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NCI To Plan Large Trial For Lung Cancer Screening
Officials of the U.S. National Cancer Institute said they will develop plans for a definitive study of a promising, but largely unproven method of lung cancer detection that is increasingly being marketed by hospitals and physicians.
The new technique, helical low-dose computed tomography scanning, also know as spiral CT scanning, can find smaller lung tumors than can be found with conventional chest x-rays. At a recent workshop and an NCI advisory group meeting, experts expressed optimism about the technique and suggested the Institute move forward on plans for a large randomized trial.
"We are quite a distance from launching such a trial, but the preliminary information suggests this could be promising, but also have potential harms," said Barnett Kramer, deputy director of the NCI Division of Cancer Prevention. "We've learned from previous experience in lung cancer screening trials where preliminary information did not bear out a benefit that we should be careful in dealing with lung cancer screening technologies."
Routine screening for lung cancer using conventional chest x-ray currently is discouraged because randomized trials in the 1970s found that screened individuals did not live any longer than those in the control group, and screening resulted in complications and even deaths due to biopsy and treatment.
According to a study published earlier this year in The Lancet, researchers at Cornell Medical Center and McGill University found that spiral CT scanning detected malignant tumors while they were still in stage I.
The study of 1,000 asymptomatic smokers or former smokers age 60 or older subjected participants to spiral CT scanning as well as conventional x-ray. The new method detected lung nodules in 233 (23 percent) of the participants, while x-ray detected nodules in 68 (7 percent). Twenty-seven of the 233 CT positives were diagnosed as malignancies, compared to seven of the 68 chest x-ray positives. Of the 27 malignancies, 23 were diagnosed as stage I, while four were at later stages. Following surgery, none of the stage I patients had radiation or chemotherapy and have no further sign of disease. The four patients with later-stage disease have died, the study said.
At a meeting of the National Cancer Advisory Board (NCAB) in September, board members encouraged NCI to move ahead cautiously with plans for definitive studies.
"What I took from the NCAB meeting was a consensus that we shouldn't declare victory short of a randomized trial with mortality endpoints," Kramer said. "Also, because of the potential loss of a window of opportunity, we ought to be thinking about a trial sooner rather than later."
Christine Berg, acting chief of the NCI lung and upper aerodigestive cancer research group, said spiral CT scanning is available in 47 percent of all diagnostic imaging units in the U.S. Thus, like several cancer screening procedures, the scans could become widely used despite the lack of evidence of its ability to improve survival. The average cost of a spiral CT scan is $500, and is not covered by insurance plans, Berg said.
Berg said her group will develop a concept for a trial or trials for presentation to the NCI Board of Scientific Counselors. "The sentiment at the workshop was for a large trial," Berg said. "I think it would be reasonable to consider smaller steps first to assess spiral CT, to make sure we know the characteristics and get diagnostic algorithms worked out. But those issues remain to be determined."
Berg said she could not predict when a concept would be finalized. "These things always take longer than you expect," she said. 
Lymphoma Vaccine Shows Anti-Tumor Effect In Small Study; NCI Plans Large Phase III Trial
For the first time, the U.S. National Cancer Institute has reported results of a recently completed lymphoma cancer vaccine study showing there is a clear anti-tumor effect in a small group of patients who were vaccinated over the course of five years.
NCI said it will launch a large-scale, randomized, phase III clinical trial in the near future to definitively test the experimental vaccine, which is custom-made from patients' own tumors.
In "Nature Medicine", Vol. 5, No. 10, (October), NCI researchers reported that 18 of 20 patients who were vaccinated against this common blood-cell tumor remain in complete remission an average of four years after vaccine therapy began, and have no evidence of microscopic disease.
Complete Molecular Remissions In 75%
Prior to vaccination, all of the patients in the phase II study had minimal disease or were in a chemotherapy-induced first remission. Complete molecular remissions were documented, using polymerase chain reaction (PCR), in 75 percent of patients after vaccination.
"Essentially, what we have done is present a tumor protein to patients in such a way that their immune systems recognize it and then destroy any cells bearing that protein," said Larry Kwak, a senior investigator in the NCI Division of Clinical Sciences and the principal investigator of the study.
By selecting only newly diagnosed patients, Kwak added, researchers maximized the likelihood that the vaccine would produce a positive immune response.
To create the vaccine, researchers fused tumor cells taken from individual patients to antibody-producing mouse cells that act as mini-factories, churning out large quantities of tumor proteins. These proteins were then shed into a tissue culture fluid, from which a particular protein of interest was plucked—in this case a receptor molecule on the outer coating of the immune system's B cells. The receptor molecule is "exquisitely specific for this type of tumor because it is an immunoglobulin," Kwak said. "And since it is unique to a given B cell, any tumor derived from that malignant B cell will have this [receptor molecule] marker."
The vaccine mixture also included a highly immunogenic carrier protein and an "adjuvant" or immune system booster. Patients received an initial injection, followed by booster shots for four months.
In the forthcoming pivotal trial, NCI hopes to enroll 390 patients who have been diagnosed with low-grade follicular lymphoma—the most common form of this cancer—at a consortium of several clinical centers in North America, to be announced, as well as at the Warren G. Magnuson Clinical Center at NIH.
