Leading lung cancer researchers said two studies presented this week at the American Society of Clinical Oncology (ASCO) annual meeting in New Orleans may very well change the standard of care in the treatment of patients with early-stage non-small-cell lung cancer (NSCLC). Both studies involved the use of chemotherapy following surgery in patients with early stage NSCLC at high risk for recurrence and found that the approach provided a significant survival benefit when compared with surgery alone.

"Taken together, the results of these studies show conclusively that postsurgical chemotherapy does significantly improve survival," said Dr. Scott Saxman of the Cancer Therapy Evaluation Program of the National Cancer Institute (NCI).

The first study, conducted by the National Cancer Institute of Canada (NCIC) Clinical Trials Group, in conjunction with clinical trials groups supported by the U.S. National Cancer Institute, compared postoperative observation versus a chemotherapy regimen of cisplatin and vinorelbine.

Overall survival in the postoperative chemotherapy group was 94 months compared with 73 months for those in the surgery-alone group; 69 percent of participants who received chemotherapy were alive after 5 years compared with 54 percent in the surgery-alone group. The second study compared chemotherapy with carboplatin and paclitaxel (Taxol) after surgery with no chemotherapy. This study - conducted by the Cancer and Leukemia Group B, one of NCI's cooperative clinical trials groups - was stopped earlier than planned when it became clear that the chemotherapy group had significantly better survival.

Chemotherapy reduced the risk of death from lung cancer by 49 percent, the researchers reported. After 4 years, 71 percent of the patients receiving chemotherapy were alive compared with 59 percent who had surgery alone.

Both study results offer "compelling data to move toward a new standard of care" in this patient group, said Dr. Timothy L. Winton, principal investigator of the NCIC-led study. They also show, he added, "that we have to treat this disease like a systemic disease and not expect local treatments like surgery to be curative on their own."

"The ASCO meeting also saw the release of new findings from a trial testing a new targeted therapy for the treatment of late-stage NSCLC. It compared the effects of erlotinib (Tarceva), an epidermal growth factor receptor (EGFR) inhibitor, with placebo in patients whose disease had progressed after one or two courses of chemotherapy. Patients given erlotinib showed improvements in progression-free survival and freedom from symptom deterioration. Median overall survival was 6.7 months with erlotinib versus 4.7 months with placebo.

The study "is the first EGFR-targeted therapy to show a significant survival benefit in this group of patients," said the trial's principal investigator, Dr. Frances Shepherd of Princess Margaret Hospital in Toronto.

"Since this study began, new information has emerged suggesting that mutations in the EGFR protein are important predictors of response to this class of drugs," noted Dr. Saxman, referring to two recent studies that showed NSCLC patients with EGFR mutations were more likely to respond to the EGFR inhibitor gefitinib (Iressa). "Analysis of the tissues of patients who participated in this trial will be important to determine whether those most likely to benefit can be identified."

The annual ASCO meeting, which concluded today in New Orleans, is always an exciting time for the cancer community. Results from many significant studies are released, and researchers and clinical oncologists from the United States and many other nations learn from leading experts about changes in treatment, the latest in prevention and diagnostics, and, increasingly so these days, advances in the area of survivorship.

Thus it's an ideal time for the release of the Annual Report to the Nation on the Status of Cancer, a collaborative effort of the American Cancer Society, the Centers for Disease Control and Prevention, NCI, and the North American Association of Central Cancer Registries. This year's report, which covers data from 1975 to 2001, delivers some excellent news: Americans' risk of being diagnosed with cancer continues to decline, while survival rates for many cancers continue to improve. Overall, observed cancer incidence rates dropped 0.5 percent annually from 1993 to 2001, while death rates from all cancers dropped 1.1 percent each year during the same period.

