Prolonged Pemetrexed Infusion Plus Gemcitabine in Refractory Metastatic Colorectal Cancer: Preclinical Rationale and Phase II Study Results.

LESSONS LEARNED: Difficulties in translating in vitro results into clinical practice are inevitable.Further efforts to verify the efficacy of alternative schedules of pemetrexed in solid tumors are encouraged. BACKGROUND: We investigated the cytotoxic activity of pemetrexed in combination with several drugs (gemcitabine, carboplatin, vinorelbine, and mitomycin C) using different exposure schedules in three colon cancer cell lines. The best results were obtained with the following schedule: a prolonged pemetrexed exposure followed by a 48-hour wash-out and then gemcitabine. This combination was then advanced to a phase II clinical trial. METHODS: Patients with metastatic colorectal cancer in progression after standard treatment were included in the study. Adequate bone marrow reserve, normal hepatic and renal function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were required. Treatment consisted of an 8-hour intravenous infusion of pemetrexed 150 mg/m2 on day 1 and a 30-minute intravenous infusion of gemcitabine 1,000 mg/m2 on day 3 of each cycle, repeated every 14 days. RESULTS: Fourteen patients were enrolled onto the study (first step). No objective responses were seen, and evidence of stable disease was observed in only one of the 12 evaluable patients. The most important grade 3-4 side effects were hematological toxicity (neutropenia 64.2%, thrombocytopenia 71.4%, anemia 28.7%), fatigue (50.0%), and stomatitis (21.5%). Median overall survival and time to progression were 5.8 months (95% confidence interval [CI]: 3.9-7.1) and 2.1 months (95% CI: 1.7-2.8), respectively. CONCLUSION: The experimental pemetrexed-gemcitabine combination proved to be inactive and moderately toxic.

[Facts and figures of clinical pathways in Italy: results from the PDTA Net project.] / I numeri dei percorsi diagnostico-terapeutici assistenziali (PDTA) in Italia: risultati dal progetto PDTA Net.

The approval of clinical pathways (CPWs) represents a key step to focus the care management on the patient. The PDTA Net project, by ReS Foundation and CINECA, aims to create a reference tool to study how the local organizational models influence healthcare and clinical outcomes. The article shows the analysis of all CPWs approved by Italian Regions and Autonomous Provinces until 31/12/2018. The search for documents was performed on the institutional websites through specific keywords. CPWs were filled into a database, according to the Region, publication year, disease of interest (distinguishing between chronic diseases with high epidemiological impact and rare diseases) and relevant clinical area. All documents were analyzed by geographical and temporal distribution, the latter also according to ministerial measures. From 2005 to 2018, 536 Regional CPWs were approved (316 for chronic diseases with a high epidemiological impact and 220 for rare diseases). The Regions with the highest number of CPWs of chronic diseases were Umbria (34 CPWs) and Piemonte (33). The most addressed clinical areas were: oncology (72), neurology (60), cardiology (34) and metabolic disorders (22). The most issued diseases were: diabetes (17), trauma/polytrauma (15), chronic obstructive pulmonary disease and multiple sclerosis (12 each), stroke (11), rheumatoid arthritis, breast cancer and colorectal neoplasms (10 each). The publication of the documents was affected by ministerial measures (Balduzzi Law, National Chronicity Plan, Diabetic Disease Plan and National Dementia Plan). The majority of CPWs on rare diseases was retrieved in Regions with activated Rare Disease Networks: Lombardia (110 CPWs), Lazio (64) and Toscana (17). This study showed that, to date, in Italy there are several CPWs published at Regional level, nevertheless their structure and application are heterogeneous and strongly influenced by the National Plans. All analyzed documents are available through the web platform of the project https://fondazioneres.it/pdta/. This project could be useful for health system stakeholders, in order to encourage the transition to new health governance and making CPWs effective governance tools.

HR+/HER2- Metastatic Breast Cancer: Epidemiology, Prescription Patterns, Healthcare Resource Utilisation and Costs from a Large Italian Real-World Database.

