Previously treated patients with advanced colorectal cancer who received the anti-angiogenesis agent bevacizumab (Avastin) in combination with an oxaliplatin (Eloxatin)-based chemotherapy regimen lived longer than patients who received chemotherapy alone, researchers announced yesterday. The Data Monitoring Committee (DMC) overseeing the NCI-sponsored clinical trial in which the patients were enrolled, E3200, recommended that the results of a recent interim analysis be made public because the study had met its primary end point of demonstrating improved overall survival.

Patients in the trial who received the combination of bevacizumab and a chemotherapy regimen called FOLFOX4 (oxaliplatin, 5-fluorouracil, and leucovorin) had a median overall survival of 12.5 months compared with 10.7 months for patients treated with FOLFOX4 alone, a 17 percent improvement. Combination therapy patients had a 26 percent reduction in the risk of death compared with those who received chemotherapy alone.

"As this treatment was, at the very least, second line, this is a real and quite remarkable finding," says the study's lead investigator, Dr. Bruce Giantonio, of the University of Pennsylvania's Abramson Cancer Center. "These data - taken along with the advances seen with the introduction of irinotecan, oxaliplatin, bevacizumab, and cetuximab for treatment of colorectal cancer - suggest that the median survival for patients with metastatic disease will be 2 years or more."

The clinical trial, conducted by the Eastern Cooperative Oncology Group, included 829 patients enrolled between October 2001 and April 2003. Trial participants, all of whom previously had received a fluorouracil-based chemotherapy and irinotecan (Camptosar), were randomized to one of three treatment groups: the FOLFOX4 regimen plus bevacizumab, the FOLFOX4 regimen alone, or bevacizumab alone. On the DMC's recommendation, study investigators suspended randomization to the bevacizumab alone arm in March 2003 because early results suggested that patients in that group might have lower overall survival than patients in the other two arms.

Part of a new class of targeted therapies, bevacizumab binds to and inhibits vascular endothelial growth factor, which is thought to help tumors grow by providing a blood supply through the formation of new blood vessels. "The use of targeted therapies is a fundamental shift in the way we treat cancers," Dr. Giantonio notes, "and here we see evidence that even in more advanced, previously treated disease, such an approach carries benefit."

According to Dr. Meg Mooney, a senior investigator in the NCI Cancer Therapy Evaluation Program, laboratory and clinical research has pointed toward anti-angiogenesis as a logical route for treating colorectal cancer. As a result, she explains, the bevacizumab/ FOLFOX approach is now being tested in the adjuvant (post-surgical) setting for colon cancer "to see if we can increase the cure rate." NCI is currently sponsoring a trial led by the National Surgical Adjuvant Breast and Bowel Project, NSABP C-08, that is testing FOLFOX with or without bevacizumab in stage II and III colon cancer. That trial comes on the heels of the MOSAIC trial, published in June in the New England Journal of Medicine, which showed that use of FOLFOX increased 3-year disease-free survival in patients with stage III colon cancer, compared to standard therapy.

Data published earlier this month have created an opinion among many in the public health and research communities that we are on the brink of significantly eliminating the threat of cervical cancer. This would be a public health boon to many developing countries, which bear the brunt of the 230,000 annual deaths from this cancer.

According to the results of a phase II clinical trial published earlier this month in The Lancet involving more than 1,100 women, a human papillomavirus (HPV) vaccine was safe and effective at preventing viral infections, as well as the abnormalities in the cells often associated with them. The vaccine targets two HPV types, 16 and 18, which together cause about 70 percent of all cervical cancers. Although the women in the Lancet study were only followed for 27 months, the study provides evidence that immunization with this type of HPV vaccine can confer a high degree of protection against infection with specific types of HPV and could be a valuable tool in the battle against the primary cause of cervical cancer. Encouragingly, similar results with longer follow-up were reported a few weeks ago at an American Society of Microbiology meeting with an HPV vaccine that targets HPV type 16.

