As survival rates among some patients with cancer continue to rise, so does the spread of these cancers to the brain - as much as 40 percent of all diagnosed brain cancers are considered metastatic, having spread from a primary cancer elsewhere in the body.

Now, scientists from The Scripps Research Institute have discovered a molecular mechanism that plays a pivotal role in controlling cancer growth in the brain. The discovery could provide a basis for potentially effective therapies for the treatment of brain metastasis.

The study was published in an online Early Edition of the journal Proceedings of the National Academy of Sciences (PNAS) the week of June 8, 2009.

“Our study could have a broad impact because it explains at a molecular level how metastatic lesions thrive in the brain,” said Scripps Research Associate Professor Brunhilde Felding-Habermann, who led the research. “This offers a potential target for inhibiting the growing problem of brain metastasis.”

For tumor cells that have invaded the brain, Felding-Habermann and her colleagues found that when activated, a tumor cell receptor known as integrin v 3 increased the supply of a growth factor involved in the development of new blood vessels (”angiogenesis”) necessary for tumor expansion within the brain tissue. In contrast, the same receptor did not influence tumor growth at the primary cancer site, in this case, the breast.

“The fact that we uncovered a link between activated v 3 and angiogenesis is quite striking,” said Senior Research Associate Mihaela Lorger, the first author of the study. “In addition, our study showed that that the ability of tumor cell v 3 to enhance angiogenesis depends very much on the microenvironment.”

This receptor’s varying effects on tumor cells depending on their location in the body reinforces a principle that the Felding-Habermann lab uncovered a few years ago.

“For tumor cells, it’s not just the presence of the receptor on the cells, but the conformation or shape of the molecule that determines how well tumor cells can do within different tissues” Felding-Habermann said. “The shape of the molecule can increase or reduce the receptor’s affinity for its natural ligands.”

In the new study, which was conducted in mouse models, the scientists showed that activated v 3 on tumor cells leads to angiogenesis in the brain by elevating the expression of the VEGF, a protein that is critical to the formation of new blood vessels.

Tumor cells normally try to recruit more blood vessels when oxygen supply runs low. When oxygen and nutrients get scarce, many tumor cells die and tumor growth slows down until new vessels have formed. But in the brain, activated v 3 promotes rapid tumor growth by enabling tumor cells to attract new blood vessels continuously, even when oxygen is still abundant.

The scientists plan to follow up on their new findings by testing if activated v 3 on tumor cells also supports brain metastasis of other types of cancer, and by investigating if targeting the activated form of v 3 can inhibit metastatic brain disease.

Notes:
In addition to Felding-Habermann and Lorger, other authors of the study, “Activation of Tumor Cell Integrin v 3 Controls Angiogenesis And Metastatic Growth in the Brain,” include Joseph S. Krueger, Melissa O’Neal, and Karin Staflin of The Scripps Research Institute. The study was supported by The National Institutes of Health, the University of California Breast Cancer Research Program, S.G. Komen, and the Government of Sweden.

Contact: Keith McKeown

Scripps Research Institute

TORONTO, June 10 — Men with locally advanced prostate cancer live longer if they are treated with a combination of radiotherapy and long-term androgen suppression, researchers said.

• Explain to interested patients that this study confirms a survival benefit in locally advanced prostate cancer when radiation therapy is combined with long-term androgen suppression.
• Note, however, that it found a shorter course of androgen suppression did not work as well.

The finding confirms the benefit seen in an earlier trial and rules out short-term androgen suppression combined with radiation, according to Michel Bolla M.D., of the Centre Hospitalier Universitaire de Grenoble in Grenoble, France, and colleagues.

The difference in five-year mortality was “modest” but the advantage of long-term suppression is likely to be maintained while any benefit from short-term suppression is likely to dissipate, Dr. Bolla and colleagues reported in the June 11 issue of the New England Journal of Medicine.

The finding comes from a prospective randomized trial aimed at seeing if six months of androgen suppression could provide the same benefit as three years of treatment, but with fewer adverse effects.

Patients in the trial had confirmed but nonmetastatic prostate cancer in either T1c to T2a-b clinical stage with pathological nodal stage N1 or N2 or stages T2c to T4 with clinical nodal stages N0 to N2.

After external beam radiation, all of the men received six months of androgen blockade with a luteinizing hormone-releasing hormone analogue — started on the first day of radiation — and a daily antiandrogen agent started a week earlier.

After the six months, patients whose disease had not progressed were randomly assigned to no further treatment (and formed the short-term therapy group) or to another 2.5 years of androgen blockade with the luteinizing hormone-releasing hormone analogue but without the antiandrogen agent.

The endpoint of the study was noninferiority in terms of overall survival but an interim analysis found that the difference in favor of long-term treatment was so great it would be futile to continue the study, the researchers said.

All told, 970 men were randomized — 483 to short-term suppression and 487 to long-term suppression.