Gains in several specific cancer sites are especially noteworthy. In women, for example, lung cancer incidence rates have dropped for the first time and death rates have leveled off. Progress in preventing and treating lung cancer is critically important - it is the number one cause of cancer death, largely because more than 50 percent of cases are diagnosed when the chances of survival are markedly diminished. And as the lead story in this week's Bulletin shows - we are making progress.

The gains made in childhood cancers represent another sterling example of progress. Over the past 20 years, we have seen an absolute survival rate increase of 20 percent in boys and 13 percent in girls. A child diagnosed with cancer now has a greater than 75 percent chance of survival, something attributable to a number of factors, including a very critical one: quality of care. Approximately 70 percent of cancer patients under age 15 are treated in pediatric cancer treatment centers, where they are more assured of receiving state-of-the-art, evidence-based care.

Just as this year's Report delivers good news, it also brings with it some disappointments - especially the continued disparities in cancer incidence and death rates among different racial and ethnic populations. Compared with non-Hispanic whites, the risk of cancer death from all sites combined was higher in every racial and ethnic population, except Asian/Pacific Islanders. African American men, for example, have a higher risk of dying of 12 cancers, compared with white men. The trend was nearly identical for African American women. NCI is committed to eliminating such disparities and, as a community, this must be one of our top priorities.

The President's Cancer Panel also issued an important new report last week that highlights the unique issues and problems that cancer survivors face (see President's Cancer Panel Finds Unmet Needs Among Cancer Survivors). Together these two reports provide a snapshot of where we have been and some valuable insight into where we are headed. They also show that progress brings its own challenges - from finding the best ways to harness new technologies to ensuring that everyone has equal access to quality oncology care. I am confident that, working together, we are up to each and every challenge. As we overcome each obstacle and solve each problem, we move closer and closer to a very noble goal.

Dr. Andrew C. von Eschenbach
Director, National Cancer Institute

On June 4, the President's Cancer Panel issued Living Beyond Cancer: Finding a New Balance, an examination of effects of cancer treatment over a life span and among separate age groups. The advisory group's report is based on a recently completed year-long series of meetings with nearly 200 cancer survivors, their caregivers, health care providers, and insurers.

With dramatic improvements in detection and treatment, there are now almost 10 million American cancer survivors, a jump from 3 million in 1971. "Now we're recognizing that their challenges often continue long after their treatment concludes," said panel chair Dr. LaSalle D. Leffall, Jr., Charles R. Drew Professor of Surgery at Howard University College of Medicine and chairman of the board of the Susan G. Komen Breast Cancer Foundation.

Survivors reported infertility or pregnancy complications, premature aging and heart disease, and late-appearing psychosocial effects, including depression and anxiety. They also reported not receiving adequate documentation from their physicians when treatment ends and lack of a thorough, follow-up health plan that covers future check-ups, possible long-term effects, and information on recurrence. And while patients may regard their cancer as beaten, insurance companies and employers may work from different sets of rules that are not always understandable or consistent.

The panel, consisting of Dr. Leffall, five-time Tour de France winner and cancer survivor Lance Armstrong, and Dr. Margaret L. Kripke, executive vice president and chief academic officer of the University of Texas M.D. Anderson Cancer Center, noted that the age at diagnosis and treatment creates specific needs and issues. Children diagnosed before age 15, for example, may need help becoming reacclimated to the classroom environment.

Adolescents or young adults might experience psychosocial problems such as depression and limited social skills. Transitioning from pediatric to adult medical care is particularly difficult. Meanwhile, survivors aged 60 and older may face job loss or forced retirement and reduced benefits.

The panel recommended that all survivors be given a complete record of their diagnosis and treatment, as well as a plan for follow-up health care that includes a schedule of screenings and examinations for known late effects of therapy. In addition, the panel endorsed the need for an electronic medical record (EMR) and called upon the U.S. Department of Health and Human Services to ensure that the concerns of cancer survivors are addressed in planning for the implementation of EMRs.