It was Drs. Mark Schiffman, Allan Hildesheim, and colleagues in the Division of Cancer Epidemiology and Genetics (DCEG) who made the initial discoveries that linked infection with HPV to the development of cervical cancer. And the companies producing these vaccines - GlaxoSmithKline (GSK) and Merck, respectively - did so based on technology developed by NCI scientists, led by Drs. John Schiller and Doug Lowy in NCI's Center for Cancer Research (CCR). Work by Drs. Lowy, Schiller, and CCR colleagues laid the foundation for a "virus-like particle" HPV vaccine and the subsequent development and testing of the vaccine in animal models and early stage human trials that set the stage for the promising results seen in these recent phase II trials. NCI involvement in HPV vaccine development has not abated. As reported recently in the NCI Cancer Bulletin, DCEG has initiated an 8-year, phase III study involving 12,000 to 15,000 women in Costa Rica to test GSK's HPV 16/18 vaccine. Costa Rica is just one of many developing countries that could benefit from an HPV vaccine. Cervical cancer rates there are alarmingly high, especially in coastal areas, where access to basic health care is extremely limited. Most developing countries do not have the infrastructure to operate cancer screening programs, lack the systems to ensure that women with a positive Pap smear get appropriate follow-up care, and must overcome cultural barriers that limit the effectiveness of available screening programs.

In addition to our efforts in HPV vaccine clinical trials, Drs. Schiller, Lowy, and colleagues are continuing their research in this area. Among other things, they have developed the first high-throughput assay that can allow researchers developing HPV vaccines to more efficiently and affordably perform tests to determine if the vaccines can induce an immune response against other oncogenic HPV types. They have made this assay available to other researchers, generating increased interest and potentially accelerating the production of vaccines that protect against multiple HPV types.

As was highlighted in the recent international issue of the Bulletin, NCI has a mandate to prevent and ease the suffering and death due to cancer worldwide. We have seen exciting advances in our international collaboration over the past decade and, with NCI leading the way in research to pursue new paths of cancer prevention and treatment, we are committed to translating these advances into a reduced global burden of cancer.

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

Canadian researchers have identified brain cancer stem cells that, even at extremely low levels, can propel tumor growth. Reporting in the November 18 Nature, Dr. Peter B. Dirks and colleagues from Toronto's Hospital for Sick Children and University of Toronto found that, in a xenograft mouse model, brain tumor cells from both pediatric and adult brain cancers that expressed the cell surface marker CD133 (CD133+) could initiate the development and growth of tumors. The architecture and cellular makeup of the tumors that developed in the mice closely resembled the human tumors from which the CD133+ cells were derived, the researchers said.

In comparison, when the researchers injected anywhere from 50,000 to 100,000 cells from these same human tumors in the mice that lacked the CD133 surface marker, they reported, "Human cells could be found in small clusters near the original injection site, but these cells did not form a nodule or mass." To confirm that the tumor-forming cells were cancer stem cells - that is, that they had the ability to self-renew - the research team performed serial transplantation, taking CD133+ cells from the tumors that developed in the first set of mice and injecting them into a second set of xenograft mice. These mice also developed tumors that closely resembled the original human tumors from which they came, as well as the tumors in the primary mice.

"The identification of cancer stem cells is a significant step in the fight against [cancer]," wrote Dr. Michael F. Clarke, of the University of Michigan in Ann Arbor, in a related commentary. "Because self-renewal is essential if tumors are to grow, agents that target such cells may be effective treatments."

Efficiency of Targeted Clinical Trials Evaluated

Targeted clinical trials can be a more efficient way to study the effectiveness of certain cancer drugs, according to a paper by NCI researchers in the October 15 Clinical Cancer Research. "Most tumors at a given site are heterogeneous with regard to their underlying molecular and genomic signatures," said Dr. Richard Simon of the Division of Cancer Treatment and Diagnosis (DCTD). "It is not reasonable to expect such tumors to have equal sensitivities to a drug that inhibits a particular target." As a result, the potential of many drugs may be hidden in standard clinical trials that use broad eligibility criteria.

