For some melanoma patients, detecting the cancer in the lymph nodes and removing the nodes early in treatment may reduce recurrences and help patients live longer, researchers said while presenting preliminary findings from a clinical trial at the American Society of Clinical Oncology (ASCO) annual meeting in Orlando, Fla., May 13th-17th.

A simple outpatient procedure called a sentinel node biopsy (SNB), which is used to determine a patient's prognosis, can detect the cancer's spread before clinical signs appear, they said.

Melanoma is the most deadly of skin cancers, and it spreads to lymph nodes in about 20 percent of cases. Several previous trials have failed to show that the early detection of affected nodes and surgery can extend a patient's life.

This study reports that among patients with intermediate-stage melanoma and affected nodes, the survival rate over 7 years was 69 percent for the screening/surgery group compared with 48 percent for patients who had the surgery later, when their tumors were large enough to be felt during a physical exam.

In addition, patients in the screening/surgery group were 6 percent less likely to experience a recurrence over 5 years compared with those in the "watch and wait" group, according to findings from the Multicenter Selective Lymphadenectomy Trial (MSLT), an international randomized phase III study involving 2,000 patients.

"These results show we can identify a large subgroup of patients with melanoma who can benefit from the early removal of their lymph nodes," said Dr. Donald Morton of the John Wayne Cancer Institute, who leads the MSLT and presented the findings.

In the early 1990s, Dr. Morton developed SNB, which detects melanoma cells in a lymph node near the tumor, to identify patients who might be candidates for a radical surgery called a lymphadenectomy.

"I see no reason to delay the removal of tumor-involved lymph nodes if we can identify those patients at the time of diagnosis," Dr Morton said. He emphasized that only patients with metastatic lymph nodes can benefit from the surgery.

Delay may allow the cancer to spread to more nodes and to distant organs, Dr. Morton noted. The SNB group averaged 1.6 affected nodes at surgery compared with 3.4 for the other group. The prognosis worsens as more nodes are involved.

"The number of affected lymph nodes is important," said Dr. Mohammed Kashani-Sabet of the University of California, San Francisco. "These findings show that by removing metastatic nodes when they're microscopic, you can affect prognosis."

This was the third of five planned analyses from MSLT, which began in 1994 and was funded by an NCI grant.

"The interim results are further evidence that doctors should be doing SNB for the staging and treatment of patients in the early stages of melanoma," said Dr. Scott Saxman of NCI's Cancer Therapy Evaluation Program.

By Edward R. Winstead

As many of the impressive research findings presented at the ASCO annual meeting over the past 5 days demonstrate, we are now deftly applying all that we have learned about the complex biology and molecular underpinnings of cancer. New, targeted agents are showing success against a growing number of cancers, as are combinations of existing therapies with targeted agents and optimized use of standard therapies - all to the benefit of patients.

When such results are combined with those from studies elucidating biological and molecular factors that can guide treatment, we have convincing evidence that clinical oncology is in the midst of a revolution - a dramatic shift that is expanding the clinical oncologist's role from care provider to clinical scientist.

It's important to consider this revolution, however, in the context of another significant event on the horizon: the revamping of the National Cancer Institute (NCI) clinical trials program. During the ASCO meeting, several members of the NCI Clinical Trials Working Group (CTWG) presented a preview of the group's forthcoming recommendations for changing the clinical trials program in a way that will deliver on the promise of everything we have accomplished and learned over the past 3 decades.

The complete recommendations will be presented at the NCI National Cancer Advisory Board (NCAB) meeting in early June, but the ASCO meeting provided an excellent opportunity for members of the cancer research community to hear some of the recommendations' overarching themes and for ASCO leaders to provide feedback on how the organization and its members can participate in this effort.

To be certain, achieving the 2015 goal of eliminating the suffering and death due to cancer depends in large part on clinical trials generating the knowledge required to allow clinical oncologists to provide personalized medicine. At the same time, through well-designed clinical trials, the delivery itself will become a discovery model. Clinical oncologists will become more involved in the clinical trials process, integrating tools such as gene microarrays, proteomics, and imaging into the delivery of care, thus driving discovery by allowing us to further unravel the mechanisms of disease and response to treatment.

