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Objective Germline BRCA1-2 pathogenic variants (gBRCApv) increase the risk of pancreatic cancer and predict for response to platinating agents and poly(ADP-ribose) polymerase inhibitors. Data on worldwide gBRCApv incidence among pancreatic ductal adenocarcinoma (PDAC) patients are sparse and describe a remarkable geographic heterogeneity. The aim of this study is to analyze the epidemiology of gBRCApv in Italian patients. Materials and methods Patients of any age with pancreatic adenocarcinoma, screened within 3 months from diagnosis for gBRCApv in Italian oncologic centers systematically performing tests without any selection. For the purposes of our analysis, breast, ovarian, pancreas, and prostate cancer in a patient's family history was considered as potentially BRCA-associated. Patients or disease characteristics were examined using the χ2 test or Fisher's exact test for qualitative variables and the Student's t-test or Mann–Whitney test for continuous variables, as appropriate. Results Between June 2015 and May 2020, 939 patients were tested by 14 Italian centers; 492 (52%) males, median age 62 years (range 28-87), 569 (61%) metastatic, 273 (29%) with a family history of potentially BRCA-associated cancers. gBRCA1-2pv were found in 76 patients (8.1%; 9.1% in metastatic; 6.4% in non-metastatic). The gBRCA2/gBRCA1 ratio was 5.4 : 1. Patients with gBRCApv were younger compared with wild-type (59 versus 62 years, P = 0.01). The gBRCApv rate was 17.1% among patients 70 years old (none out of 94 patients >73 years old). gBRCApv frequency in 845 patients, Highlights • This is the largest case series of incident PDAC patients screened for germline BRCA1-2 pathologic variants (gBRCApv). • The incidence of gBRCA1-2pv was 8.1% in the whole population; 9.1% in metastatic patients; 6.4% in non-metastatic patients. • No gBRCA1-2pv was observed over the age of 73. • These data suggest screening all PDAC patients

Epidermal growth factor receptor (EGFR) inhibitors are valuable therapeutics in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab or panitumumab, in combination with chemotherapy are effective treatment options for patients with RAS and BRAF wild-type mCRC. Nevertheless, several issues are still open concerning the optimal use of anti-EGFR drugs in the continuum of care of mCRC. Novel approaches for increasing the efficacy of anti-EGFR therapies include better molecular selection of EGFR-dependent mCRC, intensification of chemotherapy, combination of anti-EGFR MoAbs and immune checkpoint inhibitors, and reintroduction of EGFR blockade or 'rechallenge' in selected patients who have previously responded to anti-EGFR MoAb therapy. An extensive translational research program was conducted in the Cetuximab After Progression in KRAS wIld-type colorectal cancer patients-Gruppo Oncologico dell' Italia Meridionale (CAPRI-GOIM) study with the aims of determining which subgroups of patients could benefit from the continuous inhibition of EGFR, from evaluating the role of liquid biopsy-based and its concordance with tissue-based molecular testing, and from investigating novel potential mechanisms of resistance to anti-EGFR therapies. In this review, we summarize the translational and clinical findings of the CAPRI-GOIM program in the context of the current knowledge of therapeutic strategies and of ongoing research on more appropriate uses of anti-EGFR therapies in RAS and BRAF wild-type mCRC patients.

