Studio clinico di fase II in aperto multicentrico sul trattamento di prima linea con irinotecano, oxaliplatino, e 5-fluorouracile/leucovorin infusionale (FOLFOXIRI) in combinazione con bevacizumab in pazienti con carcinoma del colon-retto metastatico

Il presente studio di fase II valuta la combinazione di bevacizumab con il regime FOLFOXIRI semplificato come trattamento di prima linea per pazienti presentanti carcinoma del colon retto metastatico inizialmente non resecabile. L’obiettivo primario è valutare la percentuale di pazienti liberi da progressione al decimo mese. Sono stati arruolati nello studio un totale di 57 pazienti. Le principali tossicità di grado G3-G4 sono state: neutropenia, diarrea, trombosi venosa profonda, ipertensione. Si sono osservate: 7 risposte complete, 37 risposte parziali con un tasso di remissione del 77% e 13 pazienti con malattia stabile (tasso di controllo della malattia = 100%). Ad oggi 18 pazienti sono stati sottoposti a una resezione chirurgica post-chemioterapia delle metastasi epatiche e sono state eseguite 14 resezioni R0. Dopo un follow-up mediano di 15.3 mesi, 28 pazienti sono progrediti; la sopravvivenza libera da progressione mediana è 13,1 mesi, la sopravvivenza libera da progressione a 10 mesi è del 72%. Dodici pazienti sono deceduti, la sopravvivenza globale non è stata ancora raggiunta. Si può concludere che bevacizumab può essere combinato in maniera sicura con il regime FOLFOXIRI semplificato senza incrementare le tossicità attese; l’attività del trattamento è significativa

Vitamin D in melanoma: Controversies and potential role in combination with immune check-point inhibitors

The role of vitamin D in melanoma is still controversial. Although several Authors described a correlation between vitamin D deficiency and poor survival in metastatic melanoma patients, clinical trials exploring the effects of vitamin D supplementation in this clinical setting were mostly inconclusive. However, recent evidence suggests that vitamin D exerts both anti-proliferative effects on tumor cells and immune-modulating activities, that have been widely explored in auto-immune disorders. On the one hand, vitamin D has been shown to inhibit T-helper17 lymphocytes, notoriously involved in the pathogenesis of immune-related adverse events (iAEs) which complicate immune-checkpoint inhibitor (ICI) treatment. On the other hand, vitamin D up-regulates PDL-1 expression on both epithelial and immune cells, suggesting a synergic effect in combination with ICIs, for which further investigation is needed

Association of Upfront Peptide Receptor Radionuclide Therapy With Progression-Free Survival Among Patients With Enteropancreatic Neuroendocrine Tumors

