Panitumumab plus trifluridine/tipiracil as anti-EGFR rechallenge therapy in patients with refractory RAS wild-type metastatic colorectal cancer: Overall survival and subgroup analysis of the randomized phase II VELO trial.

The randomized phase II VELO trial showed that the addition of panitumumab to trifluridine/tipiracil significantly improves progression-free survival (PFS) as compared to trifluridine/tipiracil in third-line therapy in patients with refractory RAS wild-type (WT) metastatic colorectal cancer (mCRC). With longer follow-up, final overall survival results and posttreatment subgroup analysis are presented. Sixty-two patients with refractory RAS WT mCRC were randomly assigned to receive, as third-line therapy, trifluridine/tipiracil alone (arm A) or in combination with panitumumab (arm B). Primary endpoint was PFS; secondary endpoints included overall survival (OS) and overall response rate (ORR). Median OS was 13.1 months (95% CI 9.5-16.7) in arm A compared to 11.6 months (95% CI 6.3-17.0) in arm B (HR: 0.96, 95% CI 0.54-1.71, P = .9). To evaluate the impact of subsequent lines of treatment, subgroup analysis was performed for the 24/30 patients in arm A, that received fourth-line therapy after disease progression. Median PFS was 4.1 months (95% CI 1.44-6.83) for 17 patients treated with anti-EGFR rechallenge as compared to 3.0 months (95% CI 1.61-4.31) for seven patients that received other therapies (HR: 0.29, 95% CI 0.10-0.85, P = .024). Median OS from the start of fourth-line treatment was 13.6 months (95% CI 7.2-20), and 5.1 months (95% CI 1.8-8.3) for patients treated with anti-EGFR rechallenge vs other therapies, respectively (HR: 0.30, 95% CI 0.11-0.81, P = .019). Final results of the VELO trial support the role of anti-EGFR rechallenge in the continuum of care of patients with RAS/BRAF WT mCRC.

Perioperative FLOT plus ramucirumab for resectable esophagogastric adenocarcinoma: A randomized phase II/III trial of the German AIO and Italian GOIM.

This multicenter, randomized phase II/III study evaluated the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab to FLOT as perioperative treatment for resectable esophagogastric adenocarcinoma. Patients received either FLOT alone (Arm A) or combined with ramucirumab followed by ramucirumab monotherapy (Arm B). The primary endpoint for the phase II portion was the pathological complete or subtotal response (pCR/pSR) rate. Baseline characteristics were comparable between both arms with a high rate of tumors signet-ring cell component (A:47% B:43%). No between-arm difference in pCR/pSR rate was seen (A:29% B:26%), therefore the transition to phase III was not pursued. Nevertheless, the combination was associated with a significantly increased R0-resection rate compared with FLOT alone (A:82% B:96%; P = .009). In addition, the median disease-free survival was numerically improved in Arm B (A:21 months B:32 months, HR 0.75, P = 0.218), while the median overall survival was similar in both treatment arms (A:45 months B:46 months, HR 0.94, P = 0.803). Patients with Siewert type I tumors receiving transthoracic esophagectomy with intrathoracic anastomosis showed an increased risk of serious postoperative complications after ramucirumab treatment, therefore recruitment of those patients was stopped after the first-third of the study. Overall, surgical morbidity and mortality was comparable, whereas more non-surgical grade ≥ 3 adverse events were observed with the combination, especially anorexia (A:1% B:11%), hypertension (A:4% B:13%) and infections (A:19% B:33%). The combination of ramucirumab and FLOT as perioperative treatment shows efficacy signals, particularly in terms of R0 resection rates, for a study population with a high proportion of prognostically poor histological subtypes, and further evaluation in this subgroup seems warranted.

Liquid Biopsy at Home: Delivering Precision Medicine for Patients with Cancer During the COVID-19 Pandemic.

