Outcome on Mesenteric Mass Response of Small-Intestinal Neuroendocrine Tumors Treated by 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy: The MesenLuth Study, a National Study from the French Group of Endocrine Tumors and Endocan-RENATEN Network.

A mesenteric mass (MM), characterized by fibrotic reaction, is present in most small-intestinal neuroendocrine tumors (SI-NETs). 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) has shown its efficacy in patients with progressive SI-NETs. However, because of specific tissue characteristics of desmoplastic MMs, we hypothesize that these lesions may be refractory to 177Lu-DOTATATE PRRT. Methods: From the national French Groupe d'étude des Tumeurs Endocrines database, we identified patients with an advanced SI-NET and a MM (≥2 cm with a retractile aspect) of a SI-NET treated by at least 1 course of 177Lu-DOTATATE PRRT. The primary endpoint was a MM objective response rate (ORR) of less than 5%. Secondary endpoints were metabolic response, MM-related safety, and clinical response, as well as MM progression-free survival (PFS) and non-MM PFS. Results: In total, 52 patients were included. The MM ORR was 4% (n = 2), and the non-MM ORR was 8% (n = 4). No patient had a MM metabolic response, and the non-MM metabolic response rate was 12% (n = 6). Among the 26 patients with baseline MM-related symptoms, 46% had a clinical response. Four patients presented with gastrointestinal complications during PRRT. The median MM-related PFS was not reached, and the non-MM PFS was 50.3 mo (95% CI, 38.2-61.7 mo). Conclusion: This study confirms that 177Lu-DOTATATE PRRT does not lead to morphologic response on MMs (ORR < 5%). However, it allows MM stability, with few MM-related side effects, and has a relevant impact on MM-related symptoms.

High Tumor Uptake on 18F-FDOPA PET/CT Indicates Poor Prognosis in Patients with Metastatic Midgut Neuroendocrine Tumors: A Study from the Groupe d'étude des Tumeurs Endocrines and ENDOCAN-RENATEN Network.

PET/CT with 6-18F-fluoro-l-dopa (18F-FDOPA) has high diagnostic performance for midgut neuroendocrine tumors (NETs). We explored the prognostic role of 18F-FDOPA PET/CT uptake in metastatic midgut NETs. Methods: We included, in a test cohort (n = 166) and a full external validation cohort (n = 86), all consecutive patients with metastatic midgut NETs who underwent 18F-FDOPA PET/CT in 5 expert centers from 2010 to 2021. We measured the maximal uptake (SUVmax and SUVpeak) of the tumor and nontumor liver on each 18F-FDOPA PET/CT scan. We measured overall survival (OS) from the time of PET/CT and assessed prognostic factors using Kaplan-Meier and multivariable Cox proportional-hazards analyses in the test cohort, with replication in the validation cohort. Results: Patients had similar characteristics in both cohorts. In the test cohort, median follow-up was 60.3 mo. Patients with an SUVpeak tumor-to-liver (T/L) ratio of more than 4.2 had significantly shorter survival than those with a ratio of 4.2 or less (P = 0.01), with a 5-y OS rate of 74.1% ± 4.5% versus 95% ± 3.4%, respectively. On multivariable analysis, an SUVpeak T/L ratio of more than 4.2 remained associated with shorter OS (hazard ratio, 2.30; 95% CI, 1.02-5.22; P = 0.046) after adjustment for age, grade, number of previous lines, number of metastatic sites, and presence of carcinoid syndrome. In the validation cohort, the 5-y OS rate was 100% versus 57.8% ± 12.5% in patients with an SUVpeak T/L ratio ≤ 4.2 or > 4.2, respectively (P = 0.075). An increasing SUVpeak T/L ratio over time tended to have a pejorative prognostic impact. Conclusion: Tumor uptake on 18F-FDOPA PET/CT is an independent prognostic factor in patients with metastatic midgut NETs.

FOLFOX-bevacizumab chemotherapy in patients with metastatic neuroendocrine tumors.

Neuroendocrine tumors (NETs) are highly vascularized neoplasms. While FOLFOX chemotherapy has shown efficacy in patients with advanced NETs, its combination with antiangiogenics has been scarcely described. Here, we report the efficacy and tolerance of FOLFOX-bevacizumab in this setting. We retrospectively studied all consecutive patients with metastatic NET treated by FOLFOX-bevacizumab in two expert centers from 2013 to 2020. We assessed time to treatment failure (TTF), objective response rate (ORR) and toxicity. We explored factors associated with TTF and ORR using multivariate analyses. We included 57 patients (35.1% female, median age 61.7 years), with pancreatic (66.7%), small-intestine (14%) or lung (7%) NETs. Most patients (57.9%) had extra-hepatic metastases and G3 NETs accounted for 40.3% of cases. Patients received a median of 17 cycles of treatment, including a median of seven cycles of bevacizumab and/or 5-fluorouracile maintenance. Median TTF was 15.5 months (95% CI: 9.8-21.2) and was shorter in patients age > 60 years (HR 2.56, 95% CI: 1.16-5.64), p = .020) and >1 previous systemic treatment line (HR 4.15, 95% CI: 1.96-8.78), p < .001). The ORR was 42.9% and was higher in cases of performance status at 0 (OR 5.25, 95% CI: 1.13-24.35), p = .034) and G3 NET (OR 5.39, 95% CI: 1.23-23.52), p = .025). The FOLFOX-bevacizumab combination has promising efficacy in patients with progressive metastatic NETs and notably for G3 NETs, for which optimal treatment as yet remains ill-defined. Hence, it could be a relevant alternative to alkylating-based chemotherapy in this setting and should be further explored prospectively.