Dr. Simon and colleagues developed a model to compare the efficiency of targeted versus untargeted trials for a cancer drug that primarily benefits a specific subset of the population. They found that in most cases a targeted trial would require fewer participants to reach the same end point than a generalized trial, even when including enough patients to screen for the desired subpopulation. A targeted trial would be less efficient in cases where the drug would also be fairly effective in the general population.

Dr. Simon also noted that beyond understanding the mechanisms of drug action, being able to easily screen patients who may respond to these drugs is critical. As understanding in both areas increases, clinical trials tailored to population subsets may become more prominent for finding new therapies.

Smokeless Tobacco Causes Oral and Pancreatic Cancer; Nitrosamines Classified as Human Carcinogens

The International Agency for Research on Cancer (IARC) recently reported that smokeless tobacco, including snuff and chewing tobacco, causes oral and pancreatic cancer in humans. In a separate report, two tobacco-specific N-nitrosamines (TSNA), N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were together classified as human carcinogens. The chemicals occur in all smokeless tobacco products and are formed during the curing and processing of tobacco and during storage of manufactured smokeless tobacco products. Many studies in animals have shown that different routes of exposure to NNN and NNK cause benign and malignant tumors. Results of epidemiological studies of smokeless tobacco users and studies of the mechanisms of action of TSNA plausibly associate NNN and NNK with cancer in humans.

"The working group reaffirmed that smokeless tobacco use causes oral cancer in humans, and concluded that it causes pancreatic cancer as well. These findings reinforce that tobacco use is not safe in any form," said Dr. Deborah Winn of NCI's Division of Cancer Control and Population Sciences. Dr. Winn served on the IARC working group. Conclusions will appear at http://monographs.iarc.fr. A summary of the scientific evidence will be published in the December 2004 Lancet.

NCI's State Cancer Legislative Database Program presented a poster at the recent meeting of the American Public Health Association on events influencing state policies on colorectal cancer screening. The poster highlighted the influence of NBC Today host Katie Couric on public awareness of screening for colorectal cancer, and is excerpted here. For more information on colorectal cancer screening, see the Special Report ³ "Prostate, Colorectal Screening Affected by Numerous Factors,"NCI Cancer Bulletin, July 20, 2004; information is also available at http://www.cancer.gov/cancertopics/screening/colon-and-rectal. For additional information on the poster, contact the SCLD program office at http://www.scld-nci.net/contact_us.cfm.

• Despite its prevalence, colorectal cancer has received less attention in general than other types of cancer.
• We explored the timing and nature of efforts to increase awareness of and screening for colorectal cancer to determine whether there were similar increases in legislative attention to screening for colorectal cancer.
• We analyzed data on state laws from NCI's State Cancer Legislative Database (SCLD) Program. We also obtained Web-based statistical data, news, and literature on risk factors, symptomology, prevalence, mortality, and various public awareness campaigns.

Prevalence of and Mortality from Colorectal Cancer

• Colorectal cancers - cancers of the colon and rectum - are the second leading cause of cancer death for both men and women, surpassed only by lung cancer. Colorectal cancer is the third most commonly diagnosed cancer among men and women.
• The American Cancer Society estimates that 56,730 Americans (28,320 men and 28,410 women) likely will die of colorectal cancer and that another 146,940 new cases (73,620 men and 73,320 women) will be diagnosed in 2004.
• Incidence has decreased by 3% per year from 1998 to 2000, which researchers have attributed to increased screening and other preventive measures.
• Colorectal cancers posed the third highest lifetime risk of dying from cancer for both men and women in the United States from 1999-2001. Lung cancer was first for both men and women, prostate cancer was second for men, and breast cancer second for women.

