Zebrafish Patient-Derived Xenograft Model to Predict Treatment Outcomes of Colorectal Cancer Patients

The use of zebrafish embryos for personalized medicine has become increasingly popular. We present a co-clinical trial aiming to evaluate the use of zPDX (zebrafish Patient-Derived Xenografts) in predicting the response to chemotherapy regimens used for colorectal cancer patients. zPDXs are generated by xenografting tumor tissues in two days post-fertilization zebrafish embryos. zPDXs were exposed to chemotherapy regimens (5-FU, FOLFIRI, FOLFOX, FOLFOXIRI) for 48 h. We used a linear mixed effect model to evaluate the zPDX-specific response to treatments showing for 4/36 zPDXs (11%), a statistically significant reduction of tumor size compared to controls. We used the RECIST criteria to compare the outcome of each patient after chemotherapy with the objective response of its own zPDX model. Of the 36 patients enrolled, 8 metastatic colorectal cancer (mCRC), response rate after first-line therapy, and the zPDX chemosensitivity profile were available. Of eight mCRC patients, five achieved a partial response and three had a stable disease. In 6/8 (75%) we registered a concordance between the response of the patient and the outcomes reported in the corresponding zPDX. Our results provide evidence that the zPDX model can reflect the outcome in mCRC patients, opening a new frontier to personalized medicine

Surgery combined with intra-operative microwaves ablation for the management of colorectal cancer liver metastasis: A case-matched analysis and evaluation of recurrences

Hepatic resection is the only chance of cure for a subgroup of patients with colorectal cancer liver metastasis. As the oncologic outcomes of intra-operative microwaves ablation combined with hepatic resection still remain uncertain in this setting, we aimed to compare this approach with surgery alone in patient's candidate to metastases resection with radical intent

Mapping the landscape of immunonutrition and cancer research: A comprehensive bibliometric analysis on behalf of NutriOnc Research Group

: The ongoing global health challenge of cancer is driving the pursuit of innovative avenues for prevention, treatment, and enhanced outcomes. The convergence of nutrition and immune modulation, known as immunonutrition, is ready to act as a catalyst for transformative change in cancer research and therapy. Our study employs a bibliometric analysis to uncover the evolving trends within immunonutrition and cancer research across the past 25 years. Bibliometric data, including authors, journals, affiliations, and countries, were analyzed using the Bibliometrix R package. Clustering algorithms were applied to keywords to identify thematic areas and their evolution. A total of 489 documents were analyzed, showing an annual growth rate of 8.7%, with a collaboration index of 5.41, highlighting comprehensive multidisciplinary involvement within this landscape. Core authors demonstrated sustained productivity, while occasional authors indicated widespread interest. The Medical University of Warsaw led in institutional contributions. Country-wise, Italy, France, and the USA emerged as forerunners in fostering research productivity. Key journals like "Clinical Nutrition" served as beacons, emphasizing the multidimensional nature of this topic. The analysis highlighted growing research output and several collaborations, indicating the importance of immunoenriched nutrition in cancer treatment. The interplay of core authors and diversified engagement harmoniously accentuates the cross-disciplinary nature of this burgeoning field. International collaboration facilitated knowledge exchange. Prominent documents shaped the field, emphasizing the significance of nutritional interventions. Thematic clusters revealed varied focuses, including pharmaconutrients, surgical approaches, inflammation, and specific cancers. The expanding research output suggests further development, particularly in exploring immunoenriched nutrition's impact on cancer types and patient populations. The multidisciplinary nature and international collaborations enhance the field's progress. Gaps in research underscore the need for original studies and personalized approaches. This study guides future research, informing evidence-based nutritional interventions and advancing cancer care practices

a retrospective study of trifluridine tipiracil in pretreated metastatic colorectal cancer patients in clinical practice

n/

Prognostic and predictive role of neutrophil/lymphocytes ratio in metastatic colorectal cancer: a retrospective analysis of the TRIBE study by GONO.