Alkylating agent rechallenge in metastatic pancreatic neuroendocrine tumors.

A rechallenge is common after the initial efficacy of alkylating-based chemotherapy (ALK) in pancreatic neuroendocrine tumors (PanNET). High MGMT expression seems associated with a lower response to ALK. We aimed to evaluate the efficacy and toxicity of ALK rechallenge in PanNET, and to assess the evolution of MGMT expression under ALK. All consecutive patients with advanced PanNETs who received initial ALK (achieving tumor control) followed by a pause of > 3 months, then an ALK rechallenge (ALK2) upon progression were retrospectively studied (cohort A). The primary endpoint was progression-free survival under ALK2 (PFS2). The MGMT expression was retrospectively assessed by immunohistochemistry (H-score) in consecutive PanNET surgically resected following ALK (cohort B). We found that Cohort A included 62 patients (median Ki67 8%), for whom ALK1 followed by a pause achieved an objective response rate of 55% and a PFS1 of 23.7 months (95% IC, 19.8-27.6). ALK2 achieved no objective response and stability in 62% of patients. The median PFS2 was 9.2 months (IC 95% 7.1-11.3). At multivariable analysis, a hormonal syndrome (P = 0.032) and a pause longer than 12 months (P = 0.041) were associated with a longer PFS2. In cohort B (17 patients), the median MGMT H-score increased from 45 (IQR 18-105) before ALK to 100 (IQR 56-180) after ALK (P = 0.003). We conclude that after the initial efficacy of ALK treatment, a pause followed by ALK rechallenge might be appropriate to prolong tumor control, improve quality of life and limit long-term adverse events. Increased MGMT expression under ALK might explain the low efficacy of ALK rechallenge.

Biomarkers of Response to Etoposide-Platinum Chemotherapy in Patients with Grade 3 Neuroendocrine Neoplasms.

Etoposide-platinum (EP) chemotherapy has long been the reference treatment for grade 3 neuroendocrine neoplasms (G3 NEN). However, G3 NEN are heterogeneous, including well-differentiated tumors (NET) and poorly differentiated large (LCNEC) or small (SCNEC) cell carcinomas, whose response to EP chemotherapy varies considerably. Our aim was to evaluate predictive biomarkers for the response to EP chemotherapy in G3 NEN. We retrospectively studied 89 patients with lung (42%) and digestive (58%) G3 NEN treated by EP chemotherapy between 2006 and 2020. All cases were centrally reviewed for cytomorphology/Ki-67 and immunohistochemistry of retinoblastoma protein (Rb)/p53/p16, analyzed using a semi-quantitative score. The absence of Rb staining (Rbinap) or the absence of very intense p53 staining (p53inap) were considered inappropriate. Rb staining was also studied as a quantitative marker, the best threshold being determined by ROC curve. Intense p16 staining (p16high) also suggested cell cycle dysregulation. Our primary endpoint was the objective response rate (ORR). We included 10 G3 NET, 31 LCNEC and 48 SCNEC, which showed ORR of 20%, 32% and 75%, respectively (NET vs. NEC, p = 0.040; LCNEC vs. SCNEC, p < 0.001). The ORR was significantly higher in NEN presenting with Rbinap (63% vs. 42%, p = 0.025) and p16high (66% vs. 35%, p = 0.006). Rb < 150 optimally identified responders (AUC = 0.657, p < 0.001). The ORR was 67% in Rb < 150 (vs. 25%, p = 0.005). On multivariate analysis, only Rb < 150 was independently associated with ORR (OR 4.16, 95% CI 1.11-15.53, p = 0.034). We confirm the heterogeneity of the response to EP treatment in G3 NEN. Rb < 150 was the best predictive biomarker for the response to EP, and p53 immunostaining had no additional value.

O-positive blood type is associated with prolonged recurrence-free survival following curative resection of pancreatic neuroendocrine tumors.

BACKGROUND: The ABO blood group may influence the development and progression of cancer. In particular, the prognosis of patients with blood type O is better for pancreatic adenocarcinoma, although this has not been extensively explored in pancreatic neuroendocrine tumors (PanNET). OBJECTIVE: To assess the influence of the ABO and Rhesus blood types on the risk of recurrence in patients who underwent curative intent PanNET surgical resection. METHODS: All consecutive patients operated on for well-differentiated panNET in an expert center from 2003 to 2018 were retrospectively included. Blood group, Rhesus system, demographic and clinical data were collected. The primary endpoint was recurrence free survival (RFS). Factors associated with RFS were explored using Cox proportional hazard models. RESULTS: Overall, 300 patients (male 43%) were included, median age 54 years old (IQR 45-64). The ABO blood group distribution was similar to that of the French population. There was no association between blood group and tumor features. The median postoperative follow-up was 43.9 months (17.0-77.8). The 5- and 10-year RFS rates were 85 ± 4% and 71 ± 13% in O RhD + patients, versus 72 ± 4% and 63 ± 6% otherwise, respectively (p = 0.035). The O RhD + blood group was associated with a decreased risk of recurrence (HR 0.34, 95% CI [0.15-0.75]), p = 0.007 in multivariable analysis adjusted for age, ki67, functioning syndrome, resection margins, tumor size, lymph node status, oncogenetic syndrome. CONCLUSIONS: After curative-intent surgical resection for PanNET, patients with a non-O RhD + blood group may have an increased risk of recurrence and could benefit from closer follow-up.