• Correction: Current and novel therapeutic opportunities for systemic therapy in biliary cancer

      Marin, J. J. G.; Prete, M. G.; Lamarca, Angela; Tavolari, S.; Landa-Magdalena, A.; Brandi, G.; Segatto, O.; Vogel, A.; Macias, R. I. R.; Rodrigues, P. M.; et al. (2021)
    • External validity of somatostatin analogs trials in advanced neuroendocrine neoplasms: The GETNE-TRASGU study

      Jimenez-Fonseca, P.; Carmona-Bayonas, A.; Lamarca, Angela; Barriuso, Jorge; Castano, A.; Benavent, M.; Alonso, V.; Riesco, M. D.; Alonso-Gordoa, T.; Custodio, A.; et al. (2021)
      Introduction: Somatostatin analogues (SSA) prolong progression-free survival (PFS) in patients with well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, the eligibility criteria in randomized clinical trials (RCTs) have been restricted, which contrasts with the vast heterogeneity found in NETs. Methods: We identified patients with well-differentiated (Ki67% ?20%), metastatic GEP-NETs treated in first-line with SSA monotherapy from the Spanish R-GETNE registry. The therapeutic effect was evaluated using a Bayesian Cox model. The objective was to compare survival-based outcomes from real world clinical practice versus RCTs. Results: The dataset contained 535 patients with a median age of 62 years (range: 26-89). The median Ki67% was 4 (range: 0-20). The most common primary tumor sites were: midgut, 46%; pancreas, 34%; unknown primary, 10%; and colorectal, 10%. Half of the patients received octreotide LAR (n=266) and half, lanreotide autogel (n=269). The median PFS was 28.0 months (95% CI, 22.1-32.0) for octreotide vs 30.1 months (95% CI, 23.1-38.0) for lanreotide. The overall hazard ratio for lanreotide vs octreotide was 0.90 (95% credible interval, 0.71-1.12). The probability of effect sizes >30% with lanreotide vs octreotide was 2% and 6% for midgut and foregut NENs, respectively. Conclusion: Our study evaluated the external validity of RCTs examining SSAs in the real world, as well as the main effect-modifying factors (progression status, symptoms, tumor site, specific metastases, and analytical data).. Our results indicate that both octreotide LAR and lanreotide autogel had a similar effect on PFS. Consequently, both represent valid alternatives in patients with well-differentiated, metastatic GEP-NENs.
    • Lenvatinib in patients with advanced grade 1/2 pancreatic and gastrointestinal neuroendocrine tumors: results of the Phase II TALENT Trial (GETNE1509)

      Capdevila, J.; Fazio, N.; Lopez, C.; Teulé, A.; Valle, Juan W; Tafuto, S.; Custodio, A.; Reed, N.; Raderer, M.; Grande, E.; et al. (2021)
      Purpose: Approved systemic therapies for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have shown limited capacity to reduce tumor burden and no antitumor activity after progression to targeted agents (TAs). We investigated the efficacy and safety of lenvatinib in patients with previously treated advanced GEP-NETs. Patients and methods: This was a multicenter, single-arm, open-label, phase II trial with two parallel cohorts (ClinicalTrials.gov identifier: NCT02678780) involving 21 institutions in 4 European countries. Eligible patients had histologically confirmed advanced grade 1-2 pancreatic (panNET) or GI (GI-NET) NETs with documented tumor progression after treatment with a TA (panNET) or somatostatin analogs (GI-NET). Patients were treated with lenvatinib 24 mg once daily until disease progression or treatment intolerance. The primary end point was overall response rate by central radiology review. Secondary end points included progression-free survival, overall survival, duration of response, and safety. Results: Between September 2015 and March 2017, a total of 111 patients were enrolled, with 55 (panNET) and 56 (GI-NET) patients in each cohort. The median follow-up was 23 months. The overall response rate was 29.9% (95% CI, 21.6 to 39.6): 44.2% (panNET) and 16.4% (GI-NET). The median (range) duration of response was 19.9 (8.4-30.8) and 33.9 (10.6-38.3) months in the panNET and GI-NET groups, respectively. The median progression-free survival was 15.7 months (95% CI, 14.1 to 19.5). The most common adverse events were fatigue, hypertension, and diarrhea; 93.7% of patients required dose reductions or interruptions. Conclusion: We report the highest centrally confirmed response reported to date with a multikinase inhibitor in advanced GEP-NETs, with a particularly strong response in the panNET cohort. This study provides novel evidence for the efficacy of lenvatinib in patients with disease progression following treatment with other TAs, suggesting the potential value of lenvatinib in the treatment of advanced GEP-NETs.
    • Letter to the editor: does multiple intrahepatic cholangiocarcinoma worsen prognosis as 'M1' stage? Reply