This care model plays a critical role in the approach being recommended by CTWG, which recognizes that all those involved in the clinical research enterprise - the NCI-designated Cancer Centers, Cooperative Groups, Community Clinical Oncology Programs (CCOPs), and the NCI Intramural Program - must work not in silos, but cooperatively, so we can seamlessly integrate knowledge into practice.

Among other things, the recommendations seek to increase the transparency of the clinical trials process while expanding the participation of all stakeholders in conducting trials and making key decisions, particularly on issues such as which clinical trials should be sponsored.

As we anticipate development of an implementation plan for the CTWG recommendations, we will draw on the considerable strengths of the NCI-supported clinical research programs with minimal disruption to those conducting the trials. To allow time for full development of the implementation plan, the NCI Executive Committee recently deferred reissuance of an RFA for certain components of the CCOPs. This was done expressly with a provision that provides interim funding for continuing the programs without the need for reapplication. As other components of the oncology clinical trials enterprise come up for funding renewal, it is anticipated that similar actions may be taken to maintain the greatest flexibility while the CTWG recommendations are put into practice.

Mechanisms for continually evaluating the recommendations' implementation will be established so that, if needed, mid-course corrections can be made. Also, an NCAB subcommittee will oversee the recommendations' implementation as well as general oversight of clinical trials.

This is an exciting time with the potential to forever alter the landscape of cancer research and treatment. I encourage all clinical oncologists to respond to the CTWG's recommendations and to find ways to participate in their implementation. Your efforts will pay dividends for decades to come.

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

As the largest institute within the world's largest biomedical research institution, NCI offers premier employment to oncology professionals. But this opportunity isn't limited to the experts; there's also room for less experienced people to become involved at NCI, and it's open to people from high school through graduate programs.

The Student and Teacher Program is offered to high school students in Montgomery County, Md., who are attracted to biomedical research, as well as to middle and high school teachers who want to brush up on their lab skills or share their first-hand experiences with students. The program, cosponsored by the National Institutes of Health (NIH) Office of Science Education and the Howard Hughes Medical Institute, enrolled 21 high school students and 9 teachers last year.

Shayda Eskandary is one of the participants. She teaches introductory and advanced biology at Walter Johnson High School in Bethesda, Md., and worked for two summers in Dr. Sankar Adhya's lab, which focuses on the regulation of gene transcription, learning to transfer genes between different strains of bacteria by using viruses, a process known as transduction. "What really stood out to me is that science takes a long time. Nothing is instantaneous," she says, "so it really gives you an appreciation for hard work." Now, when Ms. Eskandary works with her students, she is able to show them the proper techniques for keeping their experiments sterile and for documenting their methods - two important aspects of the scientific process that she didn't fully appreciate before her time at NCI.

For college students, NCI runs the Introduction to Cancer Research Careers (ICRC) Program, led by Dr. Teresa Estrada and Leon Espinoza of NCI's Office of Workforce Development. Students from underrepresented and/or financially disadvantaged backgrounds apply each year for the opportunity to visit NCI and interview for internships. Approximately 20 candidates are chosen through a competitive review process conducted by intramural investigators.

"ICRC gives diverse students a window into what a career in science could be like, while also giving investigators a chance to work with interns who bring in new perspectives," says Dr. Estrada. "All students in the program want to become scientists, and NCI helps them fill in the details on their maps of how to get there." She adds that because all of the ICRC interns have some prior research experience, they're able to hit the ground running once they are assigned to an investigator and can make significant contributions to the projects.

