Studio di fase II di rechallenge con cetuximab in pazienti con mCRC, RAS e BRAF wild – type, progrediti, dopo un iniziale beneficio, ad una terapia di I linea contenente cetuximab. Studio CRICKET.

Cetuximab e panitumumab sono anticorpi monoclonali anti-EGFR, entrati da circa dieci anni a far parte dell’armamentario terapeutico per il trattamento del carcinoma colorettale metastatico (mCRC). Negli anni si è compreso che non tutti i pazienti con mCRC beneficiano di tali farmaci e che la presenza di mutazioni attivanti il pathway di EGFR (in particolare a carico dei geni della famiglia RAS, KRAS e NRAS) determina resistenza intrinseca a tali anticorpi, il cui utilizzo viene pertanto oggi ristretto ai pazienti con malattia RAS wild-type. Diversi studi hanno poi dimostrato che pazienti portatori della mutazione V600E di BRAF hanno una prognosi peggiore, mentre il ruolo di tale mutazione nel predire resistenza agli anti-EGFR resta ancora dibattuto. Evidenze crescenti hanno inoltre cercato di svelare i meccanismi alla base della resistenza acquisita agli anticorpi anti-EGFR, che si sviluppa inevitabilmente durante o dopo il trattamento e che è alla base dell’evidenza clinica di progressione di malattia. Dati recenti hanno individuato nell’ eterogeneità dei tumori colorettali, un ruolo centrale nel guidare questa resistenza. Negli ultimi anni numerose evidenze hanno mostrato come ogni tumore possa essere effettivamente visto come un microcosmo eterogeneo, costituito da diversi cloni cellulari, in continua evoluzione, dinamico dal punto di vista molecolare, pronto a modificarsi in seguito ai trattamenti. Sulla base di tali dati, si pensa dunque che il ricorso a terapie a base di anticorpi anti–EGFR in pazienti con mCRC RAS wild-type, potrebbe portare alla distruzione dei cloni cellulari RAS wild–type e alla selezione dei cloni mutati già presenti all’interno del tumore, responsabili della progressione di malattia dopo un’ iniziale riduzione tumorale. La comparsa di mutazioni dei geni RAS al momento della progressione di malattia rappresenterebbe pertanto un meccanismo di resistenza acquisita agli anti-EGFR. Nel 2012 Santini et al. hanno pubblicato uno studio retrospettivo che ha messo in luce un potenziale beneficio dal rechallenge con cetuximab, ovvero il riutilizzo del farmaco, in 39 pazienti con mCRC già progrediti ad una precedente terapia contenente cetuximab, lasciando aperto il quesito su come un tumore divenuto resistente potesse poi nuovamente divenire sensibile al farmaco anti-EGFR. Trattandosi di una preliminare esperienza retrospettiva, questi dati richiedevano una conferma prospettica. A tale proposito, è stato disegnato lo studio di fase II CRICKET a singolo braccio, multicentrico, condotto in 11 centri Italiani. Questo studio prevedeva di arruolare pazienti con mCRC KRAS, NRAS e BRAF wild-type che avessero ottenuto beneficio dal trattamento di prima linea a base di cetuximab e irinotecano e fossero progrediti entro 4 settimane dall’ultima somministrazione di cetuximab. I pazienti dovevano inoltre aver ricevuto una seconda linea di trattamento contenente oxaliplatino e bevacizumab. Lo studio prevedeva di trattare pazienti che presentassero tutte queste caratteristiche con un rechallenge in terza linea con cetuximab e irinotecano. L’end-point primario dello studio era il tasso di risposte (RR), valutato secondo i criteri RECIST v 1.1. Gli end-points secondari includevano la sopravvivenza libera da progressione (PFS), la sopravvivenza globale (OS), il profilo di tossicità valutato secondo i criteri del National Cancer Institute Common Toxicity V 4.03, e infine la valutazione di eventuali potenziali biomarcatori predittivi e/o prognostici. In accordo al disegno di Fleming single-stage, selezionando p0 (RR nell’ipotesi nulla) = 0.05, e p1 (RR nell’ipotesi alternativa) = 0.20, e considerando l’errore alpha (a 1 coda) e quello beta uguali a 0.05 e 0.20 rispettivamente, erano necessari 27 pazienti. Lo studio sarebbe stato giudicato positivo (e quindi la strategia terapeutica promettente) se almeno 4 pazienti avessero ottenuto una risposta obiettiva, confermata in almeno due rivalutazioni successive secondo i criteri RECIST v1.1. Da Agosto 2014 ad oggi, sono stati arruolati nello studio 11 pazienti, 8 maschi e 3 femmine, con età mediana di 70 anni (range 45-77), ECOG Performance Status 0/1-2 rispettivamente in 8 e 3 pazienti. Il tumore primitivo è localizzato al colon destro in 4 pazienti, colon sinistro in altri 4 e retto extraperitoneale in 2 casi. Due pazienti presentavano il primitivo in sede al momento dell’arruolamento nello studio. La malattia metastatica era sincrona in 8 pazienti, e tutti e 3 i pazienti con malattia metacrona avevano ricevuto una precedente terapia adiuvante con oxaliplatino. Due pazienti presentavano malattia limitata al fegato e 7 pazienti avevano multiple sedi metastatiche. La miglior risposta osservata su 9 pazienti attualmente valutabili, è stata la seguente: 4 risposte parziali (RP), 2 stabilità di malattia (SD), 3 progressioni di malattia (PD). Solo 3 RP sono state confermate alla seconda rivalutazione TC secondo i criteri RECIST v1.1. Un paziente non è stato valutato per la risposta perchè deceduto prima della rivalutazione TC in seguito a sepsi. L’undicesimo paziente arruolato non ha ancora eseguito la prima rivalutazione TC. Al momento dati relativi agli end-points secondari PFS e OS non sono disponibili e verranno valutati quando il follow up sarà più esteso. Lo studio CRICKET prevedeva inoltre l’analisi del DNA tumorale libero circolante (circulating free tumor DNA, cftDNA) su prelievi di plasma raccolti al momento dell’arruolamento in studio e durante il trattamento. Al momento sono disponibili i dati relativi all’analisi basale su 10 degli 11 pazienti arruolati nello studio. Sono state ricercate le seguenti mutazioni: KRAS G12D, KRAS G12V, KRAS G12C, KRAS G12A, KRAS G12R, KRAS G12S, KRAS G12D, BRAF V600E, EGFR S492R. Le analisi del cftDNA ai vari timepoints previsti dal protocollo sono in corso. Otto pazienti sono risultati wild-type per tutte le mutazioni analizzate, mentre in 2 pazienti è stata individuata la mutazione G12D di KRAS. Entrambi questi pazienti sono rapidamente progrediti senza beneficiare per niente del trattamento di rechallenge. I risultati preliminari dello studio CRICKET sono promettenti. In base a questi risultati, alcuni pazienti KRAS, NRAS e BRAF wild-type che hanno inizialmente risposto e sono poi progrediti ad una prima linea a base di irinotecano e cetuximab, sembrano beneficiare ancora, dopo una seconda linea di terapia diversa dalla prima, di una terza linea di trattamento con cetuximab e irinotecano. Lo studio è attualmente in corso, per cui dati definitivi relativi all’attività ed efficacia del trattamento saranno disponibili in futuro. L’analisi del cftDNA su plasma raccolto al momento dell’inizio del rechallenge sembra suggerire che pazienti con evidenza di mutazione di KRAS, probabilmente sviluppata come meccanismo di resistenza acquisita al trattamento di prima linea, non beneficerebbero di questa strategia