open57noIMPORTANCE Data about the optimal timing for the initiation of peptide receptor radionuclide therapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumors are lacking. OBJECTIVE To evaluate the association of upfront PRRT vs upfront chemotherapy or targeted therapy with progression-free survival (PFS) among patients with advanced enteropancreatic neuroendocrine tumors who experienced disease progression after treatment with somatostatin analogues (SSAs). DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study analyzed the clinical records from 25 Italian oncology centers for patients aged 18 years or older who had unresectable, locally advanced or metastatic, well-differentiated, grades 1 to 3 enteropancreatic neuroendocrine tumors and received either PRRT or chemotherapy or targeted therapy after experiencing disease progression after treatment with SSAs between January 24, 2000, and July 1, 2020. Propensity score matching was done to minimize the selection bias. EXPOSURES Upfront PRRT or upfront chemotherapy or targeted therapy. MAIN OUTCOMES AND MEASURES The main outcome was the difference in PFS among patients who received upfront PRRT vs among those who received upfront chemotherapy or targeted therapy. A secondary outcome was the difference in overall survival between these groups. Hazard ratios (HRs) were fitted in a multivariable Cox proportional hazards regression model to adjust for relevant factors associated with PFS and were corrected for interaction with these factors. RESULTS Of 508 evaluated patients (mean ([SD] age, 55.7 [0.5] years; 278 [54.7%] were male), 329 (64.8%) received upfront PRRT and 179 (35.2%) received upfront chemotherapy or targeted therapy. The matched group included 222 patients (124 [55.9%] male; mean [SD] age, 56.1 [0.8] years), with 111 in each treatment group. Median PFS was longer in the PRRT group than in the chemotherapy or targeted therapy group in the unmatched (2.5 years [95%CI, 2.3-3.0 years] vs 0.7 years [95%CI, 0.5-1.0 years]; HR, 0.35 [95%CI, 0.28-0.44; P < .001]) and matched (2.2 years [95% CI, 1.8-2.8 years] vs 0.6 years [95%CI, 0.4-1.0 years]; HR, 0.37 [95%CI, 0.27-0.51; P < .001]) populations. No significant differences were shown in median overall survival between the PRRT and chemotherapy or targeted therapy groups in the unmatched (12.0 years [95%CI, 10.7-14.1 years] vs 11.6 years [95%CI, 9.1-13.4 years]; HR, 0.81 [95%CI, 0.62-1.06; P = .11]) and matched (12.2 years [95% CI, 9.1-14.2 years] vs 11.5 years [95%CI, 9.2-17.9 years]; HR, 0.83 [95%CI, 0.56-1.24; P = .36]) populations. The use of upfront PRRT was independently associated with improved PFS (HR, 0.37; 95%CI, 0.26-0.51; P < .001) in multivariable analysis. After adjustment of values for interaction, upfront PRRT was associated with longer PFS regardless of tumor functional status (functioning: adjusted HR [aHR], 0.39 [95%CI, 0.27-0.57]; nonfunctioning: aHR, 0.29 [95%CI, 0.16-0.56]), grade of 1 to 2 (grade 1: aHR, 0.21 [95%CI, 0.12-0.34]; grade 2: aHR, 0.52 [95%CI, 0.29-0.73]), and site of tumor origin (pancreatic: aHR, 0.41 [95%CI, 0.24-0.61]; intestinal: aHR, 0.19 [95%CI, 0.11-0.43]) (P < .001 for all). Conversely, the advantage was not retained in grade 3 tumors (aHR, 0.31; 95%CI, 0.12-1.37; P = .13) or in tumors with a Ki-67 proliferation index greater than 10% (aHR, 0.73; 95%CI, 0.29-1.43; P = .31). CONCLUSIONS AND RELEVANCE In this cohort study, treatment with upfront PRRT in patients with enteropancreatic neuroendocrine tumors who had experienced disease progression with SSA treatment was associated with significantly improved survival outcomes compared with upfront chemotherapy or targeted therapy. Further research is needed to investigate the correct strategy, timing, and optimal specific sequence of these therapeutic options.openPusceddu, Sara; Prinzi, Natalie; Tafuto, Salvatore; Ibrahim, Toni; Filice, Angelina; Brizzi, Maria Pia; Panzuto, Francesco; Baldari, Sergio; Grana, Chiara M.; Campana, Davide; Davì, Maria Vittoria; Giuffrida, Dario; Zatelli, Maria Chiara; Partelli, Stefano; Razzore, Paola; Marconcini, Riccardo; Massironi, Sara; Gelsomino, Fabio; Faggiano, Antongiulio; Giannetta, Elisa; Bajetta, Emilio; Grimaldi, Franco; Cives, Mauro; Cirillo, Fernando; Perfetti, Vittorio; Corti, Francesca; Ricci, Claudio; Giacomelli, Luca; Porcu, Luca; Di Maio, Massimo; Seregni, Ettore; Maccauro, Marco; Lastoria, Secondo; Bongiovanni, Alberto; Versari, Annibale; Persano, Irene; Rinzivillo, Maria; Pignata, Salvatore Antonio; Rocca, Paola Anna; Lamberti, Giuseppe; Cingarlini, Sara; Puliafito, Ivana; Ambrosio, Maria Rosaria; Zanata, Isabella; Bracigliano, Alessandra; Severi, Stefano; Spada, Francesca; Andreasi, Valentina; Modica, Roberta; Scalorbi, Federica; Milione, Massimo; Sabella, Giovanna; Coppa, Jorgelina; Casadei, Riccardo; Di Bartolomeo, Maria; Falconi, Massimo; de Braud, FilippoPusceddu, Sara; Prinzi, Natalie; Tafuto, Salvatore; Ibrahim, Toni; Filice, Angelina; Brizzi, Maria Pia; Panzuto, Francesco; Baldari, Sergio; Grana, Chiara M.; Campana, Davide; Davì, Maria Vittoria; Giuffrida, Dario; Zatelli, Maria Chiara; Partelli, Stefano; Razzore, Paola; Marconcini, Riccardo; Massironi, Sara; Gelsomino, Fabio; Faggiano, Antongiulio; Giannetta, Elisa; Bajetta, Emilio; Grimaldi, Franco; Cives, Mauro; Cirillo, Fernando; Perfetti, Vittorio; Corti, Francesca; Ricci, Claudio; Giacomelli, Luca; Porcu, Luca; Di Maio, Massimo; Seregni, Ettore; Maccauro, Marco; Lastoria, Secondo; Bongiovanni, Alberto; Versari, Annibale; Persano, Irene; Rinzivillo, Maria; Pignata, Salvatore Antonio; Rocca, Paola Anna; Lamberti, Giuseppe; Cingarlini, Sara; Puliafito, Ivana; Ambrosio, Maria Rosaria; Zanata, Isabella; Bracigliano, Alessandra; Severi, Stefano; Spada, Francesca; Andreasi, Valentina; Modica, Roberta; Scalorbi, Federica; Milione, Massimo; Sabella, Giovanna; Coppa, Jorgelina; Casadei, Riccardo; Di Bartolomeo, Maria; Falconi, Massimo; de Braud, Filipp