BACKGROUND AND OBJECTIVE: Breast cancer is the second leading cause of cancer death worldwide. The economic burden of breast cancer is crucial for the sustainability of healthcare systems. The objective of this study was to estimate the burden of HR+/HER2- metastatic breast cancer (MBC) in Italy, in terms of incidence, prescription patterns, healthcare resource utilisation and costs for the National Health System (NHS). METHODS: A cohort study based on healthcare administrative data (ReS database), covering > 10 million Italians, was performed. Incident cases of HR+/HER2- MBC were identified among adult women in 2013. The cohort was followed-up for 2 years to describe healthcare utilisation and integrated costs (pharmaceuticals, hospitalisations and outpatient services) for NHS. Prescription patterns were described as first-line choice and therapeutic changes. Specific therapeutic changes were used as proxies of disease progression. A survival analysis was performed to estimate the time from diagnosis to first disease progression. RESULTS: Of 5174,723 women, 355 cases of de novo HR+/HER2- MBC were selected (incidence: 6.9 per 100,000). During the 1st follow-up year, they generated an average cost of €7543, whereas €4834 in the 2nd year. The 85.9% received a monotherapy, while the 14.1% received a combination therapy. The most used monotherapy was nonsteroidal-aromatase-inhibitors (45.9%), while the most prescribed combination was tamoxifen + luteinizing hormone releasing hormone (LHRH) analogues (6.2%). Therapeutic changes occurred in 45.4% of patients, especially from chemotherapy to nonsteroidal-aromatase-inhibitors, after an average of 276.8 days from the first treatment. Disease progression was identified in 22.5% of patients occurring after a mean 13 ± 6 months from diagnosis. CONCLUSIONS: This detailed picture of HR+/HER2- MBC, based on real-world data, could be helpful in health technology assessment and expenditure forecasts of future therapeutic strategies for this condition in Italy.

IGG practice guidelines on germ cell tumor in adult male patients.

Germ cell tumors are rare neoplasms that affect young males. Nearly 99% of patients with localized stage I disease and nearly 80% of patients with metastatic disease can be cured. Even patients who relapse following chemotherapy can achieve a long-term survival in approximately 30-40% of cases. The main objective in early stages and in good prognosis patients has changed in recent years, and it has become of major importance to reduce treatment-related morbidity without compromising the excellent long-term survival rate. In poor prognosis patients, there is a correlation between the experience of the treating institution and the long-term clinical outcome of the patients, particularly when the most sophisticated therapies are needed. So far, of utmost importance is the information from updated practice guidelines for the diagnosis and treatment of germ cell tumors. The Italian Germ cell cancer Group (IGG) has developed the following clinical recommendations, which identify the current standards in diagnosis and treatment of germ cell tumors in adult males.

Feasibility of radiotherapy after high-dose dense chemotherapy with epirubicin, preceded by dexrazoxane, and paclitaxel for patients with high-risk Stage II-III breast cancer.

PURPOSE: To verify the feasibility of, and quantify the risk of, pneumonitis from locoregional radiotherapy (RT) after high-dose dense chemotherapy with epirubicin and paclitaxel with peripheral blood progenitor cell support in patients with high-risk Stage II-III breast cancer. METHODS AND MATERIALS: Treatment consisted of a mobilizing course of epirubicin 150 mg/m2, preceded by dexrazoxane (Day 1), paclitaxel 175 mg/m2 (Day 2), and filgrastim; followed by three courses of epirubicin 150 mg/m2, preceded by dexrazoxane (Day 1), paclitaxel 400 mg/m2 (Day 2), and peripheral blood progenitor cell support and filgrastim, every 16-19 days. After chemotherapy, patients were treated with locoregional RT, which included the whole breast or the chest wall, axilla, and supraclavicular area. RESULTS: Overall, 64 of 69 patients were evaluable. The interval between the end of chemotherapy and the initiation of RT was at least 1.5-2 months (mean 2). No treatment-related death was reported. After a median follow-up of 27 months from RT (range 5-77 months), neither clinically relevant radiation pneumonitis nor congestive heart failure had been reported. Minor and transitory lung and cardiac toxicities were observed. CONCLUSION: Sequential high doses of epirubicin, preceded by dexrazoxane, and paclitaxel did not adversely affect the tolerability of locoregional RT in breast cancer patients. The risk of pneumonitis was not affected by the use of sequential paclitaxel with an interval of at least 1.5-2 months between the end of chemotherapy and the initiation of RT. Long-term follow-up is needed to define the risk of cardiotoxicity in these patients.

Dose and outcome: the hurdle of neutropenia (Review).

