From Standard of Care
In general classified as low grade neuroendocrine carcinomas( carcinoid), intermediate grade neuroendocrine carcinomas (atypical carcinoid), high-grade neuroendocrine carcinoma ( small cell carcinoma, large cell neuroendocrine carcinoma).
Primary sites include gastrointestinal tract, lung, pancreas, and thymus.
Approximately 50% present with advanced disease at diagnosis, and 65% die within 5 years.
Survival rates vary by the primary site and are higher in patients with well-differentiated tumors than those with poorly differentiated lesions and those with locoregional disease versus distant disease.
Neuroendocrine tumors (NET) are heterogeneous carcinomas that are often well differentiated and associated with an indolent course.
Of gastrointestinal and pancreatic origin include gastrointestinal carcinoid and pancreatic islet cell carcinomas.
Of gastrointestinal and pancreatic origin are rare malignancies derived from neuroendocrine cells distributed along the gastrointestinal system.
Of gastrointestinal and pancreatic origin often produce hormones and other bioactive substances.
Of gastrointestinal and pancreatic origin may present with clinical symptoms related the release of biologically active substances and diverse hormones.
Of gastrointestinal and pancreatic origin are generally slowly progressive tumors.
Pancreatic neuroendocrine tumors are increasing, and represent 1.3% of all pancreatic cancers in incidence and 10% of cases in prevalence.
Pancreatic neuroendocrine tumors are increasing in incidence, which is three cases per million persons annually.
Pancreatic neuroendocrine tumors can be associated in the majority of cases with detectable hyper secretion of hormones such as insulin, gastrin, glucagon, the vasoactive intestinal polypeptide, or somatostatin.
Most cases of pancreatic neuroendocrine tumors arise sporadically, however 80-100% of patients with MEN1 will develop a gastrinoma or a insulin noma.
Pancreatic neuroendocrine tumor incidence is increasing and the five-year survival rate is below 43%.
Pancreatic neuroendocrine tumors arise from endocrine cells of the pancreas, and surgery is the mainstay of treatment for resectable disease.
Pancreatic neuroendocrine tumors predominately metastasize to the liver.
Pancreatic neuroendocrine tumors are frequently diagnosed at a late stage with approximately 65% of patients presenting with metastatic disease or unresectable disease.
Pancreatic neuroendocrine tumors have a median survival time in patients with metastatic disease of 24 months.
Streptozotocin is the only approved therapy for pancreatic neuroendocrine tumors in the United States (2011).
Vascular endothelial growth factor (VEGF) is a key driver of angiogenesis in pancreatic neuroendocrine tumors.
Pancreatic endocrine tumors have widespread expression of platelet-derived growth factor receptors (PDGFRs) alpha and beta, stem cell factor receptor (c-kit) and VEGF receptor-2 VEGF-3.
Thoracic neuroendocrine neoplasms unlike other carcinoids are not considered benign.
Colorectal neuroendocrine tumors incidence increasing.
Colorectal NETs 1.06 per 100,000.
Colorectal neuroendocrine tumors have a poor prognosis.
Most patients with colorectal Neuroendocrine tumors present with advanced disease, and have a median survival of 10.4 months, compared with 27 and 65 months for patients with NETs of the pancreas and small intestine, respectively(Yao JC et al).
Some tumors are associated with genetic syndromes.
Small cell neuroendocrine tumors of the prostate account for 1-2% of cases of prostate cancer.
World Health Organization classification for NET: (One) Well-differentiated neuroendocrine tumor, low grade and benign behavior, (2) well-differentiated neuroendocrine carcinoma low grade but malignant, (3) poorly differentiated neuroendocrine tumor high-grade malignancy.
Many tumors have secretory capacity and produce biogenic amines add polypeptide hormones called APUDomas -amine precursor uptake and decarboxylation.
Neuroendocrine cells are found throughout the prostate and can secrete corticotropin, serotonin, chromogranin A, neuron-specific enolase, bombesin, calcitonin, and parathyroid hormone related protein.
Include multiple endocrine neoplasia type I and II and medullary carcinoma of the thyroid.
Includes carcinoid tumors, islet cell tumors, pheochromocytoma, paraganglioma, small cell carcinoma of the long, and Merkel cell carcinoma.
Can often be cured if diagnosed early enough, however their indolent nature makes early detection unlikely.
Treatment for hepatic metastases is resection, if the primary cancer has been resected or is grossly resectable and more than 90% (by volume) of the hepatic metastases are resectable.
Often are indolent in clinical course.
Clinical significance depends on the site of the primary lesion with good prognosis for pancreatic lesions, poor prognosis for prostate cancers and no apparent difference for breast lesions compared to primary lesions of these sites.
Most cases of colon neuroendocrine differentiated cancers have worse prognosis than adenocarcinomas of the colon.
10-20% of cases of NSCLC show neuroendocrine differentiation.
