or approved by the federal government, which includes NCI-funded and NCI-approved trials.

Cancer patients receiving health care coverage through federal programs—including the Department of Defense’s TRICARE, the Veterans Health Administration, and Medicare—have had their routine care covered when participating in federally sponsored cancer treatment trials for the past decade, and more private insurance companies are following the trend.

In addition to the routine coverage of care, the Centers for Medicare and Medicaid Services asked NCI to join in a pilot program several years ago that gave beneficiaries rapid access to promising new uses of technologies under controlled clinical trial conditions. The agency issued a National Coverage Determination (NCD) to cover the off-label use of certain anticancer drugs in nine specific NCI-sponsored clinical trials of colorectal cancer, as well as other cancer types.

This pilot has been successful because, as intended, it attracted more elderly patients to clinical trials; approximately one-third of the patients participating in these nine trials have been age 65 or older, representing a significantly larger proportion of older patients on trials than is typically seen. Inclusion of these older individuals in clinical trials is critical for developing evidence-based treatments for the large number of older Americans who suffer from cancer.

It has been challenging to recruit older adults to clinical trials, despite the increasing incidence of cancer with age, and the results from this pilot suggest that has been due in some part to lack of insurance coverage. The American Society of Clinical Oncology (ASCO) and geriatric oncology leaders have been actively encouraging oncologists to increase enrollment of older adults in clinical trials, and having Medicare explicitly provide details of the medical coverage for the nine trials appears to be a strategy to analyze for broader adoption.

Cancer Trial Accrual Symposium logo

To further heighten the critical component of recruitment issues such as these, NCI and ASCO are jointly sponsoring a scientific meeting on April 29–30 in Bethesda, MD, with special emphasis on strategies for targeting minority and underrepresented populations, including older adults, for enrollment in clinical trials. The “Cancer Trial Accrual Symposium: Science and Solutions” will feature key experts in the clinical trials arena who are actively conducting research and implementing strategies to improve physician and patient participation in clinical trials.

In addition to publishing the results of the symposium, NCI’s Office of Communications and Education plans to use the evidence presented at this meeting to help develop a new online resource, AccrualNet, to assist physicians and staff at clinical sites with trial recruitment.

Results from clinical trials form the basis for the modern oncologic therapies that are prolonging survival for many with cancer. Future advances could come more quickly if more patients participate in research. We encourage individuals who are leading efforts to improve accrual to consider participating in this novel symposium. Abstracts are due February 19, and further information can be found online.

Andrea M. Denicoff
Nurse Consultant, Clinical Investigations Branch, Cancer Therapy Evaluation Program
NCI Division of Cancer Treatment and Diagnosis

Dr. Jeffrey S. Abrams
Associate Director, Cancer Therapy Evaluation Program
NCI Division of Cancer Treatment and Diagnosis

Guest Commentary by Brenda Nevidjon

Oncology Nursing
This is the second article in a series of stories related to oncology nursing. Look for the symbol on the left in an upcoming issue for the next article in the series.

Health Care Changes: How Cancer Care Initiatives Can Help

Brenda Nevidjon

New year’s greetings from the Oncology Nursing Society (ONS). Depending on your perspective, 2010 is either ending a decade or beginning a new one. Nevertheless, we have begun a new year and one that brings hope that Congress will indeed come to consensus regarding health care reform.

In the discussions, debates, and deliberations about reform, nursing organizations, including ONS, have actively communicated with Congress and the White House about meaningful solutions to health care reform. As health care providers who spend the most time with patients, nurses know what their patients need and want and recognize that all of the health care disciplines must work together to increase access, ensure quality, and contain cost.

Five initiatives in cancer care could model solutions to challenges in the health care system: interdisciplinary care, patient navigation, survivorship planning, advanced practice nurse-led services, and expanding the science and its translation into care. ONS and our more than 37,000 members are focused on these initiatives.

Cancer care is built on a foundation of interdisciplinary respect and collaboration at the personal and organizational levels. Every day, physicians, nurses, pharmacists, social workers, and other professionals contribute their expertise to develop and deliver care plans. At the organizational level, ONS, along with the American Society of Clinical Oncology (ASCO), American Society for Therapeutic Radiology and Oncology, Association of Community Cancer Centers, Association of Oncology Social Work, and many other cancer professional organizations find common ground in advocating for people with cancer, in developing collaborative projects, and in educating our future oncology health care specialists.