The NCI Office of Cancer Survivorship (OCS) already is working to address some of the issues highlighted in the report. Specifically, OCS is supporting efforts on the part of the oncology community to develop a standardized treatment summary form and follow-up care guidelines. A number of related research initiatives will improve our understanding of how cancer affects family members and caregivers across the life span and whether interventions to help family members cope improve the cancer survivor's health; what information needs to be shared between survivors and health care professionals and the role of new media and technology in the distribution of that information; and how sociocultural variables affect quality of life and other aspects of survivorship.

The full report and executive summary can be found at http://pcp.cancer.gov. For more information on NCI's Office of Cancer Survivorship, go to http://dccps.nci.nih.gov/ocs/.

NCI has formed the Clinical Trials Working Group (CTWG) to advise the National Cancer Advisory Board (NCAB) on issues related to the institute's cancer clinical trials program. The CTWG is chaired by Dr. James Doroshow, director of NCI's Division of Cancer Treatment and Diagnosis; and is co-chaired by Dr. Howard Fine, chief of the Neuro Oncology Branch of NCI's intramural program, and Dr. Kenneth Buetow, director of NCI's Center for Bioinformatics. The CTWG's members include representatives from a broad range of oncology perspectives including the NCI intramural and extramural programs in cancer therapy and prevention, cancer centers, SPOREs, the clinical cancer cooperative groups, CCOPs, cancer patient advocacy groups, the pharmaceutical industry, the U.S. Food and Drug Administration, the Center for Medicare & Medicaid Services, and a variety of other clinical oncology disciplines.

The working group was charged by NCI Director Dr. Andrew C. von Eschenbach to advise the NCAB and its Subcommittee on Clinical Investigations on the development, conduct, infrastructure, and support necessary for the optimal coordination and future progress of NCI extramural and intramural clinical research trials including diagnosis, treatment, and prevention studies.

"Clinical trials are essential for the improvement of the quality of life of our patients and are a critical part of the research process," says Dr. Doroshow. "They allow basic scientific observations to progress from the laboratory to become the standard of care." There has never been a group specifically charged with the oversight of the clinical trials process throughout NCI. Using as its starting point the recommendations of NCI's Armitage Report and NCAB's P30/P50 Working Group Report, the CTWG will take on this task and will also develop a blueprint for a cancer clinical trials system of the future."

The goals of the CTWG include: establishing a process for the ongoing oversight of NCI-supported clinical trials; enhancing mechanisms for prioritizing clinical trial development; increasing the coordination of clinical trial activities across the entire spectrum of clinical trial venues supported by NCI in conjunction with the FDA, other governmental agencies, and the pharmaceutical industry; improving the timeliness of clinical trial completion, including regulatory issues that affect the rate at which studies can be implemented; and providing a blueprint for a clinical trials system for the future.

"A primary challenge in clinical cancer research is to effectively integrate experimental and clinical data, generated from different types of technologies, into a single system with a common language that cancer researchers can easily access," says Dr. Doroshow.

"To achieve this goal, clinical trial researchers must use a consistent, common language for managing and organizing information across the entire spectrum of clinical investigation, from early therapeutic studies to cancer prevention trials," Dr. Doroshow continues. "NCI's ability to develop informatics infrastructures linking investigators across the country and internationally is crucial to this working group's success. To that end, the CTWG will play an important advisory role in the development of caBIG. Major changes in bioinformatics will provide the enabling technology that will allow both patients and their physicians to participate in clinical trials more efficiently and with enhanced access. Thus, this technology really is the basis for considering how clinical trials of the future will be conducted."

CTWG will regularly communicate its mission, goals, and progress to the NCAB, its Subcommittee on Clinical Investigations, and other constituencies. These include NCI and other appropriate federal agencies; community oncologists; research institutions; cancer advocacy, voluntary, and professional organizations; clinical trial participants and patients; and the general public.

