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Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies. The vast majority of patients with advanced disease die within a year of diagnosis. Tumor microenvironment plays a critical role in tumor initiation, progression, metastasis, and response to treatment in PDAC. Pancreatic adenocarcinoma cells often appear to grow within a fibrotic, abundant, and poorly perfused stroma, with epithelial cells frequently accounting for The aim of this study was to search for novel protein biomarkers of tumor-stroma interaction for a better understanding and intervention of PDAC. Methods: 1- Co-cultures between two pancreatic adenocarcinoma cell lines (PL45 and Capan-1) and embryonic fibroblasts (LC5) were established. LC5 cell line was stably transfected with Green Fluorescent Protein (GFP) to allow their detection, and later separation by flow cytometry, of the co-cultures. 2- In addition, tumor cells were grown with fibroblasts secretome. 3- After 72 hours of co-culture, tumor cells were isolated and protein extraction was performed. 4- Proteins differentially expressed in tumor cells grown in co-cultures, or in tumor cells grown with fibroblasts secretome, versus in tumor cells monocultures, were identified by using two-dimensional electrophoresis-based proteomic tools (2D-DIGE) followed by mass spectrometry (MS/MS) of the spots of interest. Results: A total of 105 differentially expressed proteins were documented between PL45 cells growing in mono-culture, co-culture and conditioned medium. Also, 161 differentially expressed proteins were recognized under similar conditions in the Capan1 cell line. Our study identified seventeen different proteins mainly involved in cytoskeleton organization (Filamin B, Alpha-actinin-4, Annexin A2, Radixin, T-complex protein 1 subunit epsilon, Actin cytoplasmic 1); regulation of cell migration and adhesion (Prelamin-A/C, 40S ribosomal protein SA); protein biosynthesis (EF-2); DNA damage and repair response (VCP, XRCC6); nucleotide biosynthetic process (MTHFD1) and, heat-stress response (HSPD1, GRP78, STIP1, CCT5, Stress-70 protein mitochondrial). Conclusion: This in vitro model identifies several processes that might be responsible for the tumor-stromal interactions occurring in vivo, which should be considered potential targets for therapeutic interventions in PDAC, in addition to those targets already known to exist in PDAC cells. Citation Format: Elena Prieto-García, M. Teresa Agulló-Ortuño, C. Vanesa Díaz-García, Inés García-Consuegra, Jorge Adeva, M. Carmen Riesco, Lucía Parrilla, Carlos Gómez, Laura Lema, Luis Robles, Hernán Cortés-Funes, José A. López-Martín. Analysis of differential protein profiles in co-culture models of pancreatic cancer cells and fibroblasts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1539. doi:10.1158/1538-7445.AM2015-1539

Background: Hidroxyurea acts synergistically with DNA alkylating agents; pioglitazone is a ligand of PPAR-gamma, a nuclear receptor with great potential in controlling oncogenic mechanisms unexplored in clinic, upregulated after exposure to several cytotoxic agents. Purpose: To evaluate pharmacodynamic effects of the combination of carboplatin and paclitaxel, associated with either hydroxyurea or pioglitazone, within a phase 1-2 clinical study. Material and Methods: Patients with unresectable, advanced solid tumors, refractory to standard therapies were considered eligible for this randomized, dose escalating trial. Patients received weekly administration of carboplatin (AUC = 2) and paclitaxel (80 mg/m2) on days 1, 8, 15 q 28d. Patients were randomly allocated to additionally receive either pioglitazone (P) or hydroxyurea (H). The doses of P were 30, 45 and 60 mg/d, whereas the doses of H were 1000 and 1500 mg/d. The comet assay was chosen as a tool to assess the added effects of hydroxyurea, whereas UCP-2 (Uncoupling Protein 2) was selected for the evaluation of the effects of pioglitazone. These events were determined in mononuclear cells from peripheral blood, at baseline and at week 4. Alkaline comet assays were performed using a single-cell electrophoresis protocol and comet lengths were measured with the ImageJ software. UCP-2 was determined by quantitative RT-PCR. For these results, intrapatient and intercohort variations were analyzed. Results: The UCP-2 gene expression was increased after treatment in the majority of patients in our cohort. The increased expression of UCP-2 was lower in patients treated with pioglitazone versus hydroxyurea, however there were no significant differences between treatments. The rate of affected cells with double-strand breaks after treatment, was significantly higher in patients treated with hydroxyurea than in patients treated with pioglitazone (27.1% vs. 16.3% of cells affected, P Conclusions: Our study has the limitations of a small sample size, but we have seen that the use of hydroxyurea can lead further damage to cellular DNA. UCP-2 expression was increase after both treatments, and we can not attribute it to one drug in particular. We should note that we could not discriminate between the different drug doses administered to patients due to small sample. A correlation between these effects and tumor response will be analyzed and shown. Citation Format: M. Teresa Agulló-Ortuño, Carlos Pérez, C. Vanesa Díaz-García, Blanca Homet, Alba Agudo-López, Analia Rodríguez Garzotto, Elena Prieto-García, Jorge Adeva, María C. Riesco, Raquel Rodríguez, M. Luisa Durán, Elena Laguna, Carmen Montalbán, Hernán Cortés-Funes, José A. López-Martín. Pharmacodynamic evaluation of the combination of carboplatin and paclitaxel associated with either pioglitazone or hydroxyurea, within a randomized phase 1 dose escalation clinical trial in patients with advanced solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2575. doi:10.1158/1538-7445.AM2015-2575

Summary Background To evaluate the toxicity profile and efficacy of cisplatin combined with gemcitabine in patients with irresectable locally recurrent or metastatic squamous cell carcinoma of the head and neck. Patients and methods Gemcitabine was given at a dose of 800 mg/m2 on days 1, 8 and 15, plus cisplatin at a dose of 50 mg/m2 on days 1 and 8; every four weeks. Results Twenty-four patients with a median age of 59 years (range 42–74) were included. All patients were evaluable for toxicity and 22 patients were assessable for response. Eleven cases had advanced recurrent locoregional disease while 13 patients had metastatic disease. One CR (4.7%) and four PR (18%) were observed, for an overall response rate of 22.7% (95% CI: 8%–42%). The main toxicity was hematological: neutropenia grade 3–4 in 28% of the cycles and thrombocytopenia grade 3–4 in 16%. The most significant non-hematological toxicity was asthenia grade 2–3 in 24% of the cycles. Conclusions This cisplatin plus gemcitabine combination schedule has a favourable toxicity profile with a discrete activity in patients with locally recurrent or metastatic squamous-cell carcinoma of the head and neck.

This randomized clinical trial evaluated the efficacy and safety of monotherapy with cefepime for patients with solid tumors treated with high dose chemotherapy (HDC) and peripheral blood stem cell support (PBSCS) with febrile neutropenia.Patients with solid tumors treated with HDC and PBSCS, that developed fever and neutropenia (absolute neutrophil count500 cells/microL) were eligible, and randomly assigned to receive ceftazidime plus amikacin or cefepime.Fifty-one episodes were randomized, and all were evaluable (27 received ceftazidime plus amikacin arm, and 24 cefepime). Major efficacy endpoints did not show significant differences, with success rates of 44.4% and 54.2% (p = 0.481) for the combination arm and the monotherapy arm, respectively. The proportion of patients that became afebrile in the first 24 hours was significantly higher in the cefepime group (41.7% vs 11.1%, respectively; p = 0.012). However, due to its premature closure and small sample size, this study lacks the adequate power to definitely address this question.Cefepime monotherapy appeared to have an equivalent efficacy and safety as empiric treatment in febrile neutropenia episodes in a highrisk population compared with ceftazidime and amikacin. Nevertheless, this study is not adequately powered to answer this question. Given the small number of patients randomized and the single-center nature of this study, these results must be cautiously interpreted.

