胃肠胰神经内分泌肿瘤 Gastroenteropancreatic neuroendocrine tumors

转移性高分化胃肠胰神经内分泌肿瘤的治疗：ASCO 指南 (12/23/2023)

Systemic therapy for tumor control in metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: ASCO guideline

高分化转移性 1 级-2 级胃肠胰神经内分泌肿瘤的初始治疗方案的选择和进展后的治疗顺序应考虑患者和肿瘤特征, 如激素状态, 原发部位, 分级, 疾病范围和负担, 生长率, 合并症和生长抑素受体(SSTR, somatostatin receptor)阳性，并尽可能在多学科团队内进行讨论。

基线扫描: 使用 68Ga-DOTA 肽或 64Cu-DOTATATE 的 SSTR PET扫描评估患者的 SSTR 阳性情况。

转移性 1 级-2 级胃肠神经内分泌肿瘤的系统的第一线全身治疗 :

  1. 推荐生长抑素（somatostatin analogs, 奥曲肽或兰瑞肽）用于 SSTR 阳性和/或功能性肿瘤。每 3-6 个月进行一次CT或MRI监测, 对于病情稳定者可延长至 6-12 个月，包括对于小体积肿瘤并且没有肿瘤负荷性症状, 或功能性肿瘤。 对于骨转移的患者，建议采用 SSTR-PET 成像进行随访, 因为CT对这些转移的敏感性有限。 支持生长抑素用于肿瘤控制的证据在低度或中低度 SSTR 阳性肿瘤 (Ki-67 < 10%) 患者中最为有力。
  2. 对SSTR 阴性患者，依维莫司为一种全身治疗选择。

转移性 1 级-2 级胃肠神经内分泌肿瘤的二线或后期全身治疗:

  1. 肽受体放射性核素用于SSTR 阳性且在生长抑素治疗后病情进展的患者。 对于功能性肿瘤, 除了肽受体放射性核素治疗外，建议继续使用生长抑素治疗。没有足够的疗效数据表明对于疾病进展的非功能性肿瘤患者应继续进行生长抑素。 转移灶体积较小的患者应权衡肽受体放射性核素的益处与长期骨髓毒性的风险。
  2. 依维莫司推荐用于 SSTR 阴性或 SSTR 阳性的非功能性患者。该药物也可被视为功能性肿瘤的后期治疗。

转移性 1 级-2 级胰腺内分泌肿瘤的第一线全身治疗:

  1. 推荐生长抑素（奥曲肽或兰瑞肽）用于 SSTR 阳性和/或功能性肿瘤。

可以考虑每 3-6 个月进行一次CT 或 MRI, 对于疾病持续稳定的患者可延长至 6-12 个月, 包括对于小体积肿瘤并且没有肿瘤负荷性症状, 或功能性肿瘤.。 对于骨转移的患者，建议采用 SSTR-PET 成像进行随访, 因为CT对这些转移的敏感性有限。支持生长抑素用于肿瘤控制的证据在低度或中低度 SSTR 阳性肿瘤 (Ki-67 < 10%) 患者中最为有力。

  • 对于体积较高和/或有与肿瘤负荷相关症状的患者建议化疗（例如卡培他滨和替莫唑胺 [capecitabine and temozolomide]）。 在极少数情况下，对于具有较高体积和/或与肿瘤负荷相关的症状且不适合化疗的患者, 建议对 SSTR 阳性肿瘤患者进行肽受体放射性核素，或者舒尼替尼或依维莫司。  
  • 对SSTR 阴性患者, 化疗（例如卡培他滨和替莫唑胺）, 依维莫司或舒尼替尼可以为全身治疗选择。

转移性 1 级-2 级胰腺神经内分泌肿瘤的二线或后期全身治疗: 

肽受体放射性核素用于 SSTR 阳性肿瘤, 二线或后期治疗推荐化疗（例如卡培他滨和替莫唑胺）, 依维莫司或舒尼替尼, 治疗选择取决于患者特征和治疗目标。对于功能性肿瘤, 除了肽受体放射性核素外，建议继续使用生长抑素治疗； 没有足够的疗效数据表明对疾病进展的非功能性肿瘤患者应继续进行生长抑素。 转移灶体积较小的患者应权衡肽受体放射性核素 的潜在益处与长期骨髓毒性的潜在风险。在选择治疗方法时应考虑合并症； 舒尼替尼不推荐用于未控制的高血压患者, 依维莫司不推荐用于未控制的糖尿病患者。  

转移性 3 级胃肠胰腺神经内分泌肿瘤的系统治疗建议:

先前针对1 级-2 级神经内分泌肿瘤的建议选项可推荐用于分化良好的3级胃肠胰腺肿瘤。

3级胃肠胰腺肿瘤是神经内分泌肿瘤中较新定义的类别, 包括广泛的 Ki-67 增殖指数范围（即 >20%）。

在某些病例（即 SSTR 阳性、疾病体积较小, 肿瘤相关症状低, 生长速度较慢）中，单独的生长抑素可以被视为一线治疗。 对于 SSTR 阳性患者, 肽受体放射性核素联合或不联合生长抑素都是一种潜在的治疗选择, 这些患者具有生长速度较慢, 仅接受生长抑素 治疗后病情进展较小等特点。 化疗对于具有较高增殖指数/有丝分裂率, 快速生长和体积大等特征的患者可能特别有效。 化疗对于胰腺神经内分泌肿瘤有效的证据最为有力。

For patients with well-differentiated metastatic grade 1-2 gastroenteropancreatic neuroendocrine tumors selection of initial treatment regimen and sequence of treatments after progression should consider patient and tumor characteristics such as hormonal status, primary site, grade, disease extent and burden, growth rate, comorbidities, and somatostatin receptor (SSTR) status and cases be discussed within the multidisciplinary team whenever possible.