The complexity of care and insurance coverage policies can be overwhelming to patients and families. Thanks to Dr. Harold Freeman’s vision, patient navigation is evolving and being integrated into many organizations. Other specialties are viewing this model as well. At a recent meeting of specialty nursing organizations hosted by ONS, the idea of navigators made sense to many whose members care for patients with chronic diseases. So, too, does a focus on survivorship, and the cancer community is leading the way in developing approaches to living with, through, and beyond a cancer diagnosis. Integral to survivorship is attention to the psychosocial care of patients that is often lacking because of insurance issues or the lack of staff with expertise. Nurses have a holistic approach to patient care, but a recent survey conducted by ONS shows that nurses do not have the time to spend with patients to provide psychosocial support. Whether the mental health parity legislation that has been passed will help people with cancer is yet to be determined.

The goals set by the National Priorities Partnership reflect the heart of nursing and provide opportunities for advanced practice nurses (APN), both nurse practitioners and clinical nurse specialists, to lead a transformation in cancer care delivery. APNs are not only partnering with oncologists in their practices but are leading specialized clinics, such as survivor follow-up, or services, such as palliative care or pain management. ASCO’s study, funded by Susan G. Komen for the Cure, on how nonphysician practitioners (such as nurse practitioners and physician assistants) can provide services to patients with cancer has the potential to confirm what APNs can offer as we face an increasing shortage of oncologists. This study is an example of translating health services science into practice just as basic science is translated into clinical care. Since 1981, the ONS Foundation has provided nursing research funding so that our nurse scientists can continue to seek new knowledge and innovative solutions to gaps in caring for patients with cancer.

In the next 10 years, health care is going to change and so will cancer care. What will not change is the need for highly qualified, well-educated, and compassionate oncology nurses. ONS will continue to provide the resources for nurses caring for patients and will collaborate with our colleagues to ensure that health care changes deliver quality and access for all with a cancer diagnosis.

Brenda Nevidjon
President, Oncology Nursing Society

Special Report

Ovarian Cancer Study Tests Lead Time of Potential Biomarkers

Teams of scientists around the world are working to develop ways to detect early signs of ovarian cancer in blood. Considerable progress has been made in understanding the disease, but as yet there are no proven effective biological markers or panels of biomarkers for early detection.

For the most promising markers to date, a critical issue is the question of lead time. That is, how long before the disease is diagnosed can the biomarkers distinguish individuals with and without the disease? A new report provides some answers and illustrates just how difficult it can be to find markers for this relatively rare and deadly disease.

In one of the first such studies, Dr. Garnet Anderson of the Fred Hutchinson Cancer Research Center and her colleagues tested the lead times for six promising markers, using prediagnostic blood samples from 34 women with cancer and a matched comparison group. All were participants in a cancer prevention study called the Carotene and Retinol Efficacy Trial.

The analysis revealed changes in three markers several years before diagnosis, but the markers typically did not give a strong signal until less than a year before diagnosis. By the time they were diagnosed just a few months later, most women had advanced tumors, the researchers reported online in the Journal of the National Cancer Institute on December 30.

“These three markers have the potential to move diagnoses of ovarian cancer a few months earlier, but we also found evidence of changes as early as 3 years before diagnosis,” said Dr. Anderson, who co-led the study with Dr. Nicole Urban.

The study demonstrates one reason that screening regimens based on markers—or panels of markers—can fail: because the blood levels of markers do not increase early enough, said Dr. Patricia Hartge of NCI’s Division of Cancer Epidemiology and Genetics in an accompanying editorial. This information could inform the design of future early detection programs of ovarian cancer, she wrote.

“The good news is that this study shows you can find informative markers within an interval of about a year of diagnosis,” Dr. Hartge said in an interview. “The bad news is we don’t have a foolproof marker that will be put into clinical use and save women’s lives.”

The three informative markers were CA-125, HE4, and mesothelin. (The others tested were B7-H4, decoy receptor 3, and spondin-2.) While CA-125 performed the best of the three, the combination of the three markers was more informative than CA-125 alone. Doctors routinely track blood levels of CA-125 in women with ovarian cancer to monitor a treatment or see whether the cancer has come back. Levels of the marker can rise for reasons other than cancer, however, and they are not always elevated in the disease.