After a median follow-up of 6.4 years, the researchers found:

• 132 patients in the short-term group and 98 in the long-term group had died.
• The five-year overall mortality for short-term and long-term suppression was 19.0% and 15.2%, respectively.
• Prostate cancer deaths amounted to 47 in the short-term group and 29 in the long-term group and the prostate-cancer-specific survival curves were significantly different at P=0.002.
• The observed hazard ratio was 1.42 (with an upper 95.71% confidence limit of 1.79), with a significance value of P=0.65 for noninferiority.

The men in the long-term group had significantly more insomnia and hot flushes (at P=0.006 and P<0.001, respectively), and significantly less sexual interest and activity (at P<0.001 for both).

Overall quality of life did not differ significantly between the two groups and there was also no significant difference in the cumulative incidence of fatal cardiac events at five years, the researchers found.

But the study doesn’t provide a clear answer about clinical applications, according to Peter Albertsen M.D., of the University of Connecticut Health Center in Farmington, Conn.

That’s because the landscape of prostate cancer changed markedly, so that most men with newly diagnosed prostate cancer have smaller tumors and lower grade disease than those in the European trial, he said in an accompanying editorial.

“It is unclear whether the findings,” he said, “can be applied to men receiving radiation to treat low-grade, small-volume tumors.”

Until that issue is clarified by clinical trials now under way, he said, “androgen-deprivation therapy for clinically localized disease should be limited primarily to men with advanced localized disease undergoing radiation therapy and to men with clear signs of systemic disease.

“These are the patients most likely to benefit from either symptom relief or increased survival that would justify the compromise in quality of life that is associated with androgen-deprivation therapy.”

The study was supported by Ipsen Pharma, the French Ministry of Health, the Association pour la Recherche contre le Cancer, and Vlaamse Liga tegen Kanker in the Netherlands. Dr. Bolla reported no conflicts. Dr. Albertsen reported no conflicts.

Primary source: New England Journal of Medicine

Source reference:
Bolla M, et al “Duration of androgen suppression in the treatment of prostate cancer” N Engl J Med 2009; 360: 2516-27.

Additional source: New England Journal of Medicine

Source reference:
Albertsen P “Androgen deprivation in prostate cancer — Step by step” N Engl J Med 2009; 360: 2572- 74.

On June 4, the U.S. Centers for Medicare & Medicaid Services (CMS) announced that it is considering a pathway for coverage of Sodium Fluoride (NaF-18) for PET bone imaging as an alternative to Technetium-99m imaging. Currently, Tc-99m bone imaging is one of the more commonly performed procedures using this radioisotope. Technetium-99m is in scant supply because of ongoing production outages, resulting in serious delays in patient imaging studies for many medical problems, including oncologic, cardiac and neurologic conditions.

Because of the severity of the radioisotope supply crisis and the long-term duration of the anticipated outage, CMS has opened the PET National Coverage Determination (NCD) to evaluate the effectiveness of the radiotracer Sodium Fluoride (NaF-18) for PET bone imaging. PET bone imaging is a nuclear medicine procedure that is sensitive for the detection of the spread of many common cancers - such as breast, lung and prostate - to the bone. It also can be used to detect fractures when X rays do not provide a definitive diagnosis, particularly in pediatric patients.

Currently, about 80% of the world’s nuclear medicine scans are performed using Technetium-99m. However, the medical community depends on only six nuclear reactors in the world for over 30 million nuclear medicine tests performed annually with this critical isotope. A shutdown last month at one of these reactors in Chalk River, Canada, has already left thousands of hospitals in the U.S. and Canada without access to this medical isotope.

“The medical community is in crisis right now,” said Robert W. Atcher, Ph.D., M.B.A., president of SNM and chair of the society’s isotope task force. “Physicians can’t get access to essential isotopes for common nuclear medicine procedures. As a consequence, patients are being denied tests, or have to be diagnosed with procedures that involve more radiation dose, less accuracy, more cost or more invasive techniques.”

While F-18 as fluorodeoxyglucose (FDG) has been approved by the U.S. Food and Drug Administration (FDA), CMS does not currently reimburse for F-18 fluoride PET bone imaging procedures for the many Americans who would be eligible for coverage as Medicare recipients.

“This reopening paves the way for Medicare beneficiaries who need critical tests to get the coverage and support they deserve,” added Atcher. “We encourage CMS to consider the most efficient path forward to provide both themselves and the medical field with sufficient information to analyze and open access to patients across the nation.”

“This is very good news,” said Barry Siegel, M.D., chief of nuclear medicine at the Mallinckrodt Institute of Radiology, St. Louis, Mo., and co-chair of the NOPR working group. “With the potential for a coverage opening, physicians will be able to provide the evidence necessary to build the case that F-18 fluoride is a viable alternative to Tc-99m in this situation - a case the preliminary evidence suggests will be readily made.”

SNM is actively working with CMS and members of the imaging community to submit data and ensure that CMS has the necessary information to cover F-18 fluoride for PET bone imaging procedures.

Source:
Amy Shaw

Society of Nuclear Medicine