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BACKGROUND: Patients with peritoneal metastatic colorectal cancer have reduced overall survival compared with patients with metastatic colorectal cancer without peritoneal involvement. Here we further investigated the effect of the number and location of metastases in patients receiving first-line systemic chemotherapy. METHODS: We analysed individual patient data for previously untreated patients enrolled in 14 phase 3 randomised trials done between 1997 and 2008. Trials were included if protocols explicitly pre-specified and solicited for patients with peritoneal involvement in the trial data collection process or had done a formal peritoneum-focused review of individual pre-treatment scans. We used stratified multivariable Cox models to assess the prognostic associations of peritoneal metastatic colorectal cancer with overall survival and progression-free survival, adjusting for other key clinical-pathological factors (age, sex, Eastern Cooperative Oncology Group (ECOG) performance score, primary tumour location [colon vs rectum], previous treatment, and baseline BMI). The primary endpoint was difference in overall survival between populations with and without peritoneal metastases. FINDINGS: Individual patient data were available for 10 553 patients. 9178 (87%) of 10 553 patients had non-peritoneal metastatic colorectal cancer (4385 with one site of metastasis, 4793 with two or more sites of metastasis), 194 (2%) patients had isolated peritoneal metastatic colorectal cancer, and 1181 (11%) had peritoneal metastatic colorectal cancer and other organ involvement. These groups were similar in age, ethnic origin, and use of targeted treatment. Patients with peritoneal metastatic colorectal cancer were more likely than those with non-peritoneal metastatic colorectal cancer to be women (565 [41%] of 1371 vs 3312 [36%] of 9169 patients; p=0·0003), have colon primary tumours (1116 [84%] of 1334 patients vs 5603 [66%]; p

The article summarizes the expert discussion and recommendations on the use of molecular markers and of biological targeted therapies in metastatic colorectal cancer (mCRC), as well as a proposed treatment decision strategy for mCRC treatment. The meeting was conducted during the 11th ESMO/World Gastrointestinal Cancer Congress (WGICC) in Barcelona in June 2009. The manuscript describes the outcome of an expert discussion leading to an expert recommendation. The increasing knowledge on clinical and molecular markers and the availability of biological targeted therapies have major implications in the optimal management in mCRC. 21 Suppl 6 vi1 10

The article summarizes the expert discussion and recommendations on the use of molecular markers and of biological targeted therapies in metastatic colorectal cancer (mCRC), as well as a proposed treatment decision strategy for mCRC treatment. The meeting was conducted during the 11th ESMO/World Gastrointestinal Cancer Congress (WGICC) in Barcelona in June 2009. The manuscript describes the outcome of an expert discussion leading to an expert recommendation. The increasing knowledge on clinical and molecular markers and the availability of biological targeted therapies have major implications in the optimal management in mCRC. Ann Oncol

RAD51D mutations have been recently identified in breast (BC) and ovarian cancer (OC) families. Although an etiological role in OC appears to be present, the association of RAD51D mutations and BC risk is more unclear. We aimed to determine the prevalence of germline RAD51D mutations in Spanish BC/OC families negative for BRCA1/BRCA2 mutations. We analyzed 842 index patients: 491 from BC/OC families, 171 BC families, 51 OC families and 129 patients without family history but with early-onset BC or OC or metachronous BC and OC. Mutation detection was performed with high-resolution melting, denaturing high-performance liquid chromatography or Sanger sequencing. Three mutations were found in four families with BC and OC cases (0.82%). Two were novel: c.1A>T (p.Met1?) and c.667+2_667+23del, leading to the exon 7 skipping and one previously described: c.674C>T (p.Arg232*). All were present in BC/OC families with only one OC. The c.667+2_667+23del cosegregated in the family with one early-onset BC and two bilateral BC cases. We also identified the c.629C>T (p.Ala210Val) variant, which was predicted in silico to be potentially pathogenic. About 1% of the BC and OC Spanish families negative for BRCA1/BRCA2 are carriers of RAD51D mutations. The presence of several BC mutation carriers, albeit in the context of familial OC, suggests an increased risk for BC, which should be taken into account in the follow-up and early detection measures. RAD51D testing should be considered in clinical setting for families with BC and OC, irrespective of the number of OC cases in the family.

