F. De Braud

Best choice of central venous insertion site for the prevention of catheter-related complications in adult patients who need cancer therapy: a randomized trial

BACKGROUND Central venous access is extensively used in oncology, though practical information from randomized trials on the most convenient insertion modality and site is unavailable. METHODS Four hundred and three patients eligible for receiving i.v. chemotherapy for solid tumors were randomly assigned to implantation of a single type of port (Bard Port, Bard Inc., Salt Lake City, UT), through a percutaneous landmark access to the internal jugular, a ultrasound (US)-guided access to the subclavian or a surgical cut-down access through the cephalic vein at the deltoid-pectoralis groove. Early and late complications were prospectively recorded until removal of the device, patients death or ending of the study. RESULTS Four hundred and one patients (99.9%) were assessable: 132 with the internal jugular, 136 with the subclavian and 133 with the cephalic vein access. The median follow-up was 356.5 days (range 0-1087). No differences were found for early complication rate in the three groups {internal jugular: 0% [95% confidence interval (CI) 0.0% to 2.7%], subclavian: 0% (95% CI 0.0% to 2.7%), cephalic: 1.5% (95% CI 0.1% to 5.3%)}. US-guided subclavian insertion site had significantly lower failures (e.g. failed attempts to place the catheter in agreement with the original arm of randomization, P = 0.001). Infections occurred in one, three and one patients (internal jugular, subclavian and cephalic access, respectively, P = 0.464), whereas venous thrombosis was observed in 15, 8 and 11 patients (P = 0.272). CONCLUSIONS Central venous insertion modality and sites had no impact on either early or late complication rates, but US-guided subclavian insertion showed the lowest proportion of failures.

Long-term, totally implantable central venous access ports connected to a Groshong atheter for chemotherapy of solid tumours: Experience from 178 cases using a single type of device

The aim of this study was to examine the early and late complications rate of central venous access ports connected to the Groshong catheter for long-term chemotherapy delivering. All patients suffering from a neoplastic disease, who required long-term chemotherapy and underwent insertion of implantable ports during a 21-month period (1 October 1994-30 June 1996) were prospectively studied. A single type of port was used, constructed of titanium and silicone rubber (Dome Port, Bard Inc., Salt Lake City, U.S.A), connected to an 8 F silastic Groshong catheter tubing (Bard Inc.). A team of different operators (two general surgeons, one interventional radiologist and four anaesthesiologists) was involved in inserting the port. All devices were placed in the operating room under fluoroscopic control. A central venous access form was filled in by the operator after the procedure and all ports were followed prospectively for device-related and overall complications. Data from the follow-up of these patients were entered in the form and collected in a database. Follow-up continued until the device was removed, the patient died or the study was closed. 178 devices, comprising a total of 32,089 days in situ, were placed in 175 patients. Three patients received a second device after removal of the first. Adequate follow-up was obtained in all cases (median 180 days, range 4-559). 138 devices (77.5%) were still in situ when the study was closed. Early complications included six pneumothoraxes, three arterial punctures and two revisions for port and/or catheter malfunction (overall early complications in 8 patients). Late complications included 3 cases (1.68% of devices) of catheter rupture and embolisation (0.093 episodes/1000 days of use), 2 cases (1.12% of devices) of venous thrombosis (0.062 episodes/1000 days of use), 1 case (0.56% of devices) of pocket infection (0.031 episodes/1000 days of use), and 4 cases (2.24% of devices) of port-related bacteraemias (0.124 episodes/1000 days of use). Infections were caused by coagulase-negative Staphylococcus aureus (4 cases) and Bacillus subtilis (1 case); they required port removal in 3 out of 5 cases. This study represents the largest published series of patients with totally implantable access ports connected to Groshong catheters; this device is a good option for long-term access to central veins and delivery of chemotherapeutic regimens, including continuous intravenous infusions. The low incidence of major complications related to implantation and management of these devices support increased use in oncology patients.

A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors.

BACKGROUND This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors. PATIENTS AND METHODS Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD. RESULTS Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180-800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly ≤1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ≥600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts. CONCLUSION In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.

