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The majority of metastatic colorectal cancers (mCRC) are mismatch repair (MMR) proficient and unresponsive to immunotherapy, whereas MMR-deficient (MMRd) tumors often respond to immune-checkpoint blockade. We previously reported that the treatment of colorectal cancer preclinical models with temozolomide (TMZ) leads to MMR deficiency, increased tumor mutational burden (TMB), and sensitization to immunotherapy. To clinically translate these findings, we designed the ARETHUSA clinical trial whereby O6-methylguanine-DNA-methyltransferase (MGMT)–deficient, MMR-proficient, RAS-mutant mCRC patients received priming therapy with TMZ. Analysis of tissue biopsies and circulating tumor DNA (ctDNA) revealed the emergence of a distinct mutational signature and increased TMB after TMZ treatment. Multiple alterations in the nucleotide context favored by the TMZ signature emerged in MMR genes, and the p.T1219I MSH6 variant was detected in ctDNA and tissue of 94% (16/17) of the cases. A subset of patients whose tumors displayed the MSH6 mutation, the TMZ mutational signature, and increased TMB achieved disease stabilization upon pembrolizumab treatment. Significance: MMR-proficient mCRCs are unresponsive to immunotherapy. We provide the proof of concept that inactivation of MMR genes can be achieved pharmacologically with TMZ and molecularly monitored in the tissue and blood of patients with mCRC. This strategy deserves additional evaluation in mCRC patients whose tumors are no longer responsive to standard-of-care treatments. See related commentary by Willis and Overman, p. 1612. This article is highlighted in the In This Issue feature, p. 1599

Supplementary Figure from Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients

Rechallenge with epidermal growth factor (EGFR) inhibitors represents a promising therapeutic strategy in patients with refractory RAS/BRAF wild-type metastatic colorectal cancer (mCRC). The maximal benefit is observed in patients without resistance mutation at the baseline plasma circulating tumor DNA (ctDNA) evaluation. In the CAVE and VELO clinical trials, 1 out of 4 patients had ctDNA RAS/BRAF mutant disease at pretreatment liquid biopsy assessment. There was no direct association between the length of anti-EGFR drug-free interval and the presence of plasma ctDNA RAS/BRAF mutations at pretreatment liquid biopsy analysis. Interestingly, even the disappearance of mutant clones was time-dependent, and resistance mutations were found at liquid biopsy analysis in approximately 15% of patients after 18 or more months of anti-EGFR drug-free window. These results support the use of liquid biopsy to appropriately select amenable patients to EGFR inhibitor rechallenge. Rechallenge with anti-EGFR drugs represents a promising strategy in refractory RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC). We performed the pooled analysis of the CAVE and VELO studies to evaluate the percentage of patients with WT circulating tumor DNA (ctDNA) tumors and the association of mutational status with time from the last anti-EGFR drug administration. At baseline, 97/129 patients had RAS/BRAF WT plasma ctDNA, while 32/129 had RAS/BRAF mutated plasma ctDNA. Median anti-EGFR drug-free interval was 10.6 (CI 95%, 8.9-13.4) months in the plasma RAS/BRAF mutant group as compared to 13.0 (CI 95%, 11.1-16.6) months in RAS/BRAF WT group (p = 0.169). To investigate the time window of the RAS/BRAF mutant cancer cell clone disappearance, descriptive analysis using different time points was performed. No difference in the proportion of patients whose baseline plasma ctDNA was RAS/BRAF WT or mutated was found between 4 and 18 months since the last administration of anti-EGFR drugs. In contrast, 38/44 of patients with anti-EGFR drug-free interval of 18 months or more displayed a ctDNA RAS/BRAF WT status. Taken together, these results shows that the length of anti-EGFR free interval is not a sufficient criterion for patient selection, supporting the role of liquid biopsies for improving treatment efficacy.

Current therapies for chemo-refractory metastatic colorectal cancer (mCRC) have limited efficacy. Rechallenge with epidermal growth factor receptor (EGFR) inhibitors in RAS wild-type (WT) mCRC could be valuable in this setting. In VELO, a randomized two-arm phase 2 trial, anti-EGFR monoclonal antibody panitumumab plus standard-of-care trifluridine/tipiracil (31 patients, arm B) was compared to trifluridine/tipiracil (31 patients, arm A) as third-line therapy (ClinicalTrials.gov Identifier NCT05468892). Primary endpoint, progression-free survival (PFS), was met. Median PFS was 4.0 months in arm B versus 2.5 months in arm A [hazard ratio (HR): 0.48; 95% CI 0.28–0.82; P = 0.007]. Baseline plasma RAS/BRAF WT circulating tumor DNA identified patients obtaining prolonged clinical benefit with panitumumab plus trifluridine/tipiracil as compared to trifluridine/tipiracil with PFS rates at 6 months of 38.5% versus 13% and at 12 months of 15.4% versus 0%, respectively. These findings warrant further development for liquid biopsy-guided anti-EGFR rechallenge combination strategies in chemo-refractory RAS WT mCRC.

Currently, standard treatment of patients with metastatic colorectal cancer (mCRC) comprises chemotherapy (CT) and/or biological therapy (BT) and/or best supportive care (BSC). The present study performed a meta-analysis on five phase II-III randomized clinical trials, which compared CT/BT/BSC as the control arm with the immune checkpoint inhibitors (ICIs) anti-programmed cell death protein 1 (PD-1) or its ligand (PD-L1) alone or in combination with cytotoxic T lymphocyte antigen 4 or mitogen activated protein kinase kinase inhibitors as the experimental arm, to evaluate whether a standard approach could be overcome using the novel target therapy strategy. Pooled hazard ratio (HR) for progression-free survival was 0.95 in favor of the experimental arm [95% confi- dence interval (CI), 0.74-1.22; P=0.68]. Heterogeneity was significant: Cochran's Q, 21.0; P=0.0082; I2 index, 76%. Pooled HR for overall survival was 0.88 in favor of the experimental arm (95% CI, 0.75-1.02; P=0.08). Heterogeneity was not significant (Cochran's Q, 6.0; P=0.31; I2 index, 16%). The present meta-analysis demonstrated a trend toward the improvement of survival by PD-1/PD-L1 blockade in mCRC. Further homogeneous studies are necessary to strengthen these results, beyond the known benefits of ICIs in deficient mismatch repair/high microsatellite instability tumors.

Background: The role of personality in cancer incidence and development has been studied for a long time. As colorectal cancer (CRC) is one of the most prevalent cancer types and linked with lifestyle habits, it is important to better understand its psychological correlates, in order to design a more specific prevention and intervention plan. The aim of this systematic review is to analyze all the studies investigating the role of personality in CRC incidence.Methods: All studies on CRC and personality up to November 2020 were scrutinized according to the Cochrane Collaboration and the PRISMA statements. Selected studies were additionally evaluated for the Risk of Bias according to the Newcastle-Ottawa Scale (NOS).Results: Eight studies met the inclusion criteria and were eventually included in this review. Two main constructs have been identified as potential contributors of CRC incidence: emotional regulation (anger) and relational style (egoism).Conclusion: Strong conclusions regarding the influence of personality traits on the incidence of CRC are not possible, because of the small number and the heterogeneity of the selected studies. Further research is needed to understand the complexity of personality and its role in the incidence of CRC and the interaction with other valuable risk factors.