CoronaVirus disease-2019 has changed the delivery of health care worldwide and the pandemic has challenged oncologists to reorganize cancer care. Recently, progress has been made in the field of precision medicine to provide to patients with cancer the best therapeutic choice for their individual needs. In this context, the Foundation Medicine (FMI)-Liquid@Home project has emerged as a key weapon to deal with the new pandemic situation. FoundationOne Liquid Assay (F1L) is a next-generation sequences-based liquid biopsy service, able to detect 324 molecular alterations and genomic signatures, from May 2020 available at patients' home (FMI-Liquid@Home). We analyzed time and costs saving for patients with cancer, their caregivers and National Healthcare System (NHS) with FMI-Liquid@Home versus F1L performed at our Department. Different variables have been evaluated. Between May 2020 and August 2021, 218 FMI-Liquid@Home were performed for patients with cancer in Italy. Among these, our Department performed 153 FMI-Liquid@Home with the success rate of 98% (vs. 95% for F1L in the hospital). Time saving for patients and their caregivers was 494.86 and 427.36 hours, respectively, and costs saving was 13 548.70€. Moreover, for working people these savings were 1084.71 hours and 31 239.65€, respectively. In addition, the total gain for the hospital was 163.5 hours and 6785€, whereas for NHS was 1084.71 hours and 51 573.60€, respectively. FMI-Liquid@Home service appears to be useful and convenient allowing time and costs saving for patients, caregivers, and NHS. Born during the COVID-19 pandemic, it could be integrated in oncological daily routine in the future. Therefore, additional studies are needed to better understand the overall gain and how to integrate this service in different countries.

Novel Therapeutic Opportunities in Neoadjuvant Setting in Urothelial Cancers: A New Horizon Opened by Molecular Classification and Immune Checkpoint Inhibitors.

Muscle invasive bladder cancer (MIBC) is a widespread malignancy with a worse prognosis often related to a late diagnosis. For early-stage MIBC pts, a multidisciplinary approach is mandatory to evaluate the timing of neoadjuvant chemotherapy (NAC) and surgery. The current standard therapy is platinum-based NAC (MVAC-methotrexate, vinblastine, doxorubicin, and cisplatin or Platinum-Gemcitabine regimens) followed by radical cystectomy (RC) with lymphadenectomy. However, preliminary data from Vesper trial highlighted that dose-dense NAC MVAC is endowed with a good pathological response but shows low tolerability. In the last few years, translational-based research approaches have identified several candidate biomarkers of NAC esponsiveness, such as ERCC2, ERBB2, or DNA damage response (DDR) gene alterations. Moreover, the recent consensus MIBC molecular classification identified six molecular subtypes, characterized by different sensitivity to chemo- or targeted or immunotherapy, that could open a novel procedure for patient selection and also for neoadjuvant therapies. The Italian PURE-01 phase II Trial extended data on efficacy and resistance to Immune Checkpoint Inhibitors (ICIs) in this setting. In this review, we summarize the most relevant literature data supporting NAC use in MIBC, focusing on novel therapeutic strategies such as immunotherapy, considering the better patient stratification and selection emerging from novel molecular classification.

Results of the observational prospective RealFLOT study.

BACKGROUND: Perioperative FLOT (5-fluorouracil, oxaliplatin and docetaxel) has recently become the gold standard treatment for fit patients with operable gastric (GC) or gastroesophageal (GEJ) adenocarcinoma, getting a 5-year overall survival (OS) of 45%, over 23% with surgery alone. METHODS: RealFLOT is an Italian, multicentric, observational trial, collecting data from patients with resectable GC or GEJ adenocarcinoma treated with perioperative FLOT. Aim of the study was to describe feasibility and safety of FLOT, pathological complete response rate (pCR), surgical outcomes and overall response rate (ORR) in an unselected real-world population. Additional analyses evaluated the correlation between pCR and survival and the prognostic role of microsatellite instability (MSI) status. RESULTS: Of 206 patients enrolled that received perioperative FLOT at 15 Italian centers, 124 (60.2%) received at least 4 full-dose cycles, 190 (92.2%) underwent surgery, and 142 (68.9%) started the postoperative phase. Among patients who started the postoperative phase, 105 (51.0%) received FLOT, while 37 (18%) received de-intensified regimens, depending on clinical condition or previous toxicities. pCR was achieved in 7.3% of cases. Safety profile was consistent with literature. Neutropenia was the most common G 3-4 adverse event (AE): 19.9% in the preoperative phase and 16.9% in the postoperative phase. No toxic death was observed and 30-day postoperative mortality rate was 1.0%. ORR was 45.6% and disease control rate (DCR) was 94.2%. Disease-free survival (DFS) and OS were significantly longer in case of pCR (p = 0.009 and p = 0.023, respectively). A trend towards better DFS was observed among MSI-H patients. CONCLUSIONS: These real-world data confirm the feasibility of FLOT in an unselected population, representative of the clinical practice. pCR rate was lower than expected, nevertheless we confirm pCR as a predictive parameter of survival. In addition, MSI-H status seems to be a positive prognostic marker also in patients treated with taxane-containing triplets.

