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The results of two long-awaited NCI-sponsored studies of autologous bone marrow transplantation (ABMT) and high-dose chemotherapy for the treatment of breast cancer are scheduled for presentation at a plenary session of the annual meeting of the American Society of Clinical Oncology (ASCO), May 15-18, 1999, in Atlanta. The studies include the Eastern Cooperative Oncology Group (ECOG) randomized trial of ABMT in stage IV disease and the Cancer and Leukemia Group B (CALGB) study of ABMT in high-risk stage II and III patients. Also, data from Swedish and South African studies will be presented. The data are being prepared for presentation by ECOG and CALGB investigators. However, preliminary conclusions have been shared with a relatively large number of people at the cooperative groups, ASCO, and NCI.
Interviews with individuals familiar with these preliminary results indicate that:
Officials at NCI, ASCO, and the cooperative groups refused to comment on these preliminary results, which have spawned many rumors, and were the subject of a March 9, 1999 report on NBC Nightly News as well as subsequent coverage.
"I would not have confidence in preliminary data in terms of its accuracy or interpretation," said Jeff Abrams, NCI senior investigator in charge of the breast cancer treatment studies. "The investigators have not completed the analysis of the data, and we at NCI don't have anything that we would consider credible."
It took the NCI a decade to overcome resistance from patients and physicians to generate these data on ABMT. Since some physicians were making the unsubstantiated claim that the procedure represents the "best chance" in the treatment of high-risk and metastatic disease, patients resisted enrolling in trials that involved randomization to another treatment. Many patients also sued insurers to get reimbursed for the treatment.
In 1997, bone marrow transplants were performed on 4,400 breast cancer patients in the U.S. and Canada, according to the International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry. The registry estimates that 62% of those transplants were performed for metastatic disease.
In preparation for the release of the results, the NCI assembled an ad hoc group of about 20 officials, advocates, and academics who were asked to guide the Institute in communicating the results of the trials to the public. The ad hoc committee included representatives of the National Breast Cancer Coalition, the Susan G. Komen Breast Cancer Foundation, the National Alliance of Breast Cancer Organizations, and Y-ME National Breast Cancer Organization. Sources said that at a meeting last month, the group considered whether the data warrant a clinical announcement. However, the group decided that a thorough analysis would be preferable to a rushed clinical announcement.
"I feel that when something is practice-altering, it merits consideration for a clinical alert, early release, and wide dissemination," said ASCO President Allen Lichter, who took part in the meeting.
"We have tried to look at these trials under that standard, and I can say—without trying to prejudge the final data and what the discussants are going to say—that these results will not be practice-altering," said Lichter, Professor of Radiation Oncology and a Dean at the University of Michigan Medical School. "They are the first of many steps in a scientific journey to try to find the appropriate place for this therapy in the treatment of breast cancer," Lichter said to The Cancer Letter. "This is not the end of the story; this is the beginning of the story."
Since high-dose chemotherapy with bone marrow transplantation is a toxic and very expensive treatment for breast cancer, insurers are eagerly awaiting its demise. Thus, the data presented at the ASCO meeting are certain to reverberate in courtrooms all over the U.S.
The history of each of the NCI-sponsored trials of ABMT reflects the practical difficulties of testing an intervention that gains acceptance before its efficacy is established.
In December 1990, when it was begun by several Philadelphia institutions and Blue Cross/Blue Shield, the study was expected to complete accrual by January 1994. Patients were apparently deterred by the study's design, which compared an aggressive treatment with a standard one. As prospective participants were opting to receive aggressive therapy off-protocol, the study fell short of its enrollment target. The study's enrollment received a boost when a second trial, conducted by Southwest Oncology Group, was closed because of low accrual and its participants were added to the Philadelphia study.
The enrollment target was reached in late 1997, when 553 women were accrued. The ECOG data safety monitoring committee reported the trial results to the group's scientific leadership last November. Trish Bates, Communications Manager for ECOG, said some of the patients are still being treated. "The investigators are going through the data case by case," Bates said to The Cancer Letter.
The principal investigator on the trial is Edward Stadtmauer, of the University of Pennsylvania Medical Center.
While the trial was ongoing, the CALGB data safety monitoring committee decided to increase the enrollment in order to look for smaller differences. Ultimately, 874 patients were accrued. The committee decided to look for smaller differences because mortality from the procedure dropped from 15% to about 5%.