CA-125 and HE4 were the top performers in a validation study reported last spring. “The new findings reinforce the idea that these two markers are currently the best and should be evaluated in future studies,” said lead investigator Dr. Daniel W. Cramer of Brigham and Women’s Hospital, who is supported by NCI’s Early Detection Research Network. The study was a joint effort and was cosponsored by NCI's Specialized Programs of Research Excellence (SPOREs). The lead investigator among ovarian SPOREs was Dr. Urban.

Dr. Cramer cautioned against being too pessimistic about the current results, noting that the study had limitations that could be avoided in future studies. For instance, blood from the women was not drawn annually on a regular schedule as would happen in formal screening studies. The study was also small and the women were all past or current heavy smokers, so it is not clear how the findings would apply to other groups.

“When it comes to early detection for ovarian cancer, we’re not there yet,” said Dr. Anderson. “But we’re still working hard, and we still hold out hope that we’re going to find something with a significant impact for women. We think the three markers are a reasonable core we can build on and add other markers to.”

Some creative new approaches might be needed for finding informative biomarkers. Most potential biomarkers to date have come from studying the blood of women with advanced disease, but this may not be the best approach for finding markers that are elevated early in the disease, the study authors said.

Many experts agree that ovarian cancer screening will eventually involve testing biomarkers as well as an imaging component. Two ongoing trials are evaluating combinations of CA-125 and transvaginal ultrasound. The UK Collaborative Trial of Ovarian Cancer Screening requires both CA-125 and transvaginal ultrasound to be positive before referring women to surgery; the NCI-sponsored Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial requires that one or the other is positive.

“Most of us believe that multimodal screening will be needed and that means combining biomarkers with some sort of imaging technology,” said Dr. Anderson. “But we will need improvements in both imaging technologies and in biomarkers to meet our goals of developing effective screening strategies.”

––Edward R. Winstead


Oncology Nursing
This is the third article in a series of stories related to oncology nursing. Look for the symbol on the left in an upcoming issue for the next article in the series.

New Cancer Drugs Bring New Side Effects, and Nurses Respond

A patient with a moderate rash following treatment with an EGFR-inhibitor. (Image courtesy of Pamela Viale) A patient with a moderate rash following treatment with an EGFR-inhibitor. (Image courtesy of Pamela Viale)

It’s a consistent finding among patients who take cancer drugs known as EGFR inhibitors: Those who develop a severe rash, often on the face, tend to have better outcomes than those who don’t. But this rash is not inconsequential. Along with other dermatologic side effects associated with these drugs, which include increasingly popular agents such as cetuximab (Erbitux) and erlotinib (Tarceva), the rashes can produce such significant discomfort, distress, and even life-threatening infections that either the physician or the patient often decides to delay or stop treatment.

For oncology nurses, who, along with physician assistants and nurse practitioners, often take the lead on managing related side effects from cancer treatments, the skin toxicities induced by EGFR inhibitors represent a significant clinical challenge: addressing the unique toxicities of the expanding arsenal of targeted therapies. To date, unfortunately, there are few evidence-based treatments for these side effects.

“We’ve traditionally done a good job of managing problems like myelosuppression, mucositis, and nausea,” said Ms. Pamela Hallquist Viale, an oncology nurse practitioner and nursing consultant in Saratoga, CA, referring to some of the side effects common with traditional chemotherapy. “The targeted therapies work differently, so they have different side effects. And now we’re just starting to become more familiar with how to best manage them.”

How and How Much

As for why the skin is unduly affected by these agents, certain components of the epidermis also have an abundance of receptors to the epidermal growth factor, as do the tumors for which these drugs have proven effective. Blocking the receptor causes a torrent of events—including inflammation and thinning of the skin—that can produce skin damage, most often the telltale rash on the face and upper torso, but also delayed effects such as eyelash lengthening and cracked fingernails. The rash has yet to be validated as a prognostic marker of response to these drugs.

As EGFR inhibitors have transitioned from clinical trials to the clinic, a more accurate assessment of the incidence and severity of the rash is beginning to emerge. The vast majority of patients will experience some form of rash following treatment with an EGFR inhibitor. And according to one survey of oncologists, up to one-third of patients had to have their EGFR inhibitor treatment discontinued as a result of a rash.

