Advances in Treatment of Neuroendocrine Cancers

To prepare for the second annual Roswell Park Comprehensive Cancer Center patient seminar on neuroendocrine cancer on October 18, 2014, I sat down to think about the progress made in this field.

Below and in the accompanying video presentation from that event, I summarize some of these major strides, which fall into the following broad categories:

• Database studies. By systematically looking at the SEER (Surveillance, Epidemiology, and End Results) database, we now better understand the prevalence of the disease. Yao and colleagues have shown that the incidence of NETs has increased fivefold over the past 30 years, which is far higher than all other neoplasms, and the prevalence is greater than stomach and pancreatic cancer combined. More than 100,000 people are now living with NETs in the United States.
• Better understanding of biology. New targets have been identified and novel targeted therapies have been evaluated, several of which have shown promise in clinical trials. Dr. Zhang and colleagues from Roswell Park Comprehensive Cancer Center recently published a comprehensive review on the progress in this field.

Treatment Advances

Special advances in treatment have stemmed from the knowledge that NET cells possess special receptors.

• 1985: Sandostatin was the first analogue developed to treat carcinoid crisis and carcinoid syndrome following the initial report by Dr. Kvols showing how rapid reversal of carcinoid crisis can be achieved with a somatostatin analogue.
• 1998: The FDA granted approval of Sandostatin for the treatment of carcinoid syndrome. Our group (Chadha et al.) showed that higher doses of Sandostatin can stabilize disease/slow progression.
• 2009: The PROMID study showed Sandostatin LAR 30mg slowed tumor growth in GI Nets compared to placebo.
• 2014: The CLARINET study showed Lanreotide 120mg slows tumor growth compared to placebo in pancreatic and GI NETS, and was FDA approved to treat all NETs in December 2014.

Progress Through Clinical Research

Clinical trialists know how to work together to design and complete trials to answer important questions.

There have been five successful randomized phase 3 trials over the past five years! This is remarkable and has not occurred in any other disease in recent years. These successful trials have all led to changes in treatment paradigms:

• Sunitinib and everolimus were approved for pancreatic NETs.
• RADIANT 4 was just completed to confirm the results of RADIANT 2 and is expected to result in approval of everolimus for carcinoids.
• The knowledge that Somatuline and Sandostatin slow disease progression has also led to major changes in treatment algorithms.
• In 2013, Dr. Hobday and colleagues reported promising response rates to bevacizumab and temsirolimus, and in 2014 Dr. Fine and colleagues reported promising activity of temozolamide and capecitabine in NETs. Dr. Kunz and colleagues are hoping to evaluate immunotherapy in NETs. Peptide radioreceptor therapy that was once only offered in Europe is now being evaluated in the NETTER studies in the United States.

The Caring for Carcinoid Foundation, North American Neuroendocrine Tumor Society (NANETS) and American Association of Cancer Research (AACR) are just a few organizations funding trials for patients with NETs.

In addition, Roswell Park has received a grant from the National Comprehensive Cancer Network (NCCN) to lead a three-site, phase 2 trial of a novel fibroblast growth factor receptor (FGFR) inhibitor Nintedanib in advanced carcinoid patients that will open before spring 2015.

At Roswell Park, we have several other scientists doing research in this field.

• Dr. Kenneth Gross received an R01 grant from the NIH to study glucagonoma, a very rare tumor of the islet cells of the pancreas, which leads to an excess of the hormone glucagon in the blood. He has developed a glucagonoma model to study its behavior and how it metastasizes so that we may treat it more effectively.
• There are very few animal models to study neuroendocrine cancer. Dr. Steven Hochwald has developed human tumor xenografts and is studying glucose metabolism in these tumors.
• Liver resection can help neuroendocrine patients live a long time. Dr. Boris Kuvshinoff has developed computer models to simulate the tumor and liver in order to plan surgery to make it safer for patients and preserve adequate liver function.
• Fibroblasts are cells that cause scar tissue in carcinoid patients and lead to a lot of symptoms. Dr. Renuka Iyer received a grant from the NCCN to lead a multicenter trial of a drug that stops blood vessels from growing and blocks fibroblast growth factor.

At Roswell Park, we incorporate all available expertise by discussing cases at a multidisciplinary weekly conference and develop personalized care plans that can be executed by local oncologists for patients who do not live locally. We are offering the TELESTAR study, an oral tryptophan hydroxalase inhibitor for managing refractory carcinoid symptoms. Patients and families are invited to visit our website, or attend the annual patient conference that will be held in September 2015, to learn more about this illness and progress in the field.

Renuka Iyer, MD

Co-Director, Liver and Pancreas Tumor Center
Section Chief for Gastrointestinal Oncology
Associate Professor of Oncology

Roswell Park Comprehensive Cancer Center