Well-recognized experts in the field of gastric cancer discussed during the 12th European Society Medical Oncology (ESMO)/World Congress Gastrointestinal Cancer (WCGIC) in Barcelona many important and controversial topics on the diagnosis and management of patients with gastric cancer. This article summarizes the recommendations and expert opinion on gastric cancer. It discusses and reflects on the regional differences in the incidence and care of gastric cancer, the definition of gastro-esophageal junction and its implication for treatment strategies and presents the latest recommendations in the staging and treatment of primary and metastatic gastric cancer. Recognition is given to the need for larger and well-designed clinical trials to answer many open questions. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. 22 SUPPL. 5 v1 v9

This multicentre, randomised, double-blind study was designed to compare the anti-emetic efficacy and safety of single oral doses of dolasetron mesilate with that of the approved oral, multiple-dose regimen of ondansetron in 399 cancer patients receiving moderately emetogenic chemotherapy. Single oral doses of 25, 50, 100 or 200 mg of dolasetron mesilate were administered 1 h prior to the initiation of moderately emetogenic chemotherapy. Multiple doses of ondansetron (8 mg x 3 or 8 mg x 4) capsules, or matching placebo for patients randomised to dolasetron, were given 1.5 h before and 6.5, 14.5 and 22.5 h after the start of chemotherapy (total dose = 32 mg). Efficacy was evaluated for 24 h after the initiation of chemotherapy. The most frequently used moderately emetogenic chemotherapeutic agents included cyclophosphamide, doxorubicin and carboplatin (28.4, 23.1 and 20.6% of patients, respectively). A statistically significant (P0.001) linear dose-response relationship was observed over the entire dolasetron dosage range for all efficacy parameters. Complete response rates were 45.0, 49.4, 60.5 and 76.3% for 25, 50, 100 and 200 mg dolasetron mesilate, respectively, and 72.3% of ondansetron patients. A single oral 200 mg dolasetron mesilate dose was therapeutically equivalent to ondansetron for all efficacy parameters and patient satisfaction was high. Overall, there were no significant differences in the incidence of adverse events between any of the dolasetron mesilate doses, or between dolasetron and ondansetron. Headache was most frequently reported (approximately 15% for each drug). No clinically important changes in vital signs or clinical laboratory parameters were observed with either drug. In conclusion, a single oral 200 mg dolasetron mesilate dose was therapeutically equivalent to multiple-dose ondansetron in the prevention of emesis and nausea following moderately emetogenic chemotherapy.

Twenty-six patients suffering from disseminated epithelial ovarian cancer (FIGO stages III and IV) under treatment with Cisplatin (80-100 mg/m2 in 8 hours) in combination on the same day with Cyclophosphamide (500 mg/m2 IV) and Adriamycin (50 mg/m2), a severely emetogenic regimen, entered a randomized, double-blind, cross-over trial comparing the antiemetic activity of high-dose IV Metoclopramide (1 mg/kg/dose X 5 doses) with that of a combination of Metoclopramide (same schedule) plus Nortriptyline (50 mg PO X 2 doses) plus Thiethylperazine (10 mg IV X 3 doses). The antiemetic combination was designed in an attempt to act simultaneously on gastrointestinal motility and neuroreceptors at the central emetic pathways (dopamine D-2, histamine H-1 and muscarinic cholinergic). This combination significantly reduced the emesis due to chemotherapy when compared with Metoclopramide alone and was also preferred by a significant number of patients after passing through both the antiemetic arms being compared.

