Advances in the systemic treatment of pancreatic neuroendocrine tumors

Constituting about 1-2% of all tumors of the pancreas, pancreatic neuroendocrine tumors (PNETs) are a subgroup of gastroenetropancreatic neuroendocrine tumors (GEP-NETs) with distinct tumor genetics, biology, and clinicopathological features. Surgical resection is amenable only in a minority of the cases so systemic therapies are considered in most of them. The goals of medical treatment are to control the associated symptoms and signs of the specific tumors and to shrink the tumor mass. Somatostatin analogues can, not only decrease the secretion of peptides and inhibit their functions but also stop tumor growth. Other medical options for limiting tumor growth include interferon, systemic chemotherapy, and targeted therapies including, angiogenesis inhibitors, epidermal growth factor inhibitors, and mTOR inhibitors. Newer agents are tested and the treatment options expected to increase in the near future. Meanwhile optimal use of the available therapeutic strategies is critical.     

Targeted therapy in advanced well-differentiated neuroendocrine tumors

Treatments for advanced neuroendocrine tumors were, until recently, rather limited. Salvage surgery and liver-directed therapy both have relatively limited impact, and systemic cytotoxic chemotherapy has minimal efficacy. In the absence of other effective treatments, somatostatin analogs have been used for years to control disease and neuroendocrine symptoms, without cytotoxic intent. Advances in targeted therapy for neuroendocrine tumors have opened several potentially new treatment paradigms in the management of these otherwise relatively drug-resistant neoplasms. Promising results have emerged from studies evaluating radiolabeled somatostatin analogs and inhibitors of the vascular endothelial growth factor and mammalian target of rapamycin pathways. This article reviews several of the more encouraging developments in this field.     

Treatment of pulmonary neuroendocrine tumours: State of the art and future developments

The current classification of pulmonary neuroendocrine tumours includes four subtypes: low-grade typical carcinoid tumour (TC), intermediate-grade atypical carcinoid tumour (AC), and two high-grade malignancies: large cell neuroendocrine carcinoma and small cell lung cancer (SCLC).     

Use of [177Lu]Lu-DOTA-TATE in the treatment of gastroenteropancreatic neuroendocrine tumours: Results of a UK cost-effectiveness modelling study

AimTo evaluate the cost-effectiveness of [¹⁷⁷Lu]Lu-DOTA-TATE versus relevant comparators for the treatment of neuroendocrine tumours located in the gastrointestinal tract (GI-NETs) and the pancreas (P-NETs).Materials and methodsA three-state partitioned survival model was developed to perform a cost-utility analysis of [¹⁷⁷Lu]Lu-DOTA-TATE versus standard of care (high dose Octreotide LAR), everolimus and sunitinib. Effectiveness data for SoC, everolimus and sunitinib were obtained from published Kaplan–Meier survival curves. Given a lack of head-to-head effectiveness data, matching adjusted indirect comparisons (MAICs) were performed to population-adjust [¹⁷⁷Lu]Lu-DOTA-TATE survival data based on prognostic factors and derive estimates of relative effectiveness. Health state utilities were estimated from real-world evidence. Drug acquisition costs were taken from nationally published sources (BNF, NICE), and administration costs were based on treatment protocols in [¹⁷⁷Lu]Lu-DOTA-TATE studies, combined with nationally published unit costs (PSSRU, DoH reference costs). Incidence of adverse events were estimated using published sources. A discount rate of 3.5% was applied to both utilities and costs, and deterministic and probabilistic sensitivity analyses were performed. Costs were included from an NHS perspective and presented in 2017/18 GBP (and PPP Euros for base case).ResultsIn GI-NETs, the incremental cost-effectiveness ratio (ICER) of [¹⁷⁷Lu]Lu-DOTA-TATE compared to SoC and everolimus was £26,528 (€27,672) and £24,145 (€25,186) per QALY, respectively. In P-NETs, the ICER of [¹⁷⁷Lu]Lu-DOTA-TATE compared to SoC was £22,146 (€23,101) or £28,038 (€29,251) dependent on matched population, and £21,827 (€22,766) and £15,768 (€16,445) compared to everolimus and sunitinib, respectively.ConclusionsAt a willingness to pay threshold of £30,000, [¹⁷⁷Lu]Lu-DOTA-TATE is likely to be a cost-effective treatment option for GI-NET and P-NET patients versus relevant treatment comparators (NHS perspective).     

