GICS 2009: Octreotide Shows Promise in Metastatic Neuroendocrine Midgut Tumors

Roxanne Nelson

January 19, 2009

January 19, 2009 (San Francisco, California) — Octreotide LAR (Sandostatin LAR, Novartis) appears to slow the growth of metastatic neuroendocrine midgut tumors. The PROMID study is the first placebo-controlled study to confirm previous findings that suggested that octreotide could slow tumor progression in this population, and the results were presented here at the 2009 Gastrointestinal Cancers Symposium.

'Based on these results, octreotide should be considered the standard of care in patients with newly diagnosed, functionally active or inactive, well-differentiated metastatic midgut neuroendocrine tumors and a low hepatic tumor load," said study author Rudolf Arnold, MD, professor and chair of the Department of Internal Medicine at Philipps University, in Marburg, Germany.

"It is a promising treatment option for patients following cytoreductive surgery with few remaining metastases," he added.

Neuroendocrine midgut tumors are rare events and can arise from the large and small intestine, the pancreas, the stomach, and elsewhere in the digestive tract. About 50% of these tumors are malignant, and the only effective treatment is surgery, explained Dr. Arnold. "However, many of these tumors are metastatic," he said. "There is no medical treatment for these tumors thus far. The exception is pancreatic tumors, which may respond to chemotherapy."

Half of all malignant tumors are of the carcinoid type, and approximately 20% of carcinoid tumors in the small intestine will metastasize to distant sites. The 5-year survival rate among patients with distant metastases at diagnosis is about 27%.

Octreotide LAR is a somatostatin analogue that is currently used for the control of symptoms in patients with gastroenteropancreatic neuroendocrine tumors. The antiproliferative effects of octreotide have been investigated in in vitro and experimental in vivo studies, but the ability of long-acting somatostatin analogues to control the growth of well-differentiated metastatic neuroendocrine tumors is a matter of debate, explained Dr. Arnold.

Previous studies of octreotide in patients with neuroendocrine tumors have demonstrated tumor stabilization and partial regression in a subset of patients, but since these studies were not placebo controlled, it is unclear if octreotide slows disease progression.

Treatment Doubled Time to Progression

The current phase 3b randomized trial of octreotide in patients with neuroendocrine tumors was conducted at 18 centers in Germany from 2001 to 2008. All 85 patients were newly diagnosed and treatment naïve, and all received either octreotide (30 mg IM every 4 weeks) or placebo. The primary tumor was located in the midgut, and all patients were without curative therapeutic options.

The primary end point of the study was time to progression; treatment continued until computed tomography (CT) or magnetic resonance imaging (MRI) documented tumor progression, and follow-up continued until patient death. CT and/or MRI scans were evaluated by a blinded central reader, and there was no observation period before treatment to judge spontaneous tumor growth.

The researchers found that treatment with octreotide more than doubled time to progression. Patients who received active therapy had a median time to progression of 14 months, compared with 6 months for patients who received placebo. "That was significant," said Dr. Arnold.

There were no complete responses observed in either study group, and 1 patient in each group experienced a partial response. However, Dr. Arnold pointed out, the most favorable effect was tumor stabilization. Of the 42 patients who received octreotide, 28 experienced stable disease, compared with 16 of 43 who received placebo. The incidence of progressive disease was also lower among patients receiving octreotide (10 vs 23 patients).

Overall, patients treated with octreotide LAR had a 67% risk reduction in tumor progression, compared with those treated with placebo. Because of the low number of observed deaths, median survival time could not be estimated.

"The most favorable results were also seen in patients with a low hepatic tumor load," said Dr. Arnold. "Patients with a higher hepatic tumor load did not respond as well."

Although the reason for this has not yet been defined, Dr. Arnold speculated that patients with a high tumor load at diagnosis might have a more aggressive tumor type.

Confirms Effect of Octreotide

"This is a very important study, because we now have data from a randomized study confirming the effect of octreotide in patients with midgut neuroendocrine tumors, and the patients that it benefits most are those with a low tumor burden," commented Lillian Siu, MD, who served as a discussant for the paper.

"This is the only double-blind placebo-controlled trial that answered this important question, and it is safe to say that it is unlikely there will be a confirmatory study," said Dr. Siu, from the Department of Medical Oncology and Hematology at Princess Margaret Hospital, in Toronto, Ontario. "The greatest strength of this study is in the primary end point that was reached, and the adverse event profile was acceptable."

The study also had several possible limitations, she pointed out. "The role of therapy in nonprogressing patients was unclear, and there is a lack of data on adherence to follow-up visits and tests, as well as on crossover to octreotide from placebo."

"The study is also unlikely to ever address the effect of therapy on survival in these patients," she added.

The study was supported by Novartis. Dr. Sui has consulted for or served in an advisory role for Enzon Pharmaceuticals and Millennium Pharmaceuticals, Inc.

2009 Gastrointestinal Cancers Symposium (GICS). Abstract 121. Presented January 16, 2009.

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