The development of chemotherapy in the early 1970s resulted in the availability of curative therapeutic strategies for hematological malignancies and several types of solid tumors. It is evident that drugs should be used at their optimal dose and schedule, and drug combinations should be given at consistent intervals. According to the mathematical models that suggested the direct dose-response relationship in the improvement of outcomes in cancer chemotherapy, the dose intensity and, more recently, the dose-dense approach was considered one of the most important tools in conventional chemotherapy. Anticancer drugs are often associated with myelotoxicity, and reducing the dose or increasing the time interval between each cycle of treatment is a frequent empiric approach. Unfortunately, a dose reduction of >or=20% causes a loss of 50% in the cure rate, particularly in chemosensitive tumors. To accelerate bone marrow recovery and prevent the onset of severe myelosuppression and its complications, the standard use of granulocyte colony-stimulating factors (G-CSF), such as filgrastim and the long-acting pegfilgrastim, is recommended. The aim of this review is to analyze how dose intensification concepts and dose-dense regimens are able to increase the cure rate of chemosensitive solid tumors and lymphomas.

Effect of angiosonography to monitor response during imatinib treatment in patients with metastatic gastrointestinal stromal tumors.

PURPOSE: Gastrointestinal stromal tumor (GIST) metastases are typically intra-abdominal and hypervascular. We assessed the effect of angiosonography with a second-generation contrast agent to monitor response during imatinib treatment in patients with metastatic KIT+ GIST. EXPERIMENTAL DESIGN: Ten consecutive patients with known advanced KIT+ GIST were investigated with angiosonography and computerized tomography (CT). We also monitored the serum levels of the major angiogenic growth factor, vascular endothelial growth factor. RESULTS: Angiosonography showed a reduction in tumor vascularization of liver metastases during imatinib treatment in all cases. We observed a reduction in tumor vascularization before a reduction in tumor size. The tumor perfusion appeared reduced in the central part of the liver metastases. With a median follow-up of 18 months (range 3-33), a reduction in tumor vascularization was initially observed in all patients, but progressive disease was documented in four patients following imatinib treatment. CT documented tumor response according to standardized criteria in six patients, stable disease in four, and progressive disease according to angiosonography. The reduction of tumor perfusion at angiosonography correlated with the pseudocystic appearance at CT. The "nodule(s) within a mass" pattern of recurrence occurred in two patients with no difference observed between angiosonography and CT. Early decreasing serum vascular endothelial growth factor levels were observed in the two cases with higher pretreatment levels. CONCLUSIONS: Imatinib could induce antiangiogenic and/or antivascular effects in GIST, and this effect could be easily monitored with angiosonography. Angiosonography might be a useful complement for monitoring the therapeutic effect of imatinib in these patients.

Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer.

Non-small-cell lung cancer patients with locally advanced or metastatic disease at the time of diagnosis show marginal response to chemotherapy in terms of tumor shrinkage, time to progression and median survival. The identification and implementation of predictive genetic markers of response-specific cytotoxic drugs is a priority of current research and future trials. In this study, we have used quantitative PCR to analyse expression of beta-tubulin III, stathmin, RRM1, COX-2 and GSTP1 in mRNA isolated from paraffin-embedded tumor biopsies of 75 nonsmall-cell lung cancer patients treated as part of a large randomized trial. In total, 22 patients were treated with gemcitabine/cisplatin, 25 with vinorelbine/cisplatin and 28 with paclitaxel/carboplatin. There were no differences in clinical characteristics and transcript levels in the pretreatment biopsies according to treatment arm. Patients with low beta-tubulin III levels had better response in the paclitaxel/carboplatin arm (P=0.05), and those with low RRM1 levels showed a tendency to better response in the gemcitabine/cisplatin arm. Time to progression was influenced by beta-tubulin III (P=0.03) and stathmin (P=0.05) levels in the vinorelbine/cisplatin arm, and there was a tendency toward correlation between beta-tubulin III levels and time to progression in the paclitaxel/carboplatin arm. RRM1 levels influenced time to progression (P=0.05) and even more so, survival (P=0.0028) in the gemcitabine/cisplatin arm. The predictive value of beta-tubulin III, stathmin and RRM1 should be tested in prospective customized chemotherapy trials, the results of which will help tailor chemotherapy to improve patient survival.

Bolus fluorouracil and leucovorin with oxaliplatin as first-line treatment in metastatic colorectal cancer.