Purpose: The purpose of this study was to investigate survival outcomes and safety after chemoembolization using irinotecan-loaded small-size beads (DEB-IRI) in patients with colorectal liver metastases unresponsive to standard chemotherapy. Materials and methods: Between December 2013 and August 2019, fifty-five patients (32 males, median age 64.5 years) with pretreated colorectal liver metastases unresponsive to standard chemotherapy underwent 197 chemoembolization procedures (mean 3.6 ± 2.3 SD per patient). Thirty patients (30/55; 55%) had extrahepatic disease metastatic to the lungs, lymph nodes or peritoneum. Local tumor control was evaluated at 3, 6, 9 and 12 months. Median overall survival, survival rates at 1 and 2 year and adverse events were evaluated. Results: Local tumor control was achieved in 32/55 (58%), 12/55 (22%), 4/55 (7%) and 2/55 (4%) patients at 3, 6, 9 and 12 months, respectively. Median overall survival was 9.9 months (95% CI: 6.2–14.2 months) with 1- and 2-year survival rates of 45% and 15%, respectively. A total of 30 (15%) G1-G3 treatment-related adverse events occurred across all embolization procedures. No severe treatment-related adverse events occurred. Conclusion: Chemoembolization using irinotecan-loaded small-size beads is a safe and effective procedure as a salvage treatment in patients with colorectal liver metastases, showing good results in terms of liver-specific progression free survival and overall survival.

Background Although American Society of Clinical Oncology and European Society for Medical Oncology guidelines have identified the negative prognostic factors that clinicians have to consider when treating their patients with stage II colon cancer (CC), the role of histological subtype is controversial. Subjects, Materials, and Methods The randomized, multicenter, phase III TOSCA trial compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy in 3,759 patients with high-risk stage II or stage III CC. The objective of this substudy was to evaluate the influence of histological subtypes on the impact of the treatment duration of adjuvant chemotherapy in terms of relapse-free survival (RFS) and overall survival (OS) in 85 mucinous adenocarcinoma (MUC) and 389 nonmucinous adenocarcinoma (NMUC) patients with high-risk stage II, grade 3 CC. Results A significant interaction between treatment duration and histology was observed in both RFS (p = .027) and OS (p = .017). In the subgroup of patients with MUC, worse RFS (adjusted hazard ratio [HR], 3.95; 95% confidence interval [CI], 1.03–15.17; p = .045) and OS (HR, 9.56; 95% CI, 1.14–79.98; p = .037) were detected for patients treated in the 3-month arm. No statistically significant differences were found in the subgroup of patients with NMUC. Conclusion Patients with MUC, grade 3, stage II CC require special attention and may need 6 months of oxaliplatin-based chemotherapy. Larger studies are required to assess the combined use of histology and other prognostic/predictive factors to define the administration of chemotherapy in patients with stage II CC and to improve their prognosis. Implications for Practice Although ASCO and ESMO guidelines define the prognostic factors for patients with stage II colon cancer to establish the use of adjuvant chemotherapy, the influence of histological subtypes is controversial in this population. This study underscores that patients with grade 3 mucinous adenocarcinomas may need adjuvant chemotherapy with oxaliplatin and fluoropyrimidines for a duration of 6 months rather than 3 months.

Andrea Casadei-Gardini,1 Francesco Montagnani,2 Chiara Casadei,1 Francesca Arcadipane,3 Kalliopi Andrikou,4 Deborah Aloi,5 Alessandra Anna Prete,6,7 Maria Giulia Zampino,8 Antonella Argentiero,9 Giuseppe Pugliese,4 Stefania Martini,10 Giuseppe Carlo Iorio,10 Mario Scartozzi,11 Massimiliano Mistrangelo,12 Lorenzo Fornaro,13 Paola Cassoni,14 Giorgia Marisi,15 Veronica Dell’Acqua,16 Paola Simona Ravenda,8 Sara Lonardi,6 Nicola Silvestris,7 Berardino De Bari,5 Umberto Ricardi,3 Stefano Cascinu,4 Pierfrancesco Franco91Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; 2Oncology Department, SOC Oncology, ASL (Health Local Authority), Biella, Italy; 3Department of Oncology, Radiation Oncology, AOU Città della Salute e della Scienza, Turin, Italy; 4Department of Hematology and Oncology, University of Modena and Reggio Emilia, Modena, Italy; 5Radiation Oncology Department, Centre Hospitalier Régional Universitaire “Jean Minjoz”, Besançon Cedex, France; 6Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy; 7Department of Radiological, Oncological and Pathological Sciences, Policlinico Umberto I University Hospital, Rome, Italy; 8Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, Milan, Italy; 9Medical Oncology Unit, Cancer Institute Giovanni Paolo II, Bari, Italy; 10Department of Oncology, Radiation Oncology, University of Turin, Turin, Italy; 11Department of Medical Oncology, University of Cagliari, Cagliari, Italy; 12Department of Surgical Sciences, University of Turin, Turin, Italy; 13Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana University, Pisa, Italy; 14Department of Medical Sciences, Pathology Unit, University of Turin, Turin, Italy; 15Biosciences Laboratory, Istituto Scientifico Romagnolo per Lo Studio e La Cura Dei Tumori (IRST) IRCCS, Meldola, Italy; 16Department of Radiotherapy, IRCCS, European Institute of Oncology, Milan, ItalyBackground: In anal cancer, there are no markers nor other laboratory indexes that can predict prognosis and guide clinical practice for patients treated with concurrent chemoradiation. In this study, we retrospectively investigated the influence of immune inflammation indicators on treatment outcome of anal cancer patients undergoing concurrent chemoradiotherapy.Methods: All patients had a histologically proven diagnosis of squamous cell carcinoma of the anal canal/margin treated with chemoradiotherapy according to the Nigro’s regimen. Impact on prognosis of pre-treatment systemic index of inflammation (SII) (platelet x neutrophil/lymphocyte), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were analyzed.Results: A total of 161 consecutive patients were available for the analysis. Response to treatment was the single most important factor for progression-free survival (PFS) and overall survival (OS). At univariate analysis, higher SII level was significantly correlated to lower PFS (p

Simple Summary The treatments for patients with oligometastatic colorectal carcinoma are rapidly evolving. The present review focuses on the role of minimally invasive techniques since they can now be used as an alternative to surgical management in selected cases in association with systemic therapies according to ESMO and NCCN guidelines. In recent years, biomarkers (both at molecular and imaging level) have emerged as a relevant and potential criteria for treatment strategy decision and will be crucial in the future for patients selection. Tumor molecular profile impacts on local outcome of image guide ablation as well as metabolic imaging which predicts the outcome of both percutaneous and trans-arterial treatments. Oncologists should be aware of advantages and disadvantages of those treatments options as well as the potential role of molecular profile for a better patient selection. Abstract Colorectal cancer (CRC) is the third most common cancer worldwide and has a high rate of metastatic disease which is the main cause of CRC-related death. Oligometastatic disease is a clinical condition recently included in ESMO guidelines that can benefit from a more aggressive locoregional approach. This review focuses the attention on colorectal liver metastases (CRLM) and highlights recommendations and therapeutic locoregional strategies drawn from the current literature and consensus conferences. The different percutaneous therapies (radiofrequency ablation, microwave ablation, irreversible electroporation) as well as trans-arterial approaches (chemoembolization and radioembolization) are discussed. Ablation margins, the choice of the imaging guidance as well as characteristics of the different ablation techniques and other technical aspects are analyzed. A specific attention is then paid to the increasing role of biomarkers (in particular molecular profiling) and their role in the selection of the proper treatment for the right patient. In conclusion, in this review an up-to-date state of the art of the application of locoregional treatments on CRLM is provided, highlighting both technical aspects and the role of biomarkers, two sides of the same coin.