Background: By the end of 2020, coronavirus disease 2019 (COVID-19) would have indelibly marked the cancer care setting. With Italy at the forefront of pandemic, unprecedented measures were adopted to tackle the quality care issue. As a result of pausing screening programs, diagnostic delays might affect the years to come. Aim of our multicenter Italian study is to evaluate whether the COVID-19 outbreak has impacted on likelihood of receiving timely diagnosis, staging and treatment for colorectal cancer (CRC) patients (pts) after March 2020 compared to pre-pandemic time. Methods: Medical records of all consecutive newly diagnosed CRC pts referred to 4 Italian Oncology Departments between March and December 2020 were examined. Access rate (number of pts/days) and temporal intervals between date of symptoms onset, radiological and cytohistological diagnosis, treatment start and first radiological evaluation were analyzed and compared with the same months of 2019. Differences between the two years were evaluated using Fisher’s exact test or chi-square test for categorical variables and unpaired Student t test, or the Mann-Whitney U test for continuous variables. Results: A reduction (20%) in newly diagnosed CRC cases was seen when compared with 2019 (214 vs 268). The decline was greater in the lockdown period compared to the other months (percentage drop 40 % vs 12%). Newly CRC pts in 2020 were less likely to be diagnosed with early stage (stage I-II-III) CRC (67% vs 72%). Other clinical and tumor characteristics were similar regardless of the year. Looking at pts management, no differences emerged in terms of interval between symptom onset and radiological diagnosis (median 19 days in 2020 vs 28 days in 2019, p = 0.88), symptom onset and cytohistological diagnosis (25 vs 36 days, p = 0.27), symptom onset and treatment start (median 86 vs 100 days, p = 0.79). However, less CRC were discussed in multidisciplinary tumor meetings during the 2020 (45% vs 54%, p = 0.07). Conclusions: While COVID-19 repercussions will be likely felt for decades to come, our data suggest an alarming drop in early-stage CRC diagnoses during the first pandemic year. Conversely, our study draws the attention on the efforts made to ensure diagnostic-therapeutic pathways proper operation. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Mechanisms of acquired resistance to trastuzumab-based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post-progression in patients receiving chemotherapy and trastuzumab for advanced HER2-positive [immunohistochemistry (IHC) 3+ or 2+ with in-situ hybridization (ISH) amplification] gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over-expression were defined as post-trastuzumab IHC score

Background The prognostic role of Progesterone receptor (PR) expression in early invasive breast cancer (BC) remains controversial. The aim of this retrospective analysis was to investigate the impact of PR expression levels on outcome of patients with luminal-like Her2 negative early BC. Methods A population cohort of 441 primary invasive ER+/Her2- early BC patients from a single cancer center underwent surgery and received adjuvant endocrine therapy from 2000 to 2017 was retrieved. To assess the impact of the different PR levels on the prognosis, we calculated the Distant Free Survival (DFS) and the Breast Cancer Specific Survival (BCSS) according to 4 subtypes established on the basis of Ki67 value and PR expression rate (Subtype 1: PR ≥ 20%/Ki67 Results The rates of progression disease were 8%, 19%, 30% and 12% in subtype 1, 2, 3 and 4, respectively. Low PR expression ( Conclusions Our study revealed different outcomes among patients with early BC according to different PR expression levels. Noteworthy, in patients with Ki67 ≥20%, low PR expression levels ( Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure A. Diana: Travel / Accommodation / Expenses: Ipsen, Novartis, Pharmamar, Italfarmaco. F. Carlino: Travel / Accommodation / Expenses: Italfarmaco, Gentili. E. Franzese: Travel / Accommodation / Expenses: Roche. S. Centonze: Travel / Accommodation / Expenses: Thesaro, Roche, Gentili. F. De Vita: Advisory / Consultancy: Roche, Amgen, Celgene, Lilly. F. Ciardiello: Advisory / Consultancy: Merck, Roche, Lilly, Bayer, Amgen, Pfizer, Servier. M. Orditura: Honoraria (self): Epionpharma, Italfarmaco; Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): EISAI. All other authors have declared no conflicts of interest.

In the cetuximab after progression in KRAS wild-type colorectal cancer patients (CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups. Background: In the cetuximab after progression in KRAS wild-type colorectal cancer patients ( CAPRI) trial patients with metastatic colorectal cancer (mCRC) received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) and cetuximab in first line followed by 5-Fluorouracil, folinic acid, oxaliplatin (FOLFOX) with or without cetuximab until progression. Limited data are available on the efficacy and safety of anti-epidermal growth factor receptor (anti-EGFR) agents on elderly patients with mCRC. In the current study we evaluated the efficacy and safety of FOLFIRI plus cetuximab in age-defined subgroups.Methods: A post-hoc analysis was performed in CAPRI trial patients; outcomes (progression-free survival (PFS), overall response rate (ORR), safety) were analysed by agegroups and stratified according to molecular characterisation. 3 age cut-offs were used to define the elderly population (>= 65; >= 70 and >= 75 years).Results: 340 patients with mCRC were treated in first line with FOLFIRI plus cetuximab. Among those, 154 patients were > 65 years, 86 > 70 years and 35 > 75 years. Next-generation sequencing (NGS) was performed in 182 patients. Among them, 87 patients were > 65 years, 46 > 70 and 17 > 75. 104 of 182 patients were wild type (WT) for KRAS, NRAS, BRAF, PIK3CA genes. In the quadruple WT group, 51 patients were >= 65 years; 29 were >= 70; 9 were >= 75. Median PFS was similar within the age-subgroups in the intention-to-treat population, NGS cohort and quadruple WT patients, respectively. Likewise, ORR was not significantly different among age-subgroups in the 3 populations. Safety profile was acceptable and similarly reported among all age-groups, with the exception of grade >= 3 diarrhoea (55% vs 25%, p=0.04) and neutropaenia (75% vs 37%, p=0.03) in patients >= 75 years and grade >= 3 fatigue (31% vs 20%, p=0.01) in patients < 75 years.Conclusions: Tolerability of cetuximab plus FOLFIRI was acceptable in elderly patients. Similar ORR and PFS were observed according to age-groups. No differences in adverse events were reported among the defined subgroups with the exception of higher incidence of grade >= 3 diarrhoea and neutropaenia in patients >= 75 years and grade >= 3 fatigue in patients < 75 years.

