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IN AFTERMATH OF NEW ENGLAND JOURNAL OF MEDICINE ARTICLE, CRITIC BAILAR DECLARES THE DEFEAT OF CANCER TREATMENT |
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 Top In Aftermath of New... Cancer Risk from Three...Taxol Recommended for...Half of Glioblastomas Respond... |
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Undoubtedly, the conclusions of "Cancer Undefeated" will be challenged in the pages of the New England Journal of Medicine. While scientists are generally able to resolve scientific disputes, refuting a USA Today cover story titled "Billion-Dollar War on Cancer a Bust?" presents a different challenge.
Reporters have been treating Bailar and Gornik with reverence, apparently not asking for justification for their conclusions and recommendations. Asked by The Cancer Letter to explain his proposal, Bailar said that two-thirds was a "rubber number." Asked to explain how that number was derived, Bailar said: "It’s basically founded on my understanding of cancer trends and progress in cancer research over 40 years that I have tracked these matters."
"I think Dr. Bailar has gone beyond the data in order to dramatize the issues," said Barbara Rimer, chairman of the National Cancer Advisory Board and director of cancer control research at Duke University Medical Center. "Scientists have, more and more, taken liberties with data to get the attention of the media," Rimer said to The Cancer Letter. "If you want to get attention, you need to be dramatic. Trying to mandate percentages for prevention versus treatment results in an overly simplistic view of science. It’s unfortunate that Dr. Bailar frames important policy issues as dichotomies, because it can result in polarization of scientists and the public."
Bailar is chairman of the University of Chicago Department of Health Studies, a member of the New England Journal of Medicine editorial board, as well as a member of the Institute of Medicine and its National Cancer Policy Board.
Technical Issues
On May 29, 1997, at a Los Angeles "field hearing" on cancer research, Sen. Arlen Specter (Republican of Pennsylvania), chairman of the Senate Labor, Health and Human Services and Education Subcommittee, brandished a copy of that day’s USA Today. Was the government’s "Billion-Dollar War On Cancer A Bust?", as the headline suggested? After returning to Washington, Specter began to make plans for a hearing on the controversy. Ironically, the differences between Bailar’s and Gornik’s data and NCI’s are, for the most part, technical, and the figures on cancer mortality are not in dispute. While NCI adjusts the survival data using the ages of the U.S. population as they were in 1970, Bailar and Gornik used the 1990 age adjustment. Controlling for the changing of ages of the population allows researchers to track trends, including cancer mortality.
The choice of age adjustment is largely a matter of tradition. Many NIH institutes use the 1940 population. NCI uses the 1970 population, largely because that year’s census is closest to the passage of the National Cancer Act of 1971. According to NCI, with the 1970 age adjustment, cancer mortality dropped by about 2.6% between 1991 and 1995. With the 1990 age adjustment used by Bailar and Gornik, cancer mortality dropped by 1% between 1991 and 1994. "This drop may well portend larger improvements to come," Bailar and Gornik write. "Even if rates turn upward again, the decline will surely resume within the next few years as a result of reduction of smoking over recent decades."
This, too, is not disputed by NCI. "One area of agreement is that around 1991, a corner was turned, and for the first time since the beginning of the National Cancer Program, cancer mortality began to drop," said Barnett Kramer, deputy director if the NCI Division of Cancer Prevention and Control. "Also, I agree that as far as one can project, it looks like the decrease in mortality will continue for some time."
Bailar and NCI drew their data from the same source: the National Center for Health Statistics. However, before the Institute announced its findings on the drop in mortality, it obtained raw data for 1995. These data, which showed a continued downward trend, were not available to Bailar, sources said. Sources also said that even though NCI continued its tradition of presenting cancer mortality data age-adjusted for 1970, prior to the announcement of the mortality drop, the Institute ran the numbers with a 1990 age adjustment. These numbers, which were not released at the time, also showed a drop in mortality.
While Bailar’s mortality figures are not disputed, his conclusions and recommendations are. "Observed changes in mortality due to cancer primarily reflect changing incidence or early detection," the paper states. "The effect of new treatments for cancer on mortality has been largely disappointing. The most promising approach to the control of cancer is a national commitment to prevention, with a concomitant re-balancing of the focus and funding of research." Bailar acknowledges better treatment in several cancers, improvements in imaging and palliation, as well as advances in the understanding of cancer.
"The death rates at the population level reflect a huge spectrum of interventions," NCI official Kramer said to The Cancer Letter. "Some of them are preventive, some of them are early detection, some of them are clearly treatment-related, and some are combined. "Advances in all aspects of the National Cancer Program, including smoking cessation, behavioral research, treatment interventions and screening technologies, have led to decreases — and the magnitude of the decrease varies by disease.
"Perhaps the central issue is the question, can you predict the future simply by looking at the past? I would say that the nature of science is that often you can’t. The entire U.S. cancer mortality has started to turn around for the first time," Kramer said. "Since, at the population level, many interventions are delayed in their impact. The fact that the decrease in mortality has been modest doesn’t mean that the trends will not accelerate."