神经内分泌肿瘤药物临床试验进展

神经内分泌肿瘤(neuroendocrine neoplasm,NEN)是一类起源于神经内分泌细胞及肽能神经元的高度异质性的少见肿瘤。根据细胞分化的程度,NEN可分为分化好的神经内分泌瘤(neuroendocrine tumor,NET)和分化差的神经内分泌癌(neuroendocrine carcinoma,NEC)。药物治疗是进展期NEN患者首选的全身治疗方式。本文总结了近年来在NEN领域的重要药物临床试验进展,为临床治疗提供参考。     

HSP90 expression and early recurrence in gastroenteropancreatic neuroendocrine tumors: Potential for a novel therapeutic target

BackgroundHeat shock protein (HSP)-90 promotes tumor growth and is overexpressed in many malignancies. HSP90 expression profile and its potential as a therapeutic target in primary and metastatic neuroendocrine tumors (NETs) are not known.MethodsHSP90 cytoplasmic expression and Ki-67 index were re-reviewed and scored by a pathologist blinded to all other clinicopathologic variables for patients who underwent resection of primary and metastatic gastroenteropancreatic (GEP) neuroendocrine tumors at a single institution (2000–2013). Primary outcome was recurrence-free survival (RFS).ResultsOf 263 tumors reviewed, 73% (n = 191) were primary GEP NETs, and 12% (n = 31) were NET liver metastases. Of the primary GEP-NETs, mean age was 56 years, 42% were male; 53% (n = 103) were pancreatic and 23% (n = 44) were small bowel. HSP90 expression was high in 34% (n = 64) and low in 66% (n = 127). Compared to low expression, high HSP90 was associated with advanced T-stage (T3/T4) (47 vs 27%; p = 0.02). Among patients who underwent curative-intent resections for primary, non-metastatic NETs (n = 145), high HSP90 was independently associated with worse RFS (HR 5.09, 95% CI 1.65–15.74; p = 0.005), after accounting for positive margin, LN involvement, increased tumor size, site of primary tumor, and Ki-67. When assessing NET liver metastases, 13% (n = 4) had high HSP90 expression and 87% (n = 26) had low expression. Patients with liver metastases with high HSP90 tended to have worse 1- and 3-year progression-free survival (25%, 25%) compared to those with low HSP90 (69%, 49%; p = 0.059).ConclusionHSP90 exhibits differential expression in resected GEP-NETs and liver metastases. High cytoplasmic expression is associated with early disease recurrence, even after accounting for other adverse pathologic factors. HSP90 inhibition may be a potential therapeutic target for neuroendocrine tumors.     

Chemotherapy for neuroendocrine tumours: The beatson oncology centre experience

The role of chemotherapy in malignant neuroendocrine tumours is difficult to assess because of their rarity and variation in biological behaviour. We present a retrospective review of chemotherapy given to 18 patients with metastatic and one with locally advanced neuroendocrine tumours. There were eight poorly differentiated neuroendocrine tumours, six thyroid medullary carcinomas, two phaeochromocytomas, two pancreatic islet cell tumours and one undifferentiated neuroblastoma. Four patients were given 3-weekly dacarbazine, vincristine and cyclophosphamide (DOC) chemotherapy. In eight patients, this regimen was modified by substituting the dacarbazine and cisplatin and etoposide (OPEC). A further six patients were treated with dacarbazine reintroduced into the 3-weekly regimen (DOPEC). The remaining patient received cisplatin and etoposide.There were two complete responses (both with OPEC) and eight partial responses (two with DOC, three with OPEC and three with DOPEC). Five patients had stable disease and four progressed. Four received further chemotherapy on relapse, producing one complete and one partial response. The median response duration to initial chemotherapy was 10 months (range 3–34). The median survival was 12 months (range 1–42). The main toxicity was haematological, with grade 3–4 neutropenia in 12 patients; eight suffered episodes of sepsis. One death was treatment related. Other toxicity was mild although three patients discontinued vincristine with grade 2 neurotoxicity.The response rate and side effects of these three regimens appear comparable. We conclude that, although these patient numbers are small, combination chemotherapy produces an encouraging response rate (53%; 95% CI 30–75) in malignant neuroendocrine tumours, with acceptable toxicity.     

