NCI Cancer Bulletin: A Trusted Source for Cancer Research NewsNCI Cancer Bulletin: A Trusted Source for Cancer Research News
January 27, 2004 • Volume 1 / Number 4 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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Cancer Research HighlightsCancer Research Highlights

Possible Cause of Leukemia in Gene Therapy Patients Found

NCI researchers have uncovered a possible genetic explanation for several cases of leukemia in children treated with gene therapy for X-linked severe combined immunodeficiency (SCID-X). In the original trial, nine of 10 infants born with SCID were successfully treated with autologous bone marrow stem cells infected ex vivo with an IL2RG-containing retrovirus. Almost 3 years after therapy was completed, two of the children developed T-cell leukemia, calling into doubt the future of human gene therapy trials.

In a study published in the Jan. 16 issue of Science, NCI researchers, led by Dr. Neal G. Copeland, associate director of the NCI Mouse Cancer Genetics Laboratory, reported that a search of NCI's Mouse Retroviral Tagged Cancer Gene Database, which contains more than 3,000 samples, identified a rare mouse leukemia that contained independent retroviral-induced mutations in the genes IL2RG and LMO2, and was very similar to the leukemia seen in the two SCID-X children.

The probability of finding a leukemia with this genetic makeup "by random chance is exceedingly small," the researchers wrote. The finding provides genetic evidence that the two genes, under certain conditions, could work together in "a rare cell" to promote leukemia development. The findings, the researchers conclude, "bode well for future gene therapy trials," because they indicate that, in most trials, transplanted genes are unlikely to be oncogenic, and instances of cellular mutation caused by the genetically modified vector "will be low, as has been seen in other gene therapy trials conducted during the past several years."

Adjuvant Chemotherapy Improves Lung Cancer Survival

A large, randomized study has shown for the first time that adjuvant chemotherapy after complete resection of non-small cell lung cancer may result in an improvement in overall survival and disease-free survival. Results from the 1,867-patient International Adjuvant Lung Cancer Trial (IALT), published in the January 22 New England Journal of Medicine, showed that patients given three to four cycles of adjuvant chemotherapy - that is, chemotherapy initiated shortly after complete tumor resection - with a drug combination that included cisplatin had improved survival rates at 5 years compared to patients who did not receive the postoperative therapy (44.5 percent vs. 40.4 percent, respectively). The absolute 5-year survival benefit was 4.1 percent.

Although randomized trials testing adjuvant chemotherapy following tumor resection had failed to find a benefit, IALT was launched in 1995 after a 52-study meta-analysis published in the British Medical Journal reported that patients given cisplatin-based therapy had a 5 percent survival advantage 5 years after treatment. An open-choice design was used for the trial to facilitate enrollment, meaning that each participating center could decide which cancer stage to focus on, the cisplatin combination and dose per treatment cycle, and whether to use postoperative radiotherapy. Etoposide was the chemotherapy drug most commonly used in combination with cisplatin.

Approximately 180,000 non-small cell lung cancer patients worldwide would be candidates for adjuvant chemotherapy, the IALT study authors noted. "Our results indicate that roughly 7,000 deaths from non-small cell carcinoma would be averted annually with the use of adjuvant cisplatin-based chemotherapy," they wrote.

Based on the IALT results, this adjuvant chemotherapy "represents a new standard of care" for non-small cell lung cancer, "but not necessarily the only standard of care," wrote Dr. Ronald H. Blum, an oncologist at Beth Israel Medical Center and St. Luke's-Roosevelt Hospital Center, in an accompanying editorial. A number of issues with adjuvant chemotherapy are still unresolved, he noted, including the optimal chemotherapy regimen, toxicity concerns, the role of adjuvant radiotherapy, and "controversy over the sequence of surgery and chemotherapy." As a result, Dr. Blum concluded, "only a continued commitment to well-designed, adequately powered clinical trials will allow us to gather the data necessary to make evidence-based decisions."