Detection versus Treatment
Former NCI Director Samuel Broder said it is "insane" for Bailar to ascribe a part of the drop to early detection rather than advances in therapy. "His answer is, ‘No you shouldn’t take credit, because treatment didn’t do that; that’s all due to earlier diagnosis,’" said Broder, senior vice president, research and development, at IVAX Corp., of Miami, Florida. "That’s insane. You don’t treat somebody with a diagnosis. Do we have a rule that it’s unfair to fight the tumor? You have to give it a head start, or it wouldn’t be fair to diagnose it early? As though early diagnosis is not part of treatment. When you say, it doesn’t count because it’s due to earlier diagnosis, well, who brought you the earlier diagnosis? Your friendly National Cancer Program. This is really an attack on basic science under the guise of being an attack on treatment," Broder said.
Former NCI Director Vincent DeVita said Bailar’s most recent article is consistent with his previous publications. "The purpose of this paper is to throw mud on the progress being made," said DeVita, director of the Yale Cancer Center. "I don’t believe that Dr. Bailar, who always claims that we should put money into prevention, has the foggiest notion of how much money is going into prevention, and in what proportion. He didn’t when I was the [NCI] director and I doubt he does now. And yet he concludes that more money should go into prevention. He doesn’t understand the fact that molecular biology money has been the biggest investment and the best investment in prevention that we ever had. He inaccurately presents the data primarily to get a point of view across as opposed to presenting data analytically," DeVita said. "One has to question whether the New England Journal is exercising good judgment."
Ultimately, "Cancer Undefeated" and media coverage that followed its publication may harm patients, said Robert Mayer, president of ASCO and professor at Dana-Farber Cancer Institute and Harvard Medical School. "Reductions in cancer mortality have many explanations," Mayer said to The Cancer Letter. "For Bailar and Gornik to so directly dismiss widely utilized, well-accepted advances in treatment not only is absurd on their part, but is also potentially damaging to patients with newly diagnosed malignant conditions who may be influenced by the media publicity surrounding this extreme view to reject life-saving treatment." 
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CANCER RISK FROM THREE MUTATIONS LOWER THAN EXPECTED, NATIONAL CANCER INSTITUTE SAYS |
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TopIn Aftermath of New...Cancer Risk from Three...Taxol Recommended for...Half of Glioblastomas Respond... |
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The findings, published in the May 15, 1997 issue of the New England Journal of Medicine, show that for those carrying an alteration, the average risk of breast cancer by age 70 is estimated to be 56%. Results of a preliminary study, conducted last year on a smaller group with a strong family history of cancer, suggested a breast cancer risk of as much as 85%.
The latest study estimated the average risk for ovarian cancer for those with the alteration as 16%. The preliminary study estimate was 44%. According to the latest results, men who carry the gene alteration have a 16% chance of developing prostate cancer.
"Although this tells us a lot about the biology of how breast cancer develops, it still does not explain most common ordinary breast cancer," Margaret Tucker, chief of the NCI Genetic Epidemiology Branch, said at a press conference. "We find that very important, because it tells us how tumors happen, but it really explains only a very small percent of [incidence of] breast cancer," Tucker said.
Jeffrey Struewing, co-author of the study, said the findings were preliminary. "Unfortunately, we don’t know how much variability there may be in the cancer risk from one carrier to the next, nor what factors might modify that risk or might allow us to make better estimates about an individual carrier’s risk," said Struewing, a senior research investigator in the NCI Genetic Epidemiology Branch.
Researchers took blood samples from 5,318 volunteers and tested for three specific alterations: 185delAG and 5382insC in the BRCA1 gene, and 6174delT in the BRCA2 gene. DNA analysis showed 120 of the volunteers carried one of the three targeted alterations, but none carried more than one.
Struewing said NCI was not making any screening or genetic testing recommendations. "The decision about testing is a very personal, very complex issue," he said. "These are subjective things. It is not for us to say whether testing is right or wrong for a given individual." Caryn Lerman, associate professor of medicine and psychiatry at Georgetown University Medical Center, said the findings do not warrant widespread genetic testing among the Ashkenazi Jewish population. "I think the issue is not whether a Jewish person should be tested or not, but what information do we have to date that we can provide someone so that they can weigh the pros and cons and make a decision about whether they want to know," said Lerman. "Some people may decide for themselves that they do not wish to know because there is too much uncertainty, and there are not enough proven prevention strategies. That is an individual decision that a man or a woman, Jewish or not Jewish, needs to make," she said.
A follow-up study is being developed in the Washington, D.C. Jewish community to assess risk factors in addition to the BRCA alterations, and to give volunteers the option of knowing their results and receiving genetic counseling.
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TAXOL RECOMMENDED FOR KAPOSI’S SARCOMA; ONCOLOGIC DRUGS ADVISORY COMMITTEE NIXES TWO OTHER DRUGS |
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TopIn Aftermath of New...Cancer Risk from Three...Taxol Recommended for...Half of Glioblastomas Respond... |
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ODAC voted 8 to 4 to recommend full FDA approval of Taxol for the secondary treatment of AIDS-related KS patients. "The data does present reliable evidence of efficacy," said Donald Abrams, director of the AIDS Activities Division at San Francisco General Hospital, who served as a consultant to FDA on the review. "I’ve never seen dramatic improvements like those shown."
