NCI Cancer Bulletin: A Trusted Source for Cancer Research NewsNCI Cancer Bulletin: A Trusted Source for Cancer Research News
June 15, 2004 • Volume 1 / Number 24 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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Cancer Research HighlightsCancer Research Highlights

High Fracture Risk for Prostate Cancer Patients on
Androgen-Deprivation Therapy

Patients with nonmetastatic prostate cancer on androgen-deprivation therapy with drugs known as GnRH agonists are at significantly increased risk for fractures, researchers reported last week at the ASCO annual meeting in New Orleans. GnRH agonists are broadly used in prostate cancer to reduce testosterone that may fuel tumor growth and to help reduce pain, explained the study's lead author, Dr. Matthew R. Smith of Massachusetts General Hospital in Boston. Although it is known that these drugs affect bone density, data on the risk of adverse effects, such as fractures, linked to their use have been limited.

Dr. Smith and his colleagues looked at a random sample of more than 11,000 Medicare beneficiaries with nonmetastatic prostate cancer and compared the fracture risk between those who had and had not received GnRH agonists. The overall risk of developing any clinical fracture associated with a GnRH agonist was 25 percent, Dr. Smith said. More specifically, use of GnRH agonists increased the risk of hip fracture by 46 percent and vertebral fracture by 63 percent. Longer duration of GnRH use was associated with increased fracture risk, he added.

"For men who require androgen-deprivation therapy, screening for osteoporosis and interventions to prevent fractures should become the standard of care," Dr. Smith advised. "However, no studies have been done to determine how to prevent or reduce the risk of fractures in this patient population," he added. One potential option, he said, are bisphosphonates, which have been shown to increase bone mineral density in those patients who were given GnRH agonists.

Chemo Plus Radiation Improves Survival in
Often-Fatal Brain Cancer

Researchers have shown for the first time in a large study that adding a chemotherapy drug to radiation for the treatment of glioblastoma multiforme (GBM) - a common, aggressive, and highly fatal form of brain cancer - can improve survival. In the phase III international trial, 26 percent of patients with GBM treated with the chemotherapy drug temozolomide (Temodar) and radiation therapy were likely to live for 2 years after treatment, compared with 10 percent of patients treated with radiation therapy alone.

The study results, presented at the ASCO annual meeting, included 573 patients with GBM who were randomly assigned to receive the current standard therapy: surgery followed by radiation, or temozolomide daily, beginning at the same time as radiation therapy and continuing for 6 weeks following radiation. The median survival in the radiation-plus-temozolomide group was 14.6 months compared with 12.1 months in the radiation-alone group. Progression-free survival was 7.2 months in the temozolomide group and 5 months in the other group.

"Our data clearly establish a new treatment standard for GBM," said the study's lead author, Dr. Roger Stupp, of the University Hospital Multidisciplinary Oncology Center in Lausanne, Switzerland. The trial was conducted by the European Organization for Research and Treatment of Cancer and the National Cancer Institute of Canada Clinical Trials Group. Based on promising early studies of the drug, "most U.S. oncologists have been treating patients with GBM with radiation followed by temozolomide," commented Dr. Howard Fine of the NCI Center for Cancer Research (CCR). He agreed that this treatment has now shown to be effective as a first-line treatment, but added that "we have a long way to go" in developing clearly superior treatments for GBM patients.

Studies Show Survival Improvement in Advanced Prostate Cancer

Results from two similar phase III clinical trials, presented at the ASCO annual meeting, offered some hope to men with advanced, metastatic prostate cancer that has become resistant to standard hormone therapy. Both studies tested chemotherapy treatment regimens using the drug docetaxel (Taxotere) against the accepted standard of care for such patients, the two-drug regimen mitoxantrone and prednisone. The current standard has significantly limited effectiveness, with a median survival after treatment initiation of 10 to 12 months.

The first trial, led by Dr. Mario Eisenberger of Johns Hopkins School of Medicine, compared three treatment regimens: the use of prednisone and docetaxel weekly or once every 3 weeks against the standard treatment. With a median follow-up of approximately 21 months, the docetaxel regimens provided a 24 percent survival improvement (18.9 months) compared with the standard treatment (16.4 months). Patients on docetaxel regimens were also more likely to see significant reductions in PSA levels and were less likely to experience significant bouts of pain.