Anal squamous cell carcinoma (SCC) is a rare tumor, and bio-humoral predictors of response to chemo-radiation (CT-RT) are lacking. We developed a prognostic score system based on laboratory inflammation parameters. We investigated the correlation between baseline clinical and laboratory variables and disease-free (DFS) and overall (OS) survival in anal SCC patients treated with CT-RT in five institutions. The bio-humoral parameters of significance were included in a new scoring system, which was tested with other significant variables in a Cox’s proportional hazard model. A total of 308 patients was included. We devised a prognostic model by combining baseline hemoglobin level, SII, and eosinophil count: the Hemo-Eosinophils Inflammation (HEI) Index. We stratified patients according to the HEI index into low- and high-risk groups. Median DFS for low-risk patients was not reached, and it was found to be 79.5 months for high-risk cases (Hazard Ratio 3.22, 95% CI: 2.04–5.10, p &lt, 0.0001). Following adjustment for clinical covariates found significant at univariate analysis, multivariate analysis confirmed the HEI index as an independent prognostic factor for DFS and OS. The HEI index was shown to be a prognostic parameter for DFS and OS in anal cancer patients treated with CT-RT. An external validation of the HEI index is mandatory for its use in clinical practice.

Obesity and diet are associated with colorectal cancer (CRC) risk, and microbiome could mediate this risk factor. To investigate this interaction, we performed a case-control study (34 CRC cases and 32 controls) and analyzed fecal microbiota composition using 16S rRNA metabarcoding and sub-sequential shotgun analyses of genomic bacterial DNA to evaluate the role of microbiome and diet in CRC etiology, taking into account vitamin D and other risk biomarkers. Dietary habits were evaluated using a short questionnaire. Multivariate methods for data integration and mediation analysis models were used to investigate causal relationships. CRC cases were significantly more often deficient in vitamin D than controls (p = 0.04); FokI and CYP24A1 polymorphism frequency were different between cases and controls (p = 0.03 and p = 0.02, respectively). A diet poor in fatty fish and rich in carbohydrates was found to be significantly associated with CRC risk (p = 0.011). The mediation analysis confirmed the significant role of the microbiome in mediating CRC risk-increasing levels of Bifidobacteria/Escherichia genera ratio, an indicator of “healthy” intestinal microbiome, can overcome the effect of diet on CRC risk (p = 0.03). This study suggests that microbiome mediates the diet effect on CRC risk, and that vitamin D, markers of inflammation, and adipokines are other factors to consider in order to achieve a better knowledge of the whole carcinogenic process., SCOPUS: ar.j, info:eu-repo/semantics/published

Background and Aims: The standard treatment of non-metastatic anal squamous cell carcinoma (ASCC) consists of chemotherapy with mitomycin (MMC) plus 5-fluorouracil (5FU) for 1–2 cycles concomitant with pelvic radiotherapy. Subsequent studies introduced cisplatin (CDDP) combined with 5FU, with unclear results. We evaluated the doublet capecitabine (C) and CDDP as a possible alternative to MMC-5FU regimen concomitant with intensity-modulated radiation therapy (IMRT). Patients and Methods: We carried out a retrospective study on 67 patients affected by stage I–III ASCC, treated with CDDP (60–70 mg/m2 every 21 days for two courses) plus C (825 mg/m2 twice daily for 5 days/week) chemotherapy concomitant with IMRT for curative intent. Results: At a median follow up of 41 months, the clinical complete response calculated at the 6-month time-point (6-moCR), the 6-month objective response rate and the 6-month disease control rate were 93%, 94%, and 99%, respectively. Disease-free survival rates at 1, 2, and 3 years were 89%, 87%, and 85%, while the overall survival rates at 1 and 2 years were 100% and 95%. The colostomy-free survival rates were 90% at 1 year and 88% at 2 years. Grade 3–4 acute adverse events were reported in 61% of patients; predominantly skin toxicity (46%) and limited hematological toxicity (12%). Conclusion: In this retrospective study, chemotherapy with C plus CDDP concomitant with IMRT proved safe and effective, and may represent a possible alternative option to standard MMC-containing regimen for curative intent.

Background: In the last decade, a series of analyses failed to identify predictive biomarkers of resistance/susceptibility for anti-angiogenic drugs in metastatic colorectal cancer (mCRC). We conducted an exploratory preplanned analysis of serum pro-angiogenic factors (SErum aNgiogenesis-cenTRAL) in 72 mCRC patients enrolled in the phase II CENTRAL (ColorEctalavastiNTRiAlLdh) trial, with the aim to identify potential predictive factors for sensitivity/resistance to first line folinic acid-fluorouracil-irinotecan regimen (FOLFIRI) plus bevacizumab. Methods: First-line FOLFIRI/bevacizumab patients were prospectively assessed for the following circulating pro-angiogenic factors, evaluated with ELISA (enzyme-linked immunosorbent assay)-based technique at baseline and at every cycle: Vascular endothelial growth factor A (VEGF-A), hepatocyte growth factor (HGF), stromal derived factor-1 (SDF-1), placental derived growth factor (PlGF), fibroblast growth factor-2 (FGF-2), monocyte chemotactic protein-3 (MCP-3), interleukin-8 (IL-8). Results: Changes in circulating FGF-2 levels among different blood samples seemed to correlate with clinical outcome. Patients who experienced an increase in FGF-2 levels at the second cycle of chemotherapy compared to baseline, had a median Progression Free Survival (mPFS) of 12.85 vs. 7.57 months (Hazard Ratio&mdash, HR: 0.73, 95% Confidence Interval&mdash, CI: 0.43-1.27, p = 0.23). Similar results were seen when comparing FGF-2 concentrations between baseline and eight-week time point (mPFS 12.98 vs. 8.00 months, HR: 0.78, 95% CI: 0.46&ndash, 1.33, p = 0.35). Conclusions: Our pre-planned, prospective analysis suggests that circulating FGF-2 levels&rsquo, early increase could be used as a marker to identify patients who are more likely to gain benefit from FOLFIRI/bevacizumab first-line therapy.

This pilot study was performed to investigate safety and local tumor control following transarterial embolization with small-size particles loaded with irinotecan (DEB-IRI) in patients with colorectal liver metastases (CRLM). Patients with pretreated CRLM with mono- or bilobar lesions involving less than 60% of the liver parenchyma and Eastern Cooperative Oncology Group performance status 0 or 1 underwent superselective DEB-IRI embolization with 40 µm diameter embolic microspheres. Eighteen patients (11 males, 7 females, median age 61 years) underwent 80 embolization procedures (mean 4.4, range 2–12 per patient). No serious adverse events were reported within 30 days. A total of 39 treatment-related AEs occurred across all embolization procedures. No G4 or G5 treatment-related AEs occurred. Local tumor control, defined as complete response, partial response, or stable disease, was achieved in 16/18 (88.9%), 7/17 (41.2%), and 3/17 (17.6%) patients at 3, 6, and 12 months, respectively. Median liver progression-free survival was 5.9 months (range 27–409 days), and median overall survival was 13.5 months. In this small series, DEB-IRI embolization with small beads was demonstrated a safe procedure in the treatment of patients with CRLM. The promising results in terms of liver-specific progression-free survival and overall survival reported deserve further confirmation in larger prospective trials. Level 4, case series.