"They're testing things at NCI that we only hear about back home, but here, we would actually get to be a part of that research," adds Carmella Kahn, an undergraduate studying microbiology at the University of Arizona who applied to the ICRC program this year. She will be joining the Center to Reduce Cancer Health Disparities this summer to work with Dr. Roland Garcia. Ms. Kahn's goal is to learn how NCI is addressing the unequal burden of cancer and to gain tools that she can use for the work she does with the Navajo Nation, of which she is a member.

These training programs also are helpful for the researchers in the labs who host the students. Dr. Daniel McVicar has had many summer interns over the years in his lab at NCI-Frederick - some of whom are now pursuing science or medical careers - and he says that in addition to helping with the research projects, the programs give his permanent staff valuable experience, too. "My postdocs really like having the interns around," he says. "The arrangement allows their productivity to go up and also provides the supervisory experience that will help them in their next career move."

By Brittany Moya del Pino

Drug Reduces Transfusions for Some with Bone Marrow Disorder

A clinical trial of the drug lenalidomide (Revlimid) for a bone marrow disorder has found that it helped a particular subgroup of patients avoid the blood transfusions used to treat the disease, according to preliminary results from a clinical trial presented at the ASCO annual meeting.

All 148 patients in the study had a form of myelodysplastic syndrome (MDS) and a genetic flaw - the deletion of DNA from chromosome 5, which occurs in 18 to 25 percent of cases. The study was launched after earlier results suggested that the chromosomal deletion may predispose patients to respond to lenalidomide.

After 24 weeks, 64 percent of the patients in the study no longer needed a transfusion. In addition, 70 percent of those who responded had fewer bone marrow cells with the chromosomal deletion, while the deletion was undetectable in 44 percent of responders. For the patients who responded, it took about a month to avoid dependence on blood transfusions. The study is ongoing, and after a median follow-up of 9 months, 91 percent of the responders continued to respond.

Dr. Alan List of the H. Lee Moffitt Cancer Center presented the findings. He noted that the deleted region on chromosome 5 may contain a tumor suppressor gene, though none has yet been found. His group will report further on that region in an upcoming publication.

Gastric Cancer Survival Improved with Neoadjuvant Chemo

Chemotherapy before and after surgery in patients with operable cancer of the stomach and lower esophagus significantly improved both progression-free and overall survival compared with surgery alone, British researchers reported this week at the ASCO annual meeting.

In the 503-patient, phase III trial, at 5 years, 36 percent of patients in the chemotherapy arm were still alive, compared with 23 percent of patients in the surgery-alone arm. In addition, 70 percent of patients given chemotherapy saw their disease progress during that time, compared with 83 percent of patients treated only with surgery. Recurrence of gastric cancer after surgery to remove tumors is fairly common, with the cancer recurring in up to 65 percent of patients.

"This approach should be considered one of the standard treatment options for patients with these cancers," said study leader Dr. David Cunningham of the Royal Marsden Hospital.

Downsizing the tumor prior to surgery, says Dr. Udai Kammula, a senior investigator in the NCI Center for Cancer Research (CCR) Surgery Branch, is one advantage the researchers hoped to achieve with neoadjuvant chemo. It also may mean that patients will be more likely to tolerate chemotherapy, because they aren't first weakened by major surgery. More patients in this trial, for example, were able to receive chemotherapy than those in a multicenter clinical trial conducted in the United States that reported a survival benefit associated with postoperative chemotherapy and radiation.

Regardless, Dr. Kammula states, "Although these findings are promising, they need to be validated in another large trial, particularly one that has improved preoperative staging with endoscopic ultrasound and laparoscopy and greater quality control with regard to surgery."

Low-Fat Diet May Lower Risk of Breast Cancer Recurrence

Significantly lowering dietary fat may lower the risk of recurrences of breast cancer in postmenopausal women treated for early-stage breast cancer, researchers reported at the ASCO annual meeting. The findings are from the NCI-sponsored Women's Intervention Nutrition Study, the first large-scale study to examine the influence of dietary fat on breast cancer outcomes in this population.

"This could be the first randomized controlled clinical trial of a lifestyle intervention that impacts breast cancer outcomes," said study lead author Dr. Rowan T. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center.