Though the CALGB data are inconclusive and need longer follow-up, the cooperative group decided to report the data as they currently exist because the information may be useful to patients and clinicians making treatment decisions, sources said. 
NCI Issues Clinical Alert on Chemotherapy for Cervical Cancer
The NCI mailed a clinical announcement to thousands of physicians in February stating that strong consideration should be given to adding chemotherapy to radiation therapy in the treatment of invasive cervical cancer. The mailing alerts oncologists to the findings of five large, randomized clinical trials showing that women benefitted from the use of radiation therapy and chemotherapy given together. Up to now, surgery or radiation therapy alone has been considered the standard treatment for cervical cancer that has spread within the cervix or within the pelvis.
"The findings of these five trials are remarkably consistent," NCI Director Richard Klausner said. "They are likely to change the standard of care for invasive cervical cancer."
Three of the studies are scheduled to be published in the New England Journal of Medicine. Because of their potential implications for public health, the journal released the articles February 22, 1999, by making them available on the journal's website at http://www.nejm.org. The remaining two studies will be published later in 1999, NCI said.
"This is the first fundamental advance in the treatment of cervical cancer in more than 40 years," said Mitchell Morris, principal investigator of one of the studies, by the Radiation Therapy Oncology Group, and Professor of Gynecologic Oncology at the University of Texas M.D. Anderson Cancer Center. "Now that we have the data, it is vital to make chemotherapy a part of standard care for women with advanced cervical cancer. Every day that we wait to make it a part of treatment, fewer women have the opportunity to benefit."
In the RTOG study, scheduled to be published in the April 15, 1999 edition of the New England Journal of Medicine, the overall survival rate at five years for patients who were given both chemotherapy and radiation to the abdomen was 73%, compared to 58% survival rate for patients who were given only radiation to the abdomen and pelvis. Disease-free survival rates were 66% for patients who were given both chemotherapy and radiation, and 40% for those receiving only radiation.
Several hundred women were enrolled in each of the five trials, which were carried out by the NCI's Clinical Trials Cooperative Groups in centers around the country. Their cancers varied from disease confined to the cervix to disease that had spread from the cervix to other pelvic tissues. In three of the studies, women were randomly divided into groups that received either radiation alone or radiation plus concomitant chemotherapy. The chemotherapy agents used were cisplatin and 5-fluorouracil (5-FU) and cisplatin alone. In all three trials, the proportion of women alive after about three years of follow-up was higher in the groups receiving chemotherapy plus radiation than in those receiving only radiation therapy.
In the two other studies, all patients received concomitant chemotherapy and radiation. However, the chemotherapy drugs differed between the arms. In one arm of each of these trials, the chemotherapy used was hydroxyurea while in the other arms, the chemotherapy included cisplatin. In both trials, the groups that received cisplatin had better survival rates.
According to the clinical alert, although the best chemotherapy regimen for cervical cancer has not been determined, "significant results were seen using cisplatin alone or cisplatin in combination with 5-FU and other agents."
The clinical alert is posted on the NCI Web site for clinical trials at http://cancertrials.nci.nih.gov
Cancer Screening: Americans Over 50 Urged to Get Colon Cancer Tests
Three U.S. federal agencies have begun a campaign to educate Americans 50 years of age and older about the importance of colorectal cancer screening tests for early detection and prevention of the disease. The Centers for Disease Control and Prevention, Health Care Financing Administration, and the National Cancer Institute began the Screen for Life campaign as new evidence was published in the Journal of the National Cancer Institute showing significant reduction in colorectal cancer deaths associated with regular screening.
"The good news is that we can prevent many deaths from colorectal cancer through screening," Surgeon General David Satcher said in a March 2, 1999 statement. "If you've celebrated your 50th birthday and have never been screened for colorectal cancer, start now to screen for life."
The CDC recently released data showing that only 41% of men and women age 50 and older are having either of the two most commonly recommended screening tests, home-administered blood stool tests or sigmoidoscopy/proctoscopy, within the recommended time intervals.
In the March 2, 1999 issue of the Journal of the National Cancer Institute, researchers at the University of Minnesota reported on an 18-year study which extends their findings that screening for blood in the stool can reduce mortality from colorectal cancer. The team, led by Jack Mandel, Professor of Public Health, found that annual screening with a fecal occult blood test can lead to a 33% reduction in mortality, and that screening every two years results in a 21% drop in mortality.