Sacral nerve modulation for patients with fecal incontinence: long-term outcome and effects on sexual function

Double incontinence; Sacral nerve modulation; Urinary incontinenceDoble incontinencia; Modulación del nervio sacro; Incontinencia urinariaDoble incontinència; Modulació del nervi sacre; Incontinència urinàriaSacral nerve modulation has become an established treatment for fecal and urinary incontinence, and sexual disorders. The objective of this study was to evaluate the long-term outcome of sacral neuromodulation in patients with fecal or combined fecal and urinary incontinence (double incontinence), assessing its safety, efficacy, and impact on quality of life and sexual function. This was a multicentric, retrospective, cohort study including patients with fecal or double incontinence who received sacral neuromodulation at seven European centers between 2007 and 2017 and completed a 5-year follow-up. The main outcome measures included improvements of incontinence symptoms and quality of life compared with baseline, evaluated using validated tools and questionnaires at 1-, 6-, 12-, 36- and 60-month follow-up. 108 (102 women, mean age 62.4 ± 13.4 years) patients were recruited, of whom 88 (81.4%) underwent definitive implantation of the pacemaker. Patients’ baseline median Cleveland Clinic Incontinence Score was 15 (10–18); it decreased to 2 (1–4) and 1 (1–2) at the 12- and 36-month follow-up (p < 0.0001), remaining stable at the 5-year follow-up. Fecal incontinence quality of life score improved significantly. All patients with sexual dysfunction (n = 48) at baseline reported symptom resolution at the 5-year follow-up. The study was limited by the retrospective design and the relatively small patient sample. Sacral nerve modulation is an effective treatment for fecal and double incontinence, achieving satisfactory long-term success rates, with resolution of concomitant sexual dysfunction.Open access funding provided by Università degli Studi della Campania Luigi Vanvitelli within the CRUI-CARE Agreement. This research was not funded by any agency in the public, commercial, or not-for-profit sectors