Purpose To study the prognostic significance of the presence of breast cancer–specific mRNA transcripts in peripheral blood (PB), defined by serial analysis of gene expression, in high-risk breast cancer (HRBC) patients undergoing high-dose chemotherapy after receiving adjuvant chemotherapy. Methods From 1994 to 2000, 84 HRBC patients (median age, 44 years; > 10 nodes; 74%) received adjuvant chemotherapy (fluorouracil, epirubicin, and cyclophosphamide for six cycles [83%] or doxorubicin and cyclophosphamide followed by paclitaxel) before undergoing one course of cyclophosphamide plus thiotepa plus carboplatin (STAMP V). Radiotherapy or hormone therapy was administered whenever indicated. Aliquots of apheresis-mononuclear blood cells were frozen from each patient. mRNA was isolated using an automatic nucleic acid extractor based on the magnetic beads technology; reverse transcription was performed using random hexamers. Cytokeratin 19, HER-2, P1B, PS2, and EGP2 transcripts were quantified to B-glucuronidase by real-time polymerase chain reaction (RT-PCR) using a linear DNA probe marked with a quencher and reporter fluorophores used in RT-PCR. Presence of PB micrometastases, estrogen receptor and progesterone receptor status, tumor size, age, tumor grade, number of nodes affected, and treatment with paclitaxel were included in the statistical analysis. Results Median follow-up was 68.3 months (range, 6 months to 103 months). Forty-seven relapses (56%) and 35 deaths (41.7%) were registered. Both tumor size and presence of micrometastases reached statistical significance according to the Cox multivariate model. Relapse hazard ratio (HR) for those patients with PB micrometastases was 269% (P = .006); death HR, 300% (P = .011). Time relapse was 53 months longer for patients without micrometastases: 31.3 v 84.2 months (P = .021). Conclusion PB micrometastases presence after adjuvant chemotherapy predicts both relapse and death more powerful than classical factors in HRBC patients undergoing high-dose chemotherapy. Micrometastases search using a gene panel appears to be a more accurate procedure than classical approaches involving only one or two genes.

We compared ciprofloxacin alone with ciprofloxacin plus rifampin (C + R) as a prophylactic antibacterial regimen for 40 patients with solid tumors treated with high-dose chemotherapy and autologous stem cell transplantation support. No differences were found between groups in the time elapsed to the onset of fever, incidence of febrile episodes, amphotericin B use, and length of hospital stay. However, C + R combination prophylaxis significantly reduced the incidence of gram-positive bacteremia (five versus zero episodes) but was associated with a higher incidence of drug-related side effects.

The tolerability of chemotherapy has been significantly improved by the advent of effective drugs and protocols for the amelioration of chemotherapy-induced nausea and vomiting. Variables such as the timing of nausea and vomiting (acute, delayed or anticipatory) and the emetogenicity of the chemotherapy must be taken into account in developing guidelines for antiemetic prophylaxis and treatment. Although there are a number of 5-hydroxytryptamine antagonists available, the clinical differences between them are small. The use of drugs with a different mechanism of action, such as the recently introduced neurokinin-1 receptor antagonist aprepitant, may be a useful adjunct to 5-hydroxytryptamine-3 receptor antagonists or steroid prophylaxis. The addition of aprepitant to standard antiemetic regimens increases the proportion of complete responses to antiemetic therapy. For the use of highly emetogenic chemotherapy in oncology a combination of 5-hydroxytryptamine-3 receptor antagonist, dexamethasone and aprepitant is recommended in the acute phase, and dexamethasone plus aprepitant during the subsequent days (many patients do not have their symptoms controlled by 5-hydroxytryptamine-3 receptor antagonist and steroid alone). In either case, lorazepam can be added as required. For moderately emetogenic chemotherapy, a regimen of 5-hydroxytryptamine, dexamethasone and aprepitant is recommended in the acute phase, followed by aprepitant alone in the delayed phase. Alternatively, a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone can be used in the acute phase, followed by dexamethasone for prophylaxis in the delayed phase. For chemotherapy with a low emetogenicity, either dexamethasone, metoclopramide, prochlorperazine or triethyperazine alone is recommended. No prophylaxis is generally required during the delayed phase and indeed may not be necessary during the acute phase either.

BACKGROUND The objective of this study was to assess the antitumor activity and toxicity profile of weekly docetaxel in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. METHODS Patients with recurrent, metastatic, incurable squamous cell carcinoma of the head and neck were enrolled. Weekly docetaxel (30 mg/m2) was administered for 4 weeks every 5 weeks for a maximum of 6 cycles. RESULTS The activity and toxicity of docetaxel were assessed in all 38 patients who were entered on the study. No Grade 3–4 toxicities were recorded. No treatment delays were required because of toxicity or dose reductions. Responses were observed in 42% of patients (95% confidence interval, 26–58%). The median duration of response was 8.39 months, the estimated median overall survival was 11.3 months, and the 1-year survival rate was 39%. CONCLUSIONS The results of this study suggested that weekly docetaxel was an active agent for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Cancer 2006. © 2005 American Cancer Society.

To date, the clinical features and outcomes of patients with initially metastatic breast carcinoma (IMBC) have not been compared with the corresponding characteristics in patients with recurrent metastatic breast carcinoma (RBC). This issue may be particularly relevant to clinical research, as it may shed light on a potential bias with respect to the selection of patients for clinical trials.A retrospective analysis of the medical records of 1350 patients with breast carcinoma was performed. Outcome variables included overall survival, response rate, and progression-free survival.One hundred nineteen of 370 patients with metastatic breast carcinoma had IMBC, whereas the remaining 251 had RBC. The median follow-up duration was 39.4 months, and the median overall survival duration was 24 months. With regard to clinical characteristics, patients with IMBC were older than patients with RBC (61.7 years vs. 58.1 years; P0.001) and had a higher incidence of lobular carcinoma (15.9% vs. 7.7%; P = 0.018), a greater proportion of T3-4 tumors (58.8% vs. 27.9%; P0.001), a higher incidence of bone as the dominant metastatic site (41.2% vs. 21.5%; P0.001), a lower incidence of soft tissue as the dominant metastatic site (10.1% vs. 26.7%; P0.001), and a similar incidence of the viscera as the dominant metastatic site (48.7% vs. 51.8%; P = 0.78). Median overall survival duration was similar for patients with IMBC (25.1 months) and patients with RBC (23.3 months; P = 0.81). Statistical analyses also revealed nonsignificant differences between patients with IMBC and patients with RBC in terms of response rate (40.7% vs. 35.2%, respectively; P = 0.35) and median progression-free survival duration (10.2 months vs. 9.0 months, respectively; P = 0.58).Although patients with IMBC and patients with RBC exhibit distinct histologic and clinical characteristics, similar treatment efficacy results and survival outcomes are observed in these two groups.

Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are effective cytotoxic agents in the treatment of solid tumours. Continuous i.v. infusion (CI) of 5-FU is significantly more active and better tolerated than bolus i.v. 5-FU. This phase I pharmacokinetic and clinical study evaluated escalating CPT-11 doses administered every 3 weeks combined with a fixed dose of 5-FU CI over 14 days to find the maximum tolerated dose (MTD) of this combined chemotherapy.Patients with solid tumours showing failure with previous standard treatment or for whom no established curative therapy existed received CPT-11 i.v. over 90 min (six dose levels were evaluated: 150, 175, 200, 250, 300 and 350 mg/m(2)) plus a fixed dose of 5-FU CI 250 mg/m(2) per day over 14 days. If the MTD was not reached at CPT-11 level 6, then 5-FU was increased to 300 mg/m(2). In step 2, 5-FU was administered as a true protracted infusion at the recommended dose found during step 1. In step 3, the recommended dose of CPT-11 was divided and administered in a weekly schedule for 4 weeks combined with a fixed dose of 5-FU CI 250 mg/m(2), and then followed by 2-5 weeks rest.Neutropenia and diarrhoea were the main toxicities, leading to early termination of infusion in three of six patients in level 7. Therefore, CPT-11 350 mg/m(2) + 5-FU 250 mg/m(2) CI over 14 days was identified as the recommended dose. In step 2, CPT-11 dose had to be reduced to 300 mg/m(2) due to toxicity. The weekly schedule of CPT-11 75 mg/m(2) + 5-FU 250 mg/m(2) CI was feasible with only one patient experiencing severe diarrhoea. No interactions were found in the kinetics parameters of CPT-11 or 5-FU for the different dose levels studied.CPT-11 300 mg/m(2) + 5-FU 250 mg/m(2) protracted infusion is the recommended dose for phase II trials, neutropenia and diarrhoea being the dose-limiting toxicities.

Women with a family history of breast cancer (FHBC) are at increased risk for developing this disease. In this study, we have investigated the differences between two groups of women; those with family history of breast cancer (N=42) and women at population risk (N=42) in a Spanish cohort. Questionnaires assessed distress, perception of breast cancer risk, screening behaviours, coping skills, personality and quality of life. Neither group received genetic counselling before or after this study. Women with FHBC overestimated their risk of developing breast cancer. They report a subjective risk of developing breast cancer of 50%, with their actual risk, using the risk tables elaborated by Claus et al., being only 15% (p0.05). Discriminant function analysis revealed the patients' information about breast cancer, worries about breast cancer, perception of risk based on family history, perception of lifetime risk of breast cancer and quality of life were the five variables that distinguished between both groups. Only 34% of women in the FHBC group performed monthly breast self-examination, 24% (10 subjects) had never attended previously for clinical breast examination and 45% (19 subjects) had never undergone a mammogram. This group of women had a significantly lower level of general satisfaction (p0.05), an indicator of Quality of Life. The results support the need for developing psychological intervention for women with family history of breast cancer in order to increase adherence to surveillance behaviours, reduce distress, improve quality of life, and assure the earliest detection of breast cancer.

represent landmarks in the history of medicine. Almost 60% of drugs approved for cancer treatment are of natural origin. Vincristine, irinotecan, etoposide, taxanes and camptothecines are all examples of plant-derived compounds. Dactinomicine, anthracyclines, mitomycin and bleomycin are anticancer agents derived from microbial sources [1]. Although marine compounds are under-represented in current pharmacopoeia, it is anticipated that the aquatic environment will become an invaluable source of novel compounds in the future. The marine ecosystem represents 95% of the biosphere, and all except one of the 33 animal phyla are represented in aquatic environments [2]. Most sessile marine invertebrates contain a primitive immune system and produce toxic chemicals as a form of defense. Many of these products act as regulators of specific biological functions. Some of them have pharmacological activity due to their specific interactions with receptors and enzymes. Because these substances become immediately diluted by large volumes of seawater, they need to be highly potent on a molar basis, and also have to retain a relatively low solubility [3]. The development of marine compounds as therapeutic agents is still in its infancy due to the lack of an analogous ethno-medical history as compared with terrestrial habitats, together with the relative technical difficulties in collecting marine organisms. Over the last few decades significant efforts have been made, by both pharmaceutical companies and academic institutions, to isolate and identify new marine-derived, natural products. These initiatives have been accompanied by funding support from governmental agencies. Specific programs directed towards the collection and characterization of marine natural products and evaluation of their biological activity have been established [4]. This systematic investigation of marine environments is reflected in the large number of novel compounds reported in the literature over the past decade [5]. Some of these agents have entered preclinical and clinical trials, and it may be expected that this number will increase in the future. This article will review some of the technical strategies that are being employed to collect and identify novel marine products with potential antitumoral properties, and will also provide a summary of the available clinical trial information of agents with promising activity.

Pemetrexed disodium (ALIMTa, [pemetrexed], LY231514; Eli Lilly and Company; Indianapolis, IN), a novel antifolate antimetabolite with multiple enzyme targets involved in both pyrimidine and purine synthesis, has entered clinical trials due to its favorable pleclinical profile. Many studies utilizing the drug, as a single or combination agent, are currently ongoing, including Phase III trials in mesothelioma, nonsmall cell lung carcinoma (NSCLC) and pancreatic cancer. Promising feasibility and activity data have been obtained with pemetrexed in combination with platinum compounds and gemcitabine. The supplementation with daily oral folate could reduce the incidence of hematologic toxicities while preserving the antitumor activity of pemetrexed.

Background Sunitinib (SU) is a multi-targeted receptor tyrosine kinase inhibitor that is approved for the treatment of renal cell carcinoma (RCC). However, several patients either do not respond to treatment or they experience significant toxicity. Our study aims to find genetic markers of toxicity and efficacy using a commercially available DNA microarray genotyping system. Methods 30 patients with newly diagnosed metastatic RCC, from January 2010 to May 2011, were evaluated prospectively at Hospital 12 de Octubre (Madrid, Spain). Pts received SU in repeated 6-wk cycles of 50 mg/day (4 wks on followed by 2 wks off treatment). A total of 92 of single nucleotide polymorphisms (SNPs) in 34 genes in the pharmacokinetic and pharmacodynamic pathways of drugs were analyzed using Drug inCode ® pharmacogenetic service. SNPs in candidate genes, together with clinical characteristics were tested univariately for association with the number of days of SU treatment until the first reduction of dose, PFS and OS. Results Complete analysis was possible in 25 pts. Pts with CYP1A2*1/*1. a low metabolizing genotype, had an increased risk of dose reductions due to toxicity compare to allele *1F (Median time to dose reduction: 2.33 months Vs NR; p Conclusions This preliminary analysis suggests that CYP1A2 and CYP2C19 SNPs may be associated with toxicity in patients with RCC treated with SU. As CYP1A2 and CYP2C19 activity could be affected by a variety of non-genetic factors, if confirmed, these results could lead to the necessity of controlling toxic and dietary habits of pts treated with SU. SNPs associated with toxicity and survival in this preliminary analysis are being validated in an independent cohort of RCC treated with SU (Garcia-Donas J, et al. Lancet Oncol 2011) and will be presented. Disclosure All authors have declared no conflicts of interest.

Background The aim of this study was to evaluate the efficacy and toxicity of a combination of paclitaxel, cisplatin and 5-fluorouracil (PPF) as induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Methods Seventy patients with previously untreated stage III–IV SCCHN were included in this phase II trial. Induction treatment consisted of a maximum of three outpatient courses of paclitaxel 175 mg/m2 as a 3-h infusion on day 1, cisplatin 100 mg/m2 on day 2, and 5-fluorouracil (5-FU) 500–750 mg/m2/day as a 24-h continuous infusion on days 2–6, repeated every 3 weeks. The 5-FU dose was reduced from 750 mg/m2/day to 500 mg/m2/day due to the excessive toxicity observed in the first 14 patients enrolled. Local treatment consisted of radiotherapy and/or surgery. Results Two-hundred-and-one cycles were administered to 70 patients. The main toxicities of PPF were neutropenia (grade 4, 14%; febrile neutropenia, 4%), peripheral neuropathy (grade 2–3, 14%) and catheter-associated venous thrombosis (7%). There were three early deaths (two from neutropenic sepsis and one from pulmonary embolism), and 13 patients required hospitalization due to toxicity. Other side effects included mucositis, anorexia, diarrhea, myalgias and alopecia. The overall response rate to PPF was 88%, including 59% complete responses (CR) and 29% partial responses. The CR rates at the primary tumor and neck lymph nodes were 74% and 62%, respectively. With a median follow-up of 51 months (range 40–63 months), the estimated 5-year time-to-disease progression and overall survival rates were 56% and 44%, respectively. Conclusions The PPF regimen has major antitumor activity and is associated with manageable toxicity as induction treatment in SCCHN patients. The high complete response rate and favorable long-term outcome justify further evaluation of this chemotherapy combination.

