[Retrospective analysis of venlafaxine-induced hypoglycemia in patients with overdose]. / Análisis retrospectivo de las hipoglucemias inducidas por venlafaxina en pacientes con sobredosis.

INTRODUCTION: Recent publications relate the presence of hypoglycemia in venlafaxine (VLX) poisoning depending on the dose. Our aim was to analyze the clinical characteristics of patients who presented hypoglycemia induced by VLF overdose. PATIENTS AND METHODS: Retrospective study carried out in the Balearic Islands (2020-2023). INCLUSION CRITERIA: serum concentrations of VLX + O-desmethyl-venlafaxine (O-VLX)>800 ng/mL. The characteristics of patients with and without hypoglycemia were compared. RESULTS: Twenty-one patients were included, 8 (38.1%) with hypoglycemia. No differences were found in the doses referred to in both groups. Peak concentrations of VLX + O-VLX (ng/mL) were 9,783 [4,459-17,976] in patients with hypoglycemia and 1,413 [930-1,719] in patients without hypoglycemia (p<0.0001). The presence of hypoglycemia was associated with: lower age and level of consciousness; and higher frequency of suicide attempts, seizures, mydriasis, tachycardia and serotonin syndrome, invasive respiratory support, fluid therapy and ICU admission (p<0.05). CONCLUSIONS: The detection of hypoglycemia in a VLX overdose case is a readily available marker to suspect the severity of the patient. In any case, serum concentrations when available allow us to confirm intoxication.

Ketamine detection in urine samples from patients poisoned by recreational drugs: epidemiologic, clinical, and toxicologic profiles. / Detección de ketamina en pacientes intoxicados por drogas recreativas: perfil epidemiológico, clínico y toxicológico.

OBJECTIVES: To describe the epidemiologic, clinical, and toxicologic profiles of patients who used recreational ketamine and experienced acute poisoning. MATERIAL AND METHODS: Retrospective observational study of patients attended by several emergency medical services in the Balearic Islands for analytically confirmed acute poisoning after using ketamine between January 2016 and December 2020. Urine samples were analyzed by immunoassay and combined gas chromatography and mass spectrometry. RESULTS: One hundred twenty-two patients were studied. The mean (SD) age was 26.7 (6.5) years. The majority were men (77.9%) and not residents of the Balearic Islands (74.6%). Poisoning cases occurred mainly in the summer and in the island of Ibiza (84.4%). Ketamine use was declared by the patient or clinically suspected in 40.2%. The most common clinical signs were tachycardia (43.4%), hypertension (28.7%), mydriasis (27.0%), altered consciousness (25.4%), agitation/aggressiveness (25.4%), and hypothermia (21.3%). Seven patients (5.73%) required admission to the intensive care unit. The drugs most often detected along with ketamine were cocaine, in 93.4%, and 3,4-methylenedioxymethamphetamine (MDMA), in 78.7%. Multiple-drug use combining ketamine, cocaine, and MDMA, or on occasion additional substances, was detected in 98.4%. CONCLUSION: Detection of ketamine in urine samples from patients poisoned by recreational drugs is associated with a characteristic profile: young men who are not residents of the Balearic Islands, who attend electronic music concerts, and who have taken multiple drugs. A substantial percentage of such patients are unaware of drug intake.

OBJETIVO: Identificar el perfil epidemiológico, clínico y toxicológico de los pacientes consumidores de ketamina en el contexto de una intoxicación aguda por drogas recreativas. METODO: Estudio observacional retrospectivo en pacientes atendidos en varios servicios de urgencias (SU) en Baleares por intoxicaciones agudas por drogas recreativas con exposición a ketamina confirmada analíticamente, entre enero de 2016 y diciembre de 2020. El análisis toxicológico en muestras de orina se realizó mediante inmunoensayo y cromatografía de gases acoplada a espectrometría de masas. RESULTADOS: Se incluyeron 122 pacientes. La edad media fue de 26,7 (DE 6,5) años. La mayoría eran hombres (77,9%) y no residentes en las Islas Baleares (74,6%). Los casos se detectaron mayoritariamente en verano y en Ibiza (84,4%). El uso de ketamina solo fue declarado por el paciente o fue clínicamente sospechado por el médico en el 40,2%. Los signos clínicos más frecuentes fueron taquicardia (43,4%), hipertensión (28,7%), midriasis (27,0%), disminución de la consciencia (25,4%), agitación/agresividad (25,4%) e hipotermia (21,3%). Siete pacientes (5,7%) requirieron ingreso en la unidad de cuidados intensivos (UCI). La cocaína (93,4%) y la 3,4-metilendioximetanfetamina (MDMA) (78,7%) fueron las drogas más detectadas junto con la ketamina. El policonsumo fue habitual (98,4%), combinando ketamina, cocaína y MDMA, en algunos casos asociado a otras sustancias. CONCLUSIONES: La detección de ketamina en intoxicaciones por drogas recreativas se asocia a consumidores con un perfil característico (varones jóvenes, no residentes, asistentes a eventos de música electrónica y policonsumo) y un alto porcentaje desconocen de este consumo.

