Combination treatment with everolimus, an inhibitor of the mammalian target rapamycin (mTOR), and octreotide has shown to improve progression-free survival for patients with advanced neuroendocrine tumours and a history of carcinoid syndrome, according to researchers at The University of Texas MD Anderson Cancer Center.

Results of the international, randomized, placebo-controlled Phase III study are published in the Lancet.

The treatment combination of everolimus and octreotide long-acting repeatable (LAR), a somatostatin analogue that has shown antitumour activity, led to a clinically meaningful five-month delay in tumour growth, compared to octreotide alone.

Neuroendocrine tumours, also known as carcinoids, are uncommon tumours arising from various primary sites. Frequently, carcinoids spread to the liver, causing a variety of symptoms termed carcinoid syndrome.

"There are currently no Food and Drug Administration (FDA) approved drugs for oncologic control of most neuroendocrine tumours," said James C. Yao, M.D., associate professor in MD Anderson's Department of Gastrointestinal Medical Oncology. "This research offers a promising option where there were limited options previously."

According to Yao, the number of people diagnosed with neuroendocrine tumours has increased more than five-fold over the past 30 years, from one in 100,000 people per year to 5.25 in 100,000 people per year. Nearly half of patients have regional or distant metastatic disease and 65 percent of those with advanced disease die within five years of diagnosis.

Everolimus, an immunosupressant agent used to prevent rejection of organ transplants, inhibits the mTOR protein, a central regulator of tumour cell division and blood vessel growth in cancer cells. Overaction of mTOR has been implicated in the pathogenesis of neuroendocrine tumours.

Preclinical studies have shown that mTOR inhibition may control growth of neuroendocrine tumours, and an earlier Phase II study at MD Anderson showed promising anti-cancer activity for everolimus in neuroendocrine tumours.

In May of this year, an international randomized Phase III study showed everolimus improved progression-free survival in pancreatic neuroendocrine tumours, a related disease, leading to its FDA approval for treatment of those rare tumours.

Somatostatin analogues, such as octreotide, improve hormone-related symptoms associated with neuroendocrine tumours. Octreotide LAR has also shown antitumor activity, prolonging time to disease progression in patients with certain types of neuroendocrine tumours.

The study, named RADIANT-2, enrolled 429 participants with low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours and a history of carcinoid syndrome. Disease progression had been established by radiological assessment within the past 12 months.

Patients were given either 10 mg per day oral everolimus or placebo, both in conjunction with 30 mg intramuscular octreotide LAR, every 28 days. Treatment was continued until disease progression, withdrawal from treatment because of adverse effects or withdrawal of consent.

Median progression-free survival by was 16.4 months in the everolimus plus octreotide LAR group and 11.2 months in the placebo plus octreotide LAR group.

Side effects were higher but manageable in the combination arm. They included stomatitis (62 percent vs. 14 percent), fatigue (31 percent vs. 23 percent) and diarrhea (27 percent vs. 16 percent).

Source: University of Texas M. D. Anderson Cancer Center 

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