Risk Factors and Symptomology
Linkages posing higher than average risk for developing colorectal cancer:

• Family or personal history of colorectal cancer
• Age (risk increases after age 50)
• Polyps (growths protruding from inner wall of colon or rectum)
• Ulcerative colitis (causes inflammation and sores in the colon)
• Diet high in fat and calories and low in fiber
• Lack of regular exercise

• Pain, aches, or cramps in the stomach
• Blood in stool
• Change in bowel habits
• Unexplained weight loss

Summary

• More states passed laws addressing third-party reimbursement for screening tests as well as awareness resolutions after Ms. Couric's televised awareness campaign and other such activities were undertaken.
• Ms. Couric's personal interest and high profile efforts provide a unique paradigm for examination because of their apparent efficacy, as confirmed both by reported anecdotal evidence from doctors and scientific study.
• Another factor contributing to increased screening is the aging of the Baby Boomers who are far more knowledgeable about and active in seeking out preventive health care than earlier generations.
• For this presentation, we did not quantitatively analyze whether a direct association or correlation exists between the seminal events (e.g., Ms. Couric's efforts) and the state legislative actions.

1993: New Jersey enacts first state law addressing colorectal cancer screening reimbursement, but insurers are required only to offer coverage, not to provide it. 1998: Jay Monahan succumbs to the cancer at age 42, 9 months after diagnosis. September 1998: First Lady Hilary Clinton launches a public education campaign by the National Colorectal Cancer Roundtable (NCCR) to spur colorectal cancer screening. NCCR is a joint project of the American Cancer Society and the Centers for Disease Control and Prevention. April 1999: Nebraska becomes first state to adopt a colorectal cancer resolution, declaring April 23, 1999 Colorectal Cancer Awareness Day. March 12, 2000: Time magazine cover story notes impact of Ms. Couric's efforts to heighten awareness and encourage screening. 2003: Cancer Research and Prevention Foundation sponsors 20-city, year-long Colossal Colon Tour. Traveling under the tag line "Check Your Insides Out," the tour features a 40-foot long, 4-foot crawl-through replica of the human colon. University of Michigan study published in the Archives of Internal Medicine finds 20% increase in colonoscopies in the 9 months following Couric's March 2000 Today show colorectal cancer awareness campaign, dubbing the phenomenon "The Katie Couric Effect." May 2004: At the annual conference of the American College of Obstetrics and Gynecologists, results of a survey conducted by Good Housekeeping for NCCRA are announced: 40% of women over 50 reported their doctors never recommended they be screened. September 2004: A prime researcher who documented the Katie Couric Effect, Dr. A. Mark Fendrick, announces that he is studying the effects of health awareness campaigns by other celebrity spokespersons. He cites "evidence that celebrities can help eliminate the stigma associated with some diseases and encourage people to go to the doctor." 1993 1997 1998 1999 2000 2003 2004 1997: NBC Today show co-host Katie Couric learns husband, Jay Monahan, is diagnosed with colorectal cancer. March 2000: Katie Couric testifies before Congress on colorectal cancer issues and undergoes on-air colonoscopy to ease fears regarding the procedure. The Today show broadcasts the first in a series of week-long program segments focusing on colorectal cancer, which will air each March. Ms. Couric co-founds the National Colorectal Cancer Research Alliance (NCCRA) within the Entertainment Industry Foundation, which promotes colorectal cancer education, fundraising, research, and early medical screening. President Clinton proclaims National Colorectal Cancer Awareness Month, urging that such cancer screening become a routine part of preventive health care for anyone over age 50, particularly since the risk of developing colorectal cancer increases with age. May 2000: Report in the journal Cancer documents an overall colorectal survival rate of 61%, which differs by stage. Those whose cancers were detected at Stage I had a 96% survival rate while those whose cancers were detected at Stage IV had only a 5% survival rate. December 2000: Nine states have laws addressing colorectal screening reimbursement. Four states have resolutions declaring March as Colorectal Cancer Awareness Month. April 2004: NCCRA and the American Gastroenterological Association release "2004 Colorectal Cancer Legislation Report Card," grading the states on the extent of their colorectal cancer screening coverage requirements. June 30, 2004: Nineteen states and DC have laws addressing colorectal cancer screening reimbursement. Eleven states have resolutions recognizing March as Colorectal Cancer Awareness Month. 2004: Sponsored by the Cancer Research and Prevention Foundation, the Buddy Bracelet program encourages people to wear a bracelet as a reminder to have colorectal cancer screening, then pass the bracelet on to others once they have been screened.

