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Importance Thymic carcinoma (TC) is a rare aggressive tumour occurring in adults characterised by one of the lowest tumor mutational burdens (TMB). Microsatellite instability (MSI) is a mutational signature, caused by defects in the DNA MisMatch Repair (MMR) system, that predicts benefit from immunotherapy and causes high TMB. Fragmentary and unstructured evidence of these conditions co-occurring are reported in literature. Objective Review available data on the co-occurrence of these two conditions and determine its frequency in our institute case series. Design We performed a systematic analysis of literature and a retrospective evaluation of all the cases of TET treated at our institution from 2000 to 2020, selecting patients with a medical history of multiple tumours to enhance a priori probability of identifying cases with underlying predisposition. Results Literature yielded 3 cases of patients with MSI TC, for which MMR gene alteration was reported. None of them received immunotherapy. Of 366 patients with TETs treated in our institute, 32 had a medical history of multiple tumours and 25 of 32 (19 thymomas and 6 TCs) had available tissue for MMR analysis. One patient with TC showed a high TMB, and MSI due to MLH1 mutation and was treated in a phase II study with avelumab and axitinib combination obtaining a long-lasting partial response. MLH1 alterations are shared across MSI TC cases. Conclusions and relevance This analysis highlights the usefulness of MSI testing in patients with TC. The observation of cases of TC occurring in patients with Lynch syndrome and the unexpected homogeneity of gene alterations support further investigation.

The Italian Association of Medical Oncology recommendations on thymic epithelial tumors, which have been drawn up for the first time in 2020 through an evidence-based approach, report indications on all the main aspects of clinical management of this group of rare diseases, from diagnosis and staging, to new available systemic treatments, such as targeted therapies and immunotherapies. A summary of key recommendations is presented here and complete recommendations are reported as Supplementary Materials, available at https://doi.org/10.1016/j.esmoop.2021.100188., Highlights • Thymic epithelial tumors (TETs). • Multidisciplinary management of patients with TETs. • Rare cancers. • Updated recommendations.

Objective: Aim of the manuscript is to discuss how to improve margins in sacral chordoma.Background: Chordoma is a rare neoplasm, arising in half cases from the sacrum, with reported local failure in >50% after surgery.Methods: A multidisciplinary meeting of the "Chordoma Global Consensus Group" was held in Milan in 2017, focusing on challenges in defining and achieving optimal margins in chordoma with respect to surgery, definitive particle radiation therapy (RT) and medical therapies. This review aims to report on the outcome of the consensus meeting and to provide a summary of the most recent evidence in this field. Possible new ways forward, including on-going international clinical studies, are discussed.Results: En-bloc tumor-sacrum resection is the cornerstone of treatment of primary sacral chordoma, aiming to achieve negative microscopic margins. Radical definitive particle therapy seems to offer a similar outcome compared to surgery, although confirmation in comparative trials is lacking; besides there is still a certain degree of technical variability across institutions, corresponding to different fields of treatment and different tumor coverage. To address some of these questions, a prospective, randomized international study comparing surgery versus definitive high-dose RT is ongoing. Available data do not support the routine use of any medical therapy as (neo)adjuvant/cytoreductive treatment.Conclusion: Given the significant influence of margins status on local control in patients with primary localized sacral chordoma, the clear definition of adequate margins and a standard local approach across institutions for both surgery and particle RT is vital for improving the management of these patients. (C) 2020 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Soft tissue sarcomas (STS) are uncommon, heterogeneous malignant tumors of mesodermal origin. Other than conservative surgery (CS), neoadjuvant or adjuvant radiotherapy (RT) is recommended when the risk of local recurrence is high. The aim of this study is to present our Institutional experience in adjuvant RT for treatment of STS of extremities and trunk (with either brachytherapy (BRT), external beam RT (EBRT), or both) and to provide an insight of toxicity and oncological outcomes for each RT modality. According to the RT treatment approach, patients were divided into three categories: 1) BRT alone; 2) EBRT alone; 3) combined BRT+EBRT. Differences among the three groups were assessed by the Chi-squared test. Patients' follow-up was performed every 6 months for the first two years after the end of RT and then once a year. Data from 90 patients were analyzed. The overall 3-year distant relapse-free survival (DRFS), progression-free survival (PFS), and overall survival (OS) were 84%, 80%, and 97%, respectively. Acute erythema was the most frequent side effect, although severe grade 3 toxicity was present in 5 patients. Chronic toxicity of any grade was reported in 14 patients. The incidence of chronic toxicity did not show any association with treatment modality. Multivariate analysis suggested a significant correlation between acute toxicity and tumor size, RT modality, and RT dose. In conclusion, good local control and toxicity profile were observed, despite negative patients' selection at baseline. Further investigation on wider series is warranted in order to define the optimal combination with systemic therapy.

Background In our previous works, we demonstrated that patients’ sex affects the efficacy of immune checkpoint inhibitors (ICIs) in patients with several advanced solid tumors. Here, we assessed the sex-based heterogeneity of efficacy of anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed death-ligand 1 (anti-PD-L1) given as monotherapy, for advanced non-small-cell lung cancer (NSCLC) expressing high PD-L1 levels, to evaluate if available evidence supports this therapeutic option for both women and men. Methods We carried out a systematic review and meta-analysis including all randomized, controlled trials testing anti-PD-1/anti-PD-L1 drugs in monotherapy, as first-line treatment of advanced NSCLC expressing high PD-L1 levels. The primary endpoint was the difference in efficacy of anti-PD-1/anti-PD-L1 drugs versus chemotherapy, between men and women, measured in terms of the difference in overall survival (OS) log [hazard ratio (HR)] reported in male and female study participants. Results We analyzed four randomized, controlled trials, including 1672 patients, of whom 1224 (73.2%) were men and 448 (26.8%) were women. The pooled OS-HR comparing anti-PD-1/anti-PD-L1 versus chemotherapy was 0.59 [95% confidence interval (CI), 0.50-0.69] for men and only 0.84 (95% CI, 0.64-1.10) for women. The pooled ratio of the OS-HRs reported in men versus women was 0.71 (95% CI, 0.52-0.98; P-heterogeneity: 0.04), indicating a significantly greater effect for men. No heterogeneity among single-study estimates was observed in either male patients (Q = 2.39, P = 0.50, I2 = 0%) or in female patients (Q = 1.13, P = 0.50, I2 = 0%). Conclusion Evidence available indicates anti-PD-1/anti-PD-L1 monotherapy as highly effective in men but not in women, even in NSCLCs expressing high PD-L1 levels. Prospective trials testing sex-based tailored immunotherapy strategies are needed., Highlights • Sex-based heterogeneity of efficacy of immune checkpoint inhibitors. • Sex-tailored immunotherapy strategies. • NSCLC expressing high PD-L1 levels.

We describe the case of a 69-year old male with an EGFR- positive Imatinib refractory sacral chordoma with synchronous lung metastases, treated with erlotinib, a first-generation EGFR inhibitor. After disease progression following first-line Imatinib and a combination therapy with everolimus plus metformin, we made a challenge with an EGFR tyrosine kinase inhibitor (EGFR TKI), erlotinib. Despite a brief clinical benefit, the patient presented a rapid clinical deterioration leading to death, after 8 weeks of treatment.