A case of aggressive neuroendocrine carcinoma of the stomach

An 18 cm × 16 cm × 10 cm tumor of the stomach, invading the left lobe of the liver, pancreatic body and tail, and transverse colon, with peritoneal deposits on the major omentum, was resected by total gastrectomy plus left hepatic lobectomy, transverse colectomy, distal pancreatectomy, splenectomy, and omentectomy. Histopathologically, the tumor consisted of large uniform cells with significant nuclear atypia, showing solid growth patterns with occasional small nests without adenocarcinoma components. Immunohistochemical investigations of the neoplastic cells confirmed the tumor as a neuroendocrine (NE) carcinoma. Molecular analyses disclosed loss of heterozygosity at the MEN1 gene locus on chromosome 11q13. Recurrence occurred at the hepatic hilus and incurred obstructive jaundice 2 months after surgery. Following percutaneous transhepatic biliary drainage, intensive chemotherapy (20 mg/m ² cisplatin on days 1–5 div, 100 mg/m ² etoposide on days 1, 3, and 5 div, and 800 mg/m ² 5-fluorouracil on days 1–5 bolus iv) was started. The recurrent tumor shrank dramatically, and could not be detected on image modalities after five courses of chemotherapy. The patient was well and free of symptoms without biliary drainage for 5 months. Then he began to present with jaundice again, and died of acute massive dissemination 7 months after surgery. An aggressive form of NE carcinoma has been known to be associated with an extremely poor prognosis. However, it is notable that treatment with extensive surgery and intensive chemotherapy could contribute to an improvement in quality of life even if the beneficial effect lasted for only half a year. Received: May 21, 2002 / Accepted: September 17, 2002 Offprint requests to: Y. Hosoya     

21例消化系统神经内分泌癌临床病理回顾性分析

 目的　探讨消化系统神经内分泌癌的临床病理特点及其组织发生和预后。方法　回顾性分析2 1例消化系统神经内分泌癌的临床病理资料 ,对肿瘤进行光镜观察 ,并做免疫组化。结果　消化系统神经内分泌癌可分为三个临床病理类型 ,其病理学特点、生物学行为及预后均有不同。本组资料中典型类癌 6例 ,不典型类癌 7例 ,小细胞癌 8例。免疫组织化学上 ,NSE阳性 14例 ,Syn阳性 14例 ,CgA阳性 4例。随访期内三种类型生存率分别为 6 6 .7%、5 0 %、5 7.1%。结论　消化系统神经内分泌癌病理类型及临床分期与预后密切相关 ,对其治疗有指导作用 ,免疫组化的合理应用可提高神经内分泌癌的诊断率 ,组织发生上支持来自全能干细胞。     

血清嗜铬粒蛋白A在神经内分泌肿瘤诊治中的应用

目的探讨血清嗜铬粒蛋白A(CgA)对神经内分泌肿瘤(NET)的诊断意义,及其对晚期NET患者的病情监测、疗效评估和判断预后的价值。方法采用免疫放射分析法(IRMA)检测125例NET患者血清CgA水平,并对其中45例患者进行定期随访。结果 NET带瘤患者组的血清CgA水平及阳性率明显高于健康对照组及非NET肿瘤组。血清CgA对胃NET的敏感性较好,小肠和胰腺NET敏感性中等,对直肠NET敏感性差。45例患者随访显示,肿瘤进展者血清CgA水平逐渐上升,治疗有效者血清CgA水平呈下降趋势,病情稳定者血清CgA水平无明显波动,术后无复发患者血清CgA水平均在正常范围。结论血清CgA对NET诊断的特异性高,敏感性因原发部位而异;血清CgA对晚期患者的病情监测、疗效评估及判断预后有临床意义。     

Good performance of platinum-based chemotherapy for high-grade gastroenteropancreatic and unknown primary neuroendocrine neoplasms

To evaluate efficacy and safety of platinum and etoposide combination in the treatment of advanced gastroenteropancreatic (GEP) and unknown primary (CUP) neuroendocrine carcinomas (NEC), we analysed the records of 21 consecutive patients treated with this regimen from 1999 to 2012. Objective responses were obtained in 11 patients (52%) and disease stability (DS) in 5 (24%). Median progression-free survival (PFS) was 7 months (95% CI, 5.33–8.66). Median overall survival (OS) was 16 months (95% CI, 14.97–17.03). Patients with limited liver disease had a significantly (p = 0.002) better PFS than patients with extrahepatic disease at diagnosis with 9 months (95% CI, 7.14–10.85) vs. 4 months (95% CI, 1.60–6.40). Two patients experienced durable complete response (30 and 90 months). The most common grade 3–4 toxicities were neutropenia (61%), anaemia (50%), nausea and vomiting (27%) and fatigue (22%). The platinum plus etoposide regimen has an acceptable toxicity profile and is effective in patients with GEP and CUP-NECs.     