Purpose Given the cumulative neurotoxicity associated with oxaliplatin, a shorter duration of adjuvant therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods The Three or Six Colon Adjuvant trial is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III colon cancer to receive 3 months or 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Primary end-point is relapse-free survival. Results 3,759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX and 36% CAPOX. Two-thirds were stage III. The median time of follow up was 62 months and 772 relapses or deaths have been observed. The hazard ratio (HR) of the 3 months versus 6 months for relapse/death was 1.14 (95% CI, 0.99 to 1.32; P [for noninferiority] = .514) and the CI crossed the noninferiority limit of 1.20. However, the absolute difference in 3-year RFS was 1.9% (95% CI, -0.7% to 4.4%). Counter-intuitively, while the RFS curves were similar for stage III (HR, 1.07; 95% CI, 0.91 to 1.26) and for CAPOX treated patients (HR, 0.98; 95% CI, 0.77 to 1.26), they were not for stage II and for FOLFOX treated patients, with HR of 1.41 (95% CI, 1.05 to 1.89) and 1.23 (95% CI, 1.03 to 1.46), respectively, favoring the 6 months of treatment. Conclusion The Three or Six Colon Adjuvant trial failed to formally show noninferiority of 3 versus 6 months of treatment to the predefined margin of 20% relative increase. The results depended on the adjuvant regimen and risk. For CAPOX, 3 months were as good as 6 months; for FOLFOX, 6 months added extra benefit. Counter-intuitively, the low-risk patients benefitted more than the high-risk population from the 6-month duration. The choice of regimen and duration should depend on patient characteristics and be balanced against the extra toxicity of longer therapy.

Background: Previous findings suggested that bevacizumab might be able to improve response rate (RR) in colorectal cancer patients with high lactic dehydrogenase (LDH) basal levels. Methods: We conducted a phase II trial to prospectively ascertain whether bevacizumab in combination with FOLFIRI could have an improved clinical activity in patients with high LDH serum levels. Primary end point of the study was RR; secondary end points were median overall survival and median progression-free survival (mPFS). Results: A total of 81 patients were enrolled. No difference in terms of ORR (39% vs 31% for low vs high LDH level stratum, P=0.78) and mPFS (14.16 vs 10.29 months, HR: 1.07, 95% CI: 0.51–2.24, P=0.83) between the strata was observed, whereas overall survival (OS) was significantly longer for patients with low LDH (24.85 vs 15.14 months, HR: 4.08, 95% CI: 1.14–14.61, P=0.0004). In a not-pre-planned exploratory analysis using different cut-off ranges for LDH, we observed RR up to 70%, with no improvement in progression-free survival or OS. Conclusions: The CENTRAL trial failed to demonstrate that high LDH levels were related to a significantly improved RR in patients receiving first-line FOLFIRI and bevacizumab. The LDH serum levels should then no further be investigated as a predictive factor in this setting.

Importance The addition of oxaliplatin to the standard 6-month fluorouracil-based adjuvant chemotherapy in stage II colorectal cancer has been reported to reduce the risk of relapse although it does not increase survival. The Three or Six Colon Adjuvant (TOSCA) trial compared 3 months with 6 months of adjuvant fluoropyrimidine and oxaliplatin-based chemotherapy in patients with stage III colon cancer. The utility remains unknown. Objective To assess the noninferiority and toxic effects of 3 vs 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin) adjunct chemotherapy among patients with high-risk stage II resected colorectal cancer enrolled in the TOSCA trial. Design, Setting, and Participants The TOSCA study was a noninferiority phase 3 randomized clinical trial conducted from June 2007 to March 2013 in 130 Italian centers. Included patients had resected colorectal cancer located 12 cm from the anal verge by endoscopy or above the peritoneal reflection at surgery. In this preplanned study assessing the per-protocol population, 5-year relapse-free survival was evaluated in 1254 patients with high-risk stage II resected colorectal cancer who had received adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Interventions Patients were originally randomized (1:1) in the TOSCA trial to receive 3 months (experimental group) or 6 months (control) of standard doses of FOLFOX or CAPOX at the discretion of the treating physician. Main Outcome and Measures A hazard ratio of at least 1.2 between the 3-month and 6-month chemotherapy groups was set to reject the null hypothesis of noninferiority. Results Overall, 1254 patients (mean [SD] age, 62.4 [9.8] years; 565 women [45.1%]) with clinical high-risk stage II resected colorectal cancer were analyzed at a median follow-up of 62 months (interquartile range, 53-71) months. Of them, 301 patients (24.0%) had pT4N0M0 tumors, and the remaining 953 patients (76.0%) had high-risk pT3N0M0 tumors; 776 patients (61.9%) received FOLFOX and 478 (38.1%) received CAPOX. The 5-year relapse-free survival was 82.2% for the 3-month arm and 88.2% for the 6-month arm, with an estimated hazard ratio of 1.41 (95% CI, 1.05-1.89;P = .86 for noninferiority). For CAPOX, the 5-year relapse-free survival was similar in the 2 arms (difference, 0.76% favoring the 6-month arm; 95% CI, −6.28% to 7.80%), whereas for FOLFOX, the difference was pronounced: 8.56% in favor of the longer-duration arm (95% CI, 3.45%-13.67%). Nevertheless, the test for an interaction between duration and regimen was not statistically significant. Neurotoxicity was approximately 5 times lower in the shorter duration arm than in the longer duration arm. Conclusions and Relevance In the 3-month arm, the treatment was significantly less toxic than in the 6-month arm. Noninferiority was not shown for 5-year relapse-free survival. However, a possible regimen effect was observed, suggesting that either 3 months of CAPOX or 6 months of FOLFOX therapy can be used whenever an oxaliplatin doublet is indicated for treatment of patients with stage II colorectal cancer. Trial Registration ClinicalTrials.gov Identifier:NCT0064660

Purpose: To retrospectively review our experience on 84 patients with squamous cell anal canal cancer (SCAC) within 12 months after combined treatment with intensity-modulated RT (IMRT), in terms of acute and early-late toxicity, overall treatment time and interruptions, colostomy-free survival (CFS), and tumor response. Methods: Acute gastrointestinal (GI), genitourinary (GU), and cutaneous (CU) toxicities were assessed according to Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03. Early-late toxicity was scored using the Radiation Therapy Oncology Group (RTOG) late radiation morbidity scoring system. Tumor response was evaluated with response evaluation criteria in solid tumors (RECIST) v1.1. Results: Acute toxicity for 84 subjects (100%): severe (≥ G3) GI and skin toxicity was observed in 4 (5%) and 19 patients (23%), respectively. Early-late toxicity for 73 subjects (87%): severe (≥ G3) GI and vulvo-vaginal toxicity was observed in 2 (3%) and 2 (3%) patients, respectively. No acute or early-late severe GU toxicity was reported. A treatment interruption occurred in 65 patients (77%). CFS was 96% (95% CI 89–99) at 6 months and 92% (95% CI 83–96) at 12 months. At 6 months complete response (CR), partial response (PR) and progressive disease (PD) was observed in 70 (83%), 3 (4%), and 7 patients (8%), respectively. At 12 months, CR was observed in 60 patients (81%); eleven patients (15%) experienced PD. Conclusion: Our study showed an excellent clinical result and very low acute toxicity rates, confirming the IMRT as standard of care for curative treatment of anal cancer patients. The current trial was registered with the number IEO N87/11

