Researchers re-analyzing the results of a large phase III study of patients with advanced neuroendocrine tumors (NET) found that certain factors, such as bone metastases, having NETs that originate in the lung, and elevated levels of the blood biomarker chromogranin A predict which individuals are at greatest risk for neuroendocrine tumor progression and are more likely to need active therapy. The results of the study were presented at the 9th Annual Gastrointestinal Cancers Symposium being held January 19-21, 2012, at The Moscone West Building in San Francisco, CA, USA.

The re-analysis of the data also showed that combining the drug everolimus (Afinitor?, Novartis) with another drug, octreotide (Sandostatin? LAR? Depot, Novartis), halted NET growth for a much longer period than previously reported, compared to octreotide treatment alone.

Optimal treatment
?We have identified important prognostic factors that can help physicians to better determine the optimal treatment for patients with neuroendocrine tumors, which can have a widely variable course of progression,? said lead author James Yao, MD, assistant professor and deputy chair of gastrointestinal oncology at the University of Texas? M.D. Anderson Cancer Center in Houston. ?The findings will also improve our ability to stratify patients in future randomized trials on neuroendocrine tumors.?

Delay in cancer progression
In the original phase III study, called RADIANT-2, investigators showed that a combination of everolimus (marketed by Novartis as Zortress? (USA) and Certican? (Europe) in transplantation medicine and Afinitor? in oncology) and the drug octreotide led to a median 5.1 months longer delay in cancer progression compared to treatment with octreotide alone. That study included 429 patients with advanced NET that began in the gastrointestinal tract, lungs or other non-pancreas locations in the body (all of which are referred to as carcinoid syndrome). According to Yao, the study was found to have imbalances in its patient randomization, which put many more patients with a poor prognosis in the everolimus arm and potentially altered the results of the study, suggesting that everolimus may have a greater benefit than investigators originally reported.

Randomization imbalances
In the current re-analysis, Yao?s team analyzed the original phase III results to both identify and adjust for randomization imbalances. The original study had an increased risk for such imbalances, Yao said, because the appropriate prognostic factors needed to stratify patients had not been well defined at the start of the study. As part of their re-analysis, the investigators used standard statistical methods to first identify prognostic factors that predicted both good and bad outcomes in the trial, and found that certain factors were associated with a greater likelihood of NET progression. For example, patients with bone metastases had a 1.52 times greater risk than those without bone metastases for disease progression, while those individuals whose cancer originated in the lung had a 1.55 times greater risk of progression. Other factors included baseline chromogranin A and World Health Organization performance status, which measured patients? functional status.

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Prognostic indicators
The researchers found that after using these prognostic indicators to correct for the randomization imbalances, the reduction in risk of NET progression changed from 23% to 38%, meaning that the original study data may have underestimated the effectiveness of the drug. They plan to conduct a larger study to confirm these results. Everolimus is one of two drugs approved in the last year by the U.S. Food and Drug Administration for treating advanced pancreatic neuroendocrine tumors, but it has been uncertain whether the drug was also effective in treating neuroendocrine tumors that do not originate in the pancreas.

Less agressive
Advanced neuroendocrine tumors arise from neuroendocrine cells spread and can arise in nearly any part of the body with these cells. The incidence of neuroendocrine tumors has increased over five-fold from 1 per 100,000 people per year to 5.25 per 100,000 per year over the last three decades. Low to intermediate grade NETs are generally less aggressive tend to be curable in early stages with surgery. Advanced NETs are more aggressive and incurable, and most patients will die from the disease. Median overall survival is approximately four years for patients with advanced disease. Though NETs tend to progress at a slower pace than cancers that do not arise from neuroendocrine cells, they are also generally more resistant to treatment. There are currently no U.S. Food and Drug Administration-approved therapies for controlling neuroendocrine tumors arising outside of the pancreas.

For more information:Yao JC, Hainsworth JD, Wolin EM, Pavel EM, Baudin E, Gross D, Ruszniewski P, Tomassetti P, Panneerselvam A, Saletan S, Klimovsky J. Multivariate analysis including biomarkers in the phase III RADIANT-2 study of octreotide LAR plus everolimus (E+O) or placebo (P+O) among patients with advanced neuroendocrine tumors (NET). 9th Annual Gastrointestinal Cancers Symposium Abstract # 157.

What: Oral Abstract Session
Lead Author: James Yao, MD, University of Texas? M. D. Anderson Cancer Center
When: Friday, January 20, 2012 01:45 PM – 03:15 PM PT Houston, TX

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