Background: Classification of lung carcinoids into typical and atypical is a diagnostic challenge since no immunohistochemical tools are available to support pathologists in distinguishing between the two subtypes. A differential diagnosis is essential for clinicians to correctly discuss therapy, prognosis and follow-up with patients. Indeed, the distinction between the two typical and atypical subtypes on biopsies/cytological specimens is still unfeasible and sometimes limited also after radical surgeries. By comparing the gene expression profile of typical (TC) and atypical carcinoids (AC), we intended to find genes specifically expressed in one of the two subtypes that could be used as diagnostic markers. Methods: Expression profiling, with Affymetrix arrays, was performed on six typical and seven atypical samples. Data were validated on an independent cohort of 29 tumours, by means of quantitative PCR and immunohistochemistry (IHC). Results: High-throughput gene expression profiling was successfully used to identify a gene signature specific for atypical lung carcinoids. Among the 273 upregulated genes in the atypical vs typical subtype, GC (vitamin D-binding protein) and CEACAM1 (carcinoembryonic antigen family member) emerged as potent diagnostic markers. Quantitative PCR and IHC on a validation set of 17 ACs and 12 TCs confirmed their reproducibility and feasibility. Conclusions: GC and CEACAM1 can distinguish between TC and AC, defining an IHC assay potentially useful for routine cytological and histochemical diagnostic procedures. The high sensitivity and reproducibility of this new diagnostic algorithm strongly support a further validation on a wider sample size. Gene expression microarrays can be used to identify signatures specific for tumour subtypes, allowing the classification into categories with a potential impact on clinical practice. In lung cancer, expression profiling unravelled interesting aspects regarding early diagnosis

Objective In a previous study, we found that patients who were offered the possibility of participation in a clinical trial had unexpressed concerns and fears that prevented them from making free or fully knowledgeable choices about their trial participation. In a selected population of patients who were offered participation in a phase I trial, we prospectively investigated whether a face-to-face discussion about their unexpressed fears might lead to a more conscious decision about whether to accept/refuse participation in the trial. Methods After the presentation of the trial, a questionnaire was administered to assess the presence of specific fears. Before the patients decided whether to participate in the trial, they discussed any fears that they had; finally, the impact of the discussion on the patients' choice to participate was evaluated. Results The majority (86%) of the patients thought that physicians conduct clinical trials for scientific interest, 13% felt exploited as ‘guinea pigs’ and 20% believed they were offered participation because they had no further hope for improvement. These existing fears were not elicited during the trial interview because the patients were themselves unaware of having them (28%) and because of fear of the doctors (3%). The possibility of discussing these fears was felt as an opportunity and made patients feel more conscious (92%) and freer (97%) when making their choice. Conclusions Recognising and discussing misconceptions and fears, often unexpressed, make patients freer and more aware when facing the choice of whether or not \to participate in a phase I clinical trial. Copyright © 2013 John Wiley & Sons, Ltd.

We retrospectively reviewed medical charts of 54 patients who underwent orchidectomy for germ cell tumors (GCT) and received a regimen, given every 3 weeks, consisting of cisplatin 100 mg/m2 day 4 intravenous (i.v.), bleomycin 15 Units (U) day 1 i.v. push; bleomycin 10 U days 1-3 24 h i.v. continuous infusion (c.i.) and etoposide 100 mg/m2 days 1-5/i.v. (PEB). 53 of 54 patients achieved a complete remission without adjunctive surgery. At a median follow-up of 48.2 months (95%CI 41.7 - 54.8 months) all patients but one are alive with no evidence of disease recurrence. Patients receiving PEB experienced no pulmonary toxicity, nephrotoxicity nor neurological adverse events. PEB with c.i. bleomycin is an active regimen with a low rate of acute and late toxicity. The main limitations of our study are related to the retrospective analysis, the limited number of patients and the restricted follow-up time. A prolonged follow- up is necessary to evaluate long term toxicity and outcome.

Background We evaluated safety and efficacy of PTK787/ZK222584 (PTK/ZK), a novel tyrosine kinase inhibitor of KIT, platelet-derived growth factor receptors and vascular endothelial cell growth factor receptors (VEGFRs), in patients with imatinib-resistant gastrointestinal stromal tumor (GIST). This is the first study of PTK/ZK in this population. Patients and methods Patients with metastatic GIST that had progressed after ≥ 4-week treatment with imatinib mesylate were eligible. Prior VEGFR-2 inhibitor therapy was not permitted. PTK/ZK 1250 mg orally once-daily was administered to 15 patients (accrued as a two-stage procedure), most of whom (n = 11) had been unsuccessfully treated with imatinib 800 mg daily, until treatment failure. Patients were monitored at 4- to 8-week intervals. Results All 15 patients enrolled were eligible; two (13%) achieved partial response (PR), eight (53%) had stable disease (SD) ≥3 months, and five (33%) progressed. The clinical benefit rate (PR + SD) was 67% (95% CI 38% to 86%). Median time to progression was 8.5 months (range 0.9–24.8+ months). Three patients had not progressed at the time of analysis, including one PR at 24.8 months and two SDs at 16.6 and 18.6 months on treatment. PTK/ZK was generally well tolerated. Conclusion PTK/ZK 1250 mg p.o. once daily is active and well tolerated in patients with imatinib-resistant GIST.

KRAS mutations in non-small-cell lung cancer (NSCLC) are associated with poor prognosis. Trametinib, a selective inhibitor of MEK1/MEK2, demonstrated similar efficacy to docetaxel in patients with advanced KRAS-mutant NSCLC, with median progression-free survival of 12 and 11 weeks, respectively. With moderate activity as a monotherapy, trametinib-based combination regimens may show improve efficacy. Background KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC. Patients and methods Eligible patients with histologically confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2 : 1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m2 i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary. Results One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75–1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52–1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). The most frequent adverse events (AEs) in ≥20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia. Conclusion Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC. Clinicaltrials.gov registration number NCT01362296.

Background Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. This study determined the maximum tolerated dose (MTD) and pharmacokinetics of volasertib combined with nintedanib, a potent and orally bioavailable triple angiokinase inhibitor, in patients with advanced solid tumors. Patients and methods This open-label, dose-escalation trial recruited patients with advanced metastatic solid tumors following failure of conventional treatment (NCT01022853; Study 1230.7). Volasertib was administered by intravenous infusion over 2 h, starting at 100 mg in the first dose cohort. Nintedanib was administered orally at a dose of 200 mg twice daily. The first treatment cycle comprised 28 days (days 1–7 and days 9–28: nintedanib; day 8: volasertib). From cycle 2 onwards, volasertib was administered on day 1 of a 21-day cycle and nintedanib was administered days 2–21. The primary objective was the MTD of volasertib in combination with nintedanib. Results Thirty patients were treated. The MTD of volasertib plus fixed-dose nintedanib was 300 mg once every 3 weeks, the same as the recommended single-agent dose of volasertib in solid tumors. Two of 12 assessable patients treated with the MTD experienced dose-limiting toxicities [grade 3 increased alanine aminotransferase (ALT); grade 3 ALT increase and grade 3 increased aspartate aminotransferase]. Disease control [stable disease (SD)/partial response (PR)/complete response (CR)] was achieved in 18 patients (60%): 1 CR (breast cancer), 1 PR (nonsmall-cell lung cancer), and 16 patients with SD. Volasertib showed that multiexponential pharmacokinetic behavior and co-administration of nintedanib had no significant effects on its exposure. Conclusions Volasertib could be combined with fixed-dose nintedanib at the recommended single-agent dose. At this dose, the combination had a manageable safety profile without unexpected or overlapping adverse events, and showed antitumor activity.