Regina el Arculli, M.A. • Joanna M. King, J.D. • Jill Freudenwald, M.A.
NCI's State Cancer Legislative Database Program, Bethesda, Maryland • www.scld-nci.net

This funding opportunity will use the NIH investigator-initiated research project grant (R01) and the NIH exploratory/developmental grant (R21) award mechanisms.

For more information see http://cri.nci.nih.gov/4abst.cfm?initiativeparfa_id=2441. Inquiries: Dr. Wendy Nelson - nelsonw@mail.nih.gov

Decision Making in Cancer: Single-Event Decisions
PA-05-017
Application Receipt Dates: Jan. 10, May 10, Sept. 10, 2005;
Jan. 10, May 10, Sept. 10, 2006;
Jan. 10, May 10, Sept. 10, 2007

This funding opportunity will use the NIH investigator-initiated research project grant (R01) and the NIH exploratory/developmental grant (R21) award mechanisms.

For more information see http://cri.nci.nih.gov/4abst.cfm?initiativeparfa_id=2442. Inquiries: Dr. Wendy Nelson - nelsonw@mail.nih.gov

Leadership for HIV/AIDS Clinical Trials Networks
RFA-AI-05-001
Letter of Intent Receipt Dates: April 11, 2005
Application Receipt Dates: May 11, 2005

This funding opportunity will use the U01 award mechanism(s).

For more information see http://cri.nci.nih.gov/4abst.cfm?initiativeparfa_id=2440. Inquiries: NIAID Office of the Director - MMurguia@niaid.nih.gov

Name of the Trial
Phase II Study of Isolated Hepatic Perfusion with Melphalan Followed by Temozolomide in Patients with Unresectable Hepatic Metastases Secondary to Ocular Melanoma (NCI-03-C-0221). See the protocol summary at http://cancer.gov/clinicaltrials/NCI-03-C-0221.

Principal Investigator
Dr. H. Richard Alexander, NCI Center for Cancer Research

Why is This Trial Important?
Ocular melanoma is the most common cancer of the eye in adults. If left untreated, it can spread (metastasize) to other areas of the body. Most often, ocular melanoma spreads to the liver. No effective treatment currently exists for metastatic ocular melanoma.

In this study, researchers are testing a procedure called hyperthermic isolated hepatic perfusion, which involves temporarily separating the liver's blood supply from the blood circulating throughout the rest of the body. High concentrations of the drug melphalan are then administered to the liver. Once treatment with melphalan is completed, the liver's blood supply is reconnected to the rest of the circulatory system and patients are treated with the drug temozolomide.

"Isolating the liver allows us to deliver a higher dose of melphalan than could be tolerated systemically," said Dr. James Pingpank, a surgeon involved with the trial. "Isolated perfusions have been used to treat cancer in other organs, but this is the first time isolated hepatic perfusion is being used with a large number of patients. The technology just wasn't there before.

"In phase I and II testing, this therapy did produce a response in 62 percent of patients, so it does have established efficacy," said Dr. Pingpank. "Now we are trying to prolong the duration of response, which is currently about 1 year."