Lung cancer is an aggressive disease that is the leading cause of death from cancer in both males and females. Non–small cell lung cancer accounts for approximately 75% of all cases of lung cancer, and of these about 75% have locally advanced or disseminated disease. Most patients diagnosed with non–small cell lung cancer do not survive more than 2 years. Although chemotherapy has been shown to control symptoms and improve quality of life, there remains no standard, optimal chemotherapy regimen for non–small cell lung cancer. Regardless of regimen and chemotherapy agents administered, clinical trials have demonstrated response rates of 20% to 30%, median survival times between 35 and 40 weeks, and 1-year survival rates of 20% to 25%. Because traditional chemotherapy regimens have not shown substantial promise, new strategies are being explored for the treatment of lung cancer, including overcoming drug resistance, the use of antimetastatic and antiangiogenesis drugs, drugs that target novel molecular markers, signal transduction modulators, gene therapy, and vaccines. There are few but exciting new developments that may signal a more promising future for patients with lung cancer. Semin Oncol 29 (suppl 8):26-29. Copyright 2002, Elsevier Science (USA). All rights reserved.

Aim: The BIG 2-98 is a randomized phase III trial that tested the effect of adding docetaxel with anthracycline-based adjuvant chemotherapy (CT) in women with node-positive breast cancer (BC). here we present the 10 year safety and efficacy analyses and report an exploratory analysis of the predictive value of Ki67 for docetaxel efficacy. Methods: In total, 2,887 patients with node positive BC were randomly assigned to one of four treatments: (I) sequential control: doxorubicin (A, 75 mg/m2) × 4 → CMF; (II) concurrent control: AC × 4 → CMF; (III) A × 3 → docetaxel (T, 100 mg/m2) × 3 → CMF and (IV) : AT (50/75 mg/m2) × 4 → CMF. The primary objective was to evaluate the efficacy of docetaxel regardless of the schedule on disease free survival (DFS). Secondary objectives were toxicity, DFS between sequential arms and concurrent arms, and overall survival (OS). Ki67 expression was centrally evaluated by immunohistochemistry. Tumours with Ki67 ≥14% were considered to have a high proliferation index. Results: After a median follow-up 10.1 years (max 12.9 years) and 1,072 DFS events, docetaxel treatment did not improve DFS or OS compared to control arms (DFS: HR = 0.91, 95% CI = 0.81-1.04; P = 0.16; OS: HR = 0.88, 95% CI = 0.76-1.03; P = 0.11). Similar results were obtained in secondary comparisons where sequential docetaxel was compared with sequential control (DFS: HR = 0.86, 95% CI = 0.72-1.03, P = 0.1; OS: HR = 0.85, 95% CI = 0.68-1.06; P = 0.15) or with concurrent doxorubicin–docetaxel (DFS: HR = 0.88, 95% CI = 0.7-1.01; P = 0.09; OS: HR = 0.84, 95% CI = 0.7-1.01; P = 0.06). Worsening or development of treatment-related neurotoxicity following completion of adjuvant chemotherapy occurred in 1.6% and 1% of patients in the docetaxel and non-docetaxel-based regimens, respectively. Out of 1,492 patients with ER positive BC, central Ki67 evaluation was performed in 1,198 (80.2%), of whom 892 (74.4%) had Ki67 ≥ 14%. In a multivariate model, there was a trend for improved DFS and OS in patients with high Ki67 and treated with docetaxel (HR = 0.79,95% CI = 0.63-1.01; P = 0.05 and HR = 0.76,95% CI = 0.57-1.01; P = 0.06 respectively). Conclusions: At a median follow-up of 10 years, the DFS benefit previously demonstrated with docetaxel is no longer present in node-positive BC patients. However, an exploratory analysis suggested a benefit of docetaxel in patients with highly proliferative ER-positive BC. Disclosure: P. Francis: Travel support from Sanofi; J.P. Crown: Received research funding and speaking honoraria from Sanofi Aventis; M. Piccart: Board member: PharmaMar Consultant (honoraria) : Amgen, Astellas, AstraZeneca, Bayer, Eli Lilly, Invivis, MSD, Novartis, Pfizer, Roche-Genentech, sanofi Aventis, Symphogen, Synthon, Verastem Research grants to my Institute : most companies. All other authors have declared no conflicts of interest.

e19160 Background: In phase III trials CP/Pem showed a significant improvement in survival in patients (p) with non-squamous histology. Moreover CP and CB differ slightly for toxicity and efficacy;...

e22002 Background: Bevacizumab (BV) has shown increased overall response rate and survival in patients (Pt) with non-small cell lung cancer (NSCLC). No biomarkers have been described predictors of response in these Pt. The aim of this study is to investigate the usefulness of gene expression profiles of peripheral blood monocytes from patients with NSCLC before and after chemotherapy plus BV. Methods: A prospective study of blood samples from Stage IV NSCLC Pt treated with BV plus chemotherapy in our institution between 2009 and 2010 was performed. Plasma samples were collected before cycle 1 and after completion of cycle 2 (week 7). Clinical and radiological outcomes were recorded. The TaqMan Human Angiogenesis Array was used for analysis (micro fluidic card). This array contains 96 target involved in human angiogenesis and lymphangiogenesis. Amplifications were carried out on the AB 7900HT RT-PCR system, and relative gene expression values were calculated by the ΔΔCt method. Results: We present prelimin...

e17054 Background: There is an increasing number of older patients diagnosed of locally advanced head and neck cancer (LA-HNC) due to the growing life expectancy. The aim of this study is to assess the suitability of bio-chemoradiation therapy (BCRT) for these patients (Pt). Methods: This multicenter retrospective study was performed in three Spanish hospitals. LA-HNC Pt ≥ 70 years (ys) treated between 2009 and 2011 were included. Demographics, comorbidity, treatment strategies and mortality were recorded. Results: Fifty-two Pt were studied (median age, 74.1 ys; range, 70-88; male, 69%; ECOG PS 0-1, 90.4%; stage IVA/IVB, 71%; recurrent disease, 13.5%). Fifty percent of subjects had ≥ 2 comorbidities (hypertension 52%; diabetes 19%; myocardial ischemia 14%; bronchopathy 37%, chronic renal insufficiency 31%, hepatopathy 6%). Primary tumor site was: oral cavity 35%; larynx 33%; oropharynx 19%; others 13%. Most of the aged (75%) were treated with radical concomitant BCRT (19% of them had received induction ch...

e22112 Background: Detection of EGFR m in p with NSCLC is done in a routine way. Given the data published on ALK positive p detection is crucial for therapeutic decision making. ALK t should be per...

e14572 Background: Despite recent advances in multidisciplinary therapy of metastatic colorectal cancer (mCRC), 5-year overall survival rate remains under 10%. Several retrospective series publishe...

