Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic squamous cell carcinoma of the head and neck: results of the randomized phase I/II ADVANTAGE trial (phase II part).

BACKGROUND: Recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN) overexpresses αvß5 integrin. Cilengitide selectively inhibits αvß3 and αvß5 integrins and is investigated as a treatment strategy. PATIENTS AND METHODS: The phase I/II study ADVANTAGE evaluated cilengitide combined with cisplatin, 5-fluorouracil, and cetuximab (PFE) in R/M-SCCHN. The phase II part reported here was an open-label, randomized, controlled trial investigating progression-free survival (PFS). Patients received up to six cycles of PFE alone or combined with cilengitide 2000 mg once (CIL1W) or twice (CIL2W) weekly. Thereafter, patients received maintenance therapy (cilengitide arms: cilengitide plus cetuximab; PFE-alone arm: cetuximab only) until disease progression or unacceptable toxicity. RESULTS: One hundred and eighty-two patients were treated. Median PFS per investigator read was similar for CIL1W + PFE, CIL2W + PFE, and PFE alone (6.4, 5.6, and 5.7 months, respectively). Accordingly, median overall survival and objective response rates were not improved with cilengitide (12.4 months/47%, 10.6 months/27%, and 11.6 months/36%, respectively). No clinically meaningful safety differences were observed between groups. None of the tested biomarkers (expression of integrins, CD31, Ki-67, vascular endothelial growth factor receptor 2, vascular endothelial-cadherin, type IV collagen, epidermal growth factor receptor, or p16 for human papillomavirus) were predictive of outcome. CONCLUSION: Neither of the cilengitide-containing regimens demonstrated a PFS benefit over PFE alone in R/M-SCCHN patients.

Phase I/II trial of cilengitide with cetuximab, cisplatin and 5-fluorouracil in recurrent and/or metastatic squamous cell cancer of the head and neck: findings of the phase I part.

BACKGROUND: Novel therapies are needed to improve the poor prognosis of patients with recurrent and/or metastatic squamous cell cancer of the head and neck (SCCHN). METHODS: ADVANTAGE is a phase I/II, multicentre study evaluating the integrin inhibitor cilengitide combined with cetuximab and platinum-based chemotherapy in patients with recurrent and/or metastatic SCCHN. The phase I part tested cilengitide (500, 1000 and 2000 mg) twice weekly with standard doses of cetuximab, cisplatin and 5-fluorouracil. RESULTS: Ten patients (9 male, 1 female; median 56 years old) were included in the phase I part. No dose-limiting toxicities (DLTs: grade 3/4 toxicities in the first 3 weeks as defined per protocol) or deaths occurred. The most common adverse events (AEs) were constipation, rash, nausea, anorexia and fatigue. Cilengitide-related grade 3/4 AEs, all of which occurred after the DLT observation period, were anaemia, angioedema, asthenia, mucosal inflammation, nausea and vomiting (one event per category). Best overall tumour response was partial response (PR) for 4 out of 10 patients and stable disease (SD) for 6 out of 10 patients across all cohorts. Disease control rate (complete response, PR and SD) was 100%. CONCLUSION: Cilengitide combined with cetuximab and platinum-based chemotherapy was well tolerated. No DLTs or unexpected AEs were observed. Cilengitide 2000 mg was considered safe and was selected for the subsequent randomised phase II part assessing progression-free survival.

Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015.

BACKGROUND: The study aimed to demonstrate the noninferiority of capecitabine to 5-fluorouracil (5-FU)/folinic acid (FA), in relation to progression-free survival (PFS) after first-line treatment of metastatic colorectal cancer and the benefit of adding celecoxib (C) to irinotecan/fluoropyrimidine regimens compared with placebo (P). PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI: irinotecan (180 mg/m(2) i.v. on days 1, 15 and 22); FA (200 mg/m(2) i.v. on days 1, 2, 15, 16, 29 and 30); 5-FU (400 mg/m(2) i.v. bolus, then 22-h, 600 mg/m(2) infusion) or CAPIRI: irinotecan (250 mg/m(2) i.v. infusion on days 1 and 22); capecitabine p.o. (1000 mg/m(2) b.i.d. on days 1-15 and 22-36). Patients were additionally randomly assigned to receive either placebo or celecoxib (800 mg: 2 x 200 mg b.i.d.). RESULTS: The trial was closed following eight deaths unrelated to disease progression in the 85 enrolled (629 planned) patients. Response rates were 22% for CAPIRI + C, 48% for CAPIRI + P, 32% for FOLFIRI + C and 46% for FOLFIRI + P. Median PFS and overall survival (OS) times were shorter for CAPIRI versus FOLFIRI (PFS 5.9 versus 9.6 months and OS 14.8 versus 19.9 months) and celecoxib versus placebo (PFS 6.9 versus 7.8 months and OS 18.3 versus 19.9 months). CONCLUSION: Due to the small sample size following early termination, no definitive conclusions can be drawn in relation to the noninferiority of CAPIRI compared with FOLFIRI.