The 5-year study included 2,437 women, aged 48 to 79, drawn from 37 U.S. centers. The study group was placed on a low-fat diet, averaging about 33 grams of fat daily, while a control group consumed a standard diet that included approximately 52 grams of fat per day. Each group had previously received similar treatments for early-stage breast cancer, including mastectomy or lumpectomy with radiation, and postsurgical treatment protocols, depending on whether patients had estrogen-dependent cancers.

After 5 years, women on the low-fat diet showed a significant reduction in cancer recurrence compared with the control group: 9.8 percent vs. 12.4 percent. Women on the low-fat diet who had been previously treated for nonestrogen-dependent cancer - which is typically associated with a greater likelihood of recurrence - had a 42-percent reduced risk of recurrence compared with those on a standard diet.

"The effect on ER-negative disease is a surprising and potentially important observation regarding breast cancer," said Dr. Peter Greenwald, director of NCI's Division of Cancer Prevention. "These data demonstrate the possible importance of considering dietary factors in cancer therapy trials."

Childhood Cancer Survivors Pay Heavy Health Toll as Adults, Study Finds

Data presented at the ASCO annual meeting show that survivors of childhood cancers are five times more likely to suffer from severe or life-threatening health problems than their healthy siblings. The data come from the Childhood Cancer Survivor Study (CCSS), a multi-institutional research project funded by NCI to investigate long-term morbidity and mortality associated with cancer treatment among survivors of pediatric cancers.

The study included 10,397 adults aged 18 to 48 who had been diagnosed with childhood cancer between 1970 and 1986 and had survived more than 5 years. The control group contained 3,304 healthy siblings ranging in age from 18 to 56. Some of the serious health problems seen among study participants included second malignant neoplasm (excluding nonmelanoma skin and thyroid cancer), heart attack, coronary artery bypass surgery, dialysis or kidney transplant, and mental retardation requiring special education. By age 45, such problems were observed in 37.4 percent of the childhood cancer survivors, compared with only 4.6 percent of the control group.

According to the study's lead author, Dr. Kevin C. Oeffinger of the University of Texas Southwestern Medical Center, 57.1 percent of cancer survivors reported moderate health problems by age 45, compared with 18.2 percent of their healthy siblings. Such moderate health problems included scars in the lungs that required oxygen therapy, congestive heart failure, blood clots in the head or lungs, cirrhosis of the liver, ovarian or testicular failure, and loss of an eye or even blindness.

"Although contemporary treatment regimens and technologies may have lessened some late effects associated with childhood cancer treatments, the acute and long-term side effects of cancer treatment remain significant for the growth and development of these children and for the health of the adults that they become," commented Dr. Barry Anderson, CCSS program director at NCI.

Treatments for Pancreatic Cancer Show Some Benefit

Two studies presented at the 2005 ASCO annual meeting offered potentially promising news for the treatment of pancreatic cancer, a highly fatal cancer for which there are few effective new treatments.

In the first study, German researchers reported that in patients with operable pancreatic cancer, a 6-month regimen of the chemotherapy drug gemcitabine (Gemzar) following surgery nearly doubled the duration of disease-free survival compared with surgery alone. Gemcitabine has been used for nearly a decade to treat patients with inoperable pancreatic cancer.

The study involved 356 patients with operable pancreatic cancer randomized either to 6 months of gemcitabine treatment within 6 weeks of surgery or observation following surgery. Disease-free survival was 14.2 months for patients receiving gemcitabine and 7.5 months for those in the observation group.

It is too soon to tell whether the delay in disease progression will translate into longer overall survival, said study lead author Dr. Peter Neuhaus of Charité University Medical School in Berlin.

In the second study, National Cancer Institute of Canada researchers reported that in a phase III clinical trial with 569 patients with advanced pancreatic cancer, the 1-year survival was 24 percent among patients in the treatment arm that combined gemcitabine with the EGFR inhibitor erlotinib (Tarceva) and 17 percent in the gemcitabine-alone arm. The progression-free survival was 3.75 months for the gemcitabine/erlotinib arm and 3.55 for the gemcitabine plus placebo arm. The median overall survival was still poor: 6.4 months vs 5.9 months.