Trends and outcome of neoadjuvant treatment for rectal cancer: a retrospective analysis and critical assessment of a 10-year prospective national registry on behalf of the Spanish Rectal Cancer Project

Introduction: Preoperative treatment and adequate surgery increase local control in rectal cancer. However, modalities and indications for neoadjuvant treatment may be controversial. Aim of this study was to assess the trends of preoperative treatment and outcomes in patients with rectal cancer included in the Rectal Cancer Registry of the Spanish Associations of Surgeons. Method: This is a STROBE-compliant retrospective analysis of a prospective database. All patients operated on with curative intention included in the Rectal Cancer Registry were included. Analyses were performed to compare the use of neoadjuvant/adjuvant treatment in three timeframes: I)2006e2009; II) 2010e2013; III)2014e2017. Survival analyses were run for 3-year survival in timeframes I-II. Results: Out of 14,391 patients,8871 (61.6%) received neoadjuvant treatment. Long-course chemo/ radiotherapy was the most used approach (79.9%), followed by short-course radiotherapy ± chemo- therapy (7.6%). The use of neoadjuvant treatment for cancer of the upper third (15-11 cm) increased over time (31.5%vs 34.5%vs 38.6%,p ¼ 0.0018). The complete regression rate slightly increased over time (15.6% vs 16% vs 18.5%; p ¼ 0.0093); the proportion of patients with involved circumferential resection margins (CRM) went down from 8.2% to 7.3%and 5.5% (p ¼ 0.0004). Neoadjuvant treatment significantly decreased positive CRM in lower third tumors (OR 0.71, 0.59e0.87, Cochrane-Mantel-Haenszel P ¼ 0.0008). Most ypN0 patients also received adjuvant therapy. In MR-defined stage III patients, pre- operative treatment was associated with significantly longer local-recurrence-free survival (p < 0.0001), and cancer-specific survival (p < 0.0001). The survival benefit was smaller in upper third cancers. Conclusion: There was an increasing trend and a potential overuse of neoadjuvant treatment in cancer of the upper rectum. Most ypN0 patients received postoperative treatment. Involvement of CRM in lower third tumors was reduced after neoadjuvant treatment. Stage III and MRcN þ benefited the most. © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgica

Pelvic exenterations for primary rectal cancer: analysis from a 10-year national prospective database

Aim: to identify short-term and oncologic outcomes of pelvic exenterations (PE) for locally advanced primary rectal cancer (LAPRC) in patients included in a national prospective database. Methods: few studies report on PE in patients with LAPRC. For this study, we included PE for LAPRC performed between 2006 and 2017, as available, from the Rectal Cancer Registry of the Spanish Association of Surgeons [Asociación Española de Cirujanos (AEC)]. Primary endpoints included procedure-associated complications, 5-year local recurrence (LR), disease-free survival (DFS) and overall survival (OS). A propensity-matched comparison with patients who underwent non-exenterative surgery for low rectal cancers was performed as a secondary endpoint. Results: eight-two patients were included. The mean age was 61.8 ± 11.5 years. More than half of the patients experienced at least one complication. Surgical site infections were the most common complication (abdominal wound 18.3%, perineal closure 19.4%). Thirty-three multivisceral resections were performed, including two hepatectomies and four metastasectomies. The long-term outcomes of the 64 patients operated on before 2013 were assessed. The five-year LR was 15.6%, the distant recurrence rate was 21.9%, and OS was 67.2%, with a mean survival of 43.8 mo. R+ve resection increased LR [hazard ratio (HR) = 5.58, 95%CI: 1.04-30.07, P = 0.04]. The quality of the mesorectum was associated with DFS. Perioperative complications were independent predictors of shorter survival (HR = 3.53, 95%CI: 1.12-10.94, P = 0.03). In the propensity-matched analysis, PE was associated with better quality of the specimen and tended to achieve lower LR with similar OS. Conclusion: PE is an extensive procedure, justified if disease-free margins can be obtained. Further studies should define indications, accreditation policy, and quality of life in LAPRC