Background Neutrophil/lymphocyte ratio (NLR), defined as absolute neutrophils count divided by absolute lymphocytes count, has been reported as poor prognostic factor in several neoplastic diseases but only a few data are available about unresectable metastatic colorectal cancer (mCRC) patients (pts). The aim of our study was to evaluate the prognostic and predictive role of NLR in the TRIBE trial. Patients and methods Pts enrolled in TRIBE trial were included. TRIBE is a multicentre phase III trial randomizing unresectable and previously untreated mCRC pts to receive FOLFOXIRI or FOLFIRI plus bevacizumab. A cut-off value of 3 was adopted to discriminate pts with low (NLR < 3) versus high (NLR ≥ 3) NLR, as primary analysis. As secondary analysis, NLR was treated as an ordinal variable with three levels based on terciles distribution. Results NLR at baseline was available for 413 patients. After multiple imputation at univariate analysis, patients with high NLR had significantly shorter progression-free survival (PFS) [hazard ratio (HR) 1.27 (95% CI 1.05-1.55), P = 0.017] and overall survival (OS) [HR 1.56 (95% CI 1.25-1.95), P < 0.001] than patients with low NLR. In the multivariable model, NLR retained a significant association with OS [HR 1.44 (95% CI 1.14-1.82), P = 0.014] but not with PFS [HR 1.18 (95% CI 0.95-1.46), P = 0.375]. No interaction effect between treatment arm and NLR was evident in terms of PFS (P for interaction = 0.536) or OS (P for interaction = 0.831). Patients with low [HR 0.84 (95% CI 0.64-1.08)] and high [HR 0.73 (95% CI 0.54-0.97)] NLR achieved similar PFS benefit from the triplet and consistent results were obtained in terms of OS [HR 0.83 (95% CI 0.62-1.12) for low NLR; HR 0.82 (95% CI 0.59-1.12) for high NLR]. Conclusion This study confirmed the prognostic role of NLR in mCRC pts treated with bevacizumab plus chemotherapy in the first line, showing the worse prognosis of pts with high NLR. The advantage of the triplet is independent of NLR at baseline

Location of primary tumor and benefit from anti-epidermal growth factorreceptor monoclonalantibodies in patients with RAS and BRAF wild-typemetastatic colorectal cancer

Introduction. Right- and left-sided colorectal cancers (CRCs) differ in clinical and molecular characteristics. Some retrospective analyses suggested that patients with right-sided tumors derive less benefit from anti-epidermal growth factor receptor (EGFR) antibodies; however, molecular selection in those studies was not extensive. Patients and Methods. Patients with RAS and BRAF wild-type metastatic CRC (mCRC) who were treated with single-agent anti-EGFRs or with cetuximab-irinotecan (if refractory to previous irinotecan) were included in the study. Differences in outcome between patients with right- and left-sided tumors were investigated. Results. Of 75 patients, 14 and 61 had right- and left-sided tumors, respectively. None of the right-sided tumors responded according to RECIST, compared with 24 left-sided tumors (overall response rate: 0% vs. 41%; p 5 .0032), and only 2 patients with right-sided tumors (15%) versus 47 patients with left-sided tumors (80%) achieved disease control (p, .0001). The median duration of progression-free survival was 2.3 and 6.6 months in patients with right-sided and left-sided tumors, respectively (hazard ratio: 3.97;95%confidence interval: 2.09–7.53; p,.0001). Conclusion. Patients with right-sided RAS and BRAF wild-type mCRC seemed to derive no benefit from single-agent anti- EGFRs

Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO

PURPOSE To verify whether the intensification of the upfront chemotherapy backbone with a modified schedule of modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) increases the activity of fluorouracil, leucovorin, and oxaliplatin when both regimens are combined with panitumumab as initial treatment for RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC).METHODS TRIPLETE was a prospective, open-label, phase III trial in which previously untreated patients with unresectable RAS and BRAF wt mCRC were randomly assigned 1:1 to modified FOLFOX/panitumumab (control group) or mFOLFOXIRI/panitumumab (experimental group) up to 12 cycles, followed by fluorouracil/-leucovorin/panitumumab until disease progression. The primary end point was objective response rate (ORR) according to RECIST 1.1. Hypothesizing an ORR of 60% in the control group, 432 cases provided 90% power to a two-sided chi-square test for heterogeneity with a two-sided alpha error of .05 to detect &gt;= 15% differences between arms (ClinicalTrials.gov identifier: NCT03231722).RESULTS From September 2017 to September 2021, 435 patients were enrolled (control group/experimental group: 217/218) in 57 Italian sites. One hundred sixty (73%) patients treated with mFOLFOXIRI plus panitumumab and 165 (76%) patients treated with modified FOLFOX plus panitumumab achieved RECIST response (odds ratio 0.87, 95% CI, 0.56 to 1.34, P= .526). No differences in early tumor shrinkage rate (57%/58%, P = .878) and deepness of response (median: 48%/47%, P = .845) were reported, nor in RO resection rate (25%/29%, P = .317). No significant difference between arms was reported in terms of progression-free survival (median progression-free survival: 12.7 in the experimental group v 12.3 months in the control group, hazard ratio: 0.88, 95% CI, 0.70 to 1.11, P = .277).CONCLUSION The intensification of the upfront chemotherapy backbone in combination with panitumumab does not provide additional benefit in terms of treatment activity at the price of increased gastrointestinal toxicity in patients with RAS and BRAF wt mCRC. (C) 2022 by American Society of Clinical Oncolog