This phase I study was designed to develop a high-dose combination of two cycles of mitoxantrone and cyclophosphamide in patients with solid tumors, as an alternative to single-cycle high-dose regimens that use only alkylating agents. Treatment was delivered with granulocyte colony-stimulating factor (G-CSF), but without stem cell support, in order to avoid potential tumor cell reinfusion. Thirty-one patients with advanced solid tumors received two cycles of high-dose mitoxantrone (20-30 mg/m2) plus high-dose cyclophosphamide (3000-4000 mg/m2). All patients received G-CSF until hematologic recovery. Dose-escalation was performed when less than 50% of cycles per level had dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) achieved was mitoxantrone 25 mg/m2 and cyclophosphamide 4000 mg/m2. Main dose-limiting toxicities (DLTs) were hematological: grade IV neutropenia lasting more than 7 days and thrombopenia below 20 x 10(9)/l requiring more than one platelet transfusion. Non-hematological DLT consisted predominantly of grade III emesis and asthenia. Follow-up after each cycle was performed in an outpatient setting and there were no toxic deaths. In conclusion, the administration of two cycles of high-dose mitoxantrone and cyclophosphamide with G-CSF support is safe and feasible. MTD was mitoxantrone 25 mg/m2 and cyclophosphamide 4000 mg/m2. Evaluation of this regimen is being done in a phase II trial.

It has been suggested that dietary interventions may improve the effectiveness of cancer chemotherapy. We have examined the combined in vitro cytotoxicity of paclitaxel and the fatty acids gamma-linolenic acid (GLA, 18:3n-6) and oleic acid (OA, 18:1n-9) in human breast carcinoma MDA-MB-231 cells. The effect of fatty acids on paclitaxel chemosensitivity was determined by comparing IC(50) and IC(70) (50 and 70% inhibitory concentrations, respectively) obtained when the cells were exposed to IC(50) and IC(70) levels of paclitaxel alone and fatty acids were supplemented either before or during the exposure to paclitaxel. The 3-4,5-dimethylthiazol-2-yl-2,5-diphenyl-tetrazolium bromide (MTT) assay was used to determine cell growth inhibition. GLA by itself showed antiproliferative effects, and a possible GLA-paclitaxel interaction at the cellular level was assessed by the isobologram and the combination-index (CI) methods. Isobole analysis at the isoeffect levels of 50 and 70% revealed that drug interaction was predominantly synergistic when GLA and paclitaxel were added concurrently for 24 h to the cell cultures. Interaction assessment using the median-effect principle and the combination-index (CI) method showed that exposure of MDA-MB-231 cells to an equimolar combination of concurrent GLA plus paclitaxel for 24 h resulted in a moderate synergism at all effect levels, consistent with the results of the isobologram analysis. When exposure to GLA (24 h) was followed sequentially by paclitaxel (24 h) only an additive effect was observed. The GLA-mediated increase in paclitaxel chemosensitivity was only partially abolished by Vitamin E, a lipid peroxidation inhibitor, suggesting a limited influence of the oxidative status of GLA in achieving potentiation of paclitaxel toxicity. When OA (a non-peroxidisable fatty acid) was combined with paclitaxel, an enhancement of chemosensitivity was found when OA was used concurrently with paclitaxel, although less markedly than with GLA. Pretreatment of MDA-MB-231 cells with OA for 24 h prior to a 24 h paclitaxel exposure produced greater enhancement of paclitaxel sensitivity at high OA concentrations than the concurrent exposure to OA and paclitaxel. The OA-induced sensitisation to paclitaxel was not due to the cytoxicity of the fatty acid itself. When these observations were extended to three additional breast carcinoma cell lines (SK-Br3, T47D and MCF-7), simultaneous exposure to GLA and paclitaxel also resulted in synergism. GLA preincubation followed by paclitaxel resulted in additivity for all cell lines. Simultaneous exposure to paclitaxel and OA enhanced paclitaxel cytotoxicity in T47D and MCF-7 cells, but not in SK-Br3 cells, whereas preincubation with OA failed to increase paclitaxel effectiveness in all three cell lines. For comparison, the effects of other fatty acids on paclitaxel chemosensitivity were examined: GLA was the most potent at enhancing paclitaxel cytotoxicity, followed by alpha-linolenic acid (ALA; 18:3n.3), eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3), whereas linoleic acid (LA; 18:2n-6) did not increase paclitaxel toxicity. These findings provide experimental support for the use of fatty acids as modulators of tumour cell chemosensitivity in paclitaxel-based therapy.

Transitional cell carcinoma (TCC) of the urothelium is a highly chemosensitive tumour. Combination chemotherapy can provide both palliation and a modest survival advantage in patients with advanced disease. At present, the combination of cisplatin, methotrexate, doxorubicin and vinblastine (M-VAC) is the most widely used for advanced TCC with an overall response rate of 40-72% in phase II, and 35-45% in phase III studies, and a median survival of approximately 12 months. These modest results and the unsuccessful attempts to increase efficacy with dose intensive M-VAC schedules have prompted the identification of new active agents in TCC, such as the taxanes and gemcitabine. The overall response rates for two-drug regimens of cisplatin-paclitaxel, carboplatin-paclitaxel and cisplatin-gemcitabine range from 63 to 72%, 14 to 65% and 42 to 66%, respectively. The overall response rates for platinum-paclitaxel-gemcitabine three-drug regimens range from 58 to 80%. The potential clinical benefit of these new three-drug combinations in the treatment of TCC needs to be tested in future phase III studies.

BACKGROUND α-fetoprotein (AFP), human chorionic gonadotropin (HCG), and lactate dehydrogenase (LDH) closely follow the course of germ cell tumors (GCTs) and are widely used for diagnosis, prognosis, and follow-up purposes. The objective of this study was to assess the concordance of tumor markers at the time of diagnosis and recurrence. METHODS The authors reviewed the records of 794 patients with GCTs treated in three Spanish hospitals from 1977–1996 and analyzed the concordance between AFP, HCG, and LDH levels at diagnosis and first and second recurrence. A positive marker was defined as a level of AFP > 10 ng/mL, HCG > 5 IU/L, or LDH > the upper limit of normal. One hundred twenty-five patients were identified who developed a first recurrence (123 had marker levels recorded). The median age was 27 years (range, 14–78 years). Histology was seminoma in 36 patients (29%) and nonseminomatous GCT (NSGCT) in 87 patients (71%). RESULTS Seventy-nine patients (64%) had elevated tumor markers at diagnosis and 76 (62%) at first recurrence. An elevated marker was present at first recurrence in 58 of 79 patients (73%) with initially positive markers and in 18 of 44 patients (41%) with initially negative markers. In 84 of 123 patients (68%), the same marker pattern (positive or negative) was present at the time of diagnosis and at first recurrence, 78% in seminomas and 64% in NSGCTs. The earliest indicator of recurrence was an elevated marker in patients with NSGCTs and a radiologic finding in patients with seminomas. Thirty patients developed a second recurrence, 27 of whom (90%) had the same marker pattern as at first recurrence. CONCLUSIONS Tumor marker pattern at diagnosis is not a good predictor of the pattern at recurrence, particularly in patients with NSGCTs. Marker assessment should be included in the follow-up schedule regardless of levels at the time of diagnosis. Early detection of recurrence should not rely only on marker levels, even in patients with elevated levels at presentation. Cancer 2000;88:162–8. © 2000 American Cancer Society.

This study evaluated the susceptibility of Escherichia coli to quinolones in 72 stool samples collected from 31 patients with solid tumours who had undergone high dose chemotherapy (HDC) and peripheral blood stem-cell (PBSC) rescue with ciprofloxacin prophylaxis. Samples were obtained at admission, after completing prophylaxis and three months later. All E. coli strains isolated from baseline samples were susceptible to quinolones. Fluoroquinolone-resistant E. coli strains were isolated in 10 (32%) patients in the second sample. In eight of these patients isolates were susceptible 3 months later. No patient developed infection due to fluorquinolone-resistant E. coli. No differences were observed in outcome between patients with susceptible and resistant flora.