Clinical Trial to Begin on New Cervical Cancer Detection Device

An NCI-funded clinical trial slated to start later this year employing a digital device that measures fluorescence may one day lead to a change in the way cervical cancer is detected and diagnosed.

Dr. Michele Follen, of the M. D. Anderson Cancer Center, Dr. Rebecca Richards-Kortum, of the University of Texas, and colleagues have developed a new system for detecting and diagnosing cancerous and precancerous cells of the cervix. This system holds promise for becoming a one-stop, see-and-treat approach, which would replace the commonly used triad of Pap smear, colposcopy, and biopsy - a process that usually takes at least three visits to the doctor.

In addition to being time saving, the new system is being accepted by women for its ease and painlessness and has the potential to dramatically lower the costs of detecting and diagnosing cervical cancer, the third leading cancer in women around the world. The major cost advantage is that unnecessary biopsies could be reduced, saving the United States about $625 million each year. Pap smears currently have a false-positive rate of up to 40 percent. In clinical testing already completed, the new fluorescence device has proved more accurate.

Thanks to advances in imaging technology and its merger with biological knowledge, the unique team headed by Dr. Follen has put together a two-part system employing a digital colposcope hooked to a video camera that can view the whole cervix and a point probe that hones in on abnormal areas. Using this device, a doctor can screen and diagnose a woman in one visit and women with abnormalities can also be treated or start treatment, depending on the severity of the condition. The tool and its development have been funded in large part by the NCI Cancer Imaging Program in the Division of Cancer Treatment and Diagnosis.

The new apparatus relies on the fact that precancerous and cancerous cells differ from normal cells in structure, having different nuclei and more cross-linked collagen fibers for instance. By shining light on the cervix and detecting what is reflected or fluoresced back, a computer determines whether abnormalities are present. This increases the accuracy of the device and cuts back on the training needed to perform the procedure, Dr. Follen said.

She has worked with cost-efficiency experts and has estimated that the easily portable system, once it has cleared this last clinical trial, could be commercially available for about $4000. "NCI has done a remarkable job for both the developed and developing world," said Dr. Follen, by allowing her to assemble experts in gynecology, optical engineering, cost-effectiveness, and patient acceptance to develop this tool. She foresees that it could be ideal for use in developing countries, where 80 percent of cervical cancers occur.

Research Network Initiates Clinical Validation of Cancer Biomarkers

NCI-supported Group Launches First Human Clinical Validation Study for Early Detection Diagnostic for Bladder Cancer

First Human Clinical Validation Study for Early Detection Diagnostic for Bladder Cancer The NCI Early Detection Research Network (EDRN), which was formed four years ago, met Jan. 16 to launch its validation study of Microsatellite Analysis (MSA) of Urinary Sediment. The study involves the analysis of DNA obtained from bladder cells in urine samples to detect common losses in chromosomes that occur in primary and recurring bladder cancer. Preliminary evidence suggests that this analysis can detect bladder cancer as early as 18 months prior to clinical diagnosis.

The study, analogous to the rigorous testing a new drug would receive in a clinical trial, involves testing of 15 biomarkers for their utility in the early detection of bladder cancer.

"This three-year study will set the standards and compliance expectations required by the Food and Drug Administration (FDA) for validation studies of future diagnostics," said Dr. Sudhir Srivastava, Chief and Program Director of NCI's Cancer Biomarkers Research Group. The flagship trial is based on the work of Drs. David Sidransky and Mark Schoenberg of Johns Hopkins University.

The team involved in this translational research effort includes physicians, nurses, and scientists from NCI's Cancer Biomarkers Research Group, three regional cancer centers, 10 clinical research institutions, and Cangen Biotechnologies, Inc., of Rockville, Md. Cangen owns the commercial rights to the microsatellite diagnostic technology and will initiate submission to FDA for approval in clinical screening of cancer. This multi-institutional effort drove the creation of the Validation Study Information Management System (VSIMS), a common platform for data entry and analysis that maintains patient confidentiality. The developers intend to have the VSIMS serve as a standard platform for future validation studies.