Arthralgia in patients with ovarian cancer treated with bevacizumab and chemotherapy.

BACKGROUND: Chemotherapy with carboplatin, paclitaxel, and bevacizumab is the standard therapy for patients with advanced stage ovarian cancer wild-type BRCA after primary surgery. The most frequent side effects of bevacizumab in this setting are hypertension, thrombosis, hemorrhage, and proteinuria, while arthralgia has been poorly described. OBJECTIVE: To examine the incidence, duration, and reversibility of arthralgia. PATIENTS AND METHODS: A retrospective analysis was performed to describe the occurrence and outcome of arthralgia in 114 patients with advanced ovarian cancer, given first-line treatment with a combination of carboplatin, paclitaxel, and bevacizumab. Statistical analysis was performed to investigate a possible prognostic role of arthralgia, with progression-free survival as endpoint. RESULTS: 47 of 114 patients (41%) developed arthralgia during therapy. All patients had grade 1 or grade 2 arthralgia. Toxicity persisted after the end of bevacizumab in 17/47 patients (36%). Median progression-free survival for patients without arthralgia was 18 months (95% CI 14 to 24) compared with 29 months (95% CI 21 to not reached) for patients experiencing arthralgia (p=0.03). In order to avoid possible biases related to treatment duration, a multivariable Cox proportional hazards model including toxicity as a time dependent variable and age, stage, and residual disease after primary surgery was performed. In this model no variable showed a statistically significant association with progression-free survival. CONCLUSION: A high incidence of arthralgia (41%) was found and although rogression-free survival was worse for those patients who developed arthralgia, this was not maintained on multivariate analysis. Guidelines for treatment of this adverse event are needed.

Pancreatic Cancer Molecular Classifications: From Bulk Genomics to Single Cell Analysis.

Pancreatic cancer represents one of the most lethal disease worldwide but still orphan of a molecularly driven therapeutic approach, although many genomic and transcriptomic classifications have been proposed over the years. Clinical heterogeneity is a hallmark of this disease, as different patients show different responses to the same therapeutic regimens. However, genomic analyses revealed quite a homogeneous disease picture, with very common mutations in four genes only (KRAS, TP53, CDKN2A, and SMAD4) and a long tail of other mutated genes, with doubtful pathogenic meaning. Even bulk transcriptomic classifications could not resolve this great heterogeneity, as many informations related to small cell populations within cancer tissue could be lost. At the same time, single cell analysis has emerged as a powerful tool to dissect intratumoral heterogeneity like never before, with possibility of generating a new disease taxonomy at unprecedented molecular resolution. In this review, we summarize the most relevant genomic, bulk and single-cell transcriptomic classifications of pancreatic cancer, and try to understand how novel technologies, like single cell analysis, could lead to novel therapeutic strategies for this highly lethal disease.

Second line therapy with axitinib after only prior sunitinib in metastatic renal cell cancer: Italian multicenter real world SAX study final results.