"Through these clinical trial constituencies, the CTWG will work to open intramural and extramural lines of communication," says Dr. Doroshow. "This will bring together a more diverse research community to improve the procedures and outcomes of clinical research."

For additional information on the CTWG and its activities, go to http://integratedtrials.nci.nih.gov.

Statins May Significantly Reduce Colorectal Cancer Risk

Use of cholesterol-lowering drugs called statins reduced the risk of colorectal cancer in adults by 51 percent, researchers from the University of Michigan reported last week at the ASCO annual meeting in New Orleans. The population-based, case-control study compared 1,849 Israeli colorectal cancer patients with 1,959 controls. After controlling for potentially confounding factors such as family history, ethnicity, and aspirin use, the reduction in risk was 46 percent. Statins are the number one selling class of drugs in the United States and two statins, atorvastatin (Lipitor) and simvastatin (Zocor) and are the two top selling drugs, respectively.

The study results, said senior investigator Dr. Stephen B. Gruber, are "very exciting and potentially good news." But despite the study's results, he cautioned, "this is an observational study and should not yet change the standard of care or the indications for statins.

"The findings appear to reinforce findings from several earlier studies. A study published in the June 1 issue of Cancer, for example, showed that 5 years of sustained statin use decreased the risk of breast cancer in postmenopausal women.

As for the mechanism by which statins may reduce colorectal cancer risk, Dr. Gruber noted that several cholesterol-dependent molecular targets are also important cancer genes, including the genes Ras and Rho.

"Cholesterol regulates a lot of cellular proteins, so it's not surprising that [statins] may have diverse effects." His group, Dr. Gruber added, is pursuing the development of a study to examine the impact of statin use on people at high risk for colorectal cancer.

"There is a mechanistic basis for this finding," said Dr. Ernie Hawk of the NCI Division of Cancer Prevention. "We've been waiting to see whether more mature observational data like these would show a preventive benefit. There is potential with these drugs, but these findings are still very preliminary. They need confirmation in additional mechanistic and observational studies, and we need to explore their use in early phase trials before we can really say whether statins will offer any benefit in colorectal cancer risk reduction." NCI is interested in the chemopreventive potential of these agents, Dr. Hawk added, and is pursuing two phase II trials to test whether they can prevent melanoma and colon cancer.

Bortezomib Shown to Delay Disease Progression in Multiple Myeloma

Early results from an international phase III trial show that bortezomib (Velcade), a targeted cancer drug, is more effective than a standard therapy at delaying disease progression in patients with multiple myeloma that has relapsed or become resistant to other treatments. The results, presented at the ASCO annual meeting by the study's principal investigator, Dr. Paul G. Richardson of the Dana-Farber Cancer Institute, were so encouraging that the trial was stopped early and patients on the standard therapy, dexamethasone, were allowed to switch to bortezomib.

Conducted at 94 centers in the United States, Canada, Europe, and Israel, the study enrolled 669 patients with relapsed or resistant multiple myeloma, a disease that kills about 12,000 people per year in the United States.

After a median follow-up of 8 months, disease-free progression was 5.7 months for patients treated with bortezomib versus 3.6 months for dexamethasone. After 1 year, 89 percent of patients in the bortezomib group were still alive, compared with 65 percent of those in the dexamethasone group. To date, there have been 48 deaths in the bortezomib group, compared with 81 among those given dexamethasone.

"Bortezomib is a very promising new targeted agent," said Dr. Wyndham Wilson of the NCI Center for Cancer Research. "However, these results are preliminary, and further studies will be necessary before it will be clear that bortezomib sets a new standard of care for relapsed or resistant multiple myeloma."

Thromboembolism Risk Found in Children and Young Adults With Sarcomas

A significant risk for thromboembolism was found among children and young adults with sarcomas, according to the results of a study presented this week at the ASCO annual meeting.