Purpose: To determine whether a prolonged 12-day continuous infusion allows the administration of high-dose ifosfamide (IFO) with an acceptable toxicity profile when combined with full-dose doxorubicin (Adriamycin®; ADM) as first-line chemotherapy in patients with advanced soft tissue sarcomas. Patients and methods: Escalating doses of continuous infusion IFO (8-15 g/m 2 ) given on days 1 to 12 in combination with ADM 75 mg/m 2 given on day 8 and prophylactic granulocyte colony-stimulating factor support were administered every 4 weeks to 35 chemonaive patients with advanced soft tissue sarcomas. Results: The maximum tolerated dose Was IFO 15 g/m 2 . Hematological toxicity was the main dose-limiting toxicity and was dose dependent. Furthermore, thrombocytopenia was cumulative. Grade 4 (WHO) neutropenia and thrombocytopenia were recorded in 48% and 14% of courses, respectively. Eight patients experienced febrile neutropenia. A partial response was observed in 16 out of 30 assessable patients [53%, 95% confidence interval (Cl) 25-63]; median time to progression was 25 weeks (range 4-91). Conclusions: This study proved that a prolonged 12-day continuous infusion allow an increase in the total IFO dose that can he safely combined with ADM. A multicentric phase II study by the Italian Sarcoma Group to assess its antitumor activity is currently ongoing in patients with advanced soft tissue sarcomas,.

Background: Gemcitabine and paclitaxel are two of the most active agents in non-small-cell lung cancer (NSCLC), and pharmacologic investigation of the combination regimens including these drugs may offer a valuable opportunity in treatment optimization. The present study investigates the pharmacokinetics and pharmacodynamics of paclitaxel and gemcitabine in chemotherapy-naive patients with advanced NSCLC within a phase I study. Patients and methods: Patients were given i.v. paclitaxel 100 mg/m2 by one-hour infusion followed by gemcitabine 1500, 1750 and 2000 mg/m2 by 30-min administration. Plasma levels of paclitaxel, gemcitabine and its metabolite 2′,2′-difluorodeoxyuridine (dFdU) were determined by high-performance liquid chromatography (HPLC). Concentration-time curves were modeled by compartmental and non-compartmental methods and pharmacokinetic/pharmacodynamic (PK/PD) relationships were fitted according to a sigmoid maximum effect (Emax) model. Results: Paclitaxel pharmacokinetics did not change as a result of dosage escalation of gemcitabine from 1500 to 2000 mg/m2. A nonproportional increase in gemcitabine peak plasma levels (Cmax, from 18.56 ± 4.94 to 40.85 ± 14.85 μg/ml) and area under the plasma concentration-time curve (AUC, from 9.99 ± 2.75 to 25.01 ± 9.87 h·μg/ml) at 1500 and 2000 mg/m2, respectively, was observed, suggesting the occurrence of saturation kinetics at higher doses. A significant relationship between neutropenia and time of paclitaxel plasma levels ≥ 0.05 μmol/l was observed, with a predicted time of 10.4 h to decrease cell count by 50%. A correlation was also observed between percentage reduction of platelet count and gemcitabine Cmax, with a predicted effective concentration to induce a 50% decrease of 14.3 μg/ml. Conclusion: This study demonstrates the lack of interaction between drugs, the nonproportional pharmacokinetics of gemcitabine at higher doses and the Emax relationship of paclitaxel and gemcitabine with neutrophil and platelet counts, respectively. In addition, gemcitabine 1500 mg/m2 is the recommended dosage in combination with paclitaxel 100 mg/m2 for future phase II studies, due to its predictable kinetic behaviour and less severe thrombocytopenia than expected.

Lung neuroendocrine tumors are catalogued in four categories by the World Health Organization (WHO 2004) classification. Its reproducibility and prognostic efficacy was disputed. The WHO 2010 classification of digestive neuroendocrine neoplasms is based on Ki67 proliferation assessment and proved prognostically effective. This study aims at comparing these two classifications and at defining a prognostic grading system for lung neuroendocrine tumors. The study included 399 patients who underwent surgery and with at least 1 year follow-up between 1989 and 2011. Data on 21 variables were collected, and performance of grading systems and their components was compared by Cox regression and multivariable analyses. All statistical tests were two-sided. At Cox analysis, WHO 2004 stratified patients into three major groups with statistically significant survival difference (typical carcinoid vs atypical carcinoid (AC),P=0.021; AC vs large-cell/small-cell lung neuroendocrine carcinomas,PP=0.021; and G2 vs G3,P≤0.001), mitotic count (G1 ≤2, G2 >2–47, G3 >47; G1 vs G2,P≤0.001; and G2 vs G3,P≤0.001), and presence of necrosis (G1 absent, G2 10% of sample; G1 vs G2,P≤0.001; and G2 vs G3,P≤0.001) at uni and multivariable analyses. The combination of these three variables resulted in a simple and effective grading system. A three-tiers grading system based on Ki67 index, mitotic count, and necrosis with cutoffs specifically generated for lung neuroendocrine tumors is prognostically effective and accurate.

Background: Gemcitabine (GEM) and paclitaxel (TAX) are active, non-cross-resistant drugs in non-small-cell lung cancer (NSCLC). We performed a phase I study to determine the maximum-tolerated dose (MTD), antitumor activity and pharmacokinetics of GEM and TAX given weekly in chemo-naive patients with advanced NSCLC. Patients and methods: Escalating doses of GEM (800-2000 mg/m 2 ) and TAX (60-100 mg/m 2 ) were administered on days 1, 8, 15 every 4 weeks to 35 patients with advanced NSCLC. Plasma pharmacokinetics of TAX and GEM was assessed at the three higher dose-levels. Results: Dose-escalation was discontinued in absence of MTD because of increased cumulative toxicity leading to dose modification or treatment delay at levels 6 and 7 (TAX 100 mg/m 2 plus GEM 1750 and, respectively, 2000 mg/m 2 ). Hematological toxicity included grade 4 neutropenia in 3% of cycles, grade 3 thrombocytopenia in one cycle and febrile neutropenia in three cycles. Maximal non-hemathological toxicity was grade 3 elevation in serum transaminases and grade 2 neuro-sensory toxicity in 8% and 5% of cycles, respectively. At the two higher dose-levels a non-linear pharmacokinetics of GEM was observed with a remarkable variability of C max and AUC. No pharmacokinetic interactions were reported. Objectives responses were seen at all dose levels, with an overall response rate of 43% (95% confidence interval (95% CI): 25.5%-62.6%) in 30 evaluable patients. Conclusions; The weekly administration of GEM and TAX is very well tolerated, and has shown promising antitumor activity in NSCLC. In view of the cumulative toxicity and of the pharmacokinetic profile of GEM, doses of 1500 mg/m 2 of GEM and 100 mg/m 2 of TAX are recommended for phase II studies.