Dr. Lori Williams, a researcher and oncology nurse at The University of Texas M.D. Anderson Cancer Center, has a related concern. As EGFR inhibitors begin to be used in patients with earlier stage disease, she said, “I’m worried that there will be patients trying to carry on a normal life, and they might stop taking drugs because they’re scared of what they look like,” she said. “Facial rashes can be just as devastating as hair loss.”

Improving Management

Although there is a better appreciation for the side effects that EGFR inhibitors can inflict on patients, in relative terms, these are still early days for the drugs and very few randomized trials have been conducted to provide insight into how best to manage their side effects. Results from two trials have been published, with one study conducted at Memorial Sloan-Kettering Cancer Center (MSKCC) demonstrating modest efficacy in decreasing the severity of rash when patients use the oral antibiotic minocycline.

In the absence of published evidence, explained Ms. Beth Eaby, an oncology nurse at the University of Pennsylvania’s Abramson Cancer Center, the oncology community has leaned heavily on guidance from dermatologists about how best to handle the skin toxicities, which, in addition to the so-called papulopustular rashes on patients’ faces, also include severely dry skin.

“We have taken a lot from what the dermatologists have taught us, and what they say has worked in patients receiving these drugs,” she said.

Even so, managing these side effects often has come down to trial and error. The papulopustular rash is a case in point, explained Ms. Viale. Although it has been referred to as an “acne-form rash”—a term that is now widely discouraged—this severe irritation does not respond to traditional acne medicines, she said. Some acne medications actually make the problem worse, drying out the skin and abetting the development of infections. Clinical experience has shown that thick emollient creams, however, can be quite effective.

Because of the quality-of-life impact of skin toxicities and the potential to interfere with life-extending treatments, several groups have developed recommendations and algorithms on how best to manage them, including a 2009 report developed by a multidisciplinary working group convened by the National Comprehensive Cancer Network.

The data that are available suggest that prophylactic approaches to managing the rashes may have promise. In addition to the MSKCC trial, there are also the findings from a small, single-center clinical trial presented at the 2009 American Society of Clinical Oncology annual meeting. Patients in the trial had metastatic colorectal cancer and were to receive the EGFR inhibitor panitumumab (Vectibix). They were randomly assigned to receive either a reactive treatment after therapy had begun or a prophylactic approach initiated just before treatment that included a 6-week regimen of hydrocortisone, moisturizers, a moderately protective sunscreen (SPF 15 or higher) when needed, and the antibiotic doxycycline. Patients in the prophylactic arm had a greater than 50 percent reduction in severe skin toxicities and reported a better quality of life.

Dr. Williams, meanwhile, is working with dermatology colleagues at M.D. Anderson to better characterize these rashes. Although there is an established NCI-supported system for reporting and categorizing “adverse events,” including rashes, during the course of clinical trials, the work is part of an effort to establish reporting criteria for dermatologic toxicities that may be more effective in helping to gauge the seriousness of the rash and the impact of therapies on it. One idea under consideration, she explained, is using pictures of actual rashes that could help more precisely establish the different degrees of severity.

Because many of the targeted therapies are oral and taken at home, an image-based system for patients to record their symptoms could be valuable. “The fact that so many [of the targeted therapies] are oral is a big issue,” Dr. Williams noted. The increased availability of oral chemotherapy agents, she continued, “to some extent, has given health professionals a sense of loss of control over side effects.”

So, perhaps more than ever, the need to educate patients about how to understand and cope with potential side effects is critical. “We’ve got to reinforce to patients how important it is to do things like moisturize frequently or use a high SPF sun screen if they’re going to be in the sun for an extended time,” Ms. Viale said. “We’ve got to integrate that teaching component into our care, and we’re seeing progress there.”

Carmen Phillips

A Closer Look


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

Video Eases End-of-Life Care Discussions

Despite the extraordinary progress made in cancer treatment over the past several decades, the disease remains the second-most common cause of death in the United States. Every year, more than 500,000 people with cancer are confronted with the need to make end-of-life care decisions. These decisions can be complex, not only in terms of the emotional issues but also in terms of the wide range of medical options, which can have different goals.

 'I think what videos allow us to do as physicians is to broach difficult topics in a way that patients can understand what we're talking about.' -Dr. Angelo Volandes

These discussions can be further hampered by poor communication between physicians and patients, and by the fact that patients often have limited understanding of medical terminology. Uninformed decision making can lead to patients choosing end-of-life care that is not in line with their values or with how they picture their last days of life, which in turn can cause distress for them and their loved ones.