Outcome of treating advanced neuroendocrine tumours with radiolabelled somatostatin analogues

Objectives  To evaluate the initial response and outcomes (quality of life and presence of side effects) in patients with advanced neuroendocrine tumours (NET) after treatment with radiolabelled somatostatin analogues: ⁹⁰Y-DOTAT-yr3-octreotide (⁹⁰Y-DOTATOC) and ¹⁷⁷Lu-DOTA-Tyr3- octreotate (¹⁷⁷Lu-DOTATATE). Material and methods  The study included 5 patients with advanced NET referred to European centres for treatment with ⁹⁰Y-DOTATOC and ¹⁷⁷Lu-DOTATATE after lack of response to conventional treatment. The mean age was 45.6 years (29-68 years). Response to therapy was assessed according to: (1) RECIST criteria, as complete response, partial response, stable disease or disease progression, (2) post-treatment survival time and (3) quality of life, using the Karnofsky performance index. Results  All patients survived for >20 months after treatment; mean survival time was 28 months. At the time of writing, three of the patients are alive after 20, 26 and 37 months. Partial response was observed in one patient, stable disease in three and disease progression in the fifth patient. A good-to-excellent post-treatment quality of life was observed in all patients. Conclusion  Therapy with radiolabelled somatostatin analogues showed promising results in patients with advanced NET, with a partial response or disease stabilisation in four of the five patients, who have enjoyed an extended survival period and an improved quality of life.     

Primary tumour resection may improve survival in functional well-differentiated neuroendocrine tumours metastatic to the liver

Background

Functional well-differentiated neuroendocrine tumours (NET) with liver metastases represent a therapeutic challenge with few alternative options in guidelines. In these patients, the role of surgical resection of the primary tumour is controversial.

晚期胰腺癌的内科治疗

化疗是目前晚期胰腺癌内科治疗的重要手段,吉西他滨为标准用药,以其为基础的综合治疗方案在不断探索中,并取得一定进展.放疗同期化疗的应用存在一定争议,尚待进一步的研究证实.新辅助治疗的出现.使部分进展期胰腺癌患者获得了肿瘤切除的可能,对延长生存期意义重大.靶向治疗的出现为转移性胰腺癌患者带来了希望,提高了生存获益.     

复发转移性食管癌的药物治疗

顺铂联合氟尿嘧啶仍是晚期食管痛的基本治疗方案;新的细胞毒药物如紫杉醇类、拓扑异构酶抑制剂及新联合方案是研究的热点;奥沙利铂可替代顺铂,口服氟尿嘧啶衍生物可替代静脉氟尿嘧啶治疗晚期食管癌;二线治疗研究已逐渐被接受和增多;分子靶向治疗将为食管癌提供更多、更好的选择.     

Pancreatic neuroendocrine tumors G3 and pancreatic neuroendocrine carcinomas: Differences in basic biology and treatment

In 2017 the World Health Organization revised the criteria for classification of pancreatic neuroendocrine neoplasms (pNENs) after a consensus conference at the International Agency for Research on Cancer. The major change in the new classification was to subclassify the original G3 group into well-differentiated pancreatic neuroendocrine tumors G3 (pNETs G3) and poorly differentiated pancreatic neuroendocrine carcinomas (pNECs), which have been gradually proven to be completely different in biological behavior and clinical manifestations in recent years. In 2019 this major change subsequently extended to NENs involving the entire digestive tract. The updated version of the pNENs grading system marks a growing awareness of these heterogeneous tumors. This review discusses the clinicopathological, genetic and therapeutic features of poorly differentiated pNECs and compare them to those of well-differentiated pNETs G3. For pNETs G3 and pNECs (due to their lower incidence), there are still many problems to be investigated. Previous studies under the new grading classification also need to be reinterpreted. This review summarizes the relevant literature from the perspective of the differences between pNETs G3 and pNECs in order to deepen understanding of these diseases and discuss future research directions.     

GOECP/SEOR radiotherapy guidelines for thymic epithelial tumours

Thymic epithelial tumours (TET) are rare, heterogeneous neoplasms that range from resectable indolent tumours to aggressive thymic carcinomas with a strong tendency to metastasize. The pathological diagnosis is complex, in part due to the existence of several different classification systems. The evidence base for the management of TETs is scant and mainly based on non-randomised studies and retrospective series. Consequently, the clinical management of TETs tends to be highly heterogenous, which makes it difficult to improve the evidence level. The role of technological advances in the field of radiotherapy and new systemic therapies in the treatment of TETs has received little attention to date. In the present clinical guidelines, developed by the GOECP/SEOR, we review recent developments in the diagnosis and classification of TETs. We also present a consensus-based therapeutic strategy for each disease stage that takes into consideration the best available evidence. These guidelines focus primarily on the role of radiotherapy, including recent advances, in the management of TETs. The main aim of this document is to promote the standardisation of clinical practice and lay the foundations for future studies to clarify the main unresolved questions related to the optimal management of TET.