Baseline Scan: SSTR PET scan using 68Ga-DOTA peptide or 64Cu-DOTATATE to assess patients for SSTR positivity.

Systemic first-line systemic therapy for metastatic grade 1-2 gastrointestinal neuroendocrine tumors:

  1.  Somatostatin analogs (octreotide or lanreotide) are recommended for SSTR-positive and/or functional tumors. CT or MRI monitoring is performed every 3-6 months, and can be extended to 6-12 months for patients with consistently stable disease, can be considered in small-volume tumors without tumor burden symptoms, or functional tumors. For patients with bone metastases, SSTR-PET imaging is recommended for follow-up because CT has limited sensitivity for these metastases. The evidence supporting the use of somatostatin for tumor control is strongest in patients with low- or low- to moderate-grade SSTR-positive tumors (Ki-67 < 10%).
  2. For SSTR-negative patients, everolimus is a systemic treatment option.

Second-line or late-stage systemic therapy for metastatic grade 1-2 gastrointestinal neuroendocrine tumors:

  1. Peptide receptor radionuclides therapy is used in patients with SSTR-positive disease who have progressed after somatostatin therapy. For functional tumors, it is recommended to continue somatostatin therapy in addition to peptide receptor radionuclide therapy. There are insufficient efficacy data to suggest that somatostatin should be continued in patients with nonfunctional tumors whose disease has progressed. Patients with small metastases should weigh the potential benefits of peptide receptor radionuclides therapy against the potential risk of long-term bone marrow toxicity.
  2. Everolimus is recommended for SSTR-negative or SSTR-positive non-functional patients. The drug may also be considered as a late-stage treatment for functional tumors.

First-line systemic therapy for metastatic grade 1-2 pancreatic endocrine tumors:

  1. Somatostatin (octreotide or lanreotide) is recommended for SSTR-positive and/or functional tumors. CT or MRI may be considered every 3-6 months, extending to 6-12 months for patients with persistently stable disease, can be considered in small-volume tumors without tumor burden symptoms, or for functional tumors. For patients with bone metastases, SSTR-PET imaging is recommended for follow-up because CT has limited sensitivity for these metastases. The evidence supporting the use of somatostatin for tumor control is strongest in patients with low- or low- to moderate-grade SSTR-positive tumors (Ki-67 < 10%).
  2. Chemotherapy (e.g., capecitabine and temozolomide) is recommended for patients with high tumor volume and/or symptoms related to tumor burden. In rare cases, peptide receptor radionuclides therapy, or sunitinib or everolimus, are recommended for patients with SSTR-positive tumors who have high tumor volume and/or symptoms related to tumor burden and are not candidates for chemotherapy.
  3. For SSTR-negative patients, chemotherapy (e.g., capecitabine and temozolomide), everolimus, or sunitinib may be systemic treatment options.

Second-line or late-stage systemic therapy for metastatic grade 1-2 pancreatic neuroendocrine tumors:

Peptide receptor radionuclides therapy is used for SSTR-positive tumors. Chemotherapy (e.g., capecitabine and temozolomide), everolimus, or sunitinib are recommended for second-line or later-line treatment. Treatment choice depends on patient characteristics and treatment goals. For functional tumors, it is recommended that somatostatin therapy be continued in addition to peptide receptor radionuclide therapy; there are insufficient efficacy data to suggest that somatostatin should be continued in patients with non-functional tumors whose disease has progressed. Patients with small metastases should weigh the potential benefits of peptide receptor radionuclide therapy against the potential risks of long-term bone marrow toxicity. Comorbidities should be considered when selecting treatment; sunitinib is not recommended in patients with uncontrolled hypertension, and everolimus is not recommended in patients with uncontrolled diabetes.

Systemic treatment recommendations for metastatic grade 3 gastroenteropancreatic neuroendocrine tumors:

Previously suggested options for grade 1-2 neuroendocrine tumors may be recommended for well-differentiated grade 3 gastroenteropancreatic tumors. Grade 3 gastroenteropancreatic tumors are a relatively newly defined category of neuroendocrine tumors and include a broad range of Ki-67 proliferation indices (i.e., >20%).

In certain cases (i.e., SSTR-positive, small disease volume, low tumor-related symptoms, slow growth rate), somatostatin alone may be considered first-line therapy. Peptide receptor radionuclide therapy with or without somatostatin is a potential treatment option for SSTR-positive patients who have slow growth rates and slow disease progression after somatostatin treatment alone. Chemotherapy may be particularly effective in patients with characteristics such as high proliferation index/mitotic rate, rapid growth, and large size. The evidence for the effectiveness of chemotherapy is strongest for pancreatic neuroendocrine tumors.

参考文献 Reference

Del Rivero J et al. J Clin Onc 2023; 41: 5049

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