Hernán Cortés-Funes

Phase I-II Study of Paclitaxel, Cisplatin, and Gemcitabine in Advanced Transitional-Cell Carcinoma of the Urothelium

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

Trabectedin in pre-treated patients with advanced or metastatic soft tissue sarcoma: a phase II study evaluating co-treatment with dexamethasone

SummaryPurpose This study assesses the efficacy, toxicity and pharmacokinetic profile of trabectedin with or without prophylactic dexamethasone co-treatment in patients with recurrent advanced soft tissue sarcoma (STS). Patients and methods Patients were randomized to receive trabectedin as a 3-h infusion every 3xa0weeks with dexamethasone or placebo in the first cycle, with the alternate in the second cycle and with the patient’s choice subsequently. Due to toxicity, the randomized design was modified to open-label to make dexamethasone mandatory and the initial dose (1,650xa0μg/m2) was reduced to 1,500xa0μg/m2 and then to 1,300xa0μg/m2. Results Forty-one patients were enrolled and 35 were evaluable for efficacy. One partial response and 18 disease stabilizations were found. The median PFS and OS were 2.1 and 10.2xa0months, respectively, with the 3- and 6-month PFS rates indicating activity in pretreated STS. Twenty-three and 27 patients developed transient asymptomatic grade 3/4 AST and ALT elevation, respectively, and 21 patients had grade 3/4 neutropenia. Dose reduction from 1,650xa0μg/m2 to 1,300xa0μg/m2 decreased the incidence of grade 3/4 thrombocytopenia (26% vs. 0%), neutropenia (51% vs. 25%) and AST increase (76% vs. 25% of patients). Four patients died due to drug-related toxicities (3 with placebo). The total body clearance of trabectedin was 28% higher and half-life was 21% lower with dexamethasone compared to placebo, with no differences in volume of distribution. Conclusions Trabectedin has confirmed activity in patients with pretreated STS. This study shows that co-treatment with dexamethasone improves the safety of trabectedin by reducing drug-induced hepatotoxicity and myelosuppression.

Gemcitabine/paclitaxel-based three-drug regimens in advanced urothelial cancer

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

Corazón y neoplasias

La afectacion cardiaca por enfermedades neoplasicas puede deberse a invasion cardiaca por el propio tumor, a compresion del corazon y/o de los grandes vasos por neoplasias extracardiacas, embolizacion y fundamentalmente a los efectos de la terapeutica antitumoral. El tratamiento del cancer ha experimentado un importante avance en las ultimas decadas por la gran expansion de agentes quimioterapicos y el refinamiento de las tecnicas de radioterapia; no obstante, muchos de los mas efectivos farmacos antineoplasicos y la irradiacion toracica ocasionan cardiotoxicidad aguda y cronica. Asi, el seguimiento a largo plazo de pacientes que han recibido antraciclinas, farmacos cruciales en la terapia de muchas neoplasias, demuestra fallo cardiaco clinico en el 4,5 al 7% de los pacientes, incrementandose la incidencia de anomalias en la funcion cardiaca con el tiempo. Su patogenia probablemente incluya la formacion de radicales libres, alteraciones en el transporte del calcio, disfuncion adrenergica o liberacion de aminas vasoactivas. El dexrazoxano es el unico cardioprotector de uso clinico comercializado para un grupo seleccionado de pacientes con carcinoma de mama, por lo que es necesario el desarrollo de nuevos agentes que protejan de la cardiotoxicidad de este grupo de farmacos y reduzcan la morbimortalidad secundaria a los mismos.

Colony-stimulating factors for adjunctive therapy of infections in neutropenic cancer patients

Dear Editor, We read with interest the article by Schimpf, Scott and Wade concerning controversial issues on infections in cancer patients [7]. One of the issues addressed in this article was the use of cytokines [granulocyte-colony-stimulating factor (GCSF) or granulocyte macrophagecolony-stimulating factor (GMCSF)] for adjunctive therapy of infections in cancer patients with chemotherapy-induced neutropenia and fever, an area in which no randomized trials had been performed until recently. This is somewhat surprising, since both G-CSF and GM-CSF have been shown to reduce the duration of chemotherapy-induced neutropenia [2], which is an important prognostic factor for patients with neutropenic fever [1]. Limited animal studies also support a role for colony-stimulating factors (CSF) in the t reatment of infection in neutropenic hosts [5]. We recently completed a randomized trial to test the addition of G-CSF or GM-CSF to antibiotics in cancer patients on standarddose chemotherapy who developed neutropenic fever [4]. A total of 121 patients were enrolled and randomized to G-CSF (5 txg kg -1 day -1 s.c.), GM-CSF (same dose) or placebo, in addition to standard i.v. antibiotics ( recommended schedule = ceftazidime + amikacin). CSF or the placebo was to be discontinued when the absolute neutrophil count (ANC) was above 1000/mm 3 for 2 consecutive days (whether the patient remained febrile or not). Intravenous antibiotics were to be discontinued and the patient was to be discharged when he or she had been afebrile and with A N C above 1000/mm 3 for 2 consecutive days, provided that 5 days on i.v. antibiotics had been completed (7 days if cultures had been positive or a site of infection was present). Results are summarized in Table 1. Hematological recovery was faster in patients on G-CSF or GM-CSF (median time to A N C > 1000/mm3=3 days for GCSF compared to 2 for GM-CSF and 5 for placebo, P < 0.001 versus each CSF arm). The number of patients with prolonged neutropenia ( A N C < 1000/mm 3 for more than 10 days) was significantly larger in the placebo group [9 patients (20.9%) for placebo compared to 0 for G-CSF and GM-CSF, P<0.001]. The duration of fever was short and there were no significant differences among the three arms. The median hospital stay (and duration of i.v. antibiotic therapy) was significantly shorter in each of the groups t reated with CSF when compared with placebo (5 days for G-CSF and for GMCSF versus 7 for placebo, P < 0.001), and this translated into a decreased cost per patient (mean = U.S.

Phase I-II study of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma of the urothelium. Spanish Oncology Genitourinary Group.

5600 for G-CSF compared to U.S.

Incidence of contralateral germ cell testicular tumors in South Europe: report of the experience at 2 Spanish university hospitals and review of the literature.

5500 for GMCSF and U.S.

Patología del corazón de origen extracardíaco (VII) Corazón y neoplasias

6900 for placebo), bearing in mind that the time on CSF was short (median = 4 days both for G-CSF and for GM-CSF). We could not find any difference in efficacy or toxicity between GCSF and GM-CSF, except for CSFrelated fever, arbitrarily defined as fever subsiding less than 24 h after the last dose of CSF, which was found in 4 patients (10%) on GMCSF and 1 (2%) on G-CSF. Since CSF was discontinued upon hematological recovery, whether the patient remained febrile or not, CSFrelated fever did not result in prolonged duration of antibiotic thera-