“Often when these conversations about end-of-life care are held in the abstract, we’re asking our patients to imagine things that are often unimaginable, and with which they have very little experience,” said Dr. Angelo Volandes, an internal medicine physician at Massachusetts General Hospital. “We want to make sure that patients have all the information required to make an informed decision.”

Viewing Reality

Dr. Volandes and his colleagues from several hospitals in Boston and Pittsburgh are studying what role patient education plays in the types of end-of-life care that are ultimately chosen by patients. Broadly, end-of-life care can be grouped into three categories: life-prolonging care, which includes extreme measures such as cardiopulmonary resuscitation (CPR) and the use of mechanical ventilators; basic medical care, which includes medicines for infections or other treatable problems; and comfort care, which aims to keep patients pain free and relieve their symptoms but does not include life-prolonging treatment or medications for treatable conditions.

Many patients with advanced cancer choose life-prolonging care, in spite of its limited benefits for seriously ill people. (For example, CPR fails in more than 90 percent of people with advanced cancer. And of the less than 10 percent that do survive CPR and mechanical ventilation, most experience medical complications from the procedures.)

“I fear that many people may have been misinformed about the reality of what these medical interventions can provide,” said Dr. Volandes. “I think, when we’re having these conversations, often the words that our patients are using or the images in their mind are more reflective of the media, of television, of the latest episode of Grey’s Anatomy, or other such programs, rather than the clinical reality.”

Recently, the researchers tested whether a video depicting end-of-life treatment options would be better than traditional verbal explanations in helping patients understand the types of medical technology used in end-of-life care. They enrolled 50 patients with malignant glioma into a randomized clinical trial, assigning patients to a verbal explanation group (27 patients) or to a video group (23 patients). Patients in the verbal explanation group listened to a narrative describing the three categories of end-of-life care and the limitations of each type of care. Patients in the video group listened to the same verbal narrative and then watched a 6-minute video that included the same narrative, but matched to visual images of the care being described. The results appear in the January 10 issue of the Journal of Clinical Oncology.

The video included simulations from all three categories of end of life care, including CPR and intubation, administration of intravenous antibiotics, oxygen use, and receipt of pain medication. The appropriateness and accuracy of the simulations were reviewed by 10 oncologists, 3 critical care specialists, 3 palliative care physicians, and 3 medical ethicists, and edits to the script were made as needed.

Each patient’s preference for type of end-of-life care was recorded after exposure to the narrative or the video, as well as their willingness to undergo CPR. The researchers also asked about their understanding of the types of care described and their comfort with the video experience.

Truly Informed Decisions

Participants in the video group reported a larger increase in knowledge of the medical interventions being discussed. “Patients told us ‘I heard you, but I didn’t understand you. But once I saw the pictures, I understood what you meant by those words,’” recounted Dr. Volandes. All of the participants in the video group said they would definitely or probably recommend the video to another cancer patient.

After listening to the verbal narrative, 11 participants said they were willing to undergo CPR and 16 declined. After watching the video, only 2 were willing to undergo CPR and 21 declined.

Among those who only listened to the verbal narrative, 7 people preferred life-prolonging care, 15 preferred basic medical care, and 6 preferred comfort care. After watching the video, no participants preferred life-prolonging care, 1 preferred basic medical care, 21 preferred comfort care, and 1 was unsure of his preference.

Visual Learning

“When you have these difficult conversations with patients, it’s not just about what they want and how they feel—the psychology of this devastating disease,” commented Dr. Ann O’Mara, head of Palliative Care Research in NCI’s Community Oncology and Prevention Trials Research Group. “We have to teach patients because, even at the end of life, there are pieces of knowledge that they need in order to make informed decisions.”

“I think what videos allow us to do as physicians is to broach difficult topics in a way that patients can understand what we’re talking about,” said Dr. Volandes. “We need to adapt to how our patients learn today. We’re a media society. We’re visual learners, and video is one additional means by which we as physicians can educate our patients.”

The researchers are beginning a large multicenter study in 2010 that will test use of the video in a diverse group of patients with different types of cancer, from both rural and urban hospitals.