Patients in the control arm of this large-scale study will not get the tumor-specific antigen (the receptor molecule) in their vaccine mixture, but they will receive the carrier protein and granulocyte colony stimulating factor to stimulate or boost an immune system response.
Also, Kwak said, two-thirds of participants will go into the experimental arm of the trial, a departure from the traditional 50-50 randomized split seen in most clinical trials. The hope is that by making the odds higher for getting the treatment vaccine "we will make the trial more attractive to patients," Kwak said.
Depending on the rate of patient accrual and whether or not the vaccine continues to prove effective, he added, the trial will take anywhere from six to eight years. B-cell lymphoma, which strikes an estimated 41,000 Americans each year, is a cancer of the lymph glands caused by an unruly growth of B cells, white blood cells that produce the body's disease-fighting antibodies. Perhaps as many as 25,000 of these cancers are low-grade lymphomas, slow-growing tumors with a high rate of recurrence.
Molecular Analysis Using PCR
Because these tumors can recur after many years in remission, in the "Nature Medicine" study Kwak and his colleagues established surrogate endpoints to measure the vaccine's success. Using PCR, the investigators measured chromosomal or molecular changes in the peripheral blood for evidence of residual tumor cells or microscopic disease.
Cancerous cells are PCR-positive for these molecular or chromosomal changes; noncancerous cells are not. Eleven patients in the initial vaccine study were suitable for molecular analysis.
All 11 patients were PCR-positive at the beginning of the study, as well as before vaccination, despite being in complete remission—a common finding for many lymphoma patients whose persistent circulating tumor cells place them at increased risk of relapse. However, 8 of the 11 patients converted to PCR-negative status after receiving the treatment vaccine and have remained so an average of 18 months after vaccination.
The long-term clinical importance of these "molecular remissions," Kwak said, has yet to be determined, but it seems clear that the vaccine either further reduces patients' tumor burden beyond that achieved by chemotherapy or redistributes residual tumors to sites other than the peripheral blood, such as the lymph nodes.
The investigators also found that, as a result of vaccination, 19 of 20 patients showed anti-tumor activity—specifically the induction of tumor-specific cytotoxic T cells. T cells are the white blood cells that orchestrate the immune response and have the capacity to directly kill tumor cells.
FDA Grants Fast Track Status To Neurocrine's IL-4 Compound
Neurocrine Biosciences Inc. (Nasdaq: NBIX) of San Diego, said the U.S. Food and Drug Administration has granted Fast Track designation to the IL-4 Fusion Toxin compound (NBI-3001). Neurocrine Biosciences is conducting a phase II trial to assess safety and determine the maximum tolerated dose.
Twenty-two patients have been treated, the product appears to be well tolerated and the maximum tolerated dose has been determined. The ongoing phase II clinical trial will bridge into the phase III pivotal trial in the first half of next year, the company said.
Friedrich Weber, principal investigator for the European phase II clinical program for NBI-3001, said patient MRI scans displayed dramatic changes suggestive of tumor necrosis, indicating NBI 3001 has a robust anti-tumor effect. He presented these preliminary results at the 13th International Conference on Brain Tumor Research and Therapy.
FDA guidelines include a six-month goal for the review of new product applications identified as Fast Track. The Fast Track review process was authorized by the FDA Modernization Act of 1997 to expedite the review of treatments that have the potential to address unmet medical needs for serious life-threatening disease.
Preclinical data suggest that when infused directly into the glioblastoma, IL-4 Fusion Toxin kills the tumor cell but not the healthy brain cells, the company said.
IL-4 Fusion Toxin is a protein in which a blood cell derived growth factor (IL-4) has been joined with a Pseudomonas exotoxin, a potent toxin that can destroy cancer cells. IL-4 has very high affinity for-IL-4 receptors, which are highly localized on malignant brain tumors, but do not exist on normal brain cells.
IL-4 binds tightly to the IL-4 receptors on the surface of the glioblastoma cells and delivers the exotoxin directly into the cell, resulting in cell death, the company said. IL-4 Fusion Toxin is administered via catheter that permits delivery directly into the brain tumor, the company said.
FDA Approves Aromasin For Breast Cancer
Pharmacia & Upjohn has received U.S. Food and Drug Administration approval for Aromasin (exemestane tablets), a new treatment for advanced breast cancer in postmenopausal women.
Developed by Pharmacia & Upjohn, Aromasin is the first aromatase inactivator for use in advanced breast cancer in patients whose tumors stop responding to tamoxifen therapy.
The most common drug-related adverse events were hot flashes, nausea, fatigue, increased sweating, and increased appetite.
Aromasin is Pharmacia & Upjohn's second new treatment for breast cancer to receive FDA approval this year. Earlier this month, the company launched Ellence (epirubicin hydrochloride injection) in the U.S. as a component of adjuvant therapy in the treatment of primary breast cancer. Ellence is the first and only chemotherapy agent for treatment of early node-positive breast cancer following surgery.
Footnotes
© 1999 The Cancer Letter, Inc., publishers of: The Cancer Letter with Cancer Economics and The Clinical Cancer Letter. P.O. Box 9905, Washington, DC 20016 USA; Telephone: 202-362-1809; Fax: 202-362-1681; Internet: subscrib{at}www.cancerletter.com 
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