// Floriana Morgillo 1 , Carminia Maria Della Corte 1 , Anna Diana 1 , Concetta di Mauro 2 , Vincenza Ciaramella 1 , Giusi Barra 3 , Valentina Belli 1 , Elisena Franzese 1 , Roberto Bianco 2 , Evaristo Maiello 4 , Ferdinando De Vita 1 , Fortunato Ciardiello 1 and Michele Orditura 1 1 Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale “F. Magrassi”, Universita degli Studi della Campania “Luigi Vanvitelli”, Napoli, Italy 2 Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Universita degli Studi di Napoli “Federico II”, Napoli, Italy 3 Immunologia Clinica, Dipartimento di Internistica Clinica e Sperimentale “F. Magrassi”, Universita degli Studi della Campania “Luigi Vanvitelli”, Napoli, Italy 4 IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy Correspondence to: Floriana Morgillo, email: florianamorgillo@yahoo.com , floriana.morgillo@unicampana.it Keywords: AKT, breast cancer, taselisib, ipatasertib, novel drugs Received: March 22, 2017 Accepted: July 26, 2017 Published: August 22, 2017 ABSTRACT Purpose: The Phosphatidylinositol 3-kinase (PI3Ks) pathway is commonly altereted in breast cancer patients, but its role is still unclear. Taselisib, a mutant PI3Kα selective inhibitor, and ipatasertib, an AKT inhibitor, are currently under investigation in clinical trials in combination with paclitaxel or hormonal therapies in breast cancer. The aim of this study was to evaluate if PI3K or AKT inhibition can prevent resistance to chemotherapy and potentiate its efficacy. Experimental design: The efficacy of combined treatment of ipatasertib and taselisib plus vinorelbine or paclitaxel or eribulin was evaluated in vitro on human breast cancer cells (with different expression profile of hormonal receptors, HER2, and of PI3Ka mutation) on cell survival by using MTT (3,(4,5-dimethylthiazol-2)2,5 difeniltetrazolium bromide) and colony forming assays on cell apoptosis by flow-cytometry analysis. We also investigated the effect of combined treatment on downstream intracellular signaling, by western blot analysis, and on metastatic properties, by migration assays. Finally, we analyzed changes in cell cytoskeleton by immunofluorescence. Results: A significant synergism of ipatasertib or taselisib plus anti-microtubule chemotherapy in terms of anti-proliferative, pro-apoptotic and anti-metastatic effect was observed. The combined treatment completely inhibited the activation of proteins downstream of PI3K and MAPK pathways and affected the expression of survivin. Combined treatments completely disorganized the cytoskeleton in human breast cancer cells, with contemporary delocalization of survivin from cytoplasm to nucleus, thus suggesting a potential mechanism for this combination. Conclusions: Targeting PI3K may enhance the efficacy of anti-microtubule drugs in human breast cancer cells.

Background Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression. Patients and methods We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progression-free survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis. Results Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7–8.0] versus 4.5 months (95% CI 3.3–5.7); [hazard ratio (HR), 0.81; 95% CI 0.58–1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5–8.2) versus 5.3 months (95% CI 3.7–6.9); HR, 0.56 (95% CI 0.33–0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4–28.0) versus 19.8 months (95% CI 14.9–24.7); HR, 0.57 (95% CI 0.32–1.02); P = 0.056]. Conclusions Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials.