Twenty-four patients with metastatic breast cancer that had progressed after high-dose chemotherapy with peripheral blood progenitor cell (PBPC) support were given intramuscular methotrexate in combination with oral UFT (tegafur and uracil) and oral leucovorin (the MUL regimen). Of the total treated, 21 patients are currently evaluable for response and toxicity. All patients had received extensive prior chemotherapy, including a high-dose regimen with PBPC support. Of the 21 assessable patients, 8 obtained either a complete response (1) or partial response (7), for an overall objective response rate of 38%. Another 7 patients had stable disease for 3 or more months. Therefore, the MUL regimen was able to stop disease progression for 3 or more months in nearly 75% of patients. The median time to progression and median overall survival from the start of MUL were 6 and 9 months, respectively. The toxicity was mainly gastrointestinal; 6 patients (29%) had World Health Organization grade 2/3 diarrhea, leading to a UFT dose reduction. Emesis was mild and easily manageable with thiethylperazine. In conclusion, MUL chemotherapy is active and well tolerated in patients with metastatic breast cancer in progression after high-dose chemotherapy. Further studies with this regimen, either as salvage chemotherapy or as maintenance chemotherapy after high-dose chemotherapy with PBPC, are warranted.

To determine the maximum-tolerated dose and the antitumor activity of a combination of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma (TCC) of the urothelium.Patients with measurable, previously untreated, locally advanced or metastatic TCC and with Eastern Cooperative Oncology Group performance statusor = 2 and creatinine clearanceor = 55 mL/min were eligible. Cisplatin was given on day 1 at a fixed dose of 70 mg/m(2). Paclitaxel and gemcitabine were given on days 1 and 8 at increasing dose levels. Cycles were repeated every 21 days to a maximum of six cycles.Sixty-one patients were registered. In phase I, 15 patients were entered at four different dose levels. Dose-limiting toxicity consisted of early onset (after the first cycle) grade 2 asthenia (two of six patients) and grade 3 asthenia (one of six patients) at dose level 4. A paclitaxel dose of 80 mg/m(2) and gemcitabine 1,000 mg/m(2) was recommended for phase II, and 46 additional patients were entered at this level for a total of 49 patients. Main nonhematologic toxicity was grade 2 asthenia in 18 patients, with early onset in five patients, and grade 3 in four patients. Grade 3/4 neutropenia and thrombocytopenia occurred in 27 (55%) and 11 (22%) patients, respectively. Overall, febrile neutropenia was seen in 11 patients, and one toxic death occurred because of neutropenic sepsis. The combination was active at all dose levels. In total, 58 of 61 eligible patients were assessable for response; 16 complete responses (27.6%) and 29 partial responses (50%) were observed for an overall response rate of 77.6% (95% confidence interval, 60% to 98%). The median survival time (MST) available for the phase I part of the study is 24.0 months. MST has not been reached for the whole group with the current follow-up.This combination of paclitaxel, cisplatin, and gemcitabine is feasible and highly active in patients with advanced TCC of the urothelium. Further evaluation of this regimen in patients with TCC is warranted.

Background: The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease. Methods: In a retrospective, pooled analysis of individual patient data from 18 cohorts, including 2436 MBC patients, a CTC threshold of 5 cells per 7.5 ml was used for stratification based on molecular subtypes, disease location, and prior treatments. Patients with >= 5 CTCs were classified as Stage IVaggresive, those with < 5 CTCs as Stage IVindolent. Survival was analyzed using Kaplan-Meier curves and the log rank test. Results: For all patients, Stage IVindolent patients had longer median overall survival than those with Stage IVaggresive (36.3 months vs. 16.0 months, P < 0.0001) and similarly for de novo MBC patients (41.4 months Stage IVindolent vs. 18.7 months Stage IVaggresive p < 0.0001). Moreover, patients with Stage IVindolent disease had significantly longer overall survival across all disease subtypes compared to the aggressive cohort: hormone receptor-positive (44 months vs. 17.3 months, P < 0.0001), HER2-positive (36.7 months vs. 20.4 months, P < 0.0001), and triple negative (23.8 months vs. 9.0 months, P < 0.0001). Similar results were obtained regardless of prior treatment or disease location. Conclusions: We confirm the identification of two subgroups of MBC, Stage IVindolent and Stage IVaggresive, independent of clinical and molecular variables. Thus, CTC count should be considered an important tool for staging of advanced disease and for disease stratification in prospective clinical trials.

Contains fulltext : 165965.pdf (Publisher’s version ) (Closed access) Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.