Who Can Join This Trial?
Researchers seek to enroll up to 40 patients aged 18 and over who have metastatic liver tumors secondary to ocular melanoma that cannot be removed surgically (unresectable). See the list of eligibility criteria at http://cancer.gov/clinicaltrials/NCI-03-C-0221.

Where Is This Trial Taking Place?
This study is taking place at the NIH Clinical Center in Bethesda, Md.

Whom to Contact
For more information, call the NCI Clinical Studies Support Center (CSSC) at 1-888-NCI-1937. The CSSC provides information about cancer trials taking place on the NIH campus in Bethesda, Md. The call is toll free and confidential.

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

CCR Grand Rounds December 14: Dr. Christopher Logothetis; Chairman and Professor, Department of Genitourinary Medical Oncology; Director, Genitourinary Program Center; University of Texas M.D. Anderson Cancer Center, "Biological Basis for the Development and Application of Therapy for Prostate Cancer" CCR Grand Rounds will not be held on December 7, 21, or 28. They will resume on January 4. 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 Auditorium.

The latest report shows prostate cancer as the leading cancer diagnosed overall in men in the United States and breast cancer as the most common form of cancer diagnosed in U.S. women. The leading cause of cancer death for both men and women is lung cancer.

United States Cancer Statistics: 2001 Incidence and Mortality marks the third time NCI and the Centers for Disease Control and Prevention (CDC), in collaboration with the North American Association of Central Cancer Registries, have combined data to produce federal cancer statistics. The annual report provides a basis for individual states and researchers to describe the variability in cancer incidence and death rates across different populations and to focus on certain populations for evidence-based cancer control programs. Future United States Cancer Statistics reports will include data for American Indians/Alaska Natives. The full report is available at http://www.seer.cancer.gov/statistics.

2004 Outstanding Mentor Award Winners Announced
Investigators from the NCI's Center of Cancer Research (CCR) Dr. Daniel McVicar, Dr. Joost Oppenheim and Dr. Stuart Rudikoff were the winners of the 2004 Outstanding Mentor Award. 2004 Mentors of Merit were Dr. Shine Chang, Dr. Wong-Ho Chow, Dr. Adam Glick, Dr. Nancy Jenkins, Dr. Neal Copeland, Dr. Ilona Linnoila, Dr. Alan Perantoni, Dr. Paul Randazzo, and Dr. Michael Smith of CCR. These investigators were nominated by their trainees and received the highest ranking in a competitive review by an advisory committee of postdoctoral fellows. The awardees were honored at the NCI Awards Ceremony on October 28.

Input Wanted to Improve the Cancer Clinical Trials System
The Clinical Trials Working Group (CTWG), a broadly constituted panel established earlier this year and comprising researchers from academia and industry, advocates, and patients, has developed an interactive Web site to solicit input about the cancer clinical trials system.

"We are looking for insights from anyone interested in the future of cancer clinical trials," said Dr. James Doroshow, chair of CTWG and director of NCI's Division of Cancer Treatment and Diagnosis.

The Web site - http://ncicbforums.nci.nih.gov/ictQuestions/login_form - asks users to log in by first choosing a description that best identifies the group they represent. All responses are confidential. Users are also required to enter the following password - CTWGstakeholder - prior to providing their thoughts. (The password is also given on the log-in page.)

The Web site is open for feedback through Jan. 15, 2005 and addresses the following areas:

• Standardization of clinical trial procedures and infrastructure
• Coordination of clinical trials across Cancer Centers, SPORES, PO1s, and Cooperative Groups
• Enhancing interactions between the clinical research community, NCI, the pharmaceutical industry, FDA, regulatory agencies, and patient advocates
• Developing core facilities to improve scientific support for trials
• Improving clinical trial accrual management
• Refining the protocol prioritization process

TV Appearance Rescheduled
The CBS Sunday Morning feature with Dr. Julia Rowland, director of NCI's Office of Cancer Survivorship, has been rescheduled and will air in the near future.