The purpose of this study was to evaluate the activity and the toxicity of the combination of gemcitabine with ifosfamide and cisplatin (GIP) in chemonaive patients with advanced non small cell lung cancer (NSCLC). Eighty chemonaive patients with Stage IIIB-IV NSCLC were treated with the combination of gemcitabine 1 g/m2 on Days 1 and 8, ifosfamide 2 g/m2 on Day 1 and cisplatin 80 mg/m2 on Day 2. Cycles were administered on an outpatient basis every 3 weeks. Hematologic toxicity was the main side effect; Grade III-IV thrombocytopenia was observed in 54 (67%) patients and Grade III-IV leucopenia in 44 (55%) patients, with 4 episodes of febrile neutropenia and 1 toxic death. Thirteen patients received platelet transfusions and 38 were transfused with packed red cells. All patients were evaluable for response. The overall response rate was 54% (95% confidence interval 43 to 65%) with 1 complete response. In patients with Stage IIIB and IV disease, response rates were 58% and 52%, respectively. Median time to progression was 40 weeks (range 0–114) and median overall survival was 12 months (16.6 months for stage IIIB and 10.4 months for stage IV). Median and minimum follow-up were 19 and 12 months, respectively. The GIP combination shows a response rate and overall survival of clinical interest. Hematologic toxicity was the main toxic effect, especially in patients with low performance status. This regimen will be tested in a Phase III randomized trial. Int. J. Cancer 87:724–727, 2000. © 2000 Wiley-Liss, Inc.

To evaluate the feasibility of induction chemotherapy followed by concomitant chemotherapy and hyperfractionated irradiation in locally advanced, inoperable head and neck cancer.A pilot study was undertaken comprising 3 cycles of cisplatinum (100 mg/m2, day 1) and 5-fluorouracil (1000 mg/m2 in continuous intravenous infusion over the first 120 h) followed by bifractionated radiotherapy applied to tumor/involved lymph nodes up to the dose of 74.4 Gy given in 2 fractions of 1.2 Gy daily for 5 days a week combined with concomitant weekly cisplatinum infusion (50 mg/m2).Six patients were enrolled in the study. All of them completed the protocol therapy. Severe mucositis and myelotoxicity were the most common acute side effects observed in all and in 5 of the patients, respectively. Acute toxicity required interruption of concomitant chemotherapy in 5 cases and in 2 interruption of radiotherapy was necessary. Opioid analgesic parenteral therapy was administered in 4 patients. Three of them had to be hospitalized. One patient experienced cerebral stroke 1 day after the completion of therapy and died 7 days later. Due to high acute toxicity, patient accrual was terminated after 6 patients. At the mean follow-up of 17 months, 4 patients are alive, 3 of them are free of disease and in 1 local progression has been diagnosed.High acute toxicity of induction cisplatinum and 5-fluorouracil followed by concomitant cisplatinum and hyperfractionated irradiation calls for less toxic treatment schedules in locally advanced inoperable head and neck cancer.

PURPOSE Malignant pericardial effusion, although highly variable, is an uncommon complication of cancer. It is often associated with symptoms like dyspnea, chest pain, and cough, which may be severe and disabling. We analyzed the results of our current treatment policy to evaluate the effectiveness and tolerance of a new approach for this disorder. PATIENTS AND METHODS Patients with malignant pericardial effusions were treated with intracavitary thiotepa (15 mg on days 1, 3, and 5) through an indwelling pericardial cannula after extraction of as much pericardial fluid as possible on day 0. Responses were assessed by clinical examination, computed tomographic (CT) scan, and echocardiography before treatment, 1 month after treatment, and every 2 months thereafter. Twenty-three patients with malignant symptomatic pericardial effusion were treated and all were assessable for effectiveness and tolerance of the procedure. RESULTS Nine patients with breast cancer, 11 with lung cancer, two with an unknown primary tumor, and one with metastatic melanoma were treated. In all but three patients, systemic medical treatment was started after completion of intracavitary therapy. Nineteen patients responded to treatment (83%; 95% confidence interval, 61% to 95%) with a rapid improvement of symptoms. The median time to pericardial effusion progression was 8.9 months (range, 1 to 26). No significant side effects were registered, except one patient who had transient grade III thrombocytopenia and leukopenia and one patient who had grade I leukopenia. CONCLUSION A short course of intracavitary treatment with thiotepa is highly effective and well tolerated in the treatment of malignant pericardial effusion.

In a previous study, we found that patients who were offered the possibility of participation in a clinical trial had unexpressed concerns and fears that prevented them from making free or fully knowledgeable choices about their trial participation. In a selected population of patients who were offered participation in a phase I trial, we prospectively investigated whether a face-to-face discussion about their unexpressed fears might lead to a more conscious decision about whether to accept/refuse participation in the trial.After the presentation of the trial, a questionnaire was administered to assess the presence of specific fears. Before the patients decided whether to participate in the trial, they discussed any fears that they had; finally, the impact of the discussion on the patients' choice to participate was evaluated.The majority (86%) of the patients thought that physicians conduct clinical trials for scientific interest, 13% felt exploited as 'guinea pigs' and 20% believed they were offered participation because they had no further hope for improvement. These existing fears were not elicited during the trial interview because the patients were themselves unaware of having them (28%) and because of fear of the doctors (3%). The possibility of discussing these fears was felt as an opportunity and made patients feel more conscious (92%) and freer (97%) when making their choice.Recognising and discussing misconceptions and fears, often unexpressed, make patients freer and more aware when facing the choice of whether or not \to participate in a phase I clinical trial.

Although many different treatments have been evaluated in the last thirty years, advanced renal cell carcinoma still has a poor prognosis, characterised by a survival rate which is less than 5% at 3 years from diagnosis. Many different therapeutic approaches have been carried out in addition to cytotoxic chemotherapy, which shows obvious limits such as an overall response rate that does not go above 10-15%. One of the more promising treatments that has been studied the most is undoubtedly immunotherapy. We present a literature review aimed at summing up all the results obtained until now with immunotherapy of renal cell carcinoma, whether alone or in combination with cytotoxic chemotherapy. Unanswered questions of major concern are stressed, such as treatment choice, dosage, the most convenient schedules with particular regard to the cost-benefit issue.

Peptide receptor radiotherapy, which uses radiolabelled peptides that recognise tumour cell surface receptors, is a relatively new technique for delivering large quantities of radioactivity to tumours. The somatostatin analogue [DOTA0, Tyr3]octreotide (DOTATOC) has been shown to be useful for this purpose, as it is easily and stably labelled with yttrium-90. It has high affinity for the somatostatin receptor subtype 2 (sst2) and a favourable bio-distribution and safety profile in patients (Kwekkeboom et al, 2000). Tumour uptake of 90Y-DOTATOC can be revealed before treatment by scintigraphy with 111In-labelled octreotide (OctreoScan) (Krenning et al, 1993). When 90Y-DOTATOC is given to patients with cancers that express somatostatin receptors and show adequate OctreoScan uptake, a good tumour–response rate is observed (Cremonesi et al, 1999; Waldherr et al, 2001; Chinol et al, 2002).