The research, conducted by NCI's Pediatric Oncology Branch (POB), reviewed records on 122 consecutive patients treated for sarcoma, ranging in age from 4 to 32 years (median age was 18). There were 23 thromboembolic events (TEEs) recorded, affecting 19 (16 percent) of the patients in the study group. Of those events, 57 percent were detected at presentation, 22 percent during the initial treatment cycle, and 22 percent at recurrence. Incidence rates were higher among patients with metastases (23 percent) compared with those with localized disease (9 percent).

Nearly half (43 percent) of the TEEs were asymptomatic, detected in routine imaging or autopsy. By far, the most common site of thromboses was deep veins of the extremities (43 percent), followed by pulmonary (22 percent), inferior vena cava (17 percent), right atrium (9 percent), and other much less frequent sites.

Previous research had detected high rates of TEEs among adult cancer patients but data on pediatric patients has been limited, explained POB Clinical Director Dr. Alan Wayne. "Thromboembolism is a potentially life-threatening, yet manageable, complication of cancer," he said. "Patients with sarcoma and other types of cancer should be closely monitored. The appropriate use of anticoagulant therapy should decrease morbidity and mortality associated with thromboembolic events."

Rituximab Plus Chemotherapy Shows Promise in NHL, Mantle Cell Lymphoma

Three studies presented this week at the ASCO annual meeting showed that the addition of the monoclonal antibody rituximab (Rituxan) to standard treatments for different forms of lymphoma can prolong survival in some instances and improve outcomes such as progression-free survival in others. In a study led by the Eastern Cooperative Oncology Group, the use of rituximab as maintenance therapy following initial chemotherapy treatment in patients with advanced indolent (or slow-growing) non-Hodgkin's Lymphoma (NHL), significantly improved progression-free survival compared with chemotherapy alone. After 4 years, progression-free survival was 58 percent in patients given rituximab versus 34 percent in the chemotherapy-alone group. "The effect of maintenance therapy with rituximab was much more robust than we anticipated," said the study's lead author Dr. Howard S. Hochster of the New York University School of Medicine.

Meanwhile, an 18-country study, dubbed MINT, examined combining rituximab with various forms of a chemotherapy regimen (often referred to as CHOP) as a first-line treatment in patients under 60 with aggressive NHL. Compared with a CHOP regimen alone, the combination approach yielded significant improvements in "time to treatment failure," the study's primary endpoint, explained lead author Dr. Michael Pfreundschuh of Saarland University Medical School in Hamburg, Germany. In addition, at 2 years, overall survival was 95 percent in the combination therapy group and 85 percent in the chemotherapy-alone group.

Lastly, a German research group assessed the effect of adding rituximab to a CHOP chemotherapy regimen for the treatment of a rare, aggressive, and often fatal form of lymphoma called mantle cell. Patients treated with the combination therapy more often experienced complete remission (34 percent versus 7 percent) and were able to stay in remission for longer periods of time (22 months versus 14 months).

The study's lead author, Dr. Wolfgang Hiddemann of the University of Munich, said that all three studies pointed to a paradigm change in the treatment of lymphomas toward combining therapies - and doing so at different points of treatment.

Studies Show Survival Progress in Head and Neck Cancers

Improvements in overall survival among patients with head and neck cancers were seen in two studies presented this week at the ASCO annual meeting. In one study, the combination of the monoclonal antibody cetuximab (Erbitux) and high-dose radiation therapy nearly doubled survival in patients with locally advanced head and neck cancer. Patients were randomized to high-dose radiation therapy (213 patients) or radiation therapy and cetuximab (211 patients). Median survival for patients in the latter group was 54 months versus 28 months in the radiation-alone group, with a significant survival advantage at 2 and 3 years. The improvement in survival - as well as in locoregional control, the study's primary endpoint - was seen without further exacerbation of the often toxic effects of radiation therapy, said study lead author Dr. James A. Bonner, from the University of Alabama at Birmingham.