Background: Moving stage III Colon Cancer (CC) into the precision medicine space is a priority in view of the lack of molecular markers driving adjuvant treatment. Retrospective studies have demonstrated the tremendous prognostic impact of circulating tumor DNA (ctDNA) analysis after curative intent surgery, and suggested that lack of conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy reflects treatment failure. With these premises, we have designed the PEGASUS trial (EudraCT 2019-002074-32) to prove the feasibility of using liquid biopsy to guide the post-surgical and post-adjuvant clinical management of early colon cancer patients. Methods: PEGASUS is a prospective multicentric vanguard study designed to test the feasibility of performing serial interventional liquid biopsies (LB) for ctDNA determination in 140 microsatellite stable Stage-III and T4N0 Stage-II CC patients. The LUNAR1 (Guardant Health, Redwood City, CA, USA) will be used for ctDNA determination. For the efficacy analysis, the PEGASUS cohort will be compared with a cohort of 420 patients from the TOSCA trial (NCT00646607) population matched 3:1 for all known prognostic phenotypes. A post-surgical LB executed 2-4 weeks after surgery will guide a “Molecular Adjuvant” treatment as follows: i) ctDNA+ patients will receive CAPOX for 3 months and ii) ctDNA- patients will receive capecitabine (CAPE) for 6 months but will be retested after 1 cycle, and if found ctDNA+ will be switched to CAPOX treatment. Immediately after the end of “Molecular Adjuvant” treatment a further LB will be performed and instruct subsequent treatment. Positive patients (ctDNA+/+ and ctDNA-/+) will receive an up-scaled “Molecular Metastatic” systemic treatment for 6 months or until radiological progression or toxicity as follows: i) ctDNA+/+ patients will be treated with FOLFIRI; ii) ctDNA-/+ patients with CAPOX. These patients will be subjected to a LB after 3 months and at the end of treatment and in case of positivity will be switched to FOLFIRI. Patients experiencing ctDNA conversion to negative (ctDNA+/-) will receive a de-escalated treatment with CAPE for 3 months. 3 LB will be performed within 3 months and in case of positivity the patient will be switched to FOLFIRI. Patients with ctDNA-/- will be subjected to an interventional follow-up comprising 2 further LB and in case of positivity they will be switched to CAPOX treatment. PEGASUS is piggybacked to AlfaOmega (NCT04120935), a Master Observational Protocol that will follow patients from diagnosis to 5 years or recurrence/death (whichever comes first), collecting clinical data, radio images and biological samples. AlfaOmega provides a clinical and logistic ecosystem for the seamless integration of PEGASUS clinical results with the biological underpinning of colon cancer. Citation Format: Elena Elez, Filippo Pietrantonio, Andrea Sartore-Bianchi, Clara Montagut, Andres Cervantes, Stefania Sciallero, Maria Giulia Zampino, Stefania Mosconi, Valter Torri, Noelia Tarazona, Luca Lazzari, Paolo Luraghi, Susana Muñoz, Matteo Fassan, Enzo Medico, Livio Trusolino, Maria Rescigno, Salvatore Siena, Alberto Sobrero, Roberto Labianca, Josep Tabernero, Alberto Bardelli, Sara Lonardi, Silvia Marsoni. Post-surgical liquid biopsy-guided treatment of stage III and high-risk stage II colon cancer patients: The PEGASUS trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT263.

Background: The risk of venous thromboembolic events (VTE) during adjuvant chemotherapy for colorectal cancer (CRC) is unknown. We aim to evaluate if the Khorana score (KS) can predict this risk, and if it represents a prognostic factor for overall survival (OS) through a post hoc analysis of the phase III TOSCA trial of different durations (3- versus 6-months) of adjuvant chemotherapy. Methods: A logistic regression model was used to test the associations between the risk of VTE and the KS. The results are expressed as odds ratios (OR) with 95% confidence intervals (95% CI). To assess the effect of the KS on OS, multivariable analyses using Cox regression models were performed. The results are expressed as hazard ratios (HR) with 95% CI. Results: Among 1380 CRC patients with available data, the VTE risk ( n = 72 events: 5.2%) was similar in the two duration arms (5.5% versus 4.9%), with 0.2% of patients belonging to the high-risk KS group. Rates of VTE were similar in the low- and intermediate-risk groups (4.8% versus 6.4%). KS did not represent an independent predictive factor for VTE occurrence. Chemotherapy duration was not associated with VTE risk. In addition, KS was not prognostic for OS in multivariate analysis (HR: 0.92, 95% CI, 0.63–1.36; p = 0.6835). Conclusions: The use of the KS did not predict VTEs in a low–moderate thromboembolic risk population as CRC. These data did not support the use of KS to predict VTE during adjuvant chemotherapy, and suggest that other risk assessment models should be researched.

This study determines the oncologic outcome of the combined resection and ablation strategy for colorectal liver metastases. Between January 1994 and December 2015, 373 patients underwent surgery for colorectal liver metastases. There were 284 patients who underwent hepatic resection only (Group 1) and 83 hepatic resection plus ablation (Group 2). Group 2 patients had a higher incidence of multiple metastases (100% in Group 2 vs 28.2% in Group 1; P < 0.001) and bilobar involvement (76.5% in Group 2 vs 12.9% in Group 1; P < 0.001) than Group 1 cases. Perioperative mortality was nil in either group, with a higher postoperative complication rate among Group 1 versus Group 2 cases (18 vs 0, respectively). The median follow-up was 90 months (range, 1–180), with a five-year overall survival for Group 1 and Group 2 of 51 per cent and 80 per cent, respectively (P = 0.193). Mean disease-free survival for patients with R0 resection was 55 per cent, 40 per cent, and 37 per cent at one, two, and three years, respectively, and remained steadily higher (at 50%) in those patients treated with resection combined with ablation up to five years (P = 0.069). The only intraoperative ablation failure was for a large lesion (≥5 cm). Our data support the use of intraoperative ablation when complete hepatic resection cannot be achieved.

Background Type 2 diabetes mellitus (T2DM) is associated with increased risk of colon cancer (CC), whereas metformin use seems to be protective. However, the impact of metformin use on the risk of death or disease recurrence after radical surgery for CC remains uncertain. Materials and Methods This is a substudy conducted in patients with high-risk stage II or stage III CC randomized in the TOSCA trial, which compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy. Objective of the study was to investigate the impact of metformin exposure during adjuvant chemotherapy on overall survival (OS) and relapse-free survival (RFS). We also evaluated the impact of T2DM or metformin dosage on clinical outcomes. Results Out of 3,759 patients enrolled in the TOSCA trial, 133 patients with diabetes (9.2%) and 1,319 without diabetes (90.8%) were recruited in this study. After excluding 13 patients with diabetes without information on metformin exposure, 76 patients with T2DM (63.3%) were defined as metformin users and 44 (36.7%) as metformin nonusers. After a median follow-up of 60.4 months, 26 (21.7%) patients relapsed and 16 (13.3%) died. Metformin use was neither associated with OS (adjusted hazard ratio [HR], 1.51; 95% confidence interval [CI], 0.48–4.77; p = .4781) nor with RFS (HR, 1.56; 95% CI, 0.69–3.54; p = .2881). Similarly, we found no association between T2DM or metformin dosage and OS or RFS. Conclusions Metformin use and T2DM did not impact on OS or RFS in patients with resected CC treated with adjuvant fluoropyrimidine-oxaliplatin chemotherapy. Larger studies and longer follow-up are required to clarify the potential efficacy of metformin in improving the prognosis of patients with CC. Implications for Practice The role of the antidiabetic drug metformin in colon cancer prevention and treatment is highly debated. While low-dose metformin reduced the incidence of colorectal adenomas in two prospective studies, its effect in patients with already established colon cancer remains unclear. In this study, the potential impact of metformin on the survival of resected colon cancer patients who received adjuvant chemotherapy was investigated in the context of the TOSCA study. We did not find any association between metformin use or dosages and patient survival. Prospective studies are required to draw definitive conclusions about metformin impact on colon cancer recurrence and survival.