[Rapid progress of a cerebral edema due to fulminant hyponatremia]. / Rapide Entwicklung eines Hirnödems infolge einer fulminanten Hyponatriämie.

Severe acute hyponatremia is a life-threatening illness. We report the case of a 38-year-old woman with lethal cerebral edema due to acute isovolemic hyponatremia.

Failure of anti-infective mouth rinses and concomitant antibiotic prophylaxis to decrease oral mucosal colonization in autologous stem cell transplantation.

Autologous stem cell transplantation has augmented treatment successes. However, high-dose chemotherapy is still accompanied by dose-limiting toxicities, for example, severe mucositis. Mucosal lesions serve as portals of entry for infections. In order to reduce the oral microbial burden, we prospectively evaluated the microbiological impact of a complex regimen of mouth rinses consisting of concomitantly applied polyene antifungals, povidone-iodine, chlorhexidine, sage tea, and prophylactic ciprofloxacin and fluconazole. A total of 15 patients were enrolled into this longitudinal evaluation. Colony-forming units (CFU) were quantitated from saliva, buccal and palatinal swabs during high-dose chemotherapy and autologous stem cell transplantation. The number of CFU did not show any significant changes after initiation of the mouth rinses and the prophylactic antibiotics. The median CFU count was 268 x 10(6)/ml saliva before chemotherapy and decreased after initiation of intravenous antibiotics only. Neither prophylactic nor therapeutic antifungals significantly reduced the number of cultures positive for yeasts. Since 90% of our patients had febrile neutropenia at some time point during the observation period, the approach evaluated cannot be recommended as prophylaxis of febrile neutropenia as such.

A novel type of metastatically spreading subcutaneous aspergillosis without epidermal lesions following allogeneic stem cell transplantation.

Systemic mycosis is among the most feared opportunistic infections in the immunocompromised host. Difficulty and delay in diagnosis and treatment often result in poor outcomes. In this communication a metastatically spreading form of subcutaneous aspergillosis developed in a patient with a history of allogeneic stem cell transplantation for relapsed Hodgkin's lymphoma. Strikingly, necrotizing cutaneous papules or ulcerating lesions were absent. Diagnosis was accomplished after excision of a clinically non-suggestive subcutaneous nodule. Despite prompt initiation of antimycotic therapy the outcome was fatal; dosage of conventional and liposomal amphotericin B was limited due to treatment-related toxicities. This case report describes a novel form of aspergillosis and underlines the need for an aggressive diagnostic approach in severely immunocompromised patients.

Peripheral Teflon catheters: factors determining incidence of phlebitis and duration of cannulation.

BACKGROUND: Catheter-related phlebitis is a frequent problem in the clinical setting. Risk factors for catheter-related phlebitis were assessed at a single tertiary-care institution where no routine change policy for peripheral intravenous catheters is in place. METHODS: In a nonrandomized, observational trial, peripheral intravenous Teflon catheters were inserted in patients with a diagnosis of leukemia, lymphoma, solid tumor, acquired immunodeficiency syndrome, other serious infection, or autoimmune disorder. Underlying disease, age, white blood cell count at the time of insertion, physician placing the catheter, catheter bore, duration of cannulation, reason for removal of the catheter, and visual inspection of the insertion site were recorded. RESULTS: Four hundred twelve catheters were inserted in 175 patients. The number of catheterizations per episode varied between 1 and 7. Three hundred sixty-four (88.3%) catheter placements were evaluable. The mean duration of cannulation was 4.2 days. The overall incidence of phlebitis was 12.9%. Catheters in leukopenic patients showed a longer duration of cannulation compared with catheters in nonleukopenic patients, but no difference regarding the phlebitis rate. CONCLUSION: Findings in this study partly contrast with data reported in the literature. In particular, leukopenia, female gender, prolonged duration of cannulation, antibiotics, and choice of insertion site could not be shown to be risk factors.

Risk factors for the HIV-associated lipodystrophy syndrome in a cross-sectional single-centre study.