L19-TNF is an armed antibody that selectively targets human TNF to extra domain B-fibronectin on tumour blood vessels. We performed a phase I/II first-in-man trial with L19-TNF monotherapy in metastatic solid cancer patients to study safety and signs of clinical activity. Six cohorts of patients were treated with increasing (1.3–13 μg/kg) doses of intravenous L19-TNF on day 1, 3, and 5 of repeated 3-weekly cycles, and 12 colorectal cancer patients were treated at 13 μg/kg. PK, antibody formation, changes in lymphocyte subsets, 5-HIAA plasma levels as well as safety and clinical activity were analysed. Thirty-four patients received at least one L19-TNF dose. The serum half-life of L19-TNF at 13 μg/kg was 33.6 min, and maximum peak serum concentration was 73.14 μg/L. Mild chills, nausea and vomiting but no haemato- or unexpected toxicity were observed. Grade 3 lumbar pain in bone metastasis was the only dose-limiting toxicity found in one patient. Objective tumour responses were not detected. Transient stable disease occurred in 19 of 31 evaluable patients. Intravenous L19-TNF on day 1, 3, and 5 of a 3-weekly schedule was safe up to 13 μg/kg, but did not result in objective tumour responses. The maximally tolerated dose (MTD) was not reached, allowing for further dose escalation of L19-TNF possibly in combination with chemotherapy.

Background Anaplastic lymphoma kinase (ALK) is a known oncogenic driver in NSCLC, and approximately 5% of patients harbor ALK gene rearrangements. Crizotinib is a first-in-class, selective small-molecule ALK inhibitor with demonstrated clinical activity in ALK-positive NSCLC. PROFILE 1005 is a global, multicenter, open-label, single-arm phase II study evaluating the safety and efficacy of crizotinib in previously treated patients with ALK-positive advanced NSCLC. Methods Crizotinib 250 mg was administered BID to patients with ALK-positive advanced NSCLC who had received ≥1 chemotherapy for locally advanced/metastatic disease, including those with treated brain metastases. Most patients had centrally confirmed ALK-positivity by break-apart fluorescence in-situ hybridization, defined as ≥15% of tumor cells with split signals. Disease response was evaluated by RECIST 1.1 every 6 weeks. Results As of January 2012, 901 patients had been dosed. The first 261 patients who had enrolled and started crizotinib by February 2011, with a median duration of treatment of 48 weeks, were considered to be the mature population. Demographic, exposure, and efficacy results in both the overall and mature populations are provided in the table. Among all 901 patients, 15% discontinued treatment due to adverse events (AEs) and 10% had a dose reduction due to an AE. The most frequent AEs of any cause were vision disorder (54%), nausea (51%), diarrhea (44%), vomiting (44%), and constipation (37%), which were mostly grade 1/2. Conclusions Crizotinib demonstrated a high response rate that was durable, with a median progression-free survival of 8.1 months. Crizotinib has a favorable tolerability profile. These findings continue to provide strong evidence for crizotinib as a standard of care for advanced ALK-positive NSCLC. Overall population Mature population Total no. of patients, n 901 261 Response-evaluable patients, n 803 259 Demographics: Median age, years Male/female, % ECOG PS 0/1, % Adenocarcinoma, % 53 43/57 82 92 52 46/54 83 94 Duration of treatment (weeks), median (range) 20 ( 48 (1 - 94) ORR, % (95% exact CI) 46 (42–50) 60 (54–66) Duration of response (weeks), median a (95% CI) 47 (36–54) 46 (35–54) Disease control rate, % (95% exact CI): At 6 weeks At 12 weeks 80 (77–83) 61 (58–64) 86 (82–90) 75 (70–80) PFS (months), median a (95% CI) 8.1 (6.9–9.5) 8.1 (6.8–9.7) ECOG PS, Eastern Cooperative Oncology Group performance status; ORR, objective response rate; PFS, progression-free survival. a Kaplan–Meier estimate Disclosure D. Kim: Compensated advisory relationship: Pfizer. Honoraria: Pfizer. S. Lanzalone: Employment: Pfizer. Stock ownership: Pfizer. A. Polli: Employment: Pfizer. Stock ownership: Pfizer. A. Shaw: Compensated advisory relationship: Pfizer, Ariad, Chugai, Novartis, Daiichi-Sankyo. Research funding: AstraZeneca, Novartis. All other authors have declared no conflicts of interest.

Background: Vatalanib (PTK787/ZK 222584) inhibits a few tyrosine kinases including KIT, platelet-derived growth factor receptors (PDGFRs) and vascular endothelial growth factor receptors (VEGFRs). We report efficacy and safety results of vatalanib in advanced gastrointestinal stromal tumour (GIST) resistant to imatinib or both imatinib and sunitinib. Patients and methods: Forty-five patients whose metastatic GIST had progressed on imatinib were enrolled. Nineteen (42.2%) patients had received also prior sunitinib. Vatalanib 1250 mg was administered orally daily. Results: Eighteen patients (40.0% 95% confidence interval (CI), 25.7–54.3%) had clinical benefit including 2 (4.4%) confirmed partial remissions (PR; duration, 9.6 and 39.4 months) and 16 (35.6%) stabilised diseases (SDs; median duration, 12.5 months; range, 6.0–35.6+ months). Twelve (46.2%) out of the 26 patients who had received prior imatinib only achieved either PR or SD compared with 6 (31.6%, all SDs) out of the 19 patients who had received prior imatinib and sunitinib (P=0.324). The median time to progression was 5.8 months (95% CI, 2.9–9.5 months) in the subset without prior sunitinib and 3.2 (95% CI, 2.1–6.0) months among those with prior imatinib and sunitinib (P=0.992). Vatalanib was generally well tolerated. Conclusion: Vatalanib is active despite its narrow kinome interaction spectrum in patients diagnosed with imatinib-resistant GIST or with imatinib and sunitinib-resistant GIST.

Background: Ifosfamide and doxorubicin combination is an active regimen for patients with advanced soft tissue sarcomas (STS) but is burdened by high toxicity. A phase II trial was designed to assess the activity of continuous infusion ifosfamide and doxorubicin combination. Patients and Methods: Thirty-four chemotherapy-naive patients with advanced STS were treated with ifosfamide (13 g/m2/12 days as continuous infusion) and doxorubicin (75 mg/m2 on day 8) every 28 days with granulocyte colony-stimulating factor. Results: The major toxicity was hematological: grade 3/4 neutropenia, anemia and thrombocytopenia occurred in 63, 30 and 12% of patients, respectively. The disease control rate was 68% and the median time to progression was 7.1 months. Among leiomyosarcomas, 2 partial responses and 4 stable diseases were observed. Conclusions: Our study confirms that the ifosfamide and doxorubicin combination has a very low non-hematological toxicity profile. This regimen attained a high disease control rate with moderate activity. Further investigation into leiomyosarcoma is warranted.

http://hdl.handle.net/20.500.11768/96436

The aim of this study was to investigate the influence of histology and site of analysis (primary tumor versus lymph node) on the expression of genes involved in gemcitabine and cisplatin activity in non-small-cell lung cancer (NSCLC). Excision repair cross-complementing-1 (ERCC1), human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), 5'-nucleotidase (5'-NT), cytidine deaminase (CDA) and ribonucleotide-reductase regulatory subunits (RRM1 and RRM2) were analyzed by quantitative-reverse transcription-PCR in 88 microdissected samples from 69 chemonaive patients. The results showed different patterns of expression for all studied genes, suggesting a possible stratification of the patients. No difference was observed between primary tumor and lymph node metastasis, as well as in adenocarcinoma and squamous-cell carcinoma specimens, while we found a correlation between the CDA-A79C polymorphism and gene expression levels. These data suggest a similar genetic susceptibility to gemcitabine-cisplatin regimens for squamous cell and adenocarcinoma and support the use of both lymph node and primary tumor for the expression profiling of NSCLC.

