Department of Internal Medicine I, Martin-Luther University Halle/Wittenberg, Halle, Germany.
Digestion. 2017;96(2):67-75. doi: 10.1159/000477800. Epub 2017 Jul 21.
Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms accounting for less than 5% of all pancreatic malignancies. These tumors are characterized by clinical and prognostical heterogeneity and are predominantly diagnosed in a metastatic stage. Cytotoxic chemotherapy, along with alkylating agents and antimetabolites as well as molecular targeted agents (everolimus, sunitinib), is used in the treatment of advanced PNETs. After the approval of lanreotide for unresectable PNETs, an additional therapeutic option has become available; however, the best sequence of therapies and patient stratification to different treatments remains challenging. Furthermore, no randomized phase-3 trials or head-to-head comparisons are available to support treatment decisions.
The publication of 3 large single-center retrospective studies on streptozocin-(STZ)-based chemotherapy in advanced PNETs in 2015 confirmed the effectiveness of this treatment as described in previously reported trials. All studies investigated markers for progression-free and overall survival and strongly supported the value of the Ki-67 index as a robust prognostic marker. Interestingly, chemotherapy consistently displayed antitumor efficacy in different therapeutic lines. Moreover, a recent study of dacarbazine (DTIC) in a cohort of patients predominantly with PNETs demonstrated that a once monthly infusional DTIC schedule was well tolerated and yielded similar response rates (RR) as STZ-based schedules. Given the overall good tolerability of a monthly infusion and RR similar to STZ schedules, DTIC thus represents a feasible alternative or additional treatment option for PNETs. In this article, we review the current standard and summarize the most recent advances in the field of cytotoxic chemotherapy for PNET patients. Key Messages: (1) Despite the lack of phase3 trials, cytotoxic chemotherapy offers efficacy for patients with advanced PNETs; (2) the best therapeutic option and sequence remain open since comparable randomized studies are lacking; (3) careful patient selection and treatment stratification may increase overall outcome; and (4) currently, no biomarkers for clinical routine exist to predict response to chemotherapy.
胰腺神经内分泌肿瘤（PNETs）是一种罕见的肿瘤，占所有胰腺恶性肿瘤的比例不到 5%。这些肿瘤具有临床和预后异质性的特点，主要在转移阶段诊断。细胞毒性化疗、烷化剂和抗代谢物以及分子靶向药物（依维莫司、舒尼替尼）用于治疗晚期 PNETs。在批准兰瑞肽用于不可切除的 PNETs 后，又增加了一种治疗选择；然而，针对不同治疗方法的最佳治疗顺序和患者分层仍然具有挑战性。此外，目前尚无支持治疗决策的随机 3 期试验或头对头比较。
2015 年发表的 3 项关于晚期 PNETs 中链佐星（STZ）为基础的化疗的大型单中心回顾性研究证实了这种治疗方法的有效性，与之前报道的试验一致。所有研究都调查了无进展生存期和总生存期的标志物，并强烈支持 Ki-67 指数作为一种强大的预后标志物的价值。有趣的是，化疗在不同的治疗线中始终显示出抗肿瘤的疗效。此外，最近一项关于达卡巴嗪（DTIC）在主要为 PNETs 患者队列中的研究表明，每月一次的 DTIC 输注方案耐受性良好，与基于 STZ 的方案产生相似的缓解率（RR）。鉴于每月输注的总体良好耐受性和与 STZ 方案相似的 RR，DTIC 因此代表了 PNETs 的一种可行的替代或附加治疗选择。在本文中，我们回顾了目前的标准，并总结了 PNET 患者细胞毒性化疗领域的最新进展。关键信息：（1）尽管缺乏 3 期试验，但细胞毒性化疗对晚期 PNETs 患者有效；（2）由于缺乏可比的随机研究，最佳治疗选择和顺序仍然存在；（3）仔细的患者选择和治疗分层可能会提高总体疗效；（4）目前，没有用于预测化疗反应的临床常规生物标志物。