The optimal duration and intensity of first-line therapy in metastatic colorectal cancer patients once they have achieved an objective response is controversial. In a molecularly selected RAS and BRAF wild-type (wt) population, this concern is amplified. Once disease control has been achieved with a combination therapy including an anti-EGFR antibody, further exposure both to cytotoxic drugs and targeted therapy might result only in increased toxicity. In unresectable metastatic RAS and BRAF wt colorectal cancer patients, a deintensified therapy could represent a valuable option that might preserve quality of life. We designed a study to compare FOLFIRI/cetuximab to FOLFIRI/cetuximab for eight cycles followed by cetuximab alone in first-line treatment of RAS and BRAF (wt) metastatic colorectal cancer patients.

Intensity-modulated radiotherapy (IMRT) is considered the preferred option in squamous cell canal cancer (SCAC), delivering high doses to tumor volumes while minimizing dose to surrounding normal tissues. IMRT has steep dose gradients, but the technique is more demanding as deep understanding of target structures is required. To evaluate genital marginal failure in a cohort of patients with non-metastatic SCAC treated either with IMRT or 3DCRT and concurrent chemotherapy, 117 patients with SCAC were evaluated: 64 and 53 patients were treated with IMRT and 3DCRT techniques, respectively. All patients underwent clinical and radiological examination during their follow-up. Tumor response was evaluated with response evaluation criteria in solid tumors v1.1 guideline on regular basis. All patients’ data were analyzed, and patients with marginal failure were identified. Concomitant chemotherapy was administered in 97 and 77.4% of patients in the IMRT and 3DCRT groups, respectively. In the IMRT group, the median follow-up was 25 months (range 6–78). Progressive disease was registered in 15.6% of patients; infield recurrence, distant recurrence and both infield recurrence and distant recurrence were identified in 5, 4 and 1 patient, respectively. Two out of 64 patients (3.1%) had marginal failures, localized at vagina/recto-vaginal septum and left perineal region. In the 3DCRT group, the median follow-up was 71.3 months (range 6–194 months). Two out of 53 patients (3.8%) had marginal failures, localized at recto-vaginal septum and perigenital structures. The rate of marginal failures was comparable in IMRT and 3DCRT groups (χ2 test p = 0.85). In this series, the use of IMRT for the treatment of SCAC did not increase the rate of marginal failures offering improved dose conformity to the target. Dose constraints should be applied with caution—particularly in females with involvement of the vagina or the vaginal septum.

Casadei-Gardini A, Montagnani F, Casadei C, et al. Cancer Manag Res. 2019;11:3631–3642. The authors have advised that the affiliations are not correct in the published paper (page 3631). They have provided revised author and affiliations lists, as follows, and confirm that the modifications do not alter their conflicts of interest status in regard to this work. Andrea Casadei-Gardini,1,2 Francesco Montagnani,3 Chiara Casadei,1 Francesca Arcadipane,4 Kalliopi Andrikou,2 Deborah Aloi,5 Alessandra Anna Prete,6 Maria Giulia Zampino,7 Antonella Argentiero,8 Giuseppe Pugliese,2 Stefania Martini,4 Giuseppe Carlo Iorio,4 Mario Scartozzi,9 Massimiliano Mistrangelo,10 Lorenzo Fornaro,11 Paola Cassoni,12 Giorgia Marisi,13 Veronica Dell’Acqua,14 Paola Simona Ravenda,7 Sara Lonardi,6 Nicola Silvestris,8 Berardino De Bari,5 Umberto Ricardi,4 Stefano Cascinu,2 Pierfrancesco Franco4 1Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; 2Department of Hematology and Oncology, University of Modena and Reggio Emilia, Modena, Italy; 3Oncology Department, SOC Oncology, ASL (Health Local Authority), Biella, Italy; 4Department of Oncology, Radiation Oncology, University of Turin, Turin, Italy; 5Radiation Oncology Department, Centre Hospitalier Régional Universitaire “Jean Minjoz”, Besançon Cedex, France; 6Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy; 7Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, Milan, Italy; 8Medical Oncology Unit, Cancer Institute Giovanni Paolo II, Bari, Italy; 9Department of Medical Oncology, University of Cagliari, Cagliari, Italy; 10Department of Surgical Sciences, University of Turin, Turin, Italy; 11Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana University, Pisa, Italy; 12Department of Medical Sciences, Pathology Unit, University of Turin, Turin, Italy; 13Biosciences Laboratory, Istituto Scientifico Romagnolo per Lo Studio e La Cura Dei Tumori (IRST) IRCCS, Meldola, Italy; 14Department of Radiotherapy, IRCCS, European Institute of Oncology, Milan, ItalyRead the original article

Anal cancer is an uncommon malignancy, but its incidence is increasing worldwide. Chemoradiation is the standard primary treatment for patients with loco-regional limited disease. However, once patients develop metastatic spread, the prognosis is very poor. Human papillomavirus (HPV) is present in around 80 % of anal cancers, but its prognostic and/or predictive value is essentially unknown in this disease.We retrospectively evaluated 50 patients with the diagnosis of anal squamous cell carcinoma treated at our institution with combined chemoradiotherapy for loco-regional limited disease. HPV status was evaluated from paraffin-embedded tumor tissues collected at the time of diagnosis by a polymerase chain reaction analysis.Among 50 patients, 42 (84 %) were HPV-positive. Thirty-two (64 %) patients were positive to genotype 16, two (4 %) to genotype 18, and three (6 %) to both 16 and 18. Lymph nodal involvement and clinical stage at diagnosis were more advanced for HPV-positive patients. After a median follow-up of 4 years (range 0.4-13.8), 46 (92 %) patients were alive. Overall, eight patients relapsed: One regional, one loco-regional, and six distant recurrences were observed. Four patients died of metastatic disease. Five-year disease-free survival (DFS) in HPV-positive and HPV-negative patients was 92.5 and 50.0 %, respectively (P0.01). In multivariate analysis, HPV-positivity was associated with a statistically significant better 5-year DFS (HR HPV+ vs HPV- 0.10; 95 % CI 0.02-0.50). Five-year overall survival in HPV-positive and HPV-negative patients was 93.3 and 66.7 %, respectively (P = 0.12).In our study, HPV-positive anal cancers had a statistically significant improved DFS compared to HPV-negative group.