Background There is a need for active agents with a better safety profile than docetaxel, yet good activity, for patients with hormone-refractory prostate cancer (HRPC). We carried out a phase II trial to determine the activity and safety of estramustine plus oral etoposide in HRPC. Patients and methods Patients were given estramustine (280 mg twice daily) and etoposide (100 mg/day, days 1–21) in 28-day cycles until disease progression or unacceptable toxicity. Primary end points were overall response rate and safety, as determined by prostrate-specific antigen (PSA) levels and lesion assessment. Results From November 2001 to February 2007, 75 patients were enrolled. All patients were assessable for safety; 17 (22.6%) had grade 3/4 toxicity. PSA response was assessable in 69, 14 of whom had a >50% reduction in PSA. Of 10 patients with one or more measurable lesions, two (20%) had partial response and two (20%) disease stabilization. Overall, median time to progression was 4.4 months (range 1 week–43 months); median survival was 23 months (range 3 weeks–64+ months). Conclusions Estramustine plus etoposide is active and has a manageable safety profile in patients with HRPC. In asymptomatic patients with nonaggressive disease this combination could be useful to delay the start of more demanding treatments.

Summary Background: Adriamycin (ADM) and ifosfamide (IFO) are the two most active agents in the treatment of soft tissue sarcomas (STS) with a clear dose-response relationship. We evaluated the feasibility and toxicity of a high-dose IFO-plus-ADM combination. Patients and methods: Fourteen patients with advanced disease and nine patients in adjuvant setting received IFO 12.5 g/m 2 in 120-hour continuous infusion with Mesna uroprotection and ADM 20 mg/m 2 on days 1-3 and G-CSF every three weeks. Results: Twenty-three patients received 89 chemotherapy cycles (70 cycles at full dose). Seventeen patients received the planned treatment, and nine patients required dose reductions. We observed grade 3-4 neutropenia in 52 cycles (59%)/20 patients; grade 3-4 thrombocytopenia in 16 cycles (18%)/nine patients; grade 3-4 anaemia in 24 cycles (27%)/ll patients. Eight patients experienced febrile neutropenia and six patients required blood transfusions. Conclusions: While feasible, this regimen showed heavy toxicity. Nevertheless, 74% of the patients were able to complete the planned treatment. Adjustment of the schedule of IFO continuous infusion to improve this combination is currently under investigation.

http://hdl.handle.net/20.500.11768/96460

Breast metastases from extramammary primary tumors are uncommon, accounting for approximately 1.3–6.6% of all malignant mammary tumors. Apart from hematopoietic neoplasms, malignant melanoma is one of the most common neoplasms with which secondary involvement of the mammary parenchyma is known. Although they are so rare, breast metastases from such neoplasms can mimic primary breast carcinoma clinically and on imaging studies. Approximately 20% of the patients affected by malignant melanoma will develop metastases, the commonest sites being liver, lung, and brain; metastases to the breast from malignant melanoma are rare, and in about 40% of the patients affected the breast lesion is the first manifestation of disease. Correct management of metastatic disease to the breast can prevent unnecessary mutilation; in fact, in the majority of patients so far widespread metastases have appeared rapidly despite various systemic treatments, showing that major surgery gives very poor results in terms of controlling the disease. In this paper, we present the case of a 60-yearold woman with a history of a malignant cutaneous melanoma of the right thoracic wall that had been surgically excised in 1989. She was admitted to our Breast Division 14 years later because a screening mammogram and an ultrasound evaluation had revealed the presence of a nodular opacity in the right breast, without any clinical manifestations. The instrumental pattern suggested a malignant breast carcinoma. For this reason, in August 2003 the patient underwent a radioimmunoguided inner lower quadrantectomy of the right breast, and the pathological examination showed that an epithelioid cell malignant melanoma was localized in the material excised. Subsequent staging revealed the presence of disseminated lung metastases, for which the patient had been scheduled for chemotherapy according to the CVD protocol. Unfortunately, the disease was found to be progressive (presence of a double cerebral lesion), and a second-line treatment with alpha IFN and rIL-2 was scheduled.

LY355703 is a synthetic derivative of the marine cryptophycins, cytotoxic agents which induce mitotic arrest by binding at the microtubule vinca binding domain. Promising preclinical features of LY355703 were the 40–400 greater potency than paclitaxel or vinca alkaloids, the broad spectrum of antitumor activity in xenografts and the antitumour activity in multidrug resistant (MDR)-expressing murine tumours. Aims of this study were to define the maximum tolerated dose (MTD) and the dose recommended for Phase II, the pattern of toxicity, the pharmacokinetic profile and to document hints of antitumour activity of LY355703 given as 2-h infusion on day 1 every 3 weeks (Study 1) or, later on, on days 1, 8 and 15 every 4 weeks (Study 2). The latter weekly regimen was selected because of the acute dose-related toxicity reported in Study 1. The dose was escalated using a modified Continual Reassessment Method. Pharmacokinetic studies were performed on day 1 of cycle 1 in both studies; LY355703 plasma concentrations were assessed by liquid chromatography with tandem mass spectrometry. A total of 35 adult patients with solid tumours entered Study 1; the dose was escalated from 0.1 to 1.92 mg/m2; at this dose 2 of 5 patients presented grade 3 neuropathy and myalgias; 1.48 mg/m2 was then recommended for Phase II study. A total of 8 patients were treated in Study 2 at 1 mg/m2; cumulative long-lasting neuroconstipation and neurosensory toxicity precluded the completion of the cycle in 9 out of 15 cycles; the clinical development of the weekly regimen was then discontinued. Other toxicities included cardiac dysrhythmia and mild alopecia. Pharmacokinetics of LY355703 appeared to be linear over the dose range studied. The administration of LY355703 on a 3-week schedule is associated with an acute dose-dependent peripheral neuropathy and myalgia of high interpatient variability for which possible risk factors and pharmacokinetic correlates could not be identified.