"Background: Preoperative chemoradiotherapy (CRT) improves the survival of patients with oesophageal cancer when compared with surgery alone.. . Methods: We conducted a phase II, multicenter trial of FOLFOX-4 and cetuximab in patients with locally advanced oesophageal cancer (LAEC) followed by daily radiotherapy (180 cGy fractions to 5040 cGy) with concurrent weekly cetuximab. Cytokines levels potentially related to cetuximab efficacy were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, at week 8 and at week 17. Primary end point was complete pathological response rate (pCR).. . Results: In all, 41 patients were enroled. Among 30 patients who underwent surgery, a pCR was observed in 8 patients corresponding to a rate of 27%. The most frequent grade 3\/4 toxicity was skin (30%) and neutropenia (30%). The 36-month survival rates were 85 and 52% in patients with pathological CR or PR vs 38 and 33% in patients with SD or PD.. . Conclusions: Incorporating cetuximab into a preoperative regimen for LAEC is feasible; no correlation between cytokines changes and patient outcome was observed. Positron emission tomography\/computed tomography study even if influenced by the small number of patients appears to be able to predict patients outcome both as early and late metabolic response.. . " Background: Preoperative chemoradiotherapy (CRT) improves the survival of patients with oesophageal cancer when compared with surgery alone. Methods: We conducted a phase II, multicenter trial of FOLFOX-4 and cetuximab in patients with locally advanced oesophageal cancer (LAEC) followed by daily radiotherapy (180 cGy fractions to 5040 cGy) with concurrent weekly cetuximab. Cytokines levels potentially related to cetuximab efficacy were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, at week 8 and at week 17. Primary end point was complete pathological response rate (pCR). Results: In all, 41 patients were enroled. Among 30 patients who underwent surgery, a pCR was observed in 8 patients corresponding to a rate of 27%. The most frequent grade 3/4 toxicity was skin (30%) and neutropenia (30%). The 36-month survival rates were 85 and 52% in patients with pathological CR or PR vs 38 and 33% in patients with SD or PD. Conclusions: Incorporating cetuximab into a preoperative regimen for LAEC is feasible; no correlation between cytokines changes and patient outcome was observed. Positron emission tomography/computed tomography study even if influenced by the small number of patients appears to be able to predict patients outcome both as early and late metabolic response. © 2011 Cancer Research UK All rights reserved.

In the last decade dramatic improvements have been obtained in the treatment of metastatic colorectal cancer. Thanks to the introduction in the clinical practice of new drugs such as Irinotecan and Oxaliplatin, and modern biological drugs such as Bevacizumab and Cetuximab, the response rate, progression-free and overall survival are about 50-60%, 9-11 and 20-24 months respectively. Despite this progress, many questions remain unsolved especially those related to the optimal duration of treatment and the role of maintenance therapy. To treat until progression (or unacceptable toxicity) is the classical way but in the common clinical practice is frequent to perform an induction therapy (until the maximum response is obtained) followed by a complete stop and restart on progression, or by a maintenance without the drug/s responsible of the major cumulative toxicities. The following report focus on the role of different strategies respect to the classic "treatment until progression".

Capecitabine is an orally administered fluoropyrimidine carbamate which has been developed as a prodrug of 5-FU with the goal to improve its tolerability and intratumoral drug concentration. The review aims to provide an evidence-based update of clinical trials investigating the clinical efficacy, adverse-event profile, dosage and administration of this drug, alone or in combination with conventional chemotherapeutics and/or new target-oriented drugs, in the management of colorectal cancer patients. © 2010 Elsevier Ltd.

