The Randomized, Phase 2 Trial LuCAP Study

TO THE EDITOR: We read with great interest the article entitled “[¹⁷⁷Lu]Lu-DOTATATE Plus Capecitabine Versus [¹⁷⁷Lu]Lu-DOTATATE Alone in Patients with Advanced Grade 1/2 Gastroenteropancreatic Neuroendocrine Tumors (LuCAP): A Randomized, Phase 2 Trial” by Satapathy et al. (1). The authors compared the efficacy of [¹⁷⁷Lu]Lu-DOTATATE in combination with capecitabine to [¹⁷⁷Lu]Lu-DOTATATE alone in patients with grade 1/2 gastroenteropancreatic neuroendocrine tumors (GEP-NETs) who had progressive, somatostatin receptor–positive, locally advanced, or metastatic disease. The trial’s results indicated that adding low-dose capecitabine did not lead to superior radiographic responses in advanced grade 1/2 GEP-NETs. We commend the authors for their efforts to provide prospective randomized data on such a critical topic in peptide receptor radionuclide therapy (PRRT). However, we would like to share some comments regarding the study design and discussion.

We concur with the authors that this study should also be extended to patients with higher-grade neuroendocrine tumors (NETs), as chemotherapy may offer additional benefits for that population (2). The study’s higher response rates for patients with a Ki-67 greater than 10% (response rate, 0.73 vs. 1.26) support this assumption as shown in Figure 3 of the article. Although single-arm studies suggest benefits from adding capecitabine in patients with [¹⁸F]F-FDG PET–positive or grade 3 tumors (3), similar to this study, a recent phase II randomized controlled trial by Becx et al. (4) found no significant changes in progression-free survival or overall survival for patients with advanced somatostatin receptor–positive GEP-NETs or bronchopulmonary NETs when treated with a combination of [¹⁷⁷Lu]Lu-DOTATATE and capecitabine (1,650 mg/m²/d) compared with [¹⁷⁷Lu]Lu-DOTATATE alone.

The study by Satapathy et al. (1) evaluates low-dose capecitabine (1,250 mg/m²/d), rather than high-dose (1,650 mg/m²/d) regimens as used by Claringbold et al. (5). Furthermore, no combination of capecitabine with temozolomide (5), which is the chemotherapy of choice in NETs, were included. Although the dose of capecitabine is an important issue, the duration and timing of capecitabine therapy in combination protocols, notably with temozolomide and [¹⁷⁷Lu]Lu-DOTATATE, is also important and varies across several studies (2), which warrants further investigation.

We also consider the primary origin of NETs to be significant. As the authors of the Australasian CONTROL NET trial (6) discussed, the combination of PRRT and capecitabine plus temozolomide (CAPTEM) showed no additional benefits. However, this lack of benefit was primarily observed in patients with midgut NETs. The trial also indicated that, whereas P values were not statistically significant, the combination of PRRT and CAPTEM was superior to CAPTEM alone in pancreatic NETs, with an overall response rate of 72.2% compared with 33.3%. The study by Satapathy et al. (1) included a mixed patient group, comprising 12 of 36 (33%) with pancreatic NETs and 24 of 36 (67%) with gastrointestinal NETs. The differing response rates for pancreatic NETs and gastrointestinal NETs (0.75 vs. 1.3, respectively) further emphasize the potential importance of the primary tumor origin.

Additionally, the stratification of patients with NETs based on simple imaging findings, such as Krenning score, FDG PET positivity, or delineating disease extent through metastatic site involvement, remains a topic of debate. We agree on the importance of including FDG PET in clinical studies involving NETs because of its superior prognostic capabilities compared with pathologic grade scores (7). Moreover, understanding the extent and site of involvement is also crucial, particularly regarding differences in patient prognoses associated with bone involvement (8). However, with the emergence of several PET-driven tumor parametric and scoring systems, such as metabolic tumor volume (9) and the PETNET score (10), it may be possible to stratify and evaluate the experimental and control arms more effectively. These innovative techniques should be used and tested in future clinical studies, at least as part of post hoc analyses.

Lastly, we would like to conclude with the well-known limitation of study designs involving low-grade NETs. The combination of low-proliferative NETs and the relatively high disease control rates observed in both the control and experimental arms limits the study’s capacity to draw statistically robust conclusions regarding progression-free survival or overall survival. Longer follow-ups and a larger patient size are warranted.

• © 2025 by the Society of Nuclear Medicine and Molecular Imaging.

• Received for publication February 19, 2025.
• Accepted for publication February 20, 2025.