PURPOSE: A phase II trial investigated the activity and toxicity of a bolus administration schedule of oxaliplatin, fluorouracil (5-FU), and leucovorin (LV) therapy in patients with untreated advanced colorectal cancer. PATIENTS AND METHODS: Forty-five patients in this multicenter, open, nonrandomized study received oxaliplatin 130 mg/m(2) on the first day of each course and 5-FU and LV 350 mg/m(2) and 20 mg/m(2), respectively, as a daily bolus for 5 days, every 21 days, for a maximum of six courses. RESULTS: Partial responses occurred in 18 patients, giving an intent-to-treat response rate of 40.0%. Median time to response was 12.7 weeks; median duration of response was 18.4 weeks. Median progression-free survival was 5.9 months; median survival was 14 months. The independent prognostic factors for improved overall survival were good performance status and negative carcino-embryonic antigen blood level. Incidences of adverse effects were reduced after the 5-FU dose was reduced to 300 mg/m(2). Reversible neurologic toxicity occurred in 44.4% of patients. CONCLUSION: Bolus administration of oxaliplatin, 5-FU, and LV as first-line therapy for untreated advanced colorectal cancer is efficacious and safe. In addition to a more favorable safety profile, the 300 mg/m(2) dosage offered improved dose-intensity compared with the initial dosage.

Germ cell tumours of the testis.

Cancer of the testis is a relatively rare disease, accounting for about 1% of all cancers in men. Cryptorchidism is the only confirmed risk factor for testicular germ cell tumour. The majority of GCT are clinically detectable at initial presentation. Any nodular, hard, or fixed area discovered in the testis, must be considered neoplastic until proved otherwise. The appropriate surgical procedure to make the diagnosis is a radical orchidectomy through an inguinal incision. Many GCT produce tumoural markers (AFP, HCG, LDH), who are useful in the diagnosis and staging of disease; to monitor the therapeutic response and to detect tumour recurrence. In 1997 a prognostic factor-based classification for the metastatic germ cell tumours was developed by the IGCCCG: good, intermediate and poor prognosis, with 5-year survival of 91, 79 and 48%, respectively. GCT of the testis is a highly table, often curable, cancer. Germ cell testicular cancers are divided into seminoma and non-seminoma types for treatment planning because seminomatous testicular cancers are more sensitive to radiotherapy. Seminoma (all stages combined) has a cure rate of greater than 90%. For patients with low-stage disease, the cure approaches 100%. For patients with non-seminoma tumours, the cure rate is >95% in stages I and II; it is approximately 70% with standard chemotherapy and resection of residual disease, if necessary, in stages III and IV. Minimum guidelines for clinical, biochemical, and radiological follow-up have been reported by ESMO in 2001.

Cost of insurance policies for investigator-initiated cancer clinical trials in Italy.

BACKGROUND: Clinical trials with non-profit promoters are frequently performed in oncology and represent a highly valuable source of information. METHODS: To describe the costs of insurance policies and their determinants, data were collected from 12 Italian non-profit promoters of cancer trials. The cost of policies was expressed as per-patient premium. RESULTS: Sixty-two quotations issued by only two companies were collected, relative to 44 trials proposed for quotation between December 1998 and February 2003. Only the date of quotation was significantly associated with the cost (P = 0.0003) of quotations by Company A for policies with a deductible, with cost increasing over time. Date of quotation (P = 0.0002), sample size (P = 0.008) and number of study arms (P = 0.02) were independently associated with the cost of no-deductible policies quoted by Company A. Only the number of study arms was significantly associated with cost (P = 0.0001) in no-deductible policies quoted by Company B. CONCLUSION: There is insufficient competition among companies for insurance of cancer trials with non-profit promoters. Many variables that affect the trial risk profile from a clinical perspective are not associated with insurance cost. Date of quotation is among the strongest determinants of the cost, which has sharply increased over time. This trend may become a serious problem for non-profit promoters of cancer clinical trials.

Prevention and therapy of neutropenia in elderly patients.

Standard chemotherapy in elderly patients is still nowadays a difficult issue, due to the fact that marrow reserve decrease with age and the results might lead to higher toxicity of otherwise well tolerated regimen and schedule. In the literature, very few data exist of myelosuppression in patients with solid tumors, while more data have been published on non-Hodgkin's lymphoma. The burden of toxicity increase with age, leading to the fact that some patients with curable or sensitive disease do not receive appropriate treatment. One of the ways to try to circumvent neutropenia is the prophylactic use of haematopoietic growth factors with the double aim of maintaining dose-intensity and reducing toxicity. This paper will describe the patterns of marrow toxicity in treating elderly patients with cancer and the role of haematopoietic growth factors.

High-dose chemotherapy for solid tumors: results of the EBMT.