The aims of this multicentre, randomised phase III trial were to evaluate: (1) the role of levamisol (LEV); and (2) the role of folinic acid (FA), added to 5-fluorouracil (5FU) in the adjuvant treatment of colorectal cancer. Patients with histologically proven, radically resected stage II or III colon or rectal cancer were eligible. The study had a 2x2 factorial design with four treatment arms: (a) 5FU alone, (b) 5FU+LEV, (c) 5FU+FA, (d) 5FU+LEV+FA, and two planned comparisons, testing the role of LEV and of FA, respectively. From March 1991, to September 1998, 1327 patients were randomised. None of the two comparisons resulted in a significant disease-free (DFS) or overall (OAS) survival advantage. The hazard ratio (HR) of relapse was 0.89 (95\% confidence intervals (CI): 0.73-1.09) for patients receiving FA and 0.99 (95\% CI 0.80-1.21) for those receiving LEV; corresponding HRs of death were 1.02 (95\% CI: 0.80-1.30) and 0.94 (95\% CI 0.73-1.20). Nonhaematological toxicity (all grade vomiting, diarrhoea, mucositis, congiuntivitis, skin, fever and fatigue) was significantly worse with FA, while all other toxicities were similar. In the present trial, there was no evidence that the addition of FA or LEV significantly prolongs DFS and OAS of radically resected colorectal cancer patients..

Gastric cancer is still a major health problem and a leading cause of cancer mortality despite a worldwide decline in incidence. Surgical resection with curative potential is the only treatment modality of scientific proven effectiveness. Many phase III trials of adjuvant therapy have been conducted, however, postoperative treatment modalities have not proven to be superior to pos-surgical observation alone. Therefore, at present the routine use of adjuvant therapy should be regarded as an investigational approach. Improved clinical trial designs with standardized surgical techniques and the incorporation of newer active drugs are needed.

The aim of this study was to assess the safety and efficacy of biweekly irinotecan plus leucovorin-modulated 5-fluorouracil i.v. bolus in metastatic colorectal carcinoma according to the age of patients. For this purpose, we have analysed 108 patients randomly allocated to receive irinotecan 200 mg m(-2) i.v. (1-h infusion) on day 1, and L-leucovorin 250 mg m(-2) i.v. (1-h infusion) plus 5-fluorouracil 850 mg m(-2) i.v. bolus on day 2 every 2 weeks (IRIFAFU) in our previous SICOG 9801 trial. According to age, patients were retrospectively divided into three groups: younger (/=54 years, n=37), middle-aged (55-69 years, n=64), and elderly (/=70 years, n=17). Apart from gender, pretreatment characteristics were well balanced across the three groups. WHO grade/=3 neutropenia and diarrhoea affected on the whole 46 and 16 patients, respectively, without any significant difference according to age-grouping. Patients aged/=54 years stayed on therapy for a longer time (median 24 vs 14-15 weeks), and received more cycles (median 9 vs 7), than the older ones. Only one patient in the young group withdrew consent to therapy as opposed to four patients each in the aged and elderly one. Response rate was 38% for younger patients, 34% for aged, and 35% for the elderly ones. Median time to progression was 7.4, 8.0, and 5.3 months, and median survival time was 13.4, 15.3, and 13.9 months, respectively. We conclude that IRIFAFU given every other week may represent a suitable therapeutic option also for elderly patients with metastatic colorectal carcinoma.

Treatment with antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies has been restricted to metastatic colorectal cancer (mCRC) patients with RAS wild-type tumors. Next-generation sequencing (NGS) allows the assessment in a single analysis of a large number of gene alterations and might provide important predictive and prognostic information.In the CAPRI-GOIM trial, 340 KRAS exon 2 wild-type mCRC patients received first-line FOLFIRI plus cetuximab. Tumor samples (182/340, 53.5%) were assessed by NGS to search for mutations in 22 genes involved in colon cancer.Objective responses in the NGS cohort were observed in 104/182 patients [overall response rate (ORR) 57.1%; 95% confidence interval (95% CI) 52% to 66.4%] with a median progression-free survival (mPFS) of 9.8 (95% CI 8.7-11.5) months. NGS analysis was successfully completed in all 182 samples. One or more gene mutations (up to five) were detected in 124/182 (68.1%) tumors within 14/22 genes for a total of 206 mutations. KRAS exon 2 mutations were identified in 29/182 (15.9%) samples, defined as wild type by local laboratory assessment. Frequently mutated genes were: TP53 (39.6%), KRAS exons 3/4 (8.8%), NRAS exons 2/3 (7.1%), PIK3CA exons 9/20 (13.2%), BRAF (8.2%). FOLFIRI plus cetuximab treatment determined ORR of 62.0% (95% CI 55.5% to 74.6%) with mPFS of 11.1 (95% CI 9.2-12.8) months in patients with KRAS and NRAS wild-type tumors. Conversely, ORR was 46.6% (95% CI 39.9-57.5%) with mPFS of 8.9 (95% CI 7.4-9.6) months in patients with KRAS or NRAS mutations. Similarly, the subgroup of patients carrying KRAS, NRAS, BRAF, or PIK3CA mutations showed a worse outcome, although this might be due to a prognostic effect.This study demonstrates that NGS analysis in mCRC is feasible, reveals high level of intra and intertumor heterogeneity, and identifies patients that might benefit of FOLFIRI plus cetuximab treatment.