Epidemiology of gastroenteropancreatic neuroendocrine neoplasms: a review and protocol presentation for bridging tumor registry data with the Italian association for neuroendocrine tumors (Itanet) national database

: Neuroendocrine neoplasms (NENs) are rare tumors with diverse clinical behaviors. Large databases like the Surveillance, Epidemiology, and End Results (SEER) program and national NEN registries have provided significant epidemiological knowledge, but they have limitations given the recent advancements in NEN diagnostics and treatments. For instance, newer imaging techniques and therapies have revolutionized NEN management, rendering older data less representative. Additionally, crucial parameters, like the Ki67 index, are missing from many databases. Acknowledging these gaps, the Italian Association for Neuroendocrine Tumors (Itanet) initiated a national multicenter prospective database in 2019, aiming to gather data on newly-diagnosed gastroenteropancreatic neuroendocrine (GEP) NENs. This observational study, coordinated by Itanet, includes patients from 37 Italian centers. The database, which is rigorously maintained and updated, focuses on diverse parameters including age, diagnostic techniques, tumor stage, treatments, and survival metrics. As of October 2023, data from 1,600 patients have been recorded, with an anticipation of reaching 3600 by the end of 2025. This study aims at understanding the epidemiology, clinical attributes, and treatment strategies for GEP-NENs in Italy, and to introduce the Itanet database project. Once comprehensive follow-up data will be acquired, the goal will be to discern predictors of treatment outcomes and disease prognosis. The Itanet database will offer an unparalleled, updated perspective on GEP-NENs, addressing the limitations of older databases and aiding in optimizing patient care. STUDY REGISTRATION: This protocol was registered in clinicaltriasl.gov (NCT04282083)

Confronto tra analoghi della somatostatina nel trattamento dei tumori neuroendocrini

