Apple’s leader, Steve Jobs, announced to his employees in 2004 that he had been diagnosed with a cancerous tumor in his pancreas. The prognosis for pancreatic cancer is usually very grim, however he stated that he had a rare, far less aggressive type known as islet cell neuroendocrine tumor. This week it was announced that Afinitor (everolimus) tablets plus best supportive care (BSC) more than doubled progression-free survival (PFS), or time without tumor growth, versus placebo plus BSC in patients with advanced pancreatic neuroendocrine tumors.

Regulatory submissions for everolimus to treat this patient population are underway worldwide.

Neuroendocrine tumors (NET) arise from cells that can produce and secrete a variety of hormones that regulate bodily functions. There are many types of NET that can occur throughout the body; however, most are found in the gastrointestional tract, pancreas and lungs. Many patients with NET have no symptoms or nonspecific symptoms, such as flushing and diarrhea, which often lead to delays in diagnosis of five to seven years. As a result, many patients with NET often have advanced disease when diagnosed, meaning the cancer has spread to other parts of the body and has become more difficult to treat.

Unfortunately, approximately 64% of patients with pancreatic NET are diagnosed in advanced stages. No tumor growth after 18 months appeared in 34% of the patients treated with everolimus versus in 9% of those treated with placebo.

James Yao, MD, Associate Professor of Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas states:

“A patient diagnosed with advanced NET may have limited treatment options. Results from the RADIANT-3 trial are encouraging and demonstrate the potential benefit of treating advanced pancreatic NET with the mTOR inhibitor everolimus.”

Everolimus targets mTOR, a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism. In a similar fashion to other mTOR inhibitors its effect is solely on the mTORC1 protein and not on the mTORC2 protein. This can lead to a hyper-activation of the kinase AKT via inhibition on the mTORC1 negative feedback loop while not inhibiting the mTORC2 positive feedback to AKT. This AKT elevation can lead to longer survival in some cell types.

The US Food and Drug Administration has granted everolimus priority review designation for the application of advanced NET of gastrointestinal, lung or pancreatic origin based on results of RADIANT-3 and another Phase III trial, RADIANT-2. Priority review status is granted to therapies that offer major advances in treatment or provide a treatment where no adequate therapy exists. This status accelerates the standard review time for everolimus from 10 to six months.

About 95% of exocrine pancreatic cancers are adenocarcinomas. The remaining 5% include adenosquamous carcinomas, signet ring cell carcinomas, hepatoid carcinomas, colloid carcinomas, undifferentiated carcinomas, and undifferentiated carcinomas with osteoclast-like giant cells. Exocrine pancreatic tumors are far more common than pancreatic endocrine tumors, which make up about 1% of total cases.

Treatment of pancreatic cancer depends on the stage of the cancer. The Whipple procedure is the most common surgical treatment for cancers involving the head of the pancreas. This procedure involves removing the pancreatic head and the curve of the duodenum together making a bypass for food from stomach to jejunum, and attaching a loop of jejunum to the cystic duct to drain bile. It can be performed only if the patient is likely to survive major surgery and if the cancer is localized without invading local structures or metastasizing. It can, therefore, be performed in only the minority of cases.

After initially resisting the idea of conventional medical intervention and embarking on a special diet to thwart the disease, Jobs underwent a pancreaticoduodenectomy (Whipple procedure) in July 2004 that appeared to successfully remove the tumor.

Source: Novartis

Written by Sy Kraft, B.A.