Summary Purpose To determine the maximum tolerated dose of oxaliplatin (L-OHP) given as a two-hour infusion followed by raltitrexed (Tomudex® [TOM]) administered as a 15-min infusion on day 1, and bolus 5-fluorouracil (5-FU) modulated by a fixed dose of levo-folinic acid (LFA) 250 mg/m2 on day 2, recycling every two weeks, and to have preliminary evidence of activity of this combination in pretreated advanced colorectal cancer patients. Patients and methods Fifty-two patients with advanced colorectal carcinoma previously treated with one (25 cases) or two or more lines of chemotherapy, including irinotecan (26 cases), and/or modulated 5-FU (40 cases) entered this study. Starting doses of L-OHP, TOM, and 5-FU were 85, 2.5 and 750 mg/m2, respectively. Results Seven dose levels were tested. Neutropenia was the main dose limiting toxicity of the dose escalation (8 of 13 cases). The recommended doses were 130 mg/m2 of L-OHP, and 3.0 mg/m2 of TOM on day 1, followed by 250 mg/ m2 of LFA, and 1050 mg/m2 of 5-FU on day 2, every two weeks. Severe diarrhoea and stomatitis were rarely reported. Most patients complained of mild peripheral sensitive neurotoxicity, which was related to the cumulative dose of L-OHP. Twelve patients were considered as having a major responses (one complete), and an additional eight patients showed a minor response; the median time to treatment failure was twenty-four weeks. Conclusions With this regimen it is possible to give full doses of all three cytotoxic drugs every two weeks. Its activity and its manageable toxicity profile deserve further evaluation in pretreated advanced colorectal cancer patients.

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors are in clinical development in cancer treatment. Preclinical studies have shown potential antitumor efficacy of these agents in combination with chemotherapy or with radiotherapy. However, controversial results have been obtained in different clinical trials. MATERIALS AND METHODS: The effects on proliferation, cell cycle distribution and induction of apoptosis of three different anti-EGFR agents (gefitinib, ZD6474, cetuximab) were evaluated in different sequences of combination with either a platinum derivative (cisplatin, carboplatin, oxaliplatin) or a taxane (docetaxel, paclitaxel) in KYSE30 cells, a model of a human cancer cell line with a functional EGFR autocrine pathway. RESULTS: The combination of a cytotoxic drug with an EGFR inhibitor caused different antiproliferative effects on KYSE30 cancer cells depending on the treatment schedule. An antagonistic effect was observed when treatment with each EGFR inhibitor was done before chemotherapy. In contrast, a synergistic antiproliferative activity was obtained when chemotherapy was followed by treatment with EGFR antagonists. This effect was accompanied by potentiation of apoptosis and arrest of the surviving cancer cells in the G(2)/M phases of the cell cycle. CONCLUSIONS: This study provides a rationale for the evaluation of a potentially synergistic sequence of cytotoxic drugs and EGFR inhibitors in a clinical setting.

Sorafenib is considered the standard systemic therapy for hepatocellular carcinoma (HCC), in patients with well-preserved liver function (Child-Pugh A class) and advanced-stage HCC (BCLC-C) or in patients with HCC progressing after locoregional therapies, with a high grade of recommendation. The approval of sorafenib for this indication was grounded on the efficacy and the safety results reported by two international randomized, controlled trials, the SHARP and the Asia-Pacific studies. In addition, the efficacy and the safety of sorafenib in clinical practice are addressed by several field-practice experiences, including the multinational GIDEON study and the SOFIA study. Finally, further research on sorafenib is ongoing to optimize the use of this molecule. This review aims to provide an overview of the most relevant clinical data on the efficacy and the safety of sorafenib in patients with HCC.