Phase I clinical and pharmacokinetic study of trabectedin and doxorubicin in advanced soft tissue sarcoma and breast cancer

The combination of trabectedin (T) and doxorubicin (D) was brought into clinical development in soft tissue sarcoma (STS) and advanced breast cancer (ABC) because of its in vitro and in vivo additive anti-tumour effect, the fact that there are no overlapping toxicities and the anti-tumour activity of T in those tumours. Feasibility and anti-tumour activity of T+D administered every 3 weeks were evaluated in 38 patients (STS=29, ABC=9) untreated for advanced disease. D was given at 60 mg/m(2) and T at escalating doses from 600 to 800 microg/m(2), which was the maximum tolerated dose due to dose-limiting febrile neutropenia and asthenia. The recommended dose--given to 18 patients in total--was 700 microg/m(2) T with 60 mg/m(2) D. The pharmacokinetic profile of T and D at cycle 1 was analysed in 20 patients. The most common toxicities included a severe but reversible ASAT/ALAT increase (94%), nausea/vomiting, neutropenia, asthenia/fatigue, stomatitis. Partial response and stable disease were assessed in 18% and 56% of STS patients and in 55% and 33% of ABC patients. No pharmacokinetic interaction between T and D was observed. The lack of cumulative toxicity and related complications and the promising activity in STS support further development of T+D.

Low morbidity of bronchoplastic procedures after chemotherapy for lung cancer.

OBJECTIVE To evaluate if induction chemotherapy, with or without irradiation, represents an additional risk factor for early and late morbidity and perioperative mortality in bronchoplastic procedures for lung cancers. METHODS From January 1998 to January 2001, 27 patients underwent a bronchial sleeve resection after induction treatment at the European Institute of Oncology in Milan. They represent 7% of lung cancer resections (387) and 27% of those performed after neoadjuvant treatment (100 cases). Histology was: 17 epidermoid carcinoma, 8 adenocarcinoma and 2 SCLC. Twenty-four patients (89%) received a preoperative cisplatin based polichemotherapy, and three cases (11%) a chemo-radiation therapy. A right sleeve lobectomy or bilobectomy was undertaken in 21 patients (78%) and a left lobectomy in 6 (22%). A resection of tracheal carina was associated in three cases and a vascular resection in 10 (five vena cava and five pulmonary artery). Twelve patients (44%) received adjuvant mediastinal irradiation. Perioperative morbidity of the study group (group 1) was compared with that of patients submitted to sleeve resection without neoadjuvant treatment (group 2), or standard pneumonectomy after induction treatment (group 3). RESULTS There were no postoperative deaths. A major perioperative complication occurred in two patients (7%) of group 1, one patient of group 2 (3.5%), and four in group 3 (17%). Among patients of the study group, no anastomotic dehiscence or pleural empyema were observed. Only one late anastomotic stricture occurred after postoperative radiation treatment. No significant difference in early and late complication rate was found between the three groups of patients. High rate of complete resection was achieved (93%) in patients of the study group and extent of nodal dissection was similar between sleeve resections and pneumonectomy patients. CONCLUSIONS Preoperative chemotherapy or combination of chemo-radio therapy is not associated with an additional risk of anastomotic complications in bronco and angioplastic procedures. Parenchyma sparing resection is a valid option for selected patients with locally advanced lung cancer after induction treatment. A longer follow up is necessary to evaluate efficacy of the procedure in term of survival and local control.

Targeting the MET gene for the treatment of non-small-cell lung cancer

Recently, a better understanding of the specific mechanisms of oncogene addiction has led to the development of antitumor strategies aimed at blocking these abnormalities in different malignancies, including lung cancer. These abnormalities trigger constitutive activation of tyrosine kinase receptors (RTKs) involved in fundamental cell mechanisms such as proliferation, survival, differentiation and migration, and consequently the aberrant signaling of RTKs leads to cancer growth and survival. The inhibition of aberrant RTKs and downstream signaling pathways has opened the door to the targeted therapy era. In non-small-cell lung cancer (NSCLC), molecular research has allowed the discrimination of different aberrant RTKs in lung cancer tumorigenesis and progression, and thus the identification of several targetable oncogenic drivers. Following the development of small molecules (gefitinib/erlotinib and crizotinib) able to reversibly inhibit the epidermal growth factor receptor (EGFR) and signaling pathways mediated by anaplastic lymphoma kinase (ALK), respectively, the MET signaling pathway has also been recognized as a potential target. Moreover, according to current knowledge, MET could be considered both as a secondary oncogenic mechanism and as a prognostic factor. Several therapeutic strategies for inhibiting activated hepatocyte growth factor receptor (HGFR) and the subsequent downstream signaling transduction have been improved in order to block tumor growth. This review will focus on the MET pathway and its role in resistance to EGFR TK (tyrosine kinase) inhibitors, the different strategies of its inhibition, and the potential approaches to overcoming acquired resistance.