As proposed by President Clinton, new Medicare preventive benefits including colorectal cancer screening were enacted in 1997 and went into effect last year. The awareness campaign is aimed at encouraging Medicare beneficiaries and others to take advantage of screening.
The Screen for Life campaign includes public service announcements and information materials targeting Americans 50 and older. The campaign also will promote the new Medicare coverage of colorectal cancer screening procedures.
Cancer Prevention: The U.S. Department of Health and Human Services Calls for Warning Labels on Cigars; Says Teen Use High
The U.S. HHS issued a pair of reports warning about cigar use among teenagers and recommending mandatory warning labels similar to those on cigarettes and other tobacco products. The Office of the Inspector General study on "Patterns of Use and Perception of Risk" included 18 focus groups involving a mix of 227 young cigar users and non-users of different socioeconomic backgrounds from urban and suburban areas across the country. Thirteen of the focus groups comprised high school students, four involved junior high students, and one was made up of college students. The purpose of the focus groups was to explore patterns of cigar use among the participants and their peers. Specific questions focused on initiation, frequency, and variations of use, as well as the motivations and influences to use cigars.
The study found that more than a third of the teenagers who participated in the focus groups admitted to having smoked a cigar in the past 30 days, and half of the smokers said they expect to be cigar users five years into the future. They further reported widespread cigar use and experimentation among their peers and disclosed that some teens create modified cigars called "blunts" by removing some or all of the core tobacco of a cigar and replacing it with marijuana.
"These findings are of profound concern and require our immediate action to inform the public about the health risks associated with cigar smoking," said HHS Inspector General June Gibbs Brown. "There is a great need for additional research on cigars, including prevalence, patterns of use, health effects, the addictive potential of cigars as well as the practice of blunting."
"There is no safe form of tobacco," said Surgeon General David Satcher. "We should require the same sort of warning labels on cigars that we already require on packages of cigarettes and spit tobacco. The absence of such a warning on cigars could lead consumers to erroneously conclude that cigars do not carry health risks."
Although sale of cigars to minors is illegal in all 50 states, the Inspector General's report on "Federal and State Enforcement and Regulation" showed that state level enforcement is uneven and is generally given a lower priority than enforcement of unlawful cigarette and spit tobacco sales. Half the states, according to the study, are unaware of the ease with which minors can purchase cigars, the degree to which the use of cigars by minors is a problem, and the health risks caused by cigar smoking.
The Office of the Inspector General recommended that the government develop a public awareness campaign about the health effects of cigars.
European Committee Signs off on Paxene For Kaposi's Sarcoma Treatment
IVAX Corp. of Miami, FL, said the European Committee for Proprietary Medicinal Products has recommended approval of its paclitaxel drug Paxene for AIDS-related Kaposi's sarcoma.
Paxene was developed by Baker Norton Pharmaceuticals, IVAX's U.S.-based research and development subsidiary. The European approval will be held by Norton Healthcare Limited, its subsidiary in the United Kingdom.
"This approval provides a key entry for IVAX into the global oncology marketplace and adds impetus to our ongoing effort to develop and market an orally-administered system for paclitaxel," said Phillip Frost, IVAX chairman and CEO. The company also has an NDA pending in the U.S. for a generic version of the Bristol-Myers Squibb drug Taxol.
Paxene is approved for Kaposi's sarcoma in the U.S. However, its entry on the market has been blocked until expiration of the BMS market exclusivity under the Orphan Drug Act.
Clearance Given for Panretin Gel
Ligand Pharmaceuticals Inc. of San Diego, CA, said the FDA has granted marketing clearance for Panretin gel (alitretinoin) 0.1% for the topical treatment of cutaneous lesions of patients with AIDS-related Kaposi's sarcoma (KS). Panretin gel is Ligand's first approved product and is the first topical therapy approved for KS, the company said. Patients may apply Panretin gel to their KS skin lesions twice a day or as instructed by their physicians.
Ligand said it will market Panretin gel in the U.S. with its already established specialty oncology and HIV-center sales force of 26 people.
FDA clearance followed a review by its Oncologic Drugs Advisory Committee on November 16, 1998.
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