—Sharon Reynolds


Doctors Less Likely to Discuss End-of-Life Care Options with Terminally Ill Patients Who Feel Well

To determine whether doctors follow national guidelines to discuss end-of-life issues with patients who have a life expectancy of a year or less, researchers led by Dr. Nancy Keating of the Brigham and Women’s Hospital and Harvard Medical School in Boston surveyed a national sample of 4,074 doctors who care for cancer patients. They found that most did not wish to discuss end-of life issues, such as preferences for resuscitation or where patients would like to die, as long as their patients are feeling well. Instead, they preferred to wait “for onset of symptoms or until there are no more nonpalliative treatments to offer,” wrote the authors. Physicians who felt knowledgeable about discussing end-of-life care options were more likely to review do-not-resuscitate orders, hospice care, and preferred place of death with their patients in the present, rather than waiting to do it. “Education and patient, physician, and institutional interventions may be necessary to increase advance care planning for terminally ill cancer patients,” concluded the authors. The results were published online January 11 in Cancer.

Featured Clinical Trial

PARP Inhibitor and Metronomic Chemotherapy for Refractory Cancer

Name of the Trial
Phase I Study of ABT-888 and Metronomic Cyclophosphamide in Patients with Refractory Solid Tumors or Lymphoma (NCI-09-C-0048). See the protocol summary.

Dr. Shivaani Kummar Dr. Shivaani Kummar

Principal Investigator
Dr. Shivaani Kummar, NCI Center for Cancer Research

Why This Trial Is Important
Many chemotherapy drugs kill cancer cells by causing damage to DNA. However, cells can employ a number of mechanisms to repair this damage. When cells experience drug-induced breaks in their DNA strands, proteins called PARPs bind to the DNA at the sites of the breaks and recruit other proteins involved in DNA repair. This process can allow cancer cells to continue to survive and grow despite the damage caused by chemotherapy treatment.

The oral drug ABT-888 blocks the activity of PARP proteins, thereby interfering with the ability of cancer cells to repair their DNA. Combining ABT-888 with a chemotherapy drug that causes DNA strand breaks, such as cyclophosphamide, may result in a greater antitumor effect.

In this clinical trial, patients with solid tumors or lymphomas that have not responded to previous treatment (refractory cancer), or for which no effective treatment exists, will receive ABT-888 and metronomic cyclophosphamide. The term metronomic refers to the administration of drugs at lower than normal doses more frequently than usual. Metronomic chemotherapy may work differently from treatment with the same drugs at higher doses. Metronomic cyclophosphamide still causes DNA damage, but also exhibits an antiangiogenic effect, is less toxic, and can be given in pill form daily, making it more convenient for patients than intravenous cyclophosphamide.

Doctors will assess the safety, tolerability, and pharmacokinetics of this combination, as well as establish the maximum tolerated dose of ABT-888 and examine the effects of treatment on molecular markers in blood and tumor samples.

“Our goal with this study is to come up with a regimen that is not only effective but also well tolerated and orally available,” said Dr. Kummar.

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

An archive of "Featured Clinical Trial" columns is available at /clinicaltrials/ft-all-featured-trials.

CDC Update

HPV Vaccine Added to Adult Immunization Schedule

The CDC’s Advisory Committee on Immunization Practices has updated its 2010 Recommended Adult Immunization Schedule to include either of the FDA-approved human papillomavirus (HPV) vaccines for women ages 19 to 26 who have not been immunized previously against HPV. The updated recommendations appeared January 5 in the Annals of Internal Medicine.

As of October 2009, the FDA had approved two different vaccines to prevent infections from two strains of HPV associated with more than 70 percent of cervical cancers. The vaccine Cervarix protects against HPV-16 and HPV-18, the two most common cancer-causing strains of the virus. The second vaccine, Gardasil, protects against HPV-16 and HPV-18 and against two strains of HPV that cause genital warts.

According to the schedule, either HPV vaccine would optimally be given to girls between the ages of 11 and 12, but women up to age 26 may benefit from “catch-up” vaccination. Both HPV vaccines are most effective when given before a woman becomes sexually active.

In addition, for the first time the CDC included a permissive recommendation that young males ages 9 to 26 may receive Gardasil for the prevention of genital warts, although questions remain “about whether vaccinating men will aid the development of herd immunity to reduce the societal burden of HPV-associated disease,” explained Drs. Robert H. Hopkins, Jr., and Keyur S. Vyas of the University of Arkansas for Medical Sciences in an accompanying editorial. Herd immunity results when enough members of a population are vaccinated to provide protection to unvaccinated members because a disease will have few opportunities to spread.