I tumori neuroendocrini sono in grado di esprimere i recettori per la somatostatina i quali vengono legati dalla somatostatina o dai suoi analoghi sintetici. I recettori della somatostatina (SSTRs) si dividono in cinque sottotipi: SSTR1-5 i quali vengono espressi diversamente nelle varie tipologie di NET. La somatostatina nativa e i suoi analoghi sintetici (SSA) mostrano differente affinità per i 5 specifici recettori della somatostatina. Nel tempo si è accumulata evidenza di una attività antitumorale degli SSA, in particolare Octreotide LAR e Lanereotide Autogel. L’attività antiproliferativa degli SSA sembra essere mediata da meccanismo diretto di legame con i recettori SSRs, in merito ai quali Octreotide e Lanreotide presentano diverso profilo di affinità, e un meccanismo di azione indiretto, coinvolgente l’immunomodulazione e attività antiangiogenica, il cui peso nell’azione specifica di Octreotide e Lanreotide è ancora oggetto di studio. Lo studio prospettico PROMID randomizzato doppio cieco controllato con placebo ha investigato l’effetto antitumorale di Octreotide LAR nei pazienti affetti da NET ben differenziato derivante dal midgut dimostrando un vantaggio in TTP rispetto al placebo con una TTP mediana per Octrotide LAR di 14,3 mesi rispetto ai 6 mesi del gruppo trattato con placebo. Lo studio CLARINET randomizzato verso placebo ha indagato l’effetto antitumorale di Lanreotide nei NET ben e moderatamente differenziati di origine sia pancreatica che gastrointestinale e Lanreotide autogel dimostrava di prolungare significativamente la PFS (18 vs 6 mesi). Ad oggi non esiste in letteratura uno studio che confronti direttamente questi due differenti SSA. Sebbene simili i due farmaci presentano differenze nella struttura e nella affinità per i differenti recettori SSRs ed I due principali studi che hanno indagato la loro attività antitumorale presentavano differenze nella tipologia di pazienti utilizzata come campione di studio in merito a grading, sede del tumore primitivo status recettoriale espresso all’octreoscan. Nella prima parte della presente tesi, presentiamo uno studio retrospettivo volto a valutare la casistica di 130 pazienti affetti da NET localmente avanzato non resecabile o metastatico trattati in prima linea o con Octreotide LAR o Lanreotide Autogel presso il reparto di Oncologia Medica di Pisa al fine di individuare uguaglianza o differenza di efficacia tra i due trattamenti, dare una suggestione ai quesiti non ancora risolti emersi dagli studi prospettici randomizzati (attività di Octreotide in NET pancreatici, attività di Octreotide LAR per NET con ki67>2%, ruolo della caratterizzazione Octreoscan a fini predittivi di risposta al trattamento con analoghi) e quindi identificare possibili fattori predittivi di risposta al trattamento con gli SSA. Nella seconda parte, illustriamo uno studio retrospettivo condotto su un gruppo di 27 pazienti che, alla progressione dopo prima linea con SSA, sono stati sottoposti ad una seconda linea di trattamento con l’analogo della somatostatina non utilizzato in prima linea (o Lanreotide Autogel o Octreotide LAR). Scopo di questa analisi è dimostrare che l’utilizzo in sequenza di differenti SSA può risultare una strategia terapeutica efficace, probabilmente in virtù della differenze tra i due SSA riguardo ad affinità per SSRs e meccanismo di azione indiretto, e quindi meritevole di ulteriori indagini

Prognostic and predictive value of treatment response of EZH2 expression in melanoma patients at IV stage and evaluation of its relation with melanoma biological and clinical characteristics (PR.E.M.I.E.R. study)

Enhancer of zeste homolog 2 (EZH2), is the catalytic subunit of the polycomb 2 repressive complex (PRC2) with histone H3 methyltransferase function. EZH2 is a potential prognostic biomarker that predicts the aggressive clinical of neoplastic diseases. this is a retrospective exploratory clinical and translational study, on early stage and metastatic melanoma. Our aims are to correlate the immunohistochemical expression of EZH2 on primitive melanomas and metastatic melanoma lesions with histopathological parameters and melanoma TNM stage, and with the analysis of clinical / biological behavior in relation to the treatments performed. 89 patients were enrolled in this study. At diagnosis of primary melanoma, 32% patients were already in stage IV due to the presence of synchronous metastasis; 34% were in stage I or II, 34% were in stage III due to the presence of locoregional lymphnodes involvement. In stage I-II-III group, patients who develop metastasis during follow-up were 43 (48%) and patients who never develop metastasis were 17 (19%). E elevated EZH2 in the initial stages appears to be associated with a more aggressive disease with potential metastatic lymph node involvement or distant metastases ab initio. In metastatic setting, EZH2 3 seems to predict a greater activity of target therapies and EZH2 0 seems to predict a lower efficacy of ipilimumab, elements that can guide the choice of treatment between options such as BRAF + MEK inhibitors, AntiPD1 or AntiPD1+AntiCTLA4

Metastatic BRAF K601E-mutated melanoma reaches complete response to MEK inhibitor trametinib administered for over 36 months.

BACKGROUND: The BRAF K601E mutation occurs in 5% of patients with melanoma, and is the third most common type of BRAF mutation. However, treatment with BRAF and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is only approved in patients with BRAF V600-positive melanoma, and patients with K601E-mutated melanoma do not have access to such drugs. CASE PRESENTATION: A female patient was diagnosed with high tumor burden metastatic melanoma harboring the BRAF K601E mutation. After chemotherapy failure, she underwent compassionate treatment with trametinib. Trametinib showed good activity and efficacy, with 48% shrinkage of a metastatic lymphadenopathy after 4 months' treatment. However, the patient reported treatment-related skin toxicity that required dosage reduction and a personalized intermittent trametinib dosing schedule. After over 36 months from the first trametinib administration, and resection of a metastatic lymphadenopathy, the patient experienced complete response. CONCLUSIONS: This case report shows that trametinib could be a valid therapeutic option in patients with metastatic melanoma harboring the rare BRAF K601E mutation