Aim: In vitro, NSCLC cell lines with PIK3CA mutations have shown increased sensitivity to the oral pan-PI3K inhibitor buparlisib (BKM120). BASALT-1 is an open-label, two-stage, Phase II study to assess the safety and efficacy of buparlisib in patients (pts) with pre-treated metastatic NSCLC (squamous [sq] and non-squamous [non-sq] histology) and activated PI3K pathway (NCT01297491). Here we report results from the Stage 1 futility analysis (FA) for each histology. Methods: Pts (≥18 yrs) with previously treated, metastatic NSCLC (sq or non-sq histology) with activated PI3K pathway (defined as PIK3CA mutation and/or PTEN mutation and/or PTEN-negative staining [ Results: Thirty pts had been treated in each histologic group at the time of FA (>1200 pts screened). In the sq group, 21 pts were male (median age: 65.5 yrs); in the non-sq group, 19 pts were male (median age: 62.0 yrs). Median treatment exposure was 6.9 (sq group) and 7.2 (non-sq group) wks. Median PFS was 2.79 (95% CI: 1.38, 4.11) and 2.69 (95% CI: 1.41, 2.89) months for the sq and non-sq groups, respectively. PFS rate at 12 wks was 23.3% (95% CI: 9.9, 42.3) for the sq group and 20.0% (95% CI: 7.7, 38.6) for the non-sq group. Best overall responses (RECIST 1.1): partial response (1 pt [3.3%] in each group), stable disease (14 pts [46.7%] in each group), progressive disease (7 pts [23.3%] sq / 9 pts [30.0%] non-sq), unknown (8 pts [26.7%] sq / 6 pts [20.0%] non-sq). Most common (≥30%) AEs possibly related to study drug: hyperglycemia (36.7%), pruritus (33.3%), diarrhea (30%), and nausea (30%) for sq, and asthenia (30%) for non-sq. Conclusions: In this PI3K pathway-activated group of NSCLC pts, the futility criterion in Stage 1 was met in both histology groups. Thus, enrollment of Stage 2 was not initiated. Results of this study are in line with previous observations where single agents targeting the PI3K pathway have shown marginal activity. Studies of buparlisib in combination with docetaxel in pts with sq NSCLC are ongoing. Disclosure: J. Soria: - Research funds from Novartis (Instititution) - Compensated advisory board Novartis F. Grossi: Novartis advisory board; E. Felip: Advisory Board: BI, Novartis, Roche, BMS, Lilly; M. Thomas: AD-Board honoraria: Novartis, Roche, Lilly, BMS Speaker honoraria: BMS, Lilly; P. Roussou: - Novartis employee - Shares in Novartis; G. Atalla-Vidam: Novartis employee; P. Aimone: Novartis employee. All other authors have declared no conflicts of interest.

Aim: Adjuvant chemotherapy (ACT) is the standard of care for Stage II and IIIA NSCLC, and for high risk Stage IB NSCLC. However, the 5-year disease-free survival remains poor (35-50%) and about half of the patients will not receive ACT for various reasons. This Phase III trial investigated whether the recMAGE-A3 + AS15 cancer immunotherapeutic (MAGE-A3 CI) as adjuvant therapy improved disease-free survival (DFS) in patients with resected NSCLC. Methods: MAGRIT was a randomized, double-blind, placebo-controlled trial in patients with completely resected MAGE-A3-positive NSCLC Stages IB, II, and IIIA (TNM version 6) and who did or did not receive ACT. Patients were randomly assigned (2:1) to receive 13 intramuscular injections of MAGE-A3 CI or placebo over a 27-month (m) treatment period. The three co-primary endpoints were DFS in the overall and in the no-ACT population and DFS in patients with a potentially predictive gene signature (GS). Results: Out of 13,849 patients screened, 4,210 patients had a MAGE-A3 positive tumour sample and 2,272 patients were randomised and treated. Overall, 52% of the patients received ACT; 47%, 36% and 17% were Stage IB, II and IIIA, respectively. Median age was 63 years and 24% of patients were females. Mean relative dose intensity was above 98% in both groups throughout the treatment period. Median follow-up at the time of final analysis was 38.8m. Median DFS was 60.5m and 57.9m respectively for MAGE-A3 CI and placebo (HR 1.024, 95% CI 0.891-1.177; p = 0.7379). In patients who did not receive ACT, median DFS was 58.0m and 56.9m for MAGE-A3 CI and placebo groups, respectively (HR 0.970, 95% CI 0.797-1.179; p = 0.7572). The rate of grade ≥ 3 adverse events (16%) did not differ between treatment groups. Conclusions: Treatment of NSCLC patients with MAGE-A3 CI did not increase DFS compared to placebo in either the overall population or in patients who did not receive ACT. Due to the absence of treatment effect, a GS predictive of clinical benefit to MAGE-A3 CI could not be identified. Funding Source: GlaxoSmithKline Biologicals SA. Disclosure: J.F. Vansteenkiste: Pr Vansteenkiste received GSK fees as Primary investigator for the MAGRIT study; B. Cho: Dr Cho received consultancy fees from Novartis and Boehringer-ingelheim; T. De Pas: No conflicts of interest. Fee received from GSK as member of steering committee of the study; J. Jassem: Dr Jassem received grant and personal fees for Consultancy from GSK; M. Yoshimura: Pr Yoshimura received GSK fees as Primary investigator for the MAGRIT and PEARL study; H. Nakayama: Dr Nakayama received GSK fees as Primary investigator for the MAGRIT and PEARL study; T. Mitsudomi: Dr Mitsudomi received personal fees from GSK for an advisory role; B. Spiessens: Bart Spiessens is employee of GSK and do own stock options of GSK; V. Brichard: Dr Birchart is GSK employee and do own Stock options from GSK; C. Debruyne: Dr Debruyne is GSK employee and do own GSK stock options; P. Therasse: GSK employee and Stock options owner; N. Altorki: Dr Altorki received GSK fees for trial conduct of GSK studies. All other authors have declared no conflicts of interest.