TRIBE-2: A phase III, randomized, open-label, strategy trial in unresectable metastatic colorectal cancer patients by the GONO group

Background: Chemotherapy plus bevacizumab is a standard first-line treatment for unresectable metastatic colorectal cancer patients. Different chemotherapy backbones may be chosen, including one to three drugs, based on patients' general conditions and comorbidities, treatments' objectives, and disease characteristics. TRIBE trial demonstrated a significant advantage in terms of progression-free survival and overall survival for FOLFOXIRI plus bevacizumab as compared with FOLFIRI plus bevacizumab. Based on recent evidence, the de-intensification of the upfront regimen after 4-6 months of treatment is nowadays regarded as a valuable option. Moreover, the prolonged inhibition of angiogenesis, and in particular the continuation of bevacizumab beyond the evidence of disease progression, is an efficacious strategy in the treatment of metastatic colorectal cancer patients. Methods/design: TRIBE-2 is a prospective, open-label, multicentric phase III randomized trial in which unresectable and previously untreated metastatic colorectal cancer patients are randomized to receive first-line FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression or FOLFOXIRI plus bevacizumab followed by the re-introduction of the same regimen after disease progression. The primary endpoint is to compare the efficacy of the two proposed treatment strategies in terms of Progression Free Survival 2. Discussion: The TRIBE-2 study aims at answering the question whether the upfront use of FOLFOXIRI improves the clinical outcome of metastatic colorectal cancer patients, when compared with the pre-planned, sequential use of oxaliplatin-based and irinotecan-based doublets. Both proposed treatment strategies are designed to exploit the effectiveness of the prolonged inhibition of angiogenesis, alternating short (up to 4 months) induction periods and less intensive maintenance phases. Trial registration: TRIBE2 is registered at Clinicaltrials.gov: NCT02339116. January 12, 2015. TRIBE-2 is registered at EUDRACT 2014-004436-19, October 10, 2014

TRIPLETE: A randomised phase III study of modified FOLFOXIRI plus panitumumab versus mFOLFOX6 plus panitumumab as initial therapy for patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer

FOLFOXIRI plus bevacizumab is considered a standard option in the upfront treatment of clinically selected patients with metastatic colorectal cancer irrespective of RAS and BRAF molecular status. The randomised MACBETH and VOLFI studies showed that a modified FOLFOXIRI regimen in combination with cetuximab or panitumumab, respectively, achieved high therapeutic activity in RAS and BRAF wild-type patients with an acceptable toxicity profile. Drawing from these considerations, we designed TRIPLETE study aiming at comparing two different chemotherapy backbones (mFOLFOXIRI or mFOLFOX6) in combination with panitumumab in the first-line treatment of patients with RAS and BRAF wild-type metastatic colorectal cancer. Methods This is a prospective, open-label, multicentre phase III trial in which initially unresectable and previously untreated RAS and BRAF wild-type metastatic colorectal cancer patients are randomised to receive a standard treatment with mFOLFOX6 plus panitumumab or an experimental regimen with modified FOLFOXIRI (irinotecan 150 mg/m 2, oxaliplatin 85 mg/m 2, L-leucovorin 200 mg/m 2, 5-fluoruracil 2400 mg/m 2 48-hour continuous infusion) plus panitumumab up to 12 cycles, followed by panitumumab plus 5-fluorouracil and L-leucovorin until disease progression. The primary endpoint is overall response rate according to RECIST 1.1 criteria. Discussion The relative benefit of chemotherapy intensification when using an anti-EGFR-based regimen in molecularly selected patients is unknown; TRIPLETE study aims at filling this gap of knowledge. The study is sponsored by the Gruppo Oncologico Nord Ovest Cooperative Group and is currently ongoing at 42 Italian centres. Clinical trial information NCT03231722

