Systemic Therapy for Gastroenteropancreatic (GEP) Neuroendocrine Tumors and Lung Carcinoid The Medical Oncology Perspective Nevena Damjanov, MD Associate professor Abramson Cancer Center of the University of Pennsylvania April 15, 2016
Neuroendocrine Tumors Relatively rare 2-3 new cases/100,000 population per year Neuroendocrine tumors include Carcinoid tumors Pancreatic neuroendocrine tumors Functional and non functional islet cell tumors Insulinomas Glucagonomas Gastrinomas Medullary carcinoma of the thyroid Paragangliomas Pheochromocytomas 2
Where do neuroendocrine tumors come from? Neuroendocrine cells Secrete biogenic amines like neurons Secrete polypeptide hormones like endocrine cells These cells populate the aerodigestive system Lungs Stomach Pancreas Intestines 3
Most common locations of primary neuroendocrine tumors Lungs 25% Liver Pancreas Stomach Small intestine 75% Appendix Colorectal 4
Neuroendocrine Tumors Neuroendocrine tumors are classified based on their site of origin and what, if anything, they secrete Stomach Gastrin (gastrinoma) Pancreas islet cell tumors Insulin (insulinoma) Glucagon (glucagonoma) Appendix Carcinoid is the most common cancer of this organ 5
Neuroendocrine tumors Patients with functional NET have symptoms caused by the oversecretion of hormones and other substances Patients with nonfunctional NET (70% of all NET) may have no symptoms, or their symptoms may be caused by tumor growth Intestinal obstruction from gastrointestinal NET Pain and bleeding Asthma from lung NET Chronic obstructive pulmonary disease and pneumonia from lung NET 6
Carcinoid Syndrome Most commonly seen in patients whose NET has spread to the liver Diarrhea Flushing of the skin Wheezing/bronchospasm May cause carcinoid heart disease if not controlled 7
Systemic Treatment
Goals of systemic treatment Control symptoms Control cancer spread Prolong survival 9
Carcinoid Syndrome Symptom Control Octreotide (Sandostatin) and lanreotide (Somatuline) Injectable somatostatin analogs, bind receptors on tumor cells Effective in reducing hormone secretion, and thus symptoms Short and long acting formulations exist Sandostatin injections three times a day Sandostatin LAR once a month Somatuline Depot once a month Even in patients without carcinoid syndrome, octreotide/lanreotide may slow tumor growth 10
Octreotide/Lanreotide Few side effects Mild nausea Mild abdominal discomfort Bloating Loose stools Fat malabsorption Gallstones (common but usually asymptomatic) Rare ileus (intestinal paralysis) Side effects usually resolve after the first few weeks of treatment 11
Telotristat etiprate (LX1032) Telotristat etiprate is an investigational drug submitted to the FDA for approval in 2016 It comes in pill form Targets tryptophan hydroxylase This enzyme triggers excess serotonin production Unlike other treatments for carcinoid syndrome it does not reduce the release of serotonin Telotristat etiprate reduces serotonin production within tumor cells It has been shown to reduce the severity of diarrhea in patients with carcinoid syndrome 12
Foods That Can Aggravate Carcinoid Syndrome High amine containing foods aged cheese pickled meat broad beans sauerkraut soy sauce High fat foods Alcohol Large meals Caffeine, chocolate, tomato products Spices 13
Chemotherapy Used in more aggressive tumors Kills rapidly dividing cells Used when less toxic therapy is ineffective No clear standard regimens Small trials with few patients Disease with variable presentations 14
Chemotherapy Single agent therapy Streptozocin, doxorubicin, 5-FU, etoposide Dacarbazine IV temozolomide by mouth Taxanes, gemcitabine are ineffective Combinations Streptozocin and 5-FU or doxorubicin Temozolomide + thalidomide or capecitabine (cap/tem) In aggressive tumors (small cell cancers) Cisplatin/carboplatin + etoposide 15
Targeted therapy Target molecular abnormalities seen in cancers Prevent cancer growth Prevent cancer spread Less toxic than conventional chemotherapy In other cancers, some are used with conventional chemotherapy 16
Afinitor (everolimus, RAD001) Administered in pill form (also available for suspension) FDA approved for kidney cancer, mbca, and pnet It has shown efficacy in lung NETs Prevents cancer cells from dividing May kill cancer cells, as well Some patients taking Afinitor have tumor shrinkage, while most patients have tumors that stop growing Combination therapy with octreotide is well tolerated May be especially effective in insulinomas Well tolerated Side effects include Fatigue, aphthous ulcers Low blood counts Increase in blood sugar, lipids 17
Sutent (sunitinib) Administered in pill form FDA approved for kidney cancer, GIST cancer, and pnet Prevents cancer cells from dividing Some patients with NETs had tumor shrinkage Many patients had tumor stabilization Well tolerated Side effects include Fatigue, diarrhea, thyroid disorders Skin changes Low blood counts Increase in blood sugar, calcium 18
Other Systemic Treatments with Some Activity in Neuroendocrine tumors Bevacizumab Sorafenib Pazopanib Temsirolimus 19
Conclusions Targeted therapy holds promise in patients with neuroendocrine tumors Multidisciplinary care is important Patients with neuroendocrine tumors may benefit from local and systemic treatments, depending on the sites of disease 20
Summary - NET treatment Well differentiated NETs are rare, relatively indolent malignancies. Care must be individualized. For many, watchful waiting may be most appropriate initial maneuver. Indications for treatment are uncontrollable symptoms due to Tumor bulk Hormone secretion Rapid/substantial progression of tumors while under observation 21
Summary - NET treatment Somatostatin analogues are typically first therapeutic intervention. Once further therapy is needed, options exist Carcinoid tumors tend to grow slower and are more resistant to chemotherapy and targeted therapies pnets and lung NETs may be more responsive to systemic therapy Old studies of chemotherapy agents are probably not reliable. 22
Summary - NET treatment Radiolabeled somatostatins are very promising Nonetheless, new treatments are needed. Please support clinical trials of new agents and new treatment modalities. 23
Thank you for your attention! 24
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