Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA. Pancreas Center, Presbyterian Hospital, New York, NY, USA.
Clin Med Insights Oncol. 2012;6:41-51. doi: 10.4137/CMO.S7319. Epub 2012 Jan 4.
Neuroendocrine tumors (NETs) consist of a diverse family of tumors which are derived from the neuroendocrine system. Most NETs are well or moderately differentiated tumors with a relatively indolent growth pattern. However, these tumors can cause significant clinical disease due to release of functional products that mediate the carcinoid syndrome and other diverse sequela. They also can grow progressively and cause symptoms from local invasion or distant metastasis. NETs are optimally treated with surgery and somatosatin analogs (SSA's) to control symptoms but are relatively insensitive to systemic chemotherapy. As a result, patients with advanced unresectable NETs have a poor prognosis. In 2011, two targeted therapies, sunitinib and everolimus were approved in the subset of progressive pancreatic NETs (pNETs). Everolimus is an oral inhibitor of the growth stimulatory mTOR pathway. In Phase 2 trials in NETs and pNETs, everolimus was well tolerated and associated with some response and widespread disease stabilization. In follow-up, randomized Phase 3 trials, everolimus was compared to placebo. In the RADIANT-2 trial, everolimus and a somatostatin analog were used in patients with functional NETs and treatment was associated with an an improvement in progression-free survival (PFS). In the RADIANT-3 trial, patients with pNET were randomized to receive everolimus or placebo along with best supportive care. Everolimus was again associated with improvement in PFS compared to placebo and it has been approved by the FDA for patients with progressive pNET. Everolimus is associated with frequent low grade toxicity but is also notable for increased rates of infection as well as non-infectious pneumonitis. mTOR inhibition with everolimus represents a significant advance in the treatment of advanced neuroendocrine tumors.
神经内分泌肿瘤（NET）由起源于神经内分泌系统的多种肿瘤组成。大多数 NET 是分化良好或中度分化的肿瘤，具有相对惰性的生长模式。然而，由于功能性产物的释放，这些肿瘤可导致显著的临床疾病，这些产物介导类癌综合征和其他不同的后遗症。它们还可以逐渐生长，并因局部侵犯或远处转移引起症状。NET 最佳治疗方法是手术和生长抑素类似物（SSA）来控制症状，但对全身化疗相对不敏感。因此，晚期不可切除的 NET 患者预后较差。2011 年，两种靶向治疗药物舒尼替尼和依维莫司在进展性胰腺神经内分泌肿瘤（pNET）亚组中获得批准。依维莫司是一种生长刺激 mTOR 途径的口服抑制剂。在 NET 和 pNET 的 2 期试验中，依维莫司耐受性良好，与一些反应和广泛的疾病稳定相关。在随访中，随机 3 期试验将依维莫司与安慰剂进行了比较。在 RADIANT-2 试验中，依维莫司和生长抑素类似物用于功能性 NET 患者，治疗与无进展生存期（PFS）的改善相关。在 RADIANT-3 试验中，pNET 患者被随机分为接受依维莫司或安慰剂联合最佳支持治疗。与安慰剂相比，依维莫司再次与 PFS 的改善相关，并已被 FDA 批准用于进展性 pNET 患者。依维莫司与频繁的低级别毒性相关，但也值得注意的是感染率增加以及非感染性肺炎。依维莫司对 mTOR 的抑制代表了晚期神经内分泌肿瘤治疗的重大进展。
