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Also in the Feb. 10 JNCI
Date:2/10/2009

Identification of Potential Surrogate Endpoints of Long-Term Survival in Prostate Cancer

Lack of general treatment failure or distant metastases 3 years after the start of treatment may be surrogate endpoints for long-term survival in patients with early prostate cancer.

Prostate cancer is a slowly progressing malignancy in many patients. The long natural history of the disease makes evaluation of new therapies difficult because patients must be followed for many years. If researchers could identify a surrogate clinical endpoint that accurately reflects long-term clinical outcomes for prostate cancer, clinical trials would be easier and faster.

To look for possible surrogate endpoints, Michael E. Ray, M.D., Ph.D., of ThedaCare and Bellin Health Systems in Appleton and Green Bay, Wisconsin, and colleagues evaluated the ability of general treatment failure and metastasis-free survival at 3 and 5 years to predict long-term survival in patients who had taken part in a clinical trial. A total of 1,521 patients who participated in the Radiation Therapy and Oncology Group 92-02 randomized controlled trial were included in the current analysis.

The authors found that both distant metastasis and general clinical treatment failure at 3 years were consistent with the four statistical criteria developed by Prentice for surrogate endpoints. At 5 years, only three of the four criteria were potentially fulfilled because prostate-cancer specific survival was not statistically significantly different between the two trial arms.

"The potential surrogate endpoints, distant metastasis and general clinical treatment failure, should be further and prospectively evaluated in future clinical trials along with overall and prostate cancer-specific survival endpoints," the authors conclude.

In an accompanying editorial, Ross L. Prentice, Ph.D., of the Fred Hutchinson Cancer Research Center in Seattle, who developed Prentice's criteria, discusses the difficulty of establishing surrogate endpoints and the importance of doing so. "The issue of full mediation by a potential surrogate is of more than academic interest, in view of multiple examples in which a clear treatment effect on a presumed surrogate did not translate to a corresponding effect on the clinical outcome of interest," the editorialist writes.

Contacts:
Article: Michael Ray, Michael.Ray@thedacare.org
Editorial: Ross L. Prentice, rprentic@fhcrc.org


Netrin-1 and Its Dependence Receptor Implicated in Non-Small Cell Lung Cancer

Netrin-1 is overexpressed in a substantial fraction of human non-small cell lung cancer (NSCLC) tumors and interferes with apoptosis in NSCLC cells grown in culture.

Netrin-1 may promote colorectal and breast cancer. Previous studies suggest that the tumors may become dependent on its binding to particular receptors, referred to as dependence receptors. In the absence of netrin-1 binding these receptors trigger cell death. However netrin-1's potential role in NSCLC was unknown.

In the current study, Patrick Mehlen, Ph.D., of the Universit de Lyon in France, and colleagues tested 92 human tumor samples for netrin-1 expression and examined the impact of inhibiting its expression in NSCLC cells grown in vitro and in xenograft animal models.

Netrin-1 was overexpressed in 43 (47%) of the human samples tested. Inhibition of netrin-1 expression induced apoptosis in NSCLC cell lines and reduced tumor growth in animal models.

"In conclusion, our findings raise the possibility that a targeted treatment that is based on inhibition of the interaction between netrin-1 and its dependence receptors might be of benefit to patients suffering from lung cancer whose primary tumors show high netrin-1 expression," the authors write.

In an accompanying editorial, Michael P. Schn, M.D., and Margarete Schn, Ph.D., of Georg August University in Gttingen, Germany, review the phenomenon of dependence receptors in cancer and the role of netrin-1 in normal biology and tumor progression, including the newly reported data by Mehlen and colleagues. "Additional studies will be needed to determine whether selectively targeting netrin-1 will become a useful addition to the therapeutic armamentarium in NSCLCs," the editorialists conclude.

Contacts:
Article: Patrick Mehlen, mehlen@lyon.fnclcc.fr
Editorial: Stefan Weller, sweller@med.uni-goettingen.de


Meta-Analysis Shows Aspirin Can Reduce Recurrence of Colon Polyps

Regular aspirin use is associated with a statistically significant reduction in the development of colorectal adenomas, which are precursor lesions to colorectal cancer, in individuals at high risk of developing colorectal cancer.

Multiple lines of evidence, including data from randomized clinical trials, suggest that aspirin may reduce the risk of colon adenomas and perhaps cancer. A quantitative summary of the clinical data and a more precise estimate of the magnitude of the benefit associated with aspirin use has been missing.

In the current study, Bernard F. Cole, Ph.D., of the University of Vermont in Burlington, and colleagues performed a meta-analysis of all available randomized clinical trials that examined adenoma formation in participants assigned to regular aspirin use or placebo.

Among 2,698 participants who underwent colonoscopic follow-up after randomization, 37% of the participants assigned to placebo developed adenomas compared with 33% of those assigned to aspirin. Moreover 12% of the participants assigned to placebo developed advanced adenomas compared with 9% of the participants assigned to aspirin. The pooled analysis indicated that regular aspirin use resulted in an absolute risk reduction of 6.7% for developing adenomas relative to placebo.

"The substantial size of the relative reduction in risk seen in our analysis (28% for advanced adenomas) and seen in clinical trials that evaluated the effect of aspirin on colorectal cancer risk (26% reduction) indicates the potentially important health benefits of aspirin use," the authors write. "Of course, these benefits need to be considered in the context of all of the health effects of aspirin, positive and negative."

Contact: Bernard Cole, ccole@cems.uvm.edu


Nonsteroidal Anti-inflammatory Drug Use After 3 Years of Aspirin Associated with Reduction in Colorectal Adenoma Risk

Data from an observational study conducted at the end of a randomized placebo-controlled trial indicate that continued use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduction in the risk of developing colorectal adenomas, which are precursor lesions to colorectal cancer.

The randomized placebo-controlled Aspirin/Folate Polyp Prevention Study showed that regular use of low dose aspirin (81 mg) reduced the risk of colorectal polyp formation in individuals at high risk compared with placebo. To determine whether continued NSAID use might be beneficial, researchers invited the study participants to enroll in an follow-up study. This observational study examined their NSAID use and the risk of a diagnosis of colorectal adenoma at their next colonoscopy, on average 4 years after the end of randomized aspirin treatment.

In the current analysis, John Baron, M.D., of Dartmouth Medical School in Lebanon, N.H., and colleagues found that individuals who were initially assigned to low-dose aspirin in the randomized trial and continued to take NSAIDs four or more days per week during the follow-up period had a statistically significantly lower risk of adenomas than those who were assigned to placebo during the randomized trial and used NSAIDs less than two days per week during the observational study. The risk of adenomas among frequent NSAID users was 26.8 percent versus 39.9 percent among placebo subjects who later used NSAIDs sporadically.

"These findings imply that aspirin does not lose its antineoplastic properties over time and that these effects persist and may even be accentuated with prolonged NSAID use," the authors write.

Contact: John Baron, John Baron, John.A.Baron@dartmouth.edu


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Contact: Caroline McNeil
jncimedia@oxfordjournals.org
301-841-1287
Journal of the National Cancer Institute
Source:Eurekalert

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