Overall survival (OS) is considered as the standard measure of outcome in oncology. However, considering that resectable pancreatic neuroendocrine neoplasms (Pan-NENs) usually have a long OS, the feasibility of prospective studies is questionable due to a long follow-up period needed. The primary endpoint was to validate the use of disease-free survival (DFS) as a surrogate measure of OS. The secondary endpoint was to calculate the gain in sample size using DFS instead of OS in hypothetical prospective studies with two parallel groups. A systematic review of studies reporting both OS and DFS in resected Pan-NENs was carried out. Multivariate linear regression analysis was used to evaluate if DFS predicts the OS in patients undergoing radical resection. Monte Carlo simulation was performed to estimate the gain in sample size, supposing the use of DFS instead of OS, to evaluate a hypothetical adjuvant treatment after surgery in a randomized trial. Six studies reporting data about seven cohorts of resected Pan-NENs were included, for a total of 1088 patients. The median OS and DFS were 144 (27–134) and 122 (50–267) months, respectively. There was a significant correlation between DFS and OS (R 2 = 0.988; P = 0.035). Monte Carlo simulations showed that the number of patients needed to demonstrate a significant reduction of probability of a ‘target event’ in a hypothetical two-arm group exploring the hypothetical role of adjuvant therapy was reduced using DFS instead OS. This finding supports the legitimacy of using DFS as an acceptable surrogate for OS in surgical clinical trials.
Claudio Ricci, Stefano Partelli, Carlo Ingaldi, Valentina Andreasi, Davide Campana, Francesca Muffatti, Laura Alberici, Cecilia Giorgi, Riccardo Casadei and Massimo Falconi
Sara Pusceddu, Francesco Barretta, Annalisa Trama, Laura Botta, Massimo Milione, Roberto Buzzoni, Filippo De Braud, Vincenzo Mazzaferro, Ugo Pastorino, Ettore Seregni, Luigi Mariani, Gemma Gatta, Maria Di Bartolomeo, Daniela Femia, Natalie Prinzi, Jorgelina Coppa, Francesco Panzuto, Lorenzo Antonuzzo, Emilio Bajetta, Maria Pia Brizzi, Davide Campana, Laura Catena, Harry Comber, Fiona Dwane, Nicola Fazio, Antongiulio Faggiano, Dario Giuffrida, Kris Henau, Toni Ibrahim, Riccardo Marconcini, Sara Massironi, Maja Primic Žakelj, Francesca Spada, Salvatore Tafuto, Elizabeth Van Eycken, Jan Maaten Van der Zwan, Tina Žagar, Luca Giacomelli, Rosalba Miceli and NEPscore Working Group
No validated prognostic tool is available for predicting overall survival (OS) of patients with well-differentiated neuroendocrine tumors (WDNETs). This study, conducted in three independent cohorts of patients from five different European countries, aimed to develop and validate a classification prognostic score for OS in patients with stage IV WDNETs. We retrospectively collected data on 1387 patients: (i) patients treated at the Istituto Nazionale Tumori (Milan, Italy; n = 515); (ii) European cohort of rare NET patients included in the European RARECAREnet database (n = 457); (iii) Italian multicentric cohort of pancreatic NET (pNETs) patients treated at 24 Italian institutions (n = 415). The score was developed using data from patients included in cohort (i) (training set); external validation was performed by applying the score to the data of the two independent cohorts (ii) and (iii) evaluating both calibration and discriminative ability (Harrell C statistic). We used data on age, primary tumor site, metastasis (synchronous vs metachronous), Ki-67, functional status and primary surgery to build the score, which was developed for classifying patients into three groups with differential 10-year OS: (I) favorable risk group: 10-year OS ≥70%; (II) intermediate risk group: 30% ≤ 10-year OS < 70%; (III) poor risk group: 10-year OS <30%. The Harrell C statistic was 0.661 in the training set, and 0.626 and 0.601 in the RARECAREnet and Italian multicentric validation sets, respectively. In conclusion, based on the analysis of three ‘field-practice’ cohorts collected in different settings, we defined and validated a prognostic score to classify patients into three groups with different long-term prognoses.