BACKGROUND: This multi-institutional retrospective real life study was conducted in 22 Italian Oncology Centers and evaluated the role of Axitinib in second line treatment in not selected mRCC patients. METHODS: 148 mRCC patients were evaluated. According to Heng score 15.5%, 60.1% and 24.4% of patients were at poor risk, intermediate and favorable risk, respectively. RESULTS: PFS, OS, DCR and ORR were 7.14 months, 15.5 months, 70.6% and 16.6%, respectively. The duration of prior sunitinib treatment correlated with a longer significant mPFS, 8.8 vs 6.3 months, respectively. Axitinib therapy was safe, without grade 4 adverse events. The most frequent toxicities of all grades were: fatigue (50%), hypertension (26%), and hypothyroidism (18%). G3 blood pressure elevation significantly correlated with longer mPFS and mOS compared to G1-G2 or no toxicity. Dose titration (DT) to 7 mg and 10 mg bid was feasible in 24% with no statistically significant differences in mPFS and mOS. The sunitinib-axitinib sequence was safe and effective, the mOS was 41.15 months. At multivariate analysis, gender, DCR to axitinib and to previous sunitinib correlated significantly with PFS; whereas DCR to axitinib, nephrectomy and Heng score independently affected overall survival. CONCLUSIONS: Axitinib was effective and safe in a not selected real life mRCC population. Trial registration INT - Napoli - 11/16 oss. Registered 20 April 2016. http://www.istitutotumori.na.it.

Assessment of Ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line chemotherapy in patients with advanced HER-2 negative gastric or gastroesophageal junction cancers: the ARMANI phase III trial.

BACKGROUND: Platinum/fluoropyrimidine regimens are the backbone of first-line chemotherapy for advanced gastric cancer (AGC). However response rates to first line chemotherapy range from 30 to 50% and disease progression occurs after 4-6 cycles. The optimal duration of first-line therapy is still unknown and its continuation until disease progression represents the standard. However this strategy is often associated with cumulative toxicity and rapid development of drug resistance. Moreover, only about 40% of AGC pts. are eligible for second-line treatment. METHODS: This is a randomized, open-label, multicenter phase III trial. It aims at assessing whether switch maintenance to ramucirumab plus paclitaxel will extend the progression-free survival (PFS) of subjects with HER-2 negative AGC who have not progressed after 3 months of a first-line with a platinum/fluoropyrimidine regimen (either FOLFOX4, mFOLFOX6 or XELOX). The primary endpoint is to compare Progression-Free Survival (PFS) of patients in ARM A (switch maintenance to ramucirumab and placlitaxel) versus ARM B (continuation of the same first-line therapy with oxaliplatin/fluoropyrimidine). Secondary endpoints are: overall survival, time-to-treatment failure, overall response rate, duration of response, percentage of patients that will receive a second line therapy according to arm treatment, safety, quality of life. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues are planned in order to identify potential biomarkers of primary resistance and prognosis. DISCUSSION: The ARMANI study estimates if patients treated with early swich with ramucirumab plus paclitaxel received benefit when compared to those treated with continuation of first line therapy. The hypothesis is that the early administration of an active, non-cross resistant second-line regimen such as ramucirumab plus paclitaxel may prolong the time in which patients are progression-free, and consequently have a better quality of life. Moreover, this strategy may rescue all those subjects that become ineligible for second-line therapy due to the rapid deterioration of health status after the first disease progression. TRIAL REGISTRATION: ARMANI is registered at ClinicalTrials.gov ( NCT02934464 , October 17, 2016) and EudraCT(2016-001783-12, April 202,016).

Ramucirumab and paclitaxel in patients with gastric cancer and prior trastuzumab: subgroup analysis from RAINBOW study.

Aim: This subgroup analysis of the RAINBOW study evaluated the efficacy and safety of ramucirumab in patients with gastric cancer/gastroesophageal junction adenocarcinoma who received prior trastuzumab therapy. Patients & methods: Of adult patients enrolled in the RAINBOW study, 39 had received prior trastuzumab therapy. Of these, 20 patients were treated with ramucirumab plus paclitaxel and 19 patients with placebo plus paclitaxel within the RAINBOW trial. Results: Overall survival was longer with ramucirumab plus paclitaxel (11.4 months; 95% CI: 7.0-17.9) versus placebo plus paclitaxel (7.0 months; 95% CI: 3.4-14.6), hazard ratio: 0.68 (0.33-1.41); p = 0.30. Longer progression-free survival, higher objective response were observed in ramucirumab combination group. Conclusion: Ramucirumab plus paclitaxel demonstrated efficacy benefits with manageable safety profile in a subgroup of patients pretreated with trastuzumab. Clinical trial registration number: NCT01170663.