This phase-II study was conducted to investigate the potential benefit from the addition of mitomycin to a conventional anthracycline-cisplatin- and 5-fluorouracil-based chemotherapy for recurrent and metastatic undifferentiated carcinoma of nasopharyngeal type (UCNT).Between July 1989 and December 1991, 44 consecutive patients (M/F 36/8; median age: 45, range 20-72; performance status (PS) 0: 20 patients, PS 1: 14 patients, PS 2: 10 patients) with recurrent or metastatic UCNT were entered in this study after complete clinical, biological, and radiological pre-therapeutic work-ups. Chemotherapy (FMEP regimen) consisted of 800 mg/m2/day 5-fluorouracil in continuous infusion from day 1 to day 4 combined with 70 mg/m2 epirubicin, 10 mg/m2 mitomycin, and 100 mg/m2 cisplatin on day 1, every four weeks for six cycles. Mitomycin was delivered in cycles 1, 3, and 5 only. Eleven patients had isolated loco-regional recurrences, 12 patients had local recurrences associated with distant metastasis, and 21 patients had metastasis only. Toxicity and response were evaluated according to WHO criteria.Grade 3-4 neutropenia was observed in 122 of 212 evaluable cycles (57%) and 39 of 44 patients (89%); febrile neutropenia occurred in 16 patients (36%) and 24 cycles (11.3%). Grade 3-4 thrombocytopenia was observed in 27 patients (61%) and 45 cycles (21%), including 27 of 45 cycles (60%) with mitomycin. Grade 3 anemia was noted in 18 patients (40%) and 23 cycles (11%), including 18 of 23 cycles (78%) with mitomycin. Grade 3-4 mucositis occurred in 25 cycles (11%) and 14 patients (32%), mainly in those previously treated with radiation therapy in the head and neck area. There were four treatment-related deaths (9%); three of them neutropenia-related, and one of cardiac toxicity.Forty-four patients were evaluable for response: There were 23 of 44 objective responses (52%), including six complete responses (13%), and 17 partial responses (38%). Additional radiotherapy was given to 13 patients after documentation of response: Nasopharyngeal tumor + cervical nodes (eight patients) and/or on bone metastasis sites (five patients); mediastinal lymph nodes (one patient). At a median follow-up of 87 months (range 71-100), five patients are alive and in continuous complete remission. The median survival time was 14 months and the median time to progression nine months.The regimen under study is active in recurrent/metastatic UCNT, but associated with excessive toxicity.

Summary Background: The aim of this study was to determine the clinical activity and toxicity of a novel chemotherapy combination regimen of gemcitabine plus cisplatin, administered every three weeks, in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Twenty-six previously untreated stages III (14) and IV (12) patients were included. Gemcitabine was administered on days 1 and 8 at a dose of 1250 mg/m 2 and cisplatin was administered at a dose of 100 mg/m 2 on day 1, every 21 days. Results: Twenty-five patients were evaluable for response. One patient achieved a complete response, and 16 patients partial responses. The overall response rate was 65.3% (95% CI: 45%-82%). The main toxicity was hematological: neutropenia NCIC-CTC grade 3-4 in 54% of the patients, and thrombocytopenia grade 3-4 in 23%. The non-hematological toxicity was mild and tolerable. Only 13% of gemcitabine injections were dose-reduced or omitted due to toxicity. The actual dose-intensity of gemcitabine was 715 mg/m~/week, and 31 mg/nr/week for cisplatin. These figures represent the 86% and 93% of the theoretical dose intensity of both drugs, respectively. With a median follow-up of 10 months (range 7-13), 17 patients are still alive and nine have died. The median overall survival is 12 months. Conclusion: This novel combination of gemcitabine and cisplatin administered every three weeks is well tolerated and induces a remarkably high response rate. The regimen proves more interesting than the four-week schedules, particularly regarding patients who are candidates for local therapy.

Gemcitabine is a novel anticancer agent showing activity with relatively mild toxicity across a range of solid tumors including non-small cell lung cancer (NSCLC). In studies using similar doses and schedules, consistent response rates of around 20% were recorded in NSCLC. In an integrated safety study using data from 360 patients with NSCLC, gemcitabine exhibits a mild safety profile for such an active drug. Hematological toxicity is mild and short lasting, and the level of infection associated with this degree of myelosuppression was low. Mild transaminase elevations occurred frequently but were not progressive or dose limiting. There was no evidence of cumulative hepatic or renal toxicity. Nausea and vomiting were mild, rarely dose limiting and generally well controlled with standard antiemetics. Mild flu-like symptoms were experienced in a small proportion of patients and rarely resulted in discontinuation. Where edema or peripheral edema were experienced, there was no evidence of any association with cardiac, hepatic or renal failure. Hair loss was rare and there was no grade 4 alopecia. In conclusion, gemcitabine is a promising new agent in the treatment of NSCLC. Its mild toxicity which is non-overlapping with other cytotoxics has prompted investigation into its use in combination with other chemotherapy regimens.

Summary Background: Primary mediastinal non-seminomatous germ cell tumours (MNSGCT) constitute a rare malignancy. This study was performed to review our experience with cispatinbased chemotherapy in patients with MNSGCT. Patients and methods: Patients with MNSGCT treated with cisplatin-based combination chemotherapy between 1978-1995 in three university hospitals in Spain were retrospectively studied. Results: There were 25 males and two females with a median age of 26 years (range 4—71). Fifteen patients had disease confined to the mediastinum and 12 had metastatic disease. All patients were treated with cisplatin chemotherapy regimens (PVB: 7, BEP: 6, and other regimens 12) and considered for residual mass surgery (RMS) when indicated. Eleven patients (40.7%) were rendered disease-free with initial treatment: four with chemotherapy alone, one with surgery plus adjuvant chemotherapy and six with chemotherapy plus RMS. Three of these patients relapsed at two, six and seven months. The remaining 16 had unfavourable reponses (five partial response, three no change, seven progressive disease and one toxic death) . Eleven patients received salvage treatment but none of them achieved a durable response. After a median follow-up of 77 months (range 1-168), 10 patients remain alive. Actuarial survival at five years is 31.7%. No patients in this series developed a haematological malignancy. Chromosomal analysis showed that 2 out of 10 patients (20%) had a 47XXY karyotype. Conclusions' Only patients who achieved disease-free status are likely to be cured. Therefore, new up-front strategies are needed for the treatment of MNSGCT.

537 Background: At the time the ECTO was designed in 1996, taxanes were only indicated for patients with metastatic breast cancer. However, paclitaxel and docetaxel were still to be tested in the adjuvant setting. In addition there was relatively scarce information on the comparative efficacy of neoadjuvant and adjuvant regimens. The ECTO trial was designed to evaluate the addition of paclitaxel to an anthracycline-based adjuvant regimen and to compare this combination with the same regimen given as primary systemic (neoadjuvant) therapy. Methods: A total of 1,355 women with operable breast cancer were randomized to one of three treatments: 1) surgery followed by adjuvant single agent doxorubicin (A) followed by CMF (arm A); 2) surgery followed by adjuvant paclitaxel plus doxorubicin (AT) followed by CMF (arm B); 3) AT followed by CMF followed by surgery (arm C). The two co-primary objectives were to assess the effects on freedom from progression (FFP) of: 1) the addition of paclitaxel to post-operative chemotherapy (arm B versus arm A); and 2) primary versus adjuvant chemotherapy (arm B versus arm C). Results: At 10 years, in the adjuvant setting FFP remained statistically significant in favor of AT followed by CMF (arm B, HR 0.77, P=0.045). Distant FFP was similarly improved but overall survival was not (HR 0.82, P=0.24). There was no significant difference in FFP when chemotherapy was given after surgery compared with the same regimen given before surgery (arm B vs arm C, HR 0.79, P=0.07). In the primary chemotherapy arm, patients who achieved a pathological complete remission (pCR) had improved distant FFP (P < 0.001) compared to patients who did not achieve pCR. When given as primary systemic therapy, the paclitaxel-containing regimen allowed breast-sparing surgery in a significant percentage of patients, which did not translate in an increased risk of ipsilateral breast recurrence compared to the risk observed in patients in the adjuvant arms. Conclusions: Incorporating paclitaxel into anthracycline-based adjuvant therapy resulted in a significantly improved FFP and DFFP.