OBJECTIVE: Risk factors for the HIV-associated lipodystrophy syndrome (HALS) were studied in a single-centre, cross-sectional study. - PATIENTS AND METHODS: 278 consecutive HIV-infected outpatients at a German tertiary care centre were enrolled. Changes in body shape were quantified using linear analogue scales. Cumulative treatment duration for each antiretroviral drug, CD4 cells, viral load and age were investigated as potential risk factors for a clinical diagnosis of lipodystrophy syndrome by logistic regression. RESULTS: HALS was diagnosed in 88 patients. The risk of HALS increased significantly with longer protease inhibitor treatment (relative risk 1.61 (95% confidence interval, 1. 24 to 2.09, per year); older age and a history of low CD4 cell counts were cofactors in this multivariate model, but nucleoside analogues did not contribute significantly. Neither pattern nor severity of disease were predicted by these risk factors. Treatment durations and other risk factors were highly correlated with each other. CONCLUSIONS: These findings support a pathogenetic role for protease inhibitor toxicity, advanced HIV disease, and ageing. No evidence for an additional effect of nucleoside analogues was found. The high correlation of potential risk factors indicates that this and other available studies may be too small to detect multiple risk factors without major confounding.

A randomized monocentric trial in febrile neutropenic patients: ceftriaxone and gentamicin vs cefepime and gentamicin.

A prospective, randomized, controlled monocentric trial was performed to evaluate the efficacy and safety of once daily ceftriaxone 2 g plus gentamicin 5 mg/kg in comparison to cefepime 2 g t.i.d. plus gentamicin 5 mg/kg q.d. in the treatment of neutropenic fever. In case of fever (oral temperature > or =38.5 degrees C on one occasion or > or =38.0 degrees C twice within 24 h) and a granulocytopenia (neutrophil count below 500 or below 1000/microl when expected to fall below 500 within 72 h), patients with hematological malignancies or solid tumors were assigned to ceftriaxone or cefepime, each with gentamicin. The primary endpoint was defined as defervescence on day 4-6 followed by at least 7 afebrile days. Secondary endpoints were overall response, defined as defervescence on day 28 and toxicity. Two hundred eleven episodes were included. Fever of unknown origin (FUO) accounted for 124 episodes (58.8%), microbiologically defined infection (MDI) for 39 (18.5%), clinically defined infection (CDI) for 25 (11.8%), and both clinically and microbiologically defined infection (CMDI) for 19 episodes (9%). On an intent-to-treat basis 207 episodes were evaluable for the primary endpoint. Ceftriaxone plus gentamicin and cefepime plus gentamicin were successful in 49.5% and 51%, respectively. Overall response was achieved on study day 28 in 92.5% and 91%, respectively. Diarrhea was more frequent with ceftriaxone/gentamicin (6.5% vs 17%), while nausea/vomiting was less (12.1% vs 5%). Once-daily ceftriaxone plus gentamicin was not inferior to cefepime t.i.d. plus gentamicin q.d. in the empirical treatment of neutropenic fever.

Randomized controlled monocentric comparison of once daily ceftriaxone with tobramycin and cefotaxime three times daily with tobramycin in neutropenic fever.

A prospective, randomized, controlled monocentric trial was performed to evaluate the efficacy and safety of once daily ceftriaxone 2 g plus tobramycin 5 mg/kg in comparison to cefotaxime 2 g t.i.d. plus tobramycin 5 mg/kg qd in the treatment of neutropenic fever. In cases of fever > or = 38.5 degrees C and a neutrophil count below 1000/microliter, patients with hematological malignancies were assigned to ceftriaxone or cefotaxime, each with tobramycin. The primary endpoint was defined as defervescence < 37.5 degrees C on day 4-6 followed by at least 7 afebrile days. Secondary endpoints were overall response, defined as defervescence on day 25 and toxicity. There were 160 episodes of 114 patients included. Fever of unknown origin accounted for 79 episodes (51%), microbiologically defined infection for 36 (23%), clinically defined infection for 27 (17%), and both clinically and microbiologically defined infection for 14 episodes (9%). On an intent-to-treat basis 156 episodes could be evaluated for the primary endpoint. Ceftriaxone plus tobramycin and cefotaxime plus tobramycin resulted in a primary response in 46.9% and 45.3%, respectively. Overall response was achieved on study day 25 in 87.7% and 80%, respectively. No significant difference in toxicity was observed. Once-daily ceftriaxone plus tobramycin was not inferior to cefotaxime t.i.d. plus tobramycin qd in the empirical treatment of neutropenic fever.

Combination therapy of disseminated Fusarium oxysporum infection with terbinafine and amphotericin B.

A case of disseminated infection with Fusarium oxysporum following chemotherapy of acute myelogenous leukemia is reported. Antifungal treatment was successful with a 13-day course of oral terbinafine 250 mg t.i.d. in combination with amphotericin B deoxycholate 1.0-1.5 mg/kg qd and subsequently intravenous liposomal amphotericin B 5 mg/kg qd. Preceding monotherapy with amphotericin B deoxycholate 1.0-1.5 mg/kg qd had not stopped the progression of infection. The combination therapy described here represents a novel approach to the treatment of Fusarium spp. in the immunocompromised host in whom Fusarium spp. are known to cause disseminated infection with high mortality.