The impact of anastomotic leak on long-term oncological outcomes after low anterior resection for mid-low rectal cancer: extended follow-up of a randomised controlled trial

The impact of anastomotic leaks (AL) on oncological outcomes after low anterior resection for mid-low rectal cancer is still debated. The aim of this study was to evaluate overall survival (OS), disease-free survival (DFS), and local and distant recurrence in patients with AL following low anterior resection

Pelvic exenterations for primary rectal cancer : Analysis from a 10-year national prospective database

To identify short-term and oncologic outcomes of pelvic exenterations (PE) for locally advanced primary rectal cancer (LAPRC) in patients included in a national prospective database. Few studies report on PE in patients with LAPRC. For this study, we included PE for LAPRC performed between 2006 and 2017, as available, from the Rectal Cancer Registry of the Spanish Association of Surgeons [Asociación Española de Cirujanos (AEC)]. Primary endpoints included procedure-associated complications, 5-year local recurrence (LR), disease-free survival (DFS) and overall survival (OS). A propensity-matched comparison with patients who underwent non-exenterative surgery for low rectal cancers was performed as a secondary endpoint. Eight-two patients were included. The mean age was 61.8 ± 11.5 years. More than half of the patients experienced at least one complication. Surgical site infections were the most common complication (abdominal wound 18.3%, perineal closure 19.4%). Thirty-three multivisceral resections were performed, including two hepatectomies and four metastasectomies. The long-term outcomes of the 64 patients operated on before 2013 were assessed. The five-year LR was 15.6%, the distant recurrence rate was 21.9%, and OS was 67.2%, with a mean survival of 43.8 mo. R+ve resection increased LR [hazard ratio (HR) = 5.58, 95%CI: 1.04-30.07, P = 0.04]. The quality of the mesorectum was associated with DFS. Perioperative complications were independent predictors of shorter survival (HR = 3.53, 95%CI: 1.12-10.94, P = 0.03). In the propensity-matched analysis, PE was associated with better quality of the specimen and tended to achieve lower LR with similar OS. PE is an extensive procedure, justified if disease-free margins can be obtained. Further studies should define indications, accreditation policy, and quality of life in LAPRC

Non-pegylated liposomal doxorubicin in older adjuvant early breast cancer patients: cardiac safety analysis and final results of the COLTONE study

Aims: To explore the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) plus Cyclophosphamide (CTX) followed by weekly Paclitaxel, in elderly women (≥ 65&nbsp;years) with high-risk breast cancer. Previously, we described no symptomatic cardiac events within the first 12&nbsp;months from starting treatment. We now reported the updated results after a median follow-up 76&nbsp;months. Methods: The cardiac activity was evaluated with left ventricular ejection fraction (LVEF) echocardiograms assessments, before starting chemotherapy and every 6&nbsp;months, until 30&nbsp;months from baseline, then yearly for at least 5&nbsp;years. Results: Forty-seven women were recruited by two Units of Medical Oncology (Ethics Committee authorization CESM-AOUP, 3203/2011; EudraCT identification number: 2010-024067-41, for Pisa and Pontedera Hospitals). An episode of grade 3 CHF (NCI-CTCAE, version 3.0) occurred after 18&nbsp;months the beginning of chemotherapy. The echocardiograms assessments were performed comparing the LVEF values of each patient evaluated at fixed period of time, compared to baseline. We observed a slight changed in terms of mean values at 48, 60, 72 and 84&nbsp;months. At these time points, a statistically significant reduction of -&nbsp;3.2%, -&nbsp;4.6%, -&nbsp;6.4% and -&nbsp;7.1%, respectively, was observed. However, LVEF remained above 50% without translation in any relevant clinical signs. No other cardiac significant episodes were reported. To this analysis, in 13 patients (28%) occurred disease relapse&nbsp;and,&nbsp; of them, 11 (23%) died due to metastatic disease. Eight patients died of cancer-unrelated causes. Conclusions: The combination including NPL-DOX in elderly patients revealed low rate of cardiac toxic effects. Comparative trials are encouraged

European Crohn's and Colitis Organisation Topical Review on prediction, diagnosis and management of fibrostenosing Crohn's disease

This ECCO topical review of the European Crohn's and Colitis Organisation [ECCO] focused on prediction, diagnosis, and management of fibrostenosing Crohn's disease [CD]. The objective was to achieve evidence-supported, expert consensus that provides guidance for clinical practice

Infected pancreatic necrosis : outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

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