1041 Background: Early triple-negative breast cancer (TNBC) patients (p) without pathologic complete response (pCR) after neoadjuvant chemotherapy (NCT) have unsuccessful prognosis. Predictive factors for pCR are necessary in order to improve the treatment choice. The aims of the study are to determine the expression of different biomarkers (BM) in the initial biopsy (IB) of TNBC, to analyze the relationship between the BM expression and pCR, and to determine the expression changes of BM after NCT. Methods: We reviewed retrospectively the medical records of 49 TNBC p treated with NCT between 2001 and 2011 at two institutions. Expression of 14 BM in the IB and after NCT was independently analyzed by inmunohistochemistry by two pathology specialists. Staining intensity 0-1 + was considered as negative expression, and 2-3-4 + as positive. Ki 67>13% was interpreted as positive. Results: Forty-nine p with a median age of 47 years (27-79) were evaluated. Twenty-seven p (55%) had grade 3. Tumor stages were T1(2%), T2(26%), T3(39%), and T4(33%). 38p (77%) were node positive. Five p (10%) received anthracyclines and 42p (86%) anthracyclines plus taxanes. Fourteen p (29%) presented pCR, 27p (55%) partial response, 4p (8%) stable disease, 2p (4%) progressive disease, and 2p (4%) were not evaluable. The BM expression in the IB was: CD44 (88%), CK 5/6 (27%), EGFR ( 0%), Ki 67 (73%), Wt-1 (10%), p-Akt (24%), HER2 (19%), NY-ESO-1 (11%), MAGE A1 (0%), HER3 (14%), BRCA1 (84%), PTEN (12%), IGFR1 (12%) and AR (14%). Diferentially expressed BM in IB for p with and without pCR, respectively, were p-Akt 0/8(0%) vs 5/13(38%) p=0.11, CK 5/6: 4/9 (44%) vs 2/15 (13%) p=0.15 and Ki 67: 7/7(100%) vs 10/17(59%) p=0.06. The Table shows the BM expression before and after NCT for p without pCR. Conclusions: Tumor samples of TNBC show high expression of CD44, ki67, and BRCA1. Most of BM has a decrease in expression after NCT. CK 5/6, Ki 67, and p-Akt could be predictive factor for pCR, although larger prospective studies are needed. [Table: see text]

9641 Background: Hand-foot syndrome (HFS) is a dose-limiting toxicity of capecitabine (CAP), leading to significant morbidity in patients receiving this agent. Interruption or dose reduction of CAP is the only effective strategy. The purpose of our study is to define the pathophysiology and risk factors predictors of CAP-induced HFS. Previously, we had conducted a clinical trial in patients who developed HFS secondary to CAP. Topical heparin was administered in palms and soles of patients four times/day for three weeks (w), evidencing clinical improvement in 99% of patients. Methods: Paired-skin biopsies of palms at baseline and after 3w from 21 patients were obtained. An iTRAQ (isobaric tags for relative and absolute quantitation) proteomics approach was performed to identify molecular pathways associated with HFS reversion. Results: Comparative analysis between baseline and post-treatment skin samples identified 1876 proteins with high confidence (> 99%). The involvement of the identified proteins in biological networks served to characterize molecular pathways associated with HFS reversion. Conclusions: Several proteins identified in this study have a close relationship with keratinocyte terminal differentiation and keratinocyte intercellular strength. Also, we describe differential expression among proteins involved in inflammatory processes, skin immunity and cell death. In summary, our study not only served to uncover molecular mechanisms associated with HFS reversion, but also to reveal the biomarker role of several proteins in this syndrome. [Table: see text]

e12020 Background: Combining bevacizumab (BEV) with chemotherapy (CT) improves survival in HER2-negative metastatic breast cancer (MBC). We investigated the influence of age, ECOG, hormonal status, number of sites, location of metastases and patient decision on the selection of BEV combined with CT in MBC. Methods: Observational cross-sectional multicenter study in patients with HER2- negative MBC who have received first-line CT with BEV. Results: 219 patients were included: median age 51(44-63) yr; ECOG: 0=53%; 60.4% pre-menopausic; 23.9% triple-negative (TN);76.2 % hormone receptor positive (HR+).Metastatic disease: ≥3 sites=39.2% (TN: 22%; HR+: 43.9%); location: 45.2% bone, 37.4% liver, 30.1% lung. Most frequent BEV combinations were paclitaxel/BEV(60.7%) and docetaxel/BEV(12.8%); median no. of CT cycles: 6 (5- 8). A disease-free survival (DFS) ≥12 months was achieved by 82.8%; TN: 78.9%; HR+: 83.3%. Overall response rate (ORR) was 62.7%: 53.6% partial response (PR), 9.1% complete response (CR); 25.4% stable disease (SD) and 7.2% disease progression (4.8% non evaluated). TN:ORR 54.2% (47.9% PR), clinical benefit 80% (27.1% SD); HR+:ORR 65.8% (55.7% PR), clinical benefit 89.9% (24.1% SD). 66.2% presented at least one toxicity, mainly grade 1-2; 32% BEV-related: only 3 grade 3 toxicities; no grade 4. Receiving adjuvant hormonal therapy was associated to DFS ≥12 months (p

555 Background: Chemotherapy is the standard of care for patients (pts) with HER2-negative endocrine-resistant MBC. The considerable variability in overall survival (OS) within this population relates essentially to prognostic factors (PF). Increasingly, large studies based on progression-free survival (PFS) as a primary endpoint are now being questioned. An accurate PF index may help in designing innovative trials with appropriate pts selection according to overall survival (OS) prognosis. Methods: The ATHENA trial assessed the safety of first-line bevacizumab combined with non-anthracycline-containing therapy in 2264 pts treated in 37 countries from 2006 to 2009. Pt characteristics, safety, and efficacy have been reported [Breast Cancer Res Treat 2011;130:133-43]. Sixty-one HER2-positive pts were excluded. A multivariate Cox regression model selected PF generating a simple PF index. Of note, skin, lymph node, ipsi-/contra- breast, or other soft tissue involvement was scored as a single organ. Results: After a median follow-up of 20.1 months and 1171 OS events (53% of pts), median OS for the entire sample and triple-negative (TNBC) and non-TNBC subgroups was 25.2 (95% CI 23.9–26.3), 18.3 (16.3–19.7) and 27.3 (26.3–29.3) months, respectively. PF most closely associated with poorer OS were: liver mets or >2 involved organs (HR 1.6; 95% CI 1.5–1.8); DFI ≤24 months (HR 1.7; 1.5–2.0); adjuvant anthracyline and/or taxane (HR 1.1; 1.2–1.4); and TNBC (HR 1.6; 1.4–1.8). A predictive model was designed stratifying by number of PF present (0/1 vs 2 vs 3/4). The model was consistent in both TNBC and non-TNBC populations (Table). Conclusions: A PF index may estimate figures and balance arms in future trials considering OS as primary objective. A well-defined group of non-TNBC accounting for 37% of patients has an OS estimate similar to the most aggressive TNBC. [Table: see text]

e designed the present trial to assess the hypothesis that chemotherW apy results in less acute nausea and vomiting if it is administered while the patient is sleeping. Chemotherapy and radiotherapy induced nausea and vomiting erode the patient's quality of life more so than any other adverse effect associated with these treatments.' Emesis is occasionally so severe that it requires treatment withdrawal or is associated with dehydration, metabolic emergencies, suture dehiscence, Mallory-Weiss syndrome, or nutritional disorders demanding parenteral nutrition. The emetogenic potential of anticancer drugs varies widely. Cisplatin is a commonly used chemotherapeutic agent. It will produce severe vomiting in virtually every patients if vigorous prophylaxis is not instituted. Active research about cancer treatment related emesis dates back to the ~OS.~ The therapeutic achievements made during the last two decades provide us with no less than 20 different drugs with proven antiemetic p~tential.~ The use of antiemetic prophylactic regimes that combine these drugs in various ways and the increasing interest in this research area points out the lack of a simple, efficient, safe, and cheap antiemetic prophylaxis.