The second trial, led by the Southwest Oncology Group, compared the use of docetaxel and estramustine with standard treatment in men with advanced, hormone-refractory prostate cancer. According to the trial's principal investigator Dr. Daniel P. Petrylak, median survival was 18 months for patients treated with the docetaxel/estramustine regimen versus 16 months for those treated with the standard therapy, an approximately 20 percent reduction in risk of death. In both studies, the incidence of severe side effects was worse in the patients treated with docetaxel.

During a news conference, the researchers were asked whether a 2-month improvement in survival could really be considered significant. "These are people with incurable disease," responded Dr. Robert J. Mayer, from the Dana-Farber Cancer Institute, who moderated the news conference. "Multiple earlier trials have not shown that they could move the [survival] curve. The fact that two separate studies conducted at nearly the same time showed a survival improvement gives us something to build upon."

Expression Profile Changes Show Erlotinib May Have Additional Targets in Breast Cancer

New data presented at the ASCO annual meeting suggests that erlotinib (Tarceva), an investigational therapeutic agent that targets the epidermal growth factor receptor (EGFR) - which plays an important role in cancer cell proliferation - may have additional cellular targets. Previous research led by Dr. Sandra Swain of NCI's CCR using breast tumor biopsies had shown no clinical response and no proliferation changes in tumors after treatment with erlotinib. However, in one EGFR-positive tumor, expression of the EGFR protein decreased after treatment.

To conduct the new study, a team led by Drs. Swain and Xiaowei Yang, also from CCR, measured RNA expression profiles for 10 paired pre- and post-treatment breast tumor samples from patients with metastatic breast cancer. Only one tumor pair was shown to be EGFR-positive, and in that tumor the RNA levels of EGFR remained unchanged upon treatment with erlotinib. The drug did, however, alter the expression levels of 26 genes, independent of whether the tumors were EGFR-positive or EGFR-negative. These included genes that encode extracellular matrix components, proteases, signal transduction proteins, transcription factors, oncogenes/tumor suppressors, and enzymes involved in drug metabolism.

The researchers hypothesize that the reduction in EGFR protein but not RNA upon treatment in the EGFR-positive tumor may be due to accelerated degradation of the receptor. They also suggest that the fact that changes in gene expression occurred in these tumors regardless of EGFR expression status indicates that erlotinib may affect multiple targets or pathways. "This finding could provide physicians with additional information to understand drug effects in patients," said Dr. Swain. "We are in the process of analyzing the targets identified and collaborating with the U.S. Food and Drug Administration (FDA) to further study other signaling kinases that could be affected by erlotinib.

Researchers Develop "Knock-In" Mouse Model of
Plasma Cell Cancers

After manipulating genes involved in cell growth and cell death (apoptosis), researchers from the Laboratory of Genetics in NCI's CCR have developed an improved mouse model of plasma cell neoplasms. The study results, published in the June 15 Journal of Clinical Investigation, offer new possibilities for understanding what causes these cancers, as well as how to prevent and treat them.

In this study, researchers focused on two genes: Myc and Bcl-XL. Myc is involved in cell growth and proliferation, and Bcl-XL suppresses apoptosis. Deregulated expression of these genes has already been linked with plasma cell neoplasms in both humans and mice, but the mechanism of neoplastic development is not understood. Researchers inserted constitutively expressed versions of these genes into the mouse genome according to each of the three possible permutations: Myc transgenic or "knock-in" mice; Bcl-XL transgenic mice; and double transgenic Myc/Bcl-XL mice.

The study showed that after 380 days, less than 10 percent of mice carrying the Myc transgene developed B-cell tumors and all mice with the Bcl-XL mutation remained tumor free. All of the Myc/Bcl-XL transgenic mice, however, developed plasma cell tumors within 135 days. The resulting tumors produced monoclonal Ig, infiltrated the bone marrow, and produced large amounts of Myc and Bcl-XL protein - features similar to the multiple myeloma seen in humans.

"This information, and other insights gleaned from Myc/Bcl-XL mice, may lead to new interventions to inhibit the Myc/Bcl-XL collaboration for the benefit of the human plasma cell neoplasm patient," the authors concluded.