Management of metastatic disease from neuroendocrine cancers
What treatments are available for metastatic disease outside the liver?
Chemotherapy. Besides somatostatin analogues, common chemotherapeutic options for metastatic neuroendocrine cancers include interferon alfa and cytotoxic agents. The former has been shown to inhibit protein and hormone synthesis in tumor cells, inhibit angiogenesis, and stimulate the immune system. Additionally, interferon alfa has been shown to upregulate the expression of somatostatin receptors and may therefore act synergistically with somatostatin analogues in the treatment of classic carcinoid syndrome. Cytotoxic agents are typically employed as first-line treatments for malignant neuroendocrine tumors with elevated proliferation indices (Ki-67 antibody >5-10%). Traditionally, single-agent cytotoxic treatments have produced limited benefit in patients with neuroendocrine cancers, with response rates of less than 30%. Therefore, combination therapiesthe most common combination of streptozocin, 5-FU, and doxorubicin elicits a response rate in excess of 50% in malignant pancreatic tumorsare commonly utilized in the treatment algorithms of highly proliferating neuroendocrine tumors.
Radiolabelled Somatostatin Analogues. In recent years, several research groups in nuclear medicine and radiopharmacy have sought to develop radiolabelled receptor-binding somatostatin analogues which could act as vehicles to guide radioactivity to SSTR-expressing tissues, such as carcinoid metastases. The first promising dodecanetetraacetic acid-chelated somatostatin analogue90Y-1,4,7,10-tetraazacyclododecane-N,N',N",N'"-tetraacetic acid (DOTA)0, Tyr3, octreotide (90Y-DOTATOC)employed the use of a radiolabelled somatostatin analogue couple with 90Y, a pure ß-emitter. In a phase II study to evaluate the tumor response of NE tumors to high-dose targeted irradiation with 90Y-DOTATOC, Waldherr and colleagues demonstrated an objective response rate of 38% and a significant reduction in clinical symptoms. More recently, treatment with 177Lu-DOTA0, Tyr3octreotate (177Lu-DOTATATE), a compound with greater SSTR 2 affinity, has been shown to effect complete or partial tumor responses in nearly 30% of patients with neuroendocrine disease. Importantly, 90Y-DOTATOC seems to more effective in larger tumors while 177Lu-DOTATATE effects improved tumor response in smaller lesions; as such, combination therapies utilizing both 90Y-DOTATOC and 177Lu-DOTATATE are currently being explored.
Future Targeted Therapies. It is well known that the growth, differentiation, phenotype, and hormonal expression of carcinoid tumors depend upon a network of cellular signaling cascades. At this time, several pathways and individual molecules have been implicated in the tumorigenesis of carcinoids and are currently under evaluation. Novel agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) have demonstrated promising activity in patients with advanced neuroendocrine tumors. Inhibition of angiogenesis by targeting VEGF is especially promising given the highly vascular nature of neuroendocrine tumors. Recent data suggest the importance of alternative pathways, which include alterations in raf-1/MEK/ERK, Notch, and glycogen synthase kinase-3ß.