OBJECTIVE The aim of the present study is to evaluate the accuracy of Positron Emission Tomography/Computed Tomography (PET/CT) with Fluorodeoxyglucose ([18F]FDG) to predict treatment response in patients with locally advanced rectal cancer (LARC) during neoadjuvant chemoradiotherapy. PATIENTS AND METHODS Forty-one LARC patients performed [18F]FDG-PET/CT at baseline (PET0). All patients received continuous capecitabine concomitant to radiotherapy on the pelvis, followed by intermittent capecitabine until two weeks before curative surgery. [18F]FDG-PET/CT was also carried out at 40 Gy-time (PET1) and at the end of neoadjuvant therapy (PET2). PET imaging was analysed semi-quantitatively through the measurement of maximal standardised uptake value (SUVmax) and the tumour volume (TV). Histology was expressed through pTNM and Dworak tumor regression grading. Patients were categorised into responder (downstaging or downsizing) and non-responder (stable or progressive disease by comparison pretreatment parameters with clinical/pathological characteristics posttreatment/after surgery). Logistic regression was used to evaluate SUVmax and TV absolute and percent reduction as predictors of response rate using gender, age, and CEA as covariates. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Survivals were compared by the Log-Rank test. RESULTS Twenty-three responders (9 ypCR, 14 with downstaged disease) and 18 non-responders showed differences in terms of both early and posttreatment SUVmax percent reduction (median comparison: responder = 63.2%, non-responder = 44.2%, p = 0.04 and responder = 76.9%, non-responder = 61.6%, p = 0.06 respectively). The best predictive cut-offs of treatment response for early and posttreatment SUVmax percent reduction were ≥57% and ≥66% from baseline (p = 0.02 and p = 0.01 respectively). CONCLUSIONS [18F]FDG-PET/CT is a reliable technique for evaluating therapy response during neoadjuvant treatment in LARC, through a categorical classification of the SUV max reduction during treatment.

For patients with Stage II colon cancer, the use of adjuvant chemotherapy remains controversial. The purpose of this study was to identify clinical and/or pathological findings related to a worse prognosis in this category of patients.We retrospectively analyzed the data of consecutive patients, extracted by an institutional Tumour Registry, admitted to an affiliated University Hospital in Milan (European Institute of Oncology) for adenocarcinoma of the colon (all sites), between 2000 and 2005, and having a final pT3 N0 pathology staging after curative surgery. Adjuvant chemotherapy was decided as a result of a medical decision within a multidisciplinary Tumor Board.Data of 137 patients were obtained, with a median follow-up of 77 months (range 6-131). Patients who received chemotherapy were younger than patients who did not. Nine patients out of 137 (6.5 %) died as a consequence of colon cancer recurrence; four of them had received adjuvant chemotherapy. Only histological grade III and mucinous histotype were found to impact on cumulative incidence of colon-related events (p 0.03 and 0.02, respectively); no impact was found on cumulative incidence of colonic neoplasm recurrence-related deaths (p 0.74 and 0.74, respectively). Number of analyzed LNs (lymph nodes) emerged as a factor possibly affecting the cumulative incidence of colon-related events (p 0.09) as well as the cumulative incidence of colonic neoplasm recurrence-related deaths (p 0.10). The risk of events was inversely proportional to the number of dissected LNs, even over 20 up to about 25 LNs. Never-smokers exhibited a lower incidence of colon-related events, although the difference was not statistically significant (p 0.09). All other analyzed variables did not show any impact on survival rate, including age, gender, ASA score, BMI, site of colonic neoplasm, multifocality, perivascular invasion, and use of adjuvant chemotherapy.Histology grading G3 and mucinous histotype were predictors of worse outcome. Efforts to improve LN evaluation should result in clinically significant improvements in outcome, and also the quality of care for patients with radically resected stage II colon cancer.

Though totally implantable access ports (TIAP) are extensively used, information from randomized trials about the impact of insertion site on patient's quality of life (QoL) and psychological distress is unavailable.Four hundred and three patients eligible for receiving intravenous chemotherapy for solid tumours were randomly assigned to implantation of a single type of TIAP, either through a percutaneous landmark access to the internal jugular or an ultrasound-guided access to the subclavian or a surgical cut-down access through the cephalic vein at the deltoid-pectoralis groove. Patients' QoL and psychological distress were investigated at regular intervals by means of EORTC QLQ-C30 and HADS (Hospital Anxiety and Depression Scale) questionnaires, using univariate and multivariate repeated measure linear mixed models. A post hoc analysis investigated the impact of type of administered chemotherapy (adjuvant vs palliative).Three hundred and eighty-four patients (95.2%) were evaluable, 126 with the internal jugular, 132 with the subclavian and 126 with the cephalic vein access. The median follow-up was 361 days (range, 0-1,087). Mean score changes for the items of the EORTC QLQ-C30 scales were significantly associated with type of administered chemotherapy only (P0.001), and not with implantation site. Frequency distribution of patients with depression and anxiety score greater than 10 at HADS was not significantly different, with respect either to type of administered chemotherapy or TIAP implantation site.Central venous insertion sites had no impact on patients' QoL and psychological distress. Patients undergoing palliative therapies showed worse EORTC QLQ-C30 scales.

Background/Aims: The prognosis of cloacogenic carcinoma of the anorectum has rarely been investigated, and its clinical behavior is supposed to be similar to common squamous anal cancers. During the last 10 years, chemoradiation treatment (CRT) has been considered the standard of care for anal cancer. Methods: We retrospectively investigated the treatment of cloacogenic cancers treated within the framework of a multidisciplinary cancer center team during an 8-year period. The medical records of 7 patients affected by cloacogenic carcinoma were analyzed. Three patients presented distant metastases at the time of diagnosis. CRT using 5-fluorouracil + mitomycin or cisplatin was considered the gold standard for those cases amenable to cure. Results: After a mean follow-up time of 33 months (range 9–100), disease recurrence or progression was observed in 6 patients, which caused death in 3 of them. Three- and 5-year actuarial overall survival rates were 71 and 48%, respectively. Conclusions: Our data seem to suggest that the cloacogenic origin could present prognostic relevance within the wide spectrum of anal cancers. This should be carefully considered when submitting patients to aggressive and prolonged treatments. However, this hypothesis needs to be confirmed by larger series of this disease.

Purpose To evaluate the impact of neoadjuvant capecitabine, concomitant to radiotherapy, followed by capecitabine monotherapy, in operable locally advanced rectal cancer (LARC) by measuring pathologic response and conservative surgery rate, toxicity profile, and disease-free survival (DFS). Methods and Materials From October 2002 to July 2006, a total of 51 patients affected by LARC (T3–T4 or any node positive tumor), received capecitabine (825 mg/m 2 , orally, twice daily continuously) concomitant to radiotherapy on the pelvis (50.4 Gy/ 28 fractions), followed by two cycles of capecitabine (1,250 mg/m 2 , orally, twice daily, 14 days on 7 days off) up until 2 weeks before surgery. Tailored adjuvant systemic treatment was discussed according to pathologic stage. Results Of 51 patients, (median age 61 years, range 38–82 years; 19 women and 32 men; ECOG performance status 0/1/2: 46/4/1), 50 were evaluable for response: 18% complete pathologic remission; 12% T-downstaging, and 30% N-downstaging. One patient died before surgery from mesenteric stroke. Grade 3 acute toxicities were 2% diarrhea, 8% dermatitis, 2% liver function test elevation, and 2% hand–foot syndrome. Sphincter preservation rates for tumors ≤6 cm from the anal verge were 62% and 80% for the whole population. Median follow up was 43.0 months (range 0.8–68.6 months). Five-years DFS was 85.4% (95% CI=75.3–95.4%). Conclusions Based on our study results, we conclude that this regimen is well tolerated and active and compares favorably with existing capecitabine-based approaches.

