Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Osteoncology and Rare Tumors Center, Meldola, Italy,
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Osteoncology and Rare Tumors Center, Meldola, Italy.
Neuroendocrinology. 2021;111(9):895-906. doi: 10.1159/000513218. Epub 2020 Nov 20.
Neuroendocrine neoplasias (NENs) are a rare group of tumors with different prognosis and response to therapy. Their heterogeneity is dependent on the site of origin, morphology, and Ki67. Temozolomide (TEM) appears to be active in metastatic NENs (mNENs) but there is limited evidence about its efficacy in gastrointestinal NENs. We analyzed "real-world" data on the use of TEM alone or in association with capecitabine (CAPTEM) in patients with mNENs.
One hundred consecutive patients with advanced NENs treated with TEM or CAPTEM between 2009 and 2019 were included. A pretreatment tumor growth rate (TGR0) was calculated. Overall survival (OS), progression-free survival (PFS), tolerance, objective response rate (ORR), and disease control rate (DCR) were analyzed. A propensity score analysis and inverse probability of treatment weights for Cox regression models were used.
TEM-based therapy was administered to 95 patients (26.3% CAPTEM and 83.7% TEM) with a median age of 59 years (range 26-85) years. ECOG performance status was 0-2. Carcinoid syndrome was reported in 12 (12.6%) patients. Twenty (21.1%) patients with grade (G) 3 neuroendocrine carcinoma (NEC) and 9 (9.4%) with G3 neuroendocrine tumors (NETs) were included in the analysis. Median PFS of the entire group was 10.4 months (95% confidence interval [CI]: 6.0-11.5). In multivariate analysis, a higher risk of progression was observed for NEC G3 patients (hazard ratio [HR] 2.70, 95% CI: 1.25-5.84) and for a TGR ≥19.55 (HR: 2.53, 95% CI: 1.45-4.40). Median OS was 23.4 months (95% CI: 17.0-29.0) and was similar in both treatment groups (23.9 vs. 20.5 months for TEM and CAPTEM, respectively, p = 0.585). In multivariate analysis, TGR ≥19.55 was associated with a higher risk of death (HR: 2.18, 95% CI: 1.16-4.11) than TGR <19.55, as was NEC G3 (HR: 2.42, 95% CI: 1.04-5.59) with respect to NETs. No differences in terms of mPFS or mOS were seen in relation to the primary site of disease. In the 86 patients evaluable for response, ORR was 44.1% and the DCR was 70.9%. Mild adverse events (grade I-II) included anemia, neutropenia, and headache. Rare cases of G 3 neutropenia and thrombocytopenia were recorded.
TEM-based regimens are associated with a high DCR and a relatively tolerable toxicity profile in NENs of pancreatic, intestinal, and lung origin. Further investigation of these specific NETs is warranted in prospective clinical trials.
神经内分泌肿瘤（NENs）是一组预后和对治疗反应不同的罕见肿瘤。其异质性取决于起源部位、形态和 Ki67。替莫唑胺（TEM）似乎对转移性 NENs（mNENs）有效，但关于其在胃肠道 NENs 中的疗效的证据有限。我们分析了单独使用 TEM 或与卡培他滨（CAPTEM）联合用于 mNENs 患者的“真实世界”数据。
纳入了 2009 年至 2019 年间接受 TEM 或 CAPTEM 治疗的 100 例晚期 NENs 患者。计算了肿瘤生长率（TGR0）。分析了总生存期（OS）、无进展生存期（PFS）、耐受性、客观缓解率（ORR）和疾病控制率（DCR）。采用倾向评分分析和逆概率治疗加权 Cox 回归模型。
95 例患者接受了基于 TEM 的治疗（26.3%的 CAPTEM 和 83.7%的 TEM），中位年龄为 59 岁（范围 26-85）。ECOG 表现状态为 0-2。12 例（12.6%）患者有类癌综合征。20 例（21.1%）患者为 G3 神经内分泌癌（NEC），9 例（9.4%）为 G3 神经内分泌肿瘤（NETs）。整个组的中位 PFS 为 10.4 个月（95%置信区间 [CI]：6.0-11.5）。多变量分析显示，NEC G3 患者的进展风险更高（危险比 [HR] 2.70，95%CI：1.25-5.84）和 TGR≥19.55（HR：2.53，95%CI：1.45-4.40）。中位 OS 为 23.4 个月（95%CI：17.0-29.0），两组治疗结果相似（TEM 和 CAPTEM 组分别为 23.9 和 20.5 个月，p=0.585）。多变量分析显示，TGR≥19.55 与 TGR<19.55 相比，死亡风险更高（HR：2.18，95%CI：1.16-4.11），NEC G3 与 NETs 相比，死亡风险更高（HR：2.42，95%CI：1.04-5.59）。疾病的主要部位与 mPFS 或 mOS 无差异。在 86 例可评估反应的患者中，ORR 为 44.1%，DCR 为 70.9%。轻度不良反应（I 级-II 级）包括贫血、中性粒细胞减少和头痛。罕见的 G3 中性粒细胞减少症和血小板减少症。
基于 TEM 的方案在胰腺、肠和肺来源的 NENs 中具有较高的 DCR 和相对可耐受的毒性谱。需要在前瞻性临床试验中进一步研究这些特定的 NETs。