Combination of immunotherapy and other targeted therapies in advanced cutaneous melanoma

Cutaneous Melanoma (CM) is an aggressive cancer whose incidence is increasing worldwide. However, the knowledge of its biology and genes driving cell growth and survival allowed to develop new drugs that have improved PFS and OS of advanced disease. Both BRAF targeting agents and immune checkpoint inhibitors (ICIs) have been adopted for the treatment of metastatic disease and the adjuvant setting. Several melanoma patients show innate or acquired drug-resistance and thus new strategies are required for overcoming this complication. New ICIs have been developed, and strategies of combination or sequencing are under investigation in ongoing clinical trials. In addition, pre-clinical data have demonstrated that many strategies induce the release of neoantigens within the tumor microenvironment, thus suggesting the combination of new agents with ICIs. Here, we review the ongoing strategies in advanced CM including a dedicated section on treatment of brain metastases

OCTREOTIDE LAR SUITABLE TREATMENT FOR G1-G2 THORACIC NEUROENDOCRINE TUMORS (T-NET): SINGLE CENTER EXPERIENCE

Aim: Somatostatin Analogs are useful for treatment of Gastroenteropancreatic Neuroendocrine Tumor (GEP-NET) because increase patients Progression Free Survival (PFS) and Overall Survival (OS). However, limited data are available for T-NET. Therefore, we conducted a retrospective analysis of G1-G2 T-NET patients treated with Octreotide LAR at our Institution. Methods: From June 1997 to April 2012, 15 consecutive metastatic G1-G2 T-NET patients were treated with Octrotide LAR 30 mg fl i.m. every 28 days. Thirteen patients had pulmonary primary site and 2 patients thymic primary site. Nine patients were treatment naïve, 4 patients and 2 patients received one or more lines of chemotherapy, respectively. Toxicities were evaluated according to CTCAE version 4.0, and response according RECIST criteria. Results: Two (13%) patients experienced partial response, 12 (80%) stable disease, and 1 (7%) patient progressive disease. Partial response was obtained in 2 pulmonary NET. Median number of administrations was 13 (4-72). At a median follow-up of 34,7 months, median OS is not reached (9 patients are still alive). 2-year Survival is 67%. G1-G2 toxicities were diarrhea and asthenia; no G3-G4 toxicities were reported. Conclusions: In our experience, Octreotide LAR was well tolerated and showed interesting activity in T-NET patients. Despite limited data are available for Somatostatin Analogs treatment in T-NET, our analysis is in line with activity and efficacy demonstrated in prospective trials conducted in GEP-NET

Temozolomide alone or in combination with capecitabine in patients with advanced neuroendocrine neoplasms: an Italian multicenter real-world analysis.

Abstract Purpose: Temozolomide (TEM) has been reported to be active alone or in combination with capecitabine (CAP) in patients with neuroendocrine neoplasms (NENs). We retrospectively evaluated activity and toxicity of TEM-based chemotherapy in patients with advanced NENs and explored the potential correlation with clinical/biological factors. Methods: Patients received oral TEM alone or in combination with CAP. Objective response rate (ORR) [complete response + partial response (PR)], median progression-free survival (mPFS), and toxicity were calculated. The O6-methylguanine-DNA-methyltransferase (MGMT) gene inactivation status in tumor tissue was evaluated by pyrosequencing. Results: From September 2008 to April 2020, 170 patients (84% progressive on different therapies) were consecutively treated, 114 (67%) patients received TEM-CAP and 56 (33%) TEM alone. Primary tumor sites were: pancreas 98 (58%), gastrointestinal tract 21 (12%), lung 35 (21%), and unknown 16 (9%). The ORR was 28% for the whole population (33% for TEM-CAP and 18% for TEM as single agent). The median OS (mOS) and mPFS of the whole population were 35.6 months (32.6-48.7) and 14.7 months (10.1-18.3), respectively. There were 48% PR in the MGMT hypermethylated, mainly in pancreatic NENs. Vomiting and leukopenia were the most frequent grade 3/4 toxicity. Conclusions: This large retrospective analysis suggested that a TEM-based chemotherapy is active in advanced, pretreated NEN patients. It generated solid hypotheses that warrant a future prospective study in a biological homogeneous NEN population and clinical setting