Aim: ALK+ tumors are sensitive to ALK tyrosine kinase inhibitors such as crizotinib (CRZ) but resistance invariably develops. Ceritinib (LDK378), a novel ALK inhibitor (ALKi), is more potent than CRZ in vitro and is effective in CRZ-resistant disease. Updated data from ASCEND-1 (NCT01283516) are presented, focused on pts receiving ceritinib at the recommended 750 mg/day dose and with longer follow-up. Methods: Investigator assessment of efficacy is presented for pts with ALK+ NSCLC receiving ≥1 dose of ceritinib at 750 mg/day prior to 31 Oct 2013. Results with additional follow-up will be presented. Results: 246 pts with ALK+ NSCLC had 7 months median duration of follow up. Of these, 230 (93%) had received prior antineoplastic therapy, 166 (67%) with ≥2 prior regimens.163 (66%) had received prior ALKi, all of whom had received CRZ; of these, 91% had progressive disease during prior ALKi therapy and 78% had received ALKi as last prior therapy. Efficacy is shown below. Endpoint All NSCLC n = 246 ALKi-pretreated n = 163 ALKi-naive n = 83 ORR, n (%) [95% CI] 144 (58.5) [52.1, 64.8] 89 (54.6) [46.6, 62.4] 55 (66.3) [55.1, 76.3] DOR, median (months) [95% CI] 9.7 [7.0, 11.4] 7.4 [5.4, 10.1] NEa [9.6, NE] Time to first response, median (weeks) [min, max] 6.1 wks [3.0, 24.1] 6.1 wks [4.6, 24.1] 6.1 wks [3.0, 24.1] PFS, median (months) [95% CI] 8.2 [6.7, 10.1] 6.9 [5.4, 8.4] NEb [8.3, NE] aDOR rate at 12 mos 65.2% [95% CI: 46.4, 78.8] bPFS rate at 12 mos 61.3% [95% CI: 47.7, 72.3] NE = Not estimable. Discontinuation of treatment due to adverse event (AE) occurred in 24 (10%) pts with NSCLC; 17 (10%) ALKi-pretreated pts and 7 (8%) ALKi-naive pts. Among all 255 pts receiving ceritinib 750 mg/day, 99 (39%) and 51 (20%) required 1 and >1 ceritinib dose reduction, respectively. The most common AEs of any grade (>50%) were diarrhea (86%), nausea (80%), vomiting (60%), abdominal pain (54%), fatigue (52%). Most common lab abnormalities of any grade (>50%) were decreased hemoglobin (84%), increased ALT (80%), increased AST (75%), increased creatinine (58%). Most common Grade 3/4 lab abnormalities (>10%) were increased ALT (27%), increased AST (13%), increased glucose (13%). One treatment-related death (interstitial lung disease) was reported. Conclusions: Ceritinib 750 mg/day shows potent anti-tumor activity in ALK+ NSCLC pts regardless of prior ALKi treatment status. Discontinuation due to toxicity was uncommon. Disclosure: E. Felip: Advisory board: BI, Novartis, Roche, BMS, Lilly; D. Kim: Consultation for Novartis, Pfizer, Lilly; Honorarium from Pfizer, Lilly; R. Mehra: Spouse is an employee of GSK, consulting to Bristol-Myers Squibb and Novartis; L.Q. Chow: Employee: University of Washington; Research grant and research support, consultant, travel expenses and advisory board: Novartis; D.R. Camidge: Advisory boards/consultancy/honoraria for Servier, Eli Lilly, Genentech/Roche, Astex, Ariad, ImmunoGen, Clarient, Excelixis, indiPharm, Astellas, Boehringer Ingelheim, Chugai, Clovis, Array Biopharma, AstraZeneca, Aveo, Novartis, Synta, Pfizer; J.F. Vansteenkiste: Speaker for Novartis; S. Sharma: Research grant, Consultant: Novartis. Stock: Salarius Pharma, Beta Cat Pharma, ConverGene. Leadership: Board member, TheraTarget and Member, VLB Therapeutics IDMC; B. Solomon: Honoraria/Ad board: Novartis, Pfizer, Clovis, Clovis oncology, AZ, Roche; J. Wolf: Employee of University Hospital of Cologne. Ad boards, speakers bureau and research funding: AZ, Novartis, Roche, Pfizer, BI, BMS, Clovis. Research support: Novartis, Roche, BI; M. Thomas: Honoraria: Lilly, BMS, Roche. Consultant: Lilly, BMS, Roche, Novartis ; M. Schuler: Consultant: AZ, BI, Novartis, Pfizer. Research grants to institution: BI, Novartis. Honoraries for CME lectures: BI, Celgine, GSK, Lilly, Novartis, Pfizer; G. Lui: Consultant: AZ, Pfizer, Novartis; M. Geraldes: Margarida Geraldes is an employee of Novartis and is a stock owner; A.L. Boral: Antony L Boral is an employee of Novartis; A. Yovine: Alejandro Yovine is an employee of Novartis and is a stock owner; A.T. Shaw: Advisory board: Novartis, Pfizer, Ariad, Chugai, Genentech. All other authors have declared no conflicts of interest.

Duodenal adenocarcinoma is an unusual and aggressive tumor, with an overall 5-year survival rate of about 25% [1].Very few data on the activity of anticancer agents are available for patients with ...

The purpose of this study was to evaluate the activity and the toxicity of the combination of gemcitabine with ifosfamide and cisplatin (GIP) in chemonaive patients with advanced non small cell lung cancer (NSCLC). Eighty chemonaive patients with Stage IIIB-IV NSCLC were treated with the combination of gemcitabine 1 g/m(2) on Days 1 and 8, ifosfamide 2 g/m(2) on Day 1 and cisplatin 80 mg/m(2) on Day 2. Cycles were administered on an outpatient basis every 3 weeks. Hematologic toxicity was the main side effect; Grade III-IV thrombocytopenia was observed in 54 (67%) patients and Grade III-IV leucopenia in 44 (55%) patients, with 4 episodes of febrile neutropenia and 1 toxic death. Thirteen patients received platelet transfusions and 38 were transfused with packed red cells. All patients were evaluable for response. The overall response rate was 54% (95% confidence interval 43 to 65%) with 1 complete response. In patients with Stage IIIB and IV disease, response rates were 58% and 52%, respectively. Median time to progression was 40 weeks (range 0-114) and median overall survival was 12 months (16.6 months for stage IIIB and 10.4 months for stage IV). Median and minimum follow-up were 19 and 12 months, respectively. The GIP combination shows a response rate and overall survival of clinical interest. Hematologic toxicity was the main toxic effect, especially in patients with low performance status. This regimen will be tested in a Phase III randomized trial.

The therapeutic strategy used for elderly affected by malignant neoplasms should take into account the common variables present in oncological patients, and the specific alteration of the elderly metabolism and their possible morbidity. Ifosfamide is an active drug for various tumors with elevated incidence in the elderly. We analyze the principle criteria in the selection of these patients and the alterations of metabolism which correlates to aging with their consequences on the pharmacokinetics of ifosfamide. Finally, we propose clinical guidelines to optimize the use of ifosfamide in elderly patients affected by malignant tumors.

From February 1995 through October 1996, 25 patients with metastatic colorectal cancer showing a clinical resistance to 5-fluorouracil (5-FU) entered this study. Thirteen received oxaliplatin alone and 12 received it in combination with 5-FU. Oxaliplatin was administered at 130 mg/m2 over a 2-hour infusion every 3 weeks, alone or added either to 5-FU as a continuous infusion at 200 mg/m2 to 300 mg/m2 (six patients) or to a 5-FU bolus, 375 mg/m2, plus leucovorin, 100 mg/m2, daily for 5 days every 3 weeks (6 patients). Eighty-six of 98 administered cycles were evaluable for toxicity (47 for oxaliplatin plus 5-FU and 39 for oxaliplatin alone). Hematologic toxicity was mild, occurring as grade 2 leukopenia in 23% of the cycles of 5-FU and oxaliplatin and in 5% of the cycles of oxaliplatin alone. The most common toxicity was neurologic (grade 1 to 2 in 60%-6% of the cycles of the combination, respectively, and 68%-10% of oxaliplatin given alone) as hand-foot paresthesia or hypersensitivity to cold. No grade 4 toxicity was reported and only three patients in the 5-FU group developed grade 3 diarrhea. Grade 2 nausea and vomiting occurred in 33% of the cycles when both drugs were given and in 15% when oxaliplatin was administered alone. The combination of oxaliplatin and 5-FU induced four partial remissions (33%; 95% confidence interval, 6%-60%), whereas eight patients of the whole group had stable disease. No response occurred when oxaliplatin was administered as a single agent. The results of this study confirm the antitumor activity of oxaliplatin when added to 5-FU in patients who have metastatic colorectal cancer previously refractory to 5-FU. The possible therapeutic synergy with 5-FU was not accompanied by increased toxicity.