The European Group for Blood and Marrow Transplantation (EBMT), formerly known as European Group for Bone Marrow Transplantation, was established in 1974 in the Netherlands to share experiences, to promote research and clinical studies and to set up registries in the field of hematopoietic tissue transplantation. At the present time more 400 European and non-European centers are members of the EBMT group. In 1984 a new Working Party was created (Solid Tumors) with the aim to investigate the role of high-dose chemotherapy and stem cell support in the fields of adult and pediatric solid tumors. By January 2000 more than 14000 patients were registered, and at the present time this Registry is the world largest database on this subject. Several phase III randomized clinical trials have recently started on behalf of the Group in different diseases (breast carcinoma, small cell lung cancer, ovarian carcinoma, germ cell tumors and Ewing's family sarcoma). Hundreds of randomized patients will finally produce clearer information on this still experimental therapeutic modality. This paper will describe the EBMT Solid Tumors Working Party Registry updated results as well as the main ongoing studies.

Long-term outcome of salvage high-dose chemotherapy in patients with germ cell tumor with poor prognostic features.

OBJECTIVE: High-dose chemotherapy (HDCT) represents an option as salvage treatment for patients with resistant/refractory germ cell tumor (GCT). The objective of this retrospective analysis was to evaluate the long-term results of a single-center experience with salvage HDCT for GCT patients, and to validate the prognostic model proposed by Einhorn and colleagues [9]. MATERIALS AND METHODS: Between 1986 and 2003, 100 GCT patients received salvage HDCT consisting of high-doses of carboplatin, etoposide ± cyclophosphamide, or ifosfamide. Twenty-four patients underwent a second HDCT cycle, and in 1 case, a third cycle was given with a median interval time of 6 weeks (range, 5-10). RESULTS: With a median follow-up of 8 years (range, 3-17); 6 of 32 (19%) patients with resistant GCT and 1 of 19 (5%) patients with cisplatin-refractory disease have been continuously disease-free, while none of the 16 patients with absolutely cisplatin-refractory GCT were alive at 1 year from HDCT treatment. In the PBPC era, HDCT appeared to be inapplicable in 32% of patients, mainly due to progressive disease during the induction/mobilizing phase. The prognostic model by Einhorn et al. for tandem HDCT did categorize our patients treated with a single HDCT cycle or low-dose intensity regimens in a very similar manner, but with inferior overall results. CONCLUSIONS: Long-term results with a single HDCT cycle or a low dose-intensity multicycle HDCT regimen remained poor in patients with adverse prognostic features. The tandem HDCT regimen represents a major option for refractory GCTs and relapsed tumors in third-line or later therapy, while a single course of HDCT should be abandoned for these patients.

Medical treatment choices for patients affected by advanced NSCLC in routine clinical practice: results from the Italian observational "SUN" (Survey on the lUng cancer maNagement) study.

Lung cancer is the most common cancer in the world today, in terms of both incidence and mortality. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, and the majority of people diagnosed with NSCLC have locally advanced or metastatic disease. Treatment algorithms have rapidly changed in the last 10 years because of the introduction of new chemotherapeutic and targeted agents in clinical practice. SUN is a 1-year longitudinal observational multicenter study that has consecutively enrolled patients affected by stage IIIB or IV NSCLC with the aim to describe the pattern of care and evolving approaches in the treatment of advanced NSCLC. 987 consecutive NSCLC patients were enrolled between January 2007 and March 2008 at the 74 participating centers throughout Italy and a 12-month follow-up was performed. Cyto-histological diagnosis was performed mainly by broncoscopy with only 24% by CT-scan guided fine-needle aspiration biopsy. 91.4% of the patients received a first-line medical treatment and 8.6% supportive care only. Median age of patients receiving first-line treatment was 66 years. First-line chemotherapy consisted of a single agent in 20% of patients and combination chemotherapy in 80%. The most frequently used chemotherapy regimens were cisplatin plus gemcitabine and carboplatin plus gemcitabine. Median survival of patients receiving first-line chemotherapy was 9.1 months. 32% percent of patients received a second-line treatment that consisted of chemotherapy in 71% of cases and erlotinib in 29%. Overall third-line treatment was given to 7.3% of patients. These results showed a pattern of care for advanced NSCLC that reflects the current clinical practice in Italy at the study time with a high adherence to the International guidelines by the Italian Oncologists.

Decrease of CD4(+)FOXP3(+) T regulatory cells in the peripheral blood of human subjects undergoing a mental stressor.