No studies comparing the effectiveness of Gardasil and Cervarix head-to-head have been published to date.


In Memoriam: NCI's Dr. James W. Jacobson

Dr. James JacobsonDr. James Jacobson

Dr. James W. Jacobson, acting associate director of the Cancer Diagnosis Program (CDP) in NCI’s Division of Cancer Treatment and Diagnosis (DCTD), succumbed to complications from leukemia on December 23, 2009. Dr. Jacobson joined NCI in 1991 as a program director for genetics. In 1997, he became the chief of what is now the Diagnostic Biomarkers and Technology Branch and continued to hold that position when he became acting head of CDP in 2008.

Dr. Jacobson made many important contributions to NCI and the cancer research community through his leadership in developing and implementing major translational research initiatives. Most recently, he spearheaded NCI’s effort to initiate a national laboratory effort to characterize patient tumors at the molecular level and to validate predictive molecular assays in phase III clinical trials.

“He was a guiding light in developing the Strategic Partnering to Evaluate Cancer Signatures (SPECS) initiative, which has allowed large collaborative research groups to define the critical components of comprehensive molecular analyses and begin incorporating them into clinical practice,” said Dr. James H. Doroshow, DCTD director. “SPECS could not be accomplished under the traditional R01 grant, and Jim was instrumental in setting up a new type of award to push the program forward. He was an incredibly generous, kind, and encouraging leader who leaves a legacy of researchers who will continue his pursuit of reliable molecular information that will inform clinical decision making for people with cancer.”

Dr. Jacobson also played a major role in the development of the Innovative Molecular Analysis Technologies (IMAT) program, and he developed and led the Director’s Challenge initiative. Dr. Jacobson received an NIH Award of Merit for his role in the early implementation of the extramural component of the Cancer Genome Anatomy Project. Throughout his career, Dr. Jacobson convened workshops to bring scientists from different research areas in industry, academia, and government together to discuss how to improve technology development and application for patient benefit.

Dr. Jacobson graduated from Dartmouth College, earned his doctoral degree at the University of Utah, and did post-doctoral research at Yale University prior to joining the faculty of the University of Georgia. He worked for the Genex Corporation for 12 years prior to joining NCI.

NCI Sponsors Symposium on Glycomics in Cancer Detection and Diagnosis

On January 19, NCI will sponsor a meeting of the Alliance of Glycobiologists for Detection of Cancer and Cancer Risk, titled “Integrating Glycomics with other ‘Omics’ in Cancer Detection and Diagnosis.” The open symposium will be held at the Stanford University School of Medicine Bechtel Conference Center. In addition to the university, collaborators include SRI International and the OMICS Publishing Group. The Alliance is a trans-NIH initiative to discover, develop, and clinically validate cancer biomarkers for early detection and diagnosis by targeting complex carbohydrates. View the agenda and register for the meeting online.

NCI Symposium Addresses Biospecimen Quality in Cancer Research

2010 Biospecimen Research Network Symposium logo

Registration is now open for the NCI’s 3rd Annual Biospecimen Research Network Symposium, “Advancing Cancer Research Through Biospecimen Science.” The event will be held March 24–25 in Bethesda, MD.

The symposium will address the significant impact biospecimen quality has on cancer research and molecular medicine. Participants will hear presentations and engage in interactive discussions about the issue of biospecimen variables and ways to address it. Hosted by NCI’s Office of Biorepositories and Biospecimen Research, the meeting will bring together leaders in the fields of biospecimen research, genomics, proteomics, oncology, pathology, biobanking, hospital administration, and pharmaceuticals, as well as patient advocates.

Go online to register and to get the latest information about speakers, topics, and participation.

NCI's Recovery Act Web Site Showcases Funded Researchers

NCI’s Recovery Act Web site is bringing ARRA-funded research to life through a new feature on the people behind the science. The Impact on Communities page showcases work being done in cancer research and the impact stimulus funding is making in communities across the country. Under the heading Funded Researchers, visitors can scroll through profiles and photos of various researchers funded by the Recovery Act and learn about the projects that are shaping the future of cancer care.

If you are a recipient of Recovery Act funding and would like to add your profile to the site, contact the staff that update the site with new submissions.