      Lamarca, Angela; Santos-Laso, A.; Utpatel, K.; La Casta, A.; Stock, S.; Forner, A.; Adeva, J.; Folseraas, T.; Fabris, L.; Macias, R. I. R.; et al. (2021)
    • Liver metastases of intrahepatic cholangiocarcinoma: implications for a potential new staging system

      Lamarca, Angela; Santos-Laso, A.; Utpatel, K.; La Casta, A.; Stock, S.; Forner, A.; Adeva, J.; Folseraas, T.; Fabris, L.; Ir Macias, R.; et al. (2020)
      Background: Intrahepatic cholangiocarcinoma (iCCA) with liver metastases (LM) are perceived to have a poor prognosis but the American Joint Committee on Cancer (AJCC) classifies them as early stage in the absence of lymph nodes or extrahepatic spread. Methods: Patients with iCCA from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) and Surveillance, Epidemiology, and End Results (SEER) registries with survival/staging (AJCCv.7) data were eligible. Modified staging was used (mAJCCv.7): Group-A: stages-I-III (excluding T2bN0); Group-B: stage-IVa (excluding T2bN1M0); Group-C: LM (T2bN0/1) and Group-D: stage-IVb (extra-hepatic metastases). Survival analysis (Kaplan Meier and Cox Regression) was performed in an ENS-CCA training cohort (TC) and findings internally [ENS-CCA (iVC)] and externally [SEER] validated. The aim was to assess if LM (Group-C) had a shorter survival compared to other early stages (Group-A). A modified version of AJCCv.8 (mAJCCv.8) is proposed. Results: Total of 574 and 4,171 patients from the ENS-CCA and SEER registries were included. Following the new classification, 19.86% and 17.31% of patients from the ENS-CCA and SEER registries were reclassified into the Group-C, respectively. In the ENS-CCA TC, multivariable Cox Regression was adjusted for obesity (p-value 0.026) and performance status (p-value <0.001); patients in Group-C (HR 2.53 (95%CI 1.18-5.42); p-value 0.017) had a higher risk of death (vs Group-A). Findings were validated in the ENS-CCA iVC (HR 2.93 (95%CI 2.04-4.19); p-value <0.001) and in the SEER registry (HR of 1.88 (95%CI 1.68-2.09); p-value <0.001). Conclusions: iCCA LM have a worse outcome than other early stages. As AJCCv.8 does not take this into consideration, a modification of AJCC v.8 (mAJCCv.8) including "liver metastases: multiple liver lesions, with or without vascular invasion" as a novel "M1a stage" is suggested.
    • Reply to (20-1119.R1) Surgery for advanced intrahepatic cholangiocarcinoma warrants further investigation

      Lamarca, Angela; Santos-Laso, A.; Utpatel, K.; La Casta, A.; Stock, S.; Forner, A.; Adeva, J.; Folseraas, T.; Fabris, L.; Macias, R. I.; et al. (2021)
      We thank Jansson & Sparrelid for their Letter to the Editor(1)regarding our publication(2). We stated that "based on our results, patients with liver metastases should not be offered therapeutic strategies suitable for early stages, in view of poor survival". Jansson(1) argues that "the role of surgery in multiple intrahepatic cholangiocarcinoma (iCCA) should not be dismissed without further analysis"; similar to Zhang's views(3).