We have previously shown that acute psychological stress alerts the adaptive immune response causing an increase in antigen-experienced effector T cells in the peripheral blood. T regulatory cells (Tregs) play a central role in maintaining self-tolerance and controlling autoimmune responses. Here, we analyzed for the first time the behaviour of Tregs in the context of a stress-induced activation of the adaptive immune response. 31 healthy young males underwent a brief laboratory stressor and, in a crossover design, served as their own unstressed controls. We quantified effects of acute stress on CD4(+)FOXP3(+) T regulatory cells and other T cell subpopulations using flow cytometry. In addition, the expression of Treg-related effector molecules and stress hormone receptors were analyzed in the subjects' peripheral T cells. We confirmed our previous observation of a stress-induced decrease in CD45RA(+)CCR7(+) "naïve" and CD45RA(-)CCR7+ "central memory" T cells while CD45RA(-)-CCR7(-) "memory effector" and CD45RA(+)CCR7(-) "terminally differentiated" effector T cells remained stable or increased. Importantly, we found acute psychological stress to cause a concomitant decrease in CD4(+)FOXP3(+) Tregs and in CD4(+) T cells expressing Treg-related effector molecules cytotoxic T-lymphocyte antigen-4 (CTLA-4) and latency associated peptide (LAP). Finally, we observed beta(1)-adrenergic and glucorticoid alpha receptors to be overexpressed in Tregs, suggesting that these molecules might mediate stress-related effects on Tregs. In conclusion, inhibiting components of the adaptive immune response, like Tregs, are down-regulated during a stress-induced activation of the adaptive immune response. In situations of chronic stress, this scenario might result in an exacerbation of inflammatory conditions such as autoimmune diseases.

What is the impact of antithrombotic therapy and risk factors on the frequency of thrombovascular events in patients with metastatic breast cancer receiving epoetin beta?

UNLABELLED: PURPOSE, PATIENTS AND METHODS: This retrospective analysis of the BRAVE study evaluated the impact of baseline risk factors and antithrombotic therapy on the risk of thrombovascular events (TVEs) in patients receiving epoetin compared to patients not receiving epoetin. RESULTS: Baseline risk factors have a significant impact on TVE risk under epoetin therapy. More than 2 risk factors increased the risk of TVEs in patients receiving epoetin (hazard ratio [HR] 2.89, confidence interval [CI] 1.04-8.02, p value [p]=0.04). In patients on epoetin without antithrombotic therapy, the risk for TVEs was higher (HR 4.11, CI 1.37-12.4, p=0.01) compared to those who received antithrombotics (HR 1.37, CI 0.59-3.18, p=0.45). CONCLUSIONS: Our analysis has identified several risk factors which may impact the risk of TVEs under epoetin therapy. These data suggest that antithrombotic therapy may have the potential to reduce the risk of TVEs under epoetin therapy. These findings are hypothesis-generating and need to be confirmed in a prospective, randomised study.

Incidence and clinical implications of venous thromboembolism in advanced colorectal cancer patients: the 'GISCAD-alternating schedule' study findings.

AIM OF THE STUDY: To investigate the incidence and clinical implications of venous thromboembolism (VTE) in advanced colorectal cancer (ACC) patients treated and followed-up through a prospective randomised trial, comparing FOLFIRI chemotherapy given as an intermittent or as a continuous schedule. PATIENTS, MATERIALS AND METHODS: A total of 266 patients were randomised by 15 experimental centres: 168 (63.2%) were males, median age: 64.6 years, age range: 37-76 years. Almost all (95.5%) patients had metastatic disease, while the remainder were classified with locally advanced irresectable disease. For 138 (51.9%) of the patients, the chemotherapy treatment was intermittent FOLFIRI and the remaining patients received continuous treatment. All toxicities, including VTE, were prospectively collected. RESULTS: During the study protocol, the central data management gathered two cases of VTE. Our analysis retrieved 27 (10.2%) patients who developed a VTE, almost all (89%) during the course of chemotherapy treatment: 20 out of 27 during FOLFIRI, the remaining 7 during following lines or follow-up. VTE was the most frequent grade 3/4 toxicity. The incidence of VTE was significantly increased in the patients receiving continuous rather than intermittent treatment (HR 2.67, 95% CI 1.17-6.10; p<0.02). CONCLUSION: VTE is a common complication among advanced colorectal cancer patients and yet this type of toxicity is widely underestimated. In this randomised trial, VTE was the most frequent grade 3/4 toxicity. Use of an intermittent schedule is associated with a reduced risk of developing VTE.