338 Background: We retrospectively assessed long-term outcomes of cisplatin-based chemotherapy for stage II/IIII germ cell tumors (GCTs) at Medical Oncology Department of 12 Octubre University Hospital, Madrid (Spain). Methods: Two hundred fourteen (214) consecutive males with advanced GCTs of the testis or extragonadal origin who received standard cisplatin-based chemotherapy regimens between 1982 and 2012 were analyzed. Results: Demographic features: Median age 26.4 years (range 14- 72 years). Right and left testicular tumor present in 71 (37%) and 78 (41%) patients respectively and cryptorchidism in 11 (5%). Histology: 12% of the patients had seminomatous and 88% non-seminomatous histology. Stage distribution (TNM): Stage II 105p (49%), Stage III 109 p (51%). Twenty-five primary (11%) were extragonadal. Risk assessment according to IGCCCG - good 115 p (54%) intermediate 34 p (16%) and poor 62 p (29%). All patients received chemotherapy with cisplatin (BEP-73%, EP-15%, BOPM-EPI 5%, PVB 6%, others 1%). Survival analysis: The median follow-up period was 117 months (0 - 329). Totally, 158 patients (74%) achieved complete remission (CR). CR was achieved in 128 p (60%) after induction therapy (first line chemotherapy). Salvage treatment: surgery +/-chemotherapy was given to 72 (33%) and 85 (39%) patients respectively. High-dose chemotherapy (with carboplatin based- schemes at dosage (AUC20) as salvage therapy was performed in 65 patients (30%). Of them 35 p (53.4%) had complete remission of disease without relapse and the median progression free survival was of 47.2 months. Severe AEs were < to 5%, and classically already described renal impairment, ototoxicity and neurophaty with non chemotherapy-related toxic deaths. Conclusions: Improvement of medical management and survival during platinum-based chemotherapy and the development of several regimens for salvage chemotherapy seemed to contribute to improving outcomes of patients with advanced GCTs even for patients with platinum-refractory disease. However, we continue to investigate in the search for genetic and molecular mechanisms that help us change it.

Background. The primary objective of this study was to compare the single-biochemical modulation of 5-fluo-rouracil (5-FU) and leucovorin with that of the double-biochemical modulation of methotrexate and leucovorin. Because of the Martin et al. study in which an experimental model showed similar effects of 5-FU at maximum tolerated doses to the modulation with leucovorin at standard doses, a third treatment arm of 5-FU alone was also studied. Methods. A randomized trial was performed using a 500-mg/m2 intravenous (i.v.) 1-hour infusion of methotrexate, and 12 hours later, a 600-mg/m2 i.v. bolus of 5-FU plus a 200-mg/m2 i.v. 1-hour infusion of leucovorin (MFL) every 2 weeks versus 5-FU plus leucovorin at an equal dose and schedule (FL), versus a 1200-mg/m2 i.v dose of 5-FU every 2 weeks. Of 186 patients included in the study, 178 were evaluable. Results. In a preliminary analysis with 94 evaluable patients, two significant statistical differences were shown. First, the toxicity rate of the 5-FU—alone (F) treatment arm was higher than that of the other arms (MFL vs. F, P = 0.0002; FL vs. F, P = 0.00001). Second, the median survival was worse in the F treatment arm with a rate of 12.6 months for the MFL and FL arms and 7.5 months for the F arm (P < 0.05). Considering these results, the F treatment arm was discontinued. The Final results included 70 evaluable patients for MFL and 74 patients for FL. No difference was found in the distribution of prognostic factors. The response rates were 25.7% for MFL (95% CI, 16-37.5) and 14.8% for FL (95% CI, 7.6-25), (P = 0.1). The median survival was 14.3 months for patients treated with MFL and 12.3 months for those treated with FL. The hematologic toxicity was mild, with no grade 3/4 leukopenia in either treatment arm. The major nonhematologic toxicity in the MFL and FL treatment arms was ocular; nongrade 3/4 diarrhea also was observed. Conclusions. The results of MFL double-biochemical modulation failed to show a significant statistical difference from that of single-biochemical modulation for this dose and schedule. Cancer 1995;75:1238-44.

Background: Nab-paclitaxel (Nab-P) is a nanoparticle albumin-bound form of paclitaxel that is thought to exploit natural albumin pathways to enhance the selective uptake and accumulation of paclitaxel at the site of the tumour, thus reducing its diffusion to normal tissues. Nab-P has been approved for the treatment of metastatic breast cancer patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline-containing therapy is not indicated. Toxicity profile of Nab-P is well characterized with significantly less haematological toxicities compared with conventional paclitaxel (P). Nab-P derived grade III neuropathy is short-lasting and more reversible than conventional P-derived neuropathy, probably due to absence of Cremophor solvent, or due to P itself. However there is still a lack of clinical and physiological characterisation of Nab-P induced neuropathy. The Current used tools for early detection and continuous evaluation of neurotoxicity are not optimal. Most used toxicity scales are limited, as they do not provide a detailed information of the severity of the neuropathy, its impact on quality of life, or physiopathology mechanisms. In addition, an inter-individual variability exists in terms of neurotoxicity predisposition when taxanes are used; it seems to be related to polymorphic differences in genes implicated in transport and metabolism of these drugs. Specific aims: Primary objective is to characterize neurotoxicity according to Total Neuropathy Score (TNS) and electromyographic changes. Secondary endpoints are determine the rate of neuropathy chemo-induced, the predictive value of some genetic variants (SNPs) for the development of neuropathy, clinical activity, toxicity profile and safety of treatments and quality of life (EORTC QLQ-C30 and CIPN20). Trial design: Phase II open-label randomised clinical trial with four parallel arms: a) conventional paclitaxel 80 mg/m2 on days 1, 8 and 15; b) Nab-P 100 mg/m2 on days 1, 8 and 15; c) Nab-P 150 mg/m2 on days 1, 8 and 15; d) Nab-P 150 mg/m2 on days 1 and 15. Study treatments will be administered in a 28-day cycle until progression disease, intolerable toxicity or investigator's decision. Eligibility criteria: Women >18 years, with cytological or histological confirmation of HER2-negative breast cancer, metastatic disease, not prior chemotherapy for advanced disease, no prior grade > 1 neuropathy from any cause, measurable or evaluable disease, ECOG >2 and adequate bone marrow, renal and hepatic functions. No Relevant comorbidities. Statistical methods: This is an exploratory safety study to better characterize neurotoxicity in patients treated with Nab-P compared toP. Therefore no formal sample size or power calculations will be performed. We expect to recruit 60 patients, 15 in each treatment arm, in 18 months. Recruitment will start on October 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-3-05.