Bristol-Myers Squibb presented results from two phase II trials. The first was a study of 29 patients conducted at NCI, and the second was a study of 56 patients conducted at the University of Southern California and Harvard Medical School. The studies showed response rates of 59% and 69%, with high efficacy in patients who received prior systemic therapy, anthracyclines, or who were resistant or intolerant to prior therapy. Of the 85 patients enrolled in the studies, 59 had received prior systemic therapy, and 38 had prior anthracyclines.
"Prolonged therapy with Taxol was tolerated in these immunosuppressed, heavily pretreated patients with advanced stage Kaposi’s sarcoma," the company said in its presentation. "The safety profile was comparable to that of patients with previously treated carcinomas of the ovary and of the breast." The company recommended a dosage of 135 mg/m2 every three weeks.
FDA raised concerns over sample size, lack of comparative arms, inadequate controls in follow-up, and lack of pharmacokinetic and drug interaction data. FDA also questioned the recommended 135 mg/m2 dosage, raising concerns over additional toxicity. Reports showed that 17% of the patients studied died within 30 days of beginning the Taxol regimen. Officials said the deaths cannot be specifically linked to therapy.
The ODAC panel voted to recommend full approval of the drug based on consistency of data and strong evidence of efficacy in tumor reduction. The four members who voted against recommending full approval said Taxol should go through FDA’s accelerated approval, which would require a phase IV trial while the drug is being marketed. Bristol said it has begun a phase III randomized trial in conjunction with the Eastern Cooperative Oncology Group to study the effects of Taxol in combination with protease inhibitors for the treatment of KS, and a separate phase III trial of Taxol in combination with Sequus Pharmaceutical’s Doxil (liposomal doxirubicin).
Bristol-Myers Squibb was issued a patent for the infusion of paclitaxel in doses between 135 and 175 mg/m2, for the treatment of breast and ovarian cancer.
Small Study Cited for Zyrkamine
Zyrkamine, a polyamine inhibitor indicated for AIDS-related non-Hodgkin’s lymphoma, was submitted to FDA by Ilex Oncology in October. The submitted data reported results from two phase II studies on 90 patients who had failed standard therapy or who relapsed after remission. The committee voted unanimously against recommendation of Zyrkamine based on the small number of patients in the study, and the uncertain efficacy of the drug.
Liazal also Rejected
Liazal, marketed by Johnson & Johnson’s subsidiary, Janssen Pharmaceutica, was also unanimously voted against.
The company presented results from three trials to show Liazal as an effective treatment for prostate cancer in patients who relapse after first-line therapy. The drug is designed as an oral therapeutic to inhibit the production of retinoic acid.
ODAC said the drug’s efficacy was not proven in Janssen’s presentation. The committee also said the presented studies showed Liazal to be inferior to Pharmacia & Upjohn’s prednisone, and Schering AG’s cyproterone acetate.
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HALF OF GLIOBLASTOMAS RESPOND TO THALIDOMIDE |
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TopIn Aftermath of New...Cancer Risk from Three...Taxol Recommended for...Half of Glioblastomas Respond... |
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Both phase II trials are supported by NCI and co-sponsored by EntreMed and Bristol-Myers Squibb, the company said. The trials were conducted at the Dana-Farber Cancer Institute, M.D. Anderson Cancer Center, and the Georgetown University Lombardi Cancer Center.
Results of the brain cancer trials were presented at the American Society of Clinical Oncology meeting by Howard Fine, principal investigator on the trial and director of the brain tumor program at Dana-Farber. Fine said that of the 32 patients evaluated with progressive glioblastoma multiformae and anaplastic gliomas, half of the patients showed some response when treated with thalidomide for at least two months. This includes 12 patients whose disease stabilized, two patients whose tumors were reduced by 50%, and two whose tumors were reduced by less than 50%, the company said.
"The results of this study clearly indicate the important role thalidomide could play as an antiangiogenic therapy," Fine said. "These data support discussions regarding further phase II and phase III studies for thalidomide in glioblastoma."
Lauri Welles and Robert Yarchoan, NCI investigators on the Kaposi’s sarcoma trial, presented their findings at the National AIDS Malignancy Conference held in June. Results showed three of the five patients who received thalidomide achieved a greater than 50% reduction in lesions, the company said. "We think that thalidomide holds significant promise as an antiangiogenic drug for next-generation cancer therapeutics," said John Holaday, president and CEO of EntreMed. "By using thalidomide in cancer studies, we are actually attempting to teach an old drug a new trick. The application of thalidomide in angiogenic disorders has the potential of playing a very important role in health and disease."
In December 1995, EntreMed formed a strategic partnership with Bristol-Myers Squibb to further the preclinical and clinical development of Angiostatin protein and thalidomide analogs, the company said. The partnership gave Bristol exclusive worldwide licensing rights to antiangiogenic compounds developed by EntreMed.
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FOOTNOTES |
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TopIn Aftermath of New...Cancer Risk from Three...Taxol Recommended for...Half of Glioblastomas Respond... |
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