Analisi farmacodinamiche di fattori angiogenici circolanti in pazienti con carcinoma colorettale metastatico: esperienza traslazionale dallo studio di fase III BEBYP di chemioterapia +/- bevacizumab

Negli ultimi anni, uno degli obiettivi principali della ricerca in oncologia è stato lo studio dei fattori predittivi di efficacia e di resistenza ai trattamenti, in particolare da quando sono stati introdotti nella pratica clinica i farmaci a bersaglio molecolare. La disponibilità di più agenti diversi tra loro ha reso sempre più rilevante l’individuazione di fattori predittivi di resistenza intrinseca e acquisita, allo scopo di ottimizzare la scelta della terapia per ogni singolo paziente, in ogni momento della sua storia clinica. Il farmaco antiangiogenico bevacizumab si è dimostrato efficace nel trattamento di pazienti affetti da carcinoma colorettale metastatico, e ad oggi la maggior parte di questi riceve in 1a linea bevacizumab in associazione alla chemioterapia. E’ stato ampiamente dimostrato che la “pressione farmacologica” induce cambiamenti dinamici nelle cellule tumorali, che sviluppano meccanismi di resistenza al trattamento: infatti, dopo una prima fase di risposta, in cui la malattia può regredire o stabilizzarsi, il tumore diviene “resistente” e riprende la sua crescita. Il panorama delle opzioni da utilizzare al momento della prima progressione, e quindi nella 2a linea di trattamento è in continua evoluzione, e due importanti studi di fase III (TML e BEBYP) hanno recentemente dimostrato che la prosecuzione di bevacizumab oltre la progressione di malattia può essere una strategia efficace. Sulla base delle evidenze di studi precedenti, di laboratorio e clinici, che hanno dimostrato la variazione dei livelli plasmatici di alcuni fattori angiogenici in relazione al trattamento con bevacizumab, abbiamo condotto un’analisi farmacodinamica su una coorte di pazienti arruolati nello studio di fase III BEBYP. Lo studio clinico ha incluso 185 pazienti randomizzati a proseguire o meno bevacizumab dopo la progressione ad un regime di terapia di 1a linea già comprendente bevacizumab. L’obiettivo della presente analisi era descrivere la modulazione plasmatica di diversi fattori angiogenici (sVEGFr2, PlGF, PDGF-C, sTie-2, Ang-2, bFGF) durante la terapia, le eventuali differenze in base al braccio di trattamento (con o senza bevacizumab) ed il potenziale prognostico/predittivo di tali determinanti molecolari. La prima evidenza riscontrata conferma l’effetto della somministrazione di bevacizumab sui livelli plasmatici di alcuni fattori angiogenetici. In particolare, i livelli di PlGF aumentano durante il trattamento con chemioterapia+bevacizumab, e non nel gruppo che riceve solo chemioterapia. Il rialzo dei livelli di PlGF potrebbe spiegare la capacità delle cellule tumorali di attivare vie di segnale alternative a quelli di VEGF. In secondo luogo, il nostro studio ha rilevato come nei pazienti con elevati livelli plasmatici basali di sVEGFr2, rispetto alla concentrazione mediana, si ottenga un beneficio significativo dalla prosecuzione di bevacizumab in termini di prolungamento della sopravvivenza libera da progressione. Quest’ultimo dato è corroborato dalla significatività del test d’interazione. I dati così presentati suggeriscono quindi il possibile ruolo di sVEGFr2 come marker farmacodinamico di beneficio dalla prosecuzione di bevacizumab oltre la progressione. Tali dati se ulteriormente confermati potrebbero indirizzare la scelta terapeutica rispetto al farmaco antiangiogenico da utilizzare nella 2a linea di trattamento, ovvero mentre i pazienti con alti livelli basali di VEGFr2 potrebbero beneficiare maggiormente dalla prosecuzione di bevacizumab, quelli con bassi livelli di tale fattore potrebbero essere candidati a strategie terapeutiche alternative