Phase I clinical and pharmacokinetic study of trabectedin and cisplatin in solid tumours.

AIM OF THE STUDY To define the maximum tolerated dose (MTD) and toxicity of trabectedin (T) and cisplatin (C) given on days 1 and 8 every 3 weeks to adult patients with advanced solid tumours. Plasma pharmacokinetics at cycle 1 and a preliminary anti-tumour activity assessment in ovarian and non-small cell lung cancer (OC, NSCLC) were secondary objectives. METHODS In the dose finding part (DFP) of the study the dose of T given at each administration was escalated by 100 microg/m(2) increments from 300 microg/m(2) up to the MTD, with a fixed dose of C of 40 mg/m(2). The recommended dose (RD) was assessed in the previously treated and untreated OC and NSCLC patients in the expansion of the RD (ERD) part of the study. T was administered with corticosteroids pre-medication as 3-h infusion and C as 30-min infusion. RESULTS Thirty-nine patients were treated in the DFP and 10 in the ERD. The MTD of T was 700 microg/m(2) due to dose-limiting neutropaenia and the RDs in the previously treated/untreated patients were 500 and 600 microg/m(2), respectively. Most common toxicities were nausea/vomiting (67%), asthenia/fatigue (55%) and reversible ASAT/ALAT elevation (51%). Time to recovery from myelosuppression was dose-dependent and treatment could be repeated after > or = 4 weeks in the majority of patients at 600 microg/m(2). Confirmed partial responses were observed in 4 of 13 evaluable OC patients and in 1 with uterine leiomyosarcoma. No pharmacokinetic interaction was observed. CONCLUSION The administration of T and C on days 1 and 8 resulted in prolonged neutropaenia requiring treatment delay. The evaluation of a single every 3 week schedule is worthwhile because of the hints of anti-tumour activity observed in OC.

Ifosfamide in the elderly: clinical considerations for a better drug management.

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.

A phase I, dose-escalation study of volasertib combined with nintedanib in advanced solid tumors.

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.

Phase I study of PF-03446962, a fully human monoclonal antibody against activin receptor–like kinase 1 in patients with hepatocellular carcinoma

BACKGROUND This expansion cohort of a multicenter, dose-escalation, phase I study (NCT00557856) evaluated safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamic effects of the anti-activin receptor-like kinase-1 (ALK-1) monoclonal antibody PF-03446962 in advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS Patients with HCC and disease progression after prior antiangiogenic therapy or intolerance to treatment received PF-03446962 7 mg/kg intravenously biweekly, as recommended in the dose-escalation part of the study. RESULTS Twenty-four patients received PF-03446962. The most frequent treatment-related adverse events (AEs) were thrombocytopenia (33.3%), asthenia (29.2), and chills (16.7%). Two patients experienced treatment-related telangiectasia, suggesting an in vivo knockout of ALK-1 function through ALK-1 pathway inhibition. Overall, treatment-related grade 3-4 AEs were reported in eight patients (33.3%). Treatment-related grade 3-4 thrombocytopenia was noted in four patients. No complete or partial responses were reported. Twelve (50%) patients achieved stable disease, which lasted ≥12 weeks in seven (29.2%) patients. The median time to progression was 3 months. Biomarker analyses showed higher mean tumor expression of c-tumor mesenchymal-epithelial transition factor and higher mean serum levels of bone morphogenetic protein-9 in patients with disease control (DC) for ≥12 weeks versus patients with disease progression. Conversely, lower mean serum transforming growth factor-β and vascular endothelial growth factor receptor-3 levels were detected in patients with DC versus patients with progression. CONCLUSIONS The observed safety, tolerability, pharmacokinetic profile, and clinical activity support further evaluation of PF-03446962 in patients with HCC and other solid malignancies, as single agent or in combination with other antiangiogenic, chemotherapeutic, or immunotherapeutic agents. TRIAL REGISTRATION NUMBER NCT00557856.