Estimating Survival Probabilities of Advanced Gastric Cancer Patients in the Second-Line Setting: The Gastric Life Nomogram.

OBJECTIVE: We built and externally validated a nomogram for predicting the overall survival (OS) probability of advanced gastric cancer patients receiving second-line treatment. METHODS: The nomogram was developed on a set of 320 Italian patients and validated on two independent sets (295 Italian and 172 Korean patients). Putative prognostic variables were selected using a random forest model and included in the multivariable Cox model. The nomogram's performance was evaluated by calibration plot and C index. RESULTS: ECOG performance status, neutrophils to lymphocytes ratio, and peritoneal involvement were selected and included into the multivariable model. The C index was 0.72 (95% CI 0.68-0.75) in the development set, 0.69 (95% CI 0.65-0.73) in the Italian validation set, but only 0.57 (95% CI 0.52-0.62) in the Korean set. While Italian calibrations were quite good, the Korean one was poor. Regarding 6-month OS predictions, calibration was best in both Caucasian cohorts and worst the in Asian one. CONCLUSIONS: Our nomogram may be a useful tool to predict 3- or 6-month OS in Caucasian gastric cancer patients eligible for second-line therapy. Based on three easy-to-collect variables, the Gastric Life nomogram may help clinicians improve patient selection for second-line treatments and assist in clinical trial enrollment.

Triple-Negative Breast Cancers: Systematic Review of the Literature on Molecular and Clinical Features with a Focus on Treatment with Innovative Drugs.

PURPOSE OF REVIEW: Triple-negative breast cancer (TNBC) accounts for 15-20% of diagnosed breast tumours, with higher incidence in young and African-American women, and it is frequently associated with BRCA germline mutations. Chemotherapy is the only well-established therapeutic option in both early- and advanced-stages of the disease. TNBC tumours relapse earlier after standard anthracycline- and/or taxane-based chemotherapy treatments, generally within 1-3 years after the diagnosis, and often develop visceral metastases, representing the subtype with a worse prognosis among all breast cancers. In the present review, we will provide an updated overview of the available results of recent clinical trials for this disease and we will describe the implications of the known molecular pathways representing novel targets for development of future therapies for TNBC patients. RECENT FINDINGS: Over the past decade, the advent of gene expression micro-array technology has led to the identification of different actionable targets including various genomic alterations, androgen receptor, PARP, PI3K, VEGF and other proteins of the angiogenic pathway. Thus, novel targeted drugs have been tested in clinical trials reporting promising results in specific TNBC molecular subgroups. Although cytotoxic chemotherapy remains the mainstay of treatment for TNBC patients, the identification of novel 'drugable' targets and pathways for developing personalized treatments represents a promising investigational approach in the management of the TNBC subtype.

Ramucirumab in HER-2-positive gastroesophageal adenocarcinoma: an argument for overcoming trastuzumab resistance.

AIM: Patients with advanced gastric cancer have a relatively poor prognosis with few therapeutic alternatives beyond first-line therapy. The purpose of this manuscript is to highlight the potential for prolonged responses in patients with HER-2-positive disease. Patients, materials & methods: We analyzed the data of patients diagnosed with HER-2-positive-advanced gastric cancer who progressed on trastuzumab-based combination therapy and subsequently received second-line therapy consisting of ramucirumab in combination with paclitaxel. RESULTS: Most patients had a stable disease after ramucirumab-based therapy (50%, 5/10), median duration to disease control was 8 months. CONCLUSION: The prolonged duration of response that we observed indicates that an interaction between the EGF pathway and the angiogenesis pathway requires further clinical investigations.