Rectal cancer is an important tumour from an epidemiological point of view and represents the benchmark for an optimal use of integrated treatments (surgery, radiotherapy and chemotherapy) in the oncological practice. The conventional use of total mesorectal excision and the integration with radiochemotherapy, better if preoperatively, are now able to increase survival, to decrease the occurrence of pelvic recurrence and to ameliorate the quality of life of patients. Updated recommendations for the management of these patients are here reported.

Second-line chemotherapy in patients with metastatic gastric cancer (MGC) pre-treated with cisplatin is not a standard option. We studied a combination of irinotecan, fluorouracil and folates.Patients progressive to cisplatin-based chemotherapy were enrolled. Irinotecan 180 mg/m(2), folinic acid 200 mg/m(2), and fluorouracil 400 mg/m(2) were given on day 1, immediately followed by fluorouracil 2,400 mg/m(2) 46 h continuous infusion (simplified FOLFIRI), every 2 weeks.Between June 2002 and May 2003, 28 patients were treated. Median age was 57 years (range 38-68). Most patients had a distal primary (90%), and metastatic disease (71%). Partial response was obtained in six patients (21%, 95% CI 8-41) and stable disease in eight (21%, 95% CI 13-41). Among the six responsive patients three were refractory to docetaxel. At a median follow-up of 2.9 years median time to progression was 4 months (95% CI: 2-5), and median overall survival was 5 months (95% CI 4-9). Toxicity was mild, without treatment-related deaths or life-treating adverse events.Simplified FOLFIRI was moderately active and well tolerated in unselected patients with MGC pre-treated with cisplatin-based chemotherapy. Its role in patients refractory to taxanes is promising and warrants further investigation.

Cetuximab is a monoclonal antibody that is effective in the treatment of metastatic colorectal cancer (mCRC). Cetuximab blocks epidermal growth factor receptor (EGFR)-ligand interaction and inhibits downstream RAS-ERK activation. However, only some activating mutations in RAS affect cetuximab efficacy, and it is not clear what else mediates treatment success. Here we hypothesized that cetuximab induces immunogenic cell death (ICD) that activates a potent antitumor response. We found that cetuximab, in combination with chemotherapy, fostered ICD in CRC cells, which we measured via the endoplasmic reticulum (ER) stress response and an increase in phagocytosis by dendritic cells. ICD induction depended on the mutational status of the EGFR signaling pathway and on the inhibition of the splicing of X-box binding protein 1 (XBP1), an unfolded protein response (UPR) mediator. We confirmed the enhanced immunogenicity elicited by cetuximab in a mouse model of human EGFR-expressing CRC. Overall, we demonstrate a new, immune-related mechanism of action of cetuximab that may help to tailor personalized medicine.

BACKGROUND. Gefitinib, an orally active inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, combined with chemotherapy, has shown efficacy as second-line treatment for advanced colorectal cancer (CRC). Gefitinib combined with FOLFOX6 (oxaliplatin plus folinic acid and 5-fluorouracil) was tested as a first-line therapy. METHODS. Patients with metastatic EGFR-positive CRC received gefitinib at a dose of 250 mg/day combined with simplified FOLFOX6. Gefitinib was continued as maintenance treatment in nonprogressing patients. Responses were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and adverse events were assessed with the National Cancer Institute Common Toxicity Criteria (NCI-CTC) scale. RESULTS. A total of 56 patients were recruited. There were 26 men and 30 women, with a median age of 57.5 years. The Eastern Cooperative Oncology Group (ECOG) performance status was as follows: 0 in 39 patients, 1 in 12 patients, and 2 in 5 patients. Thirty-nine patients (69.6%) had stage IV disease at diagnosis, 92.9% had liver involvement, and 46.4% had ≥2 metastatic sites. All patients were evaluated for safety, and 53 were evaluated for response: 40 patients (71.4%; 95% confidence interval [95% CI], 57.8%–82.6%) had complete or partial responses, and 11 patients (19.6%) had stable disease. Median time to progression was 7 months (range, 2.1–33.0 months; 95% CI, 6.2–9.0 months). Radical surgery or thermoablation of metastatic sites was performed in 14 patients (25%). NCI-CTC grade 3–4 events occurred in 36 patients (64.3%): diarrhea in 9 patients (16.1%), and hematologic toxicity in 13 patients (23.2%). Four patients (7.1%) were withdrawn for drug-related adverse events. CONCLUSIONS. The regimen has shown promising efficacy with manageable toxicity as a first-line treatment for patients with advanced CRC. Cancer 2007. © 2007 American Cancer Society.

The present study determines the oncologic outcome of the combined resection and ablation strategy for colorectal liver metastases (CRLM). Between January 1994 and December 2014, 360 patients underwent surgery for CRLM. There were 280 patients who underwent hepatic resection only (group 1) and 80 hepatic resection plus ablation (group 2). group 2 patients had a higher incidence of multiple metastases than group 1 cases (100% in group 2 vs. 28.2% in group 1; P

Anal cancer is a rare disease with an increasing incidence worldwide but, unfortunately, even today the scientific community still has a limited knowledge and limited options of treatment. More than 50% of patients with anal cancer presenting at diagnosis with locoregional disease have good chances of cure with chemoradiotherapy (CT–RT). However, once patients develop metastatic spread, the prognosis is very poor. Human papillomavirus (HPV) is present in more than 80% of anal cancers and while multiple etiologic connections between HPV infection and anal cancer have already been well elucidated, its prognostic and/or predictive role is currently under investigation, especially among immunocompetent patients affected by this disease. In a single-institutional set, we have retrospectively analysed clinical data of 50 consecutive cases homogeneously treated with CT–RT for stage I–III anal squamous cell carcinoma. We found that HPV-positive anal cancers had a statistically significant improved five-year disease-free survival (DFS) compared to HPV-negative group. These findings could be explained by an increased chemo/radiosensitivity of HPV-positive tumours. Further efforts should be directed towards a better understanding of HPV-related oncogenesis and towards designing novel tailored strategies for the management of this disease both in terms of prevention and treatment.

Following progression on first-line platinum and fluoropyrimidine-based chemotherapy, prognosis for advanced gastric cancer patients is extremely poor. Thus, new and effective treatments are required. Based on positive results of recent randomized controlled trials, second-line monochemotherapies with either irinotecan or taxanes confer a median overall survival of approximately 5 months in gastro-esophageal and gastric adenocarcinoma. Combination of weekly paclitaxel and ramucirumab, a novel anti-angiogenic VEGFR2 antibody, pushes the overall survival up to over 9.5 months, whereas apatinib, a novel oral VEGFR2 tyrosine kinase inhibitor, seems to be promising in heavily pretreated patients. In contrast, the role of EGFR/HER2 and mTOR inhibitors is controversial. Studies are heterogeneous for tumor population, geographical areas, quality of life assessment, type of first-line therapy and response to that, making clinical practice application of the trial results difficult. Furthermore, sustainability is challenging due to high cost of novel biotherapies.