The difference in median overall survival was statistically significant, said Dr. James Abbruzzese, from the NCI Pancreatic Cancer Specialized Program of Research Excellence at M.D. Anderson Cancer Center. But any enthusiasm about the result, he added, has to be tempered by factors such as the increased toxicity seen in the gemcitabine/erlotinib arm. More work is needed, he suggested, to determine which patients would benefit from receiving erlotinib in addition to gemcitabine.

Early Ovarian Cancer Screening Test Studied

A blood test that measures four proteins detects 96 percent of early ovarian cancers in blinded trials, according to an article published in the May 10 early online edition of the Proceedings of the National Academy of Sciences.

To arrive at the 4-protein panel, researchers at Yale, George Washington University, and the Nevada Cancer Institute screened blood samples from 28 healthy women, 18 women with newly diagnosed ovarian cancer, and 40 women with recurrent disease. Microarray analysis highlighted 35 proteins that were expressed at significantly different levels between the control and patient groups.

The researchers pared down this list based on the biological function and analytic reproduciblity of each highlighted protein. They selected the final four - leptin, prolactin, osteopontin, and insulin-like growth factor II - because each can be measured with off-the-shelf ELISA tests.

The researchers then recruited two new groups: 106 healthy volunteers and 100 women with disease. Blinded ELISA tests measured the blood concentration of each protein in these women. An algorithm then assigned each woman a score of one to four; a one indicated one protein level was abnormal, whereas a four indicated abnormal levels of all four proteins.

After unblinding the tests, the algorithm correctly identified 96 of 100 patients with ovarian cancer, including 23 of 24 patients with stage I or stage II disease. In the healthy group, 6 of 106 women (5.6 percent) were incorrectly identified as having disease.

Underscoring these results as preliminary, Dr. Sudhir Srivastava, director of NCI's Early Detection Research Network, commented, "While the results are exciting, the panel of biomarkers needs to be validated with an expanded number of cases and confounding controls to check the accuracy and specificity, respectively." The Network is discussing collaborating on such validation studies with the study authors.

Featured Meetings and Events A comprehensive calendar of cancer-related scientific meetings and events sponsored by NCI and other scientific organizations, is available at: http://calendar.cancer.gov/

Sen. Specter was following up on a question he posed to Dr. von Eschenbach during an April 6 Appropriations Subcommittee hearing on the NCI and NIH budgets. "When you appeared here last month I asked what it would take to move the 2015 goal achievement date back to 2010," said Sen. Specter, who chairs the Senate Appropriations Subcommittee on Labor, HHS, and Education (NCI Cancer Bulletin ³, April 12).

Dr. von Eschenbach responded that a plan has been developed to address the chairman's question. "The proposal is now going through review by NIH and HHS prior to being officially submitted to Congress and to you specifically," he noted. The plan has three components, he said: funding the National Advanced Technologies Initiative for Cancer; increasing NCI's Comprehensive Cancer Centers network by adding 15 centers; and expanding and integrating the clinical research infrastructure.

"What will be the cost to do all of that?" asked Sen. Specter. Dr. von Eschenbach responded that NCI has proposed a budget to support those initiatives that would amount to approximately $600 million in new federal funding a year.

The discussion of accelerating progress toward the 2015 goal was a sidelight at the May 11 hearing in which Sen. Specter discussed legislation to increase public awareness of gynecological cancers. The senator is sponsoring a bill called "Johanna's Law" to support a federal program to create and distribute information on early symptoms of gynecological cancers. The program would also explain screening options for women with those symptoms.