Systemic-inflammation-based score can predict prognosis in metastatic gastric cancer patients before first-line chemotherapy.

AIM: Systemic inflammatory response affects survival of gastric cancer (GC) patients. This study was carried out to create a prognostic inflammatory-based score to predict survival in metastatic GC (mGC) before first-line chemotherapy. MATERIALS & METHODS: We studied the prognostic value of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio in 151 patients with mGC at the diagnosis. RESULTS: Median overall survival (OS) was significantly lower in patients with high NLR. Performance status 1-2 according to the Eastern Cooperative Oncology Group scale and NLR were predictors of shorter OS at multivariate analysis. Based on these results, we defined a prognostic OS score, showing a better median OS in favorable risk group. CONCLUSION: Elevated pretreatment NLR and Eastern Cooperative Oncology Group are independent predictors of shorter OS in mGC patients before first-line chemotherapy.

What's New in Gastric Cancer: The Therapeutic Implications of Molecular Classifications and Future Perspectives.

Despite some remarkable innovations and the advent of novel molecular classifications the prognosis of patients with advanced gastric cancer (GC) remains overall poor and current clinical application of new advances is disappointing. During the last years only Trastuzumab and Ramucirumab have been approved and currently used as standard of care targeted therapies, but the systemic management of advanced disease did not radically change in contrast with the high number of molecular drivers identified. The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) classifications paved the way, also for GC, to that more contemporary therapeutic approach called "precision medicine" even if tumor heterogeneity and a complex genetic landscape still represent a strong barrier. The identification of specific cancer subgroups is also making possible a better selection of patients that are most likely to respond to immunotherapy. This review aims to critically overview the available molecular classifications summarizing the main druggable molecular drivers and their possible therapeutic implications also taking advantage of new technologies and acquisitions.

Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Rilotumumab is a fully human monoclonal antibody that selectively targets the ligand of the MET receptor, hepatocyte growth factor (HGF). We aimed to assess the efficacy, safety, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine, and to assess potential biomarkers, in patients with advanced MET-positive gastric or gastro-oesophageal junction adenocarcinoma. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study was done at 152 centres in 27 countries. We recruited adults (aged ≥18 years) with unresectable locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, MET-positive tumours (≥25% of tumour cells with membrane staining of ≥1+ staining intensity), and evaluable disease, who had not received previous systemic therapy. Eligible patients were randomly assigned (1:1) via a computerised voice response system to receive rilotumumab 15 mg/kg intravenously or placebo in combination with open-label chemotherapy (epirubicin 50 mg/m2 intravenously; cisplatin 60 mg/m2 intravenously; capecitabine 625 mg/m2 orally twice daily) in 21-day cycles for up to ten cycles. After completion of chemotherapy, patients continued to receive rilotumumab or placebo monotherapy until disease progression, intolerability, withdrawal of consent, or study termination. Randomisation was stratified by disease extent and ECOG performance status. Both patients and physicians were masked to study treatment assignment. The primary endpoint was overall survival, analysed by intention to treat. We report the final analysis. This study is registered with ClinicalTrials.gov, number NCT01697072. FINDINGS: Between Nov 7, 2012, and Nov 21, 2014, 609 patients were randomly assigned to rilotumumab plus epirubicin, cisplatin, and capecitabine (rilotumumab group; n=304) or placebo plus epirubicin, cisplatin, and capecitabine (placebo group; n=305). Study treatment was stopped early after an independent data monitoring committee found a higher number of deaths in the rilotumumab group than in the placebo group; all patients in the rilotumumab group subsequently discontinued all study treatment. Median follow-up was 7·7 months (IQR 3·6-12·0) for patients in the rilotumumab group and 9·4 months (5·3-13·1) for patients in the placebo group. Median overall survival was 8·8 months (95% CI 7·7-10·2) in the rilotumumab group compared with 10·7 months (9·6-12·4) in the placebo group (stratified hazard ratio 1·34, 95% CI 1·10-1·63; p=0·003). The most common grade 3 or worse adverse events in the rilotumumab and placebo groups were neutropenia (86 [29%] of 298 patients vs 97 [32%] of 299 patients), anaemia (37 [12%] vs 43 [14%]), and fatigue (30 [10%] vs 35 [12%]). The frequency of serious adverse events was similar in the rilotumumab and placebo groups (142 [48%] vs 149 [50%]). More deaths due to adverse events occurred in the rilotumumab group than the placebo group (42 [14%] vs 31 [10%]). In the rilotumumab group, 33 (11%) of 298 patients had fatal adverse events due to disease progression, and nine (3%) had fatal events not due to disease progression. In the placebo group, 23 (8%) of 299 patients had fatal adverse events due to disease progression, and eight (3%) had fatal events not due to disease progression. INTERPRETATION: Ligand-blocking inhibition of the MET pathway with rilotumumab is not effective in improving clinical outcomes in patients with MET-positive gastric or gastro-oesophageal adenocarcinoma. FUNDING: Amgen.