Neuroendocrine differentiation found in all histologic types of lung cancer but is more frequent in adenocarcinoma and large cell carcinoma.
Stage I carcinomas of the lung with neuroendocrine differentiation and synaptophysin positive have a poor prognosis and higher frequency of recurrence and lower survival rates.
Overall radiologic response rates of 25% to combination of Temozolomide and thalidomide with 45% response rate for pancreatic tumors, 33% for pheochromocytomas and 7% for carcinoid tumors.
Thoracic thymus neuroendocrine tumors represent less than 5% of all mediastinal tumors and behave aggressively in 80% of cases.
Thoracic neuroendocrine carcinomas of thymic origin are more commonly associated with MEN type I lesions.
Thymic neuroendocrine carcinomas associated with polyneuropathy, proximal neuropathy, peripheral neuropathy, MEN II syndrome, hyperparathyroidism, SIADH, Eaton-Lambert syndrome ACTH secretion, hypertrophic osteoarthropathy, secretion of calcitonin, beta lipoprotein, and parathyroid hormone.
Tumor localization relies on imaging techniques such as CT scan, MRI and ultrasound for staging and followup and molecular imaging modalities using radiopharmaceuticals targeting metabolic pathways and receptors were used.
Surgery principal treatment for patients with localized disease, but surgery with cytoreductive intent in patients with advanced disease has limited progression free survival benefit.
In a series of 170 patients undergoing hepatectomy for metastatic NE tumors, 84% experience recurrence by 5 years with 5 and 10 year survival rates 61% and 35%, respectively (Sarmiento JM et al).
In a retrospective study of patients undergoing subtle reductive surgery they had a longer median overall survival time of 43 months compared to those undergoing embolization therapy at 24 months (Osburne DA et al).
Orthotopic liver transplantation among 31 patients with advanced neuroendocrine tumors, the overall survival rate was higher with metastatic carcinoid at 69% at five years, than with metastatic pancreatic and eight APUDs, 8% at four years (Le Treut YP et al).
Hepatic arterial embolization for carcinoid has a better response rate of 67% versus 35% ,and a long robe progression free survival of 23 months versus 16 months, and overall survival of 34 months versus 23 months, than those of pancreatic neuroendocrine tumors (Gupta S et al).
Chemotherapy for low grade neuroendocrine tumors is not usually associated with a major reduction in tumor size, but time to progression and extendion of survival and increase quality of life may occur.
More metabolically active neuroendocrine tumors of intermediate grade, moderately differentiated, atypical carcinoid are all more likely to respond to chemotherapy with a major tumor shrinkage compared to low-grade tumors.
Combination chemotherapy with 5-FU, streptozotocin and dacarbazine have modest response rates.
Stretozotocin plus doxorubicin plus 5FU and cisplatinum regimens have a lower response rate and/or more toxic than newer regimens containing capecitabine plus temozolomide.
Responses in neuroendocrine tumors to capecitabine and temozolomide can be predicted by measuring methyl guanine methyl transferase, which is low in responding patients.
Everolimus, a derivative of rapamycin, can disrupt neuroendocrine tumor cell growth, its proliferation and can prolong progression free survival from 4.6 months to 11 months in patients with pancreatic neuroendocrine tumors.
Autocrine activation of the mTOR signaling pathway that is mediated via insulin-like growth factor has been Implicated in the proliferation of pancreatic neuroendocrine tumors.
RAD001 in Advanced Neuroendocrine Tumor third trial (RADIANT-3) studied 10 mg per day of everolimus in patients with pancreatic neuroendocrine tumors: associated with prolonged progression free survival with a low rate of severe adverse events.
Everolimus is efficacious in carcinoid tumors (Yu et al).
Bevacizumab, has a response rate of about 25% in neuroendocrine tumors.
Sunitinib can block metabolic targets in a neuroendocrine tumors and inhibit tumor growth, inhibits vascular endothelial growth factor receptor, and platelet derived growth factor receptor, which play a role in angiogenesis: a randomized trial utilizing this agent increased progression free survival in pancreatic neuroendocrine tumors from 5.5 to 11.1 months.
In a phase 3 study daily administration of improves progression free survival, overall survival and objective response rate compared to placebo in patients with advanced pancreatic neuroendocrine tumors (Raymond E et al).
In the above study 171 patients were randomly assigned best supportive care with sunitinib or placebo: median progression free survival 11.4 months in the sunitinib group compared to 5.5 monthsin the placebo group, the objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group ( Raymond E et al).
Somatostatin analogues can stop the growth of neuroendocrine cells: PROMID study of 85 patients with mid gut carcinoids comparing octreotide to placebo, the average progression free survival was 14.3 months versus six months, respectively and at six months 64% of the patients treated with octreotide remained without progressive disease versus 37.2% in the placebo group (Arnold R et al).