TV star and author Fran Drescher, a 5-year survivor of uterine cancer, testified in support of the bill. "Unfortunately, it took me 2 years and eight doctors to get a proper diagnosis," she said. Like many women with gynecological cancer, her early symptoms were misdiagnosed and attributed to other conditions. Ms. Drescher was initially diagnosed with a perimenopausal condition and treated with hormone replacement therapy that "actually exacerbated my cancer." Patients need to know the early signs and insist upon proper screening, she urged.

Dr. von Eschenbach outlined NCI's research and education programs for gynecological cancers. The Institute spent $213 million in FY 2004 for "multipronged, multidisciplinary efforts in molecular biology, epidemiology, prevention, treatment, and survivorship issues of gynecological cancers," he noted.

CCR Grand Rounds May 24: Dr. Sam T. Hwang, Senior Investigator, Dermatology Branch, CCR, NCI. "Chemokine Receptors in Organ-Selective Cancer Metastasis" May 31: Dr. Peter H. Duesberg, Professor of Molecular and Cell Biology, University of California, Berkeley. "Aneuploidy and Cancer: From Correlation to Causation" CCR Grand Rounds are held 8:30 to 9:30 a.m. at the NIH campus in Bethesda, Md., in the Clinical Center's Lipsett Amphitheater.

Clanton Wins HHS Award
Dr. Mark Clanton, NCI deputy director for cancer care delivery systems, has been awarded the HHS Secretary's Distinguished Service Award. The award recognizes service that significantly advances the department's mission and goals and reinforces the importance of achievement through teams. Dr. Clanton was recognized for his participation on the Healthcare Quality Implementation team, chaired by Dr. Scott Young of the Agency for Healthcare Research and Quality. The team reported to the Medicare Governance Council and was charged with developing implementation plans for the sections of the Medicare Modernization Act (MMA) that address quality of care and quality-of-care demonstration projects within Medicare. Dr. Clanton led the subcommittee responsible for section 1016, which pertained to the Cancer Center Loan provision of the MMA. The award will be presented on May 25.

Workshop on Palliative Care Set for June
On June 13-15, ASCO and the EPEC™ Project will sponsor a train-the-trainer workshop, "Education in Palliative and End-of-Life Care for Oncology (EPEC-O)," at the Hyatt Regency Reston in Reston, Va. The workshop curriculum was developed with major funding from NCI and supplemental support from the Lance Armstrong Foundation. It is designed to give cancer care professionals the information and skills to train others about best practices in supportive oncology and end-of-life care. Attendance is limited to 100 people; the registration deadline is May 26. For more information and to register, go to www.asco.org/epeco.

Search the NCI Cancer Bulletin
In response to reader requests, NCI has developed a method for searching the 2005 NCI Cancer Bulletin database of articles and other features. The search function can be accessed by clicking on the "Bulletin Archive/Search" link at the top right of the HTML version of the Bulletin. The destination page offers the search capability as well as links to each weekly issue. All issues from 2004 will be searchable within the next 2 weeks.

Roberts Elected to AAAS
Dr. Anita Roberts, principal investigator in the Laboratory of Cell Regulation and Carcinogenesis in NCI's CCR, was elected to membership as a Fellow in the American Academy of Arts and Sciences on April 22. Fellows are recognized for their contributions to the sciences, scholarship, public affairs, business, and the arts. Founded in 1780, the Academy addresses issues of intellectual consequence to the nation through interdisciplinary and collaborative projects and publications.

Carrington Delivers Ceppellini Lecture
Dr. Mary N. Carrington, a principal investigator in NCI's CCR, delivered the 2005 Ceppellini Lecture in Istanbul, Turkey, last month at the annual meeting of the European Federation of Immunogenetics. Dr. Carrington was honored for her substantial contribution to the field of immunogenetics. The lecture is named in honor of Ruggero Ceppellini, an Italian geneticist who was influential in the field of human leukocyte antigens (HLA). Dr. Carrington is head of the HLA Typing Section in the Laboratory of Genomic Diversity. She received her Ph.D. from Iowa State University; before joining NCI, she was a faculty member in the Immunology Department at Duke University.