Pancreatic stump closure after pancreatoduodenectomy in elderly patients: a retrospective clinical study.

BACKGROUND: Pancreatic fistula (PF) after pancreatoduodenectomy (PD) represents the major source of morbidity. Derivative procedures are preferred by pancreatic surgeons, but the optimal management of remnant pancreatic stump remains controversial. AIMS: The purpose of this retrospective study is to evaluate the efficacy and safety of pancreatic stump closure in selected elderly patients (>65 years). METHODS: Clinical data of 44 PD undergone mechanical closure of the pancreatic stump performed between 2001 and 2014 in two department of general and oncologic surgery were retrospectively collected. Considering the age, patients were divided into two groups: 21 patients of less than 65 years (Group A) and 23 patients of more than 65 years (Group B). RESULTS: A soft pancreatic parenchyma with a not-dilated duct (diameter <3 mm) was reported in all the 44 patients. A grade-A PF, which did not required further treatments, developed in 20 cases (45.4%; 13 in group A and 7 in group B; p < 0.05), grade-B in 5 patients (11.4%; 3 in group A and 2 in group B; statistically not significant) and a grade-C PF was observed only in one patient (2.2%; 1 in group A and 0 in group B). DISCUSSION: In selected "high risk" elderly patients (>65 years) with soft pancreatic texture, the closure of the pancreatic stump can be a useful tool in the surgical armamentarium with the aim to reduce the incidence of age-related complications. CONCLUSIONS: Prospective randomized controlled trial to better evaluate PF risk factors is needed.

NAB-paclitaxel and gemcitabine in metastatic pancreatic ductal adenocarcinoma (PDAC): from clinical trials to clinical practice.

BACKGROUND: Pancreatic adenocarcinoma is an aggressive disease with poor prognosis. In a randomized phase III trial, combination of Nab-paclitaxel (Nab-P) plus gemcitabine showed superior activity and efficacy in first-line treatment compared with gemcitabine alone. METHODS: Nab-P is not dispensed in Italy; however, we obtained this drug from our Ethics Committee for compassionate use. The aim of this study was to evaluate the efficacy and safety profile of this Nab-P and gemcitabine combination in a cohort of patients treated outside clinical trials. From January 2012 to May 2014, we included 41 patients with advanced pancreatic adenocarcinoma receiving combination of 125 mg/m(2) Nab-P and 1 g/m(2) gemcitabine on days 1, 8 and 15 of a 28-day cycle, as first-line treatment. Median age of patients was 67 (range 41-77) years, and 11 patients were aged ≥70 years. RESULTS: Eastern Co-operative Oncology Group performance status was 0 or 1 in 32 patients (78 %) and 2 in nine patients (22 %). Primary tumor was located in the pancreatic head or body/tail in 24 (58.5 %) and 17 (41.5 %) patients, respectively, and nine patients had received biliary stent implantation before starting chemotherapy. Median carbohydrate antigen 19-9 level was 469 U/l (range 17.4-61546 U/l) and 29 patients (70.7 %) had referred pain at the time of diagnosis. Patients received a median six cycles (range 1-14) of treatment. Overall response rate was 36.6 %; median progression-free survival was 6.7 months [(95 % confidence interval (CI) 5.966-8.034), and median overall survival was 10 months (95 % CI 7.864-12.136). Treatment was well tolerated. No grade 4 toxicity was reported. Grade 3 toxicity included neutropenia in 10 patients (24.3 %), thrombocytopenia in five (12 %), anemia in three (7.3 %), diarrhea in four (9.7 %), nausea and vomiting in two (4.9 %), and fatigue in six (14.6 %). Finally, pain control was achieved in 24 of 29 patients (82.3 %) with a performance status improvement of 10 % according to the Karnofsky scale. CONCLUSIONS: Our results confirm that combination of gemcitabine plus Nab-P is effective both in terms of overall response rate, progression-free survival and overall survival, with a good safety profile.