A second study found that treating patients with locally advanced head and neck cancer not amenable to surgery with a platinum drug-based chemotherapy regimen that included the drug docetaxel (Taxotere) improved overall and progression-free survival rates compared with the same regimen without docetaxel. Advances in such patients are needed, said the study's principal investigator, Dr. Jan B. Vermorken of the University of Antwerp in Belgium, because 5-year survival rates are below 10 percent, with most patients dying within 18 months. The median progression-free survival for patients on the docetaxel regimen was 12.7 months, compared with 8.4 months for those on standard therapy. Median overall survival was 18.6 months versus 14.5 months.

NCAB Quarterly Meeting
The National Cancer Advisory Board (NCAB) held its quarterly meeting June 2-3 on the NIH campus in Bethesda, Md. NCAB advises the HHS Secretary and the NCI Director with respect to the institute's activities, including reviewing and recommending for support grants and cooperative agreements following technical and scientific peer review.

In addition to hearing the NCI Director's report, the President's Cancer Panel (PCP) Report, and other NCI reports and plans, NCAB and PCP members recognized the late Dr. Paul Calabresi by announcing an award in his honor (see note below).

NCAB membership consists of leading representatives of the health and scientific disciplines; the general public, including leaders in fields of public policy, law, health policy, economics, and management; and experts in environmental carcinogenesis. In addition, there are 12 nonvoting members from various federal agencies.

Award Named for Calabresi
At its June 2 meeting, NCAB announced the creation of the Paul Calabresi Award for Clinical Oncology in memory of Dr. Calabresi's contributions to cancer research. The award's purpose is to increase the number of physicians and basic scientists who are trained to perform patient-oriented oncology research; to design, test, participate in, and manage clinical protocols; and to work together to accelerate the translation of research to delivery. As a K-12 award, it will support career development programs in institutes with the capability to train investigators who will focus on translational therapeutic research.

Dr. Calabresi, who died of cancer in October 2003, was a pioneer in the pharmacological treatment of cancer and early translational research. He is remembered for his dedication to patients, his mentorship of young clinicians, his development of the clinical oncology field, and his service to NCI as a member of the PCP and chair of the NCAB. Dr. Calabresi also served on the steering committee for the National Dialogue on Cancer and the National Cancer Legislation Advisory Committee, through which he participated in the strategic development of the Nation's War on Cancer.

Science Writer Seminar Postponed
Due to the National Day of Mourning in honor of President Reagan, the science writer's seminar scheduled for June 11 has been postponed. The Bulletin will provide more details as they become available.

NCI Director Delivers Message of Hope to Cancer Survivors
NCI Director Dr. Andrew C. von Eschenbach delivered the keynote address at the annual National Cancer Survivor's Day Luncheon, sponsored by CanCare of Houston, Texas. In addition to highlighting recent advances in cancer survivorship research, Dr. von Eschenbach discussed his own battle with cancer, stressing the importance of emotional support during therapy.

The luncheon featured the ceremonial lighting of hundreds of votive candles in remembrance of those who have faced cancer. Founded in 1990, CanCare is an interfaith cancer support network made up of cancer survivors who provide free one-on-one, long-term emotional support to cancer patients and their families.

Breast Cancer Surveillance Consortium Report Available NCI's Breast Cancer Surveillance Consortium (BCSC) has released Evaluating Screening Performance in Practice, a report describing BCSC and its unique research contributions. The report provides an overview of BCSC's mission, history, and structure and also describes BCSC's current areas of research and other accomplishments to date. Findings from published studies and a discussion of the challenges that lie ahead for the Consortium are also included. The full report is available at http://breastscreening.cancer.gov/ espp.pdf.

Correction In the May 11 issue of the NCI Cancer Bulletin, the receipt dates for applications for PA-04-102 were incomplete; the dates shown referred only to revised applications. New applications may also be submitted by June 1, 2004; Oct. 1, 2004; Feb. 1, 2005; and June 1, 2005.