Is complete mesocolic excision with central vascular ligation safe and effective in the surgical treatment of right-sided colon cancers? A prospective study.

PURPOSE: Complete mesocolic excision (CME) with central vascular ligation (CVL) has been proposed for treatment of colon cancers based on the same principles as total mesorectal excision. Impressive outcomes have been reported, however, direct comparisons with the classic procedure are lacking. METHODS: Forty-five consecutive patients operated on in the last 5 years with CME and CVL right hemicolectomy entered the study. Fifty-eight right-sided colon cancer patients operated in the previous 5 years with classic approach constituted the control group. Intra- and postoperative course assessed the safety of the procedure. Primary end-points for oncological adequacy were recurrence and survival rate. RESULTS: All operations were successful with no increase in postoperative complications (p = 0.85). Number of harvested nodes and length of vascular ligation were shown to be significantly better in the CME group (p < 0.01). A higher number of tumor deposits were harvested thus allowing chemotherapy in newly upstaged patients. Locoregional recurrences were never experienced in CME patients (p = 0.03). The risk of cancer-related death was reduced by over one half in all CME patients, and even by three quarters in node-positive tumors. The classic operation was significantly associated with poor outcome (p < 0.01). CONCLUSION: This study shows that CME with CVL is a safe and effective surgical approach for right colon cancer, thus confirming the previously reported oncological adequacy. The procedure was shown to significantly decrease local recurrences and to improve the survival rate, particularly in node-positive patients. Urgent diffusion of this technique is warranted.

Biweekly combination of trastuzumab, docetaxel and gemcitabine for HER2-positive metastatic breast cancer: results of a Phase II GOIM study.

AIMS: Clinical activity of chemotherapy plus trastuzumab in HER2 overexpressing advanced breast cancer has been documented. We report the activity and safety results of biweekly combination of trastuzumab, docetaxel and gemcitabine as first-line therapy in HER2-positive advanced breast cancer. PATIENTS & METHODS: Patients were biweekly treated with trastuzumab (4 mg/kg), gemcitabine (1000 mg/m(2)) and docetaxel (50 mg/m(2)). The primary end point was overall response rate, secondary time to progression, clinical benefit rate (partial response plus complete response plus stable disease for ≥ 24 weeks) and tolerability. RESULTS: A total of 65 patients with HER2-positive advanced breast cancer have been enrolled. In total, 47 patients responded (73%; 95% CI, 60-84), 11 achieved complete response (17%; 95% CI: 8.9-28.7), 36 achieved partial response (56%; 95% CI: 43-68.6). The clinical benefit rate was 87.5% (95% CI: 77-94). Three patients (4.7%) experienced progressive disease. The median time to progression was 14.2 months (95% CI: 10.6-17.8), the median overall survival was 39.3 months and the 36-month survival rate was 55.5% (95% CI: 58-73). The worst toxicities were grade 3 neutropenia (12%), thrombocytopenia (6%) and diarrhea (6%). No cardiac toxicity was reported. CONCLUSION: As first-line therapy, this combination allowed the delivery of polychemotherapy in association to targeted therapy, with clinical activity and mild toxicity. The promising results should be further explored in Phase III randomized clinical trials.