Detection of unsuspected cathinone and piperazine-type drugs in urine samples positive for methamphetamine and amphetamine collected in emergency departments. / Detección no sospechada de catinonas y piperacinas en pacientes consumidores de metanfetamina y anfetamina atendidos en servicios de urgencias hospitalarios.

OBJECTIVES: To detect the presence of unsuspected and/or undeclared cathinone and piperazine-type designer drugs in methamphetamine (METH) and amphetamine users treated in emergency departments, and to compare clinical and toxicologic profiles. MATERIAL AND METHODS: Retrospective observational study of emergency department patients treated for confirmed acute intoxication by recreational drugs (METH and amphetamines) between March 2019 and December 2020. We ordered high-performance liquid chromatography with tandem mass spectrometry to detect cathinones (methylone, fluoromethcathinone, mexedrone, fluoromethamphetamine, mephedrone, methylenedioxypyrovalerone) and synthetic piperazines (meta-chlorophenylpiperazine and trifluoromethylphenylpiperazine). Demographic, clinical, and toxicologic variables were analyzed with SPSS software (version 23). RESULTS: Thirty-nine patients were included: 24 (61.5%) had used METH and 15 (38.5%) an amphetamine. Synthetic cathinones were detected in samples from 11 patients (28.2%), 10 (90.9%) in the METH group and 1 (9.1%) in the amphetamine group (P = .028). The METH users had taken mephedrone (8 patients) or methylone (2 patients); the amphetamine user had taken mephedrone. None of the patients had declared use of a cathinone; nor was use suspected. The mean (SD) number of substances involved was higher among users of cathinones (3.5 [1.13] vs 2.5 [1.40] in those who took no cathinones; P = .036). Among the cathinone users, 90.9% were men, 90.9% had used METH, and 45.5% had practiced chemsex. HIV positivity was significantly associated with cathinone use (in 45.5% vs 10.7% of those not using cathinones; P = .028). All 5 of the patients who had taken cathinones and also practiced chemsex were HIV positive. Significantly more patients who had taken cathinones presented with anxiety (72.7% vs 21.43%; P = .007). No differences in clinical management were found. CONCLUSION: Detection of METH in intoxicated patients should raise suspicion of probable use of a synthetic cathinone. Patients in whom new psychoactive substances are detected should be kept under observation, and clinical protocols should include referring them to addiction treatment centers.

OBJETIVO: Determinar la incidencia de catinonas y piperazinas, no sospechadas y/o declaradas en consumidores de metanfetamina (MANF) y anfetamina (ANF) atendidos en servicios de urgencias hospitalarios (SUH) y comparar los perfiles clínicos y toxicológicos. METODO: Estudio retrospectivo de pacientes con intoxicación aguda por drogas recreativas con MANF y ANF confirmadas analíticamente atendidos en 3 SUH entre marzo de 2019 y diciembre de 2020. Se detectaron por HPLC-MS/MS las catinonas [metilona, fluorometcatinona, mecedrona, fluorometanfetamina, mefedrona, metilendioxipirovalerona (MDPV)] y las piperazinas sintéticas [meta-clorofenilpiperazina (mCPP), trifluorometilfenilpiperazina (TFMPP)]. RESULTADOS: Se incluyeron 39 pacientes: 24 (61,5%) en el grupo MANF y 15 (38,5%) en el ANF. En 11 (28,2%), se detectaron catinonas sintéticas (grupo CAT), 10 en el grupo MANF (8 mefedrona, 2 metilona) y 1 en el grupo ANF (1 mefedrona) (90,9% vs 9,1%; p = 0,028). Ninguno de los pacientes declaró consumo de catinonas. El número de drogas implicadas en la intoxicación fue superior en el grupo CAT (3,5 [1,13] vs 2,5 [1,40]; p = 0,036). El perfil clínico del grupo CAT fue: varón (90,9%), consumidor de MANF (90,9%) y usuario de chemsex (45,5%). El diagnóstico de VIH se asoció significativamente al grupo CAT (45,5% vs 10,7%; p = 0,028). Los pacientes del grupo CAT presentaron mayor ansiedad (72,7% vs 21,4%; p = 0,007). No se hallaron diferencias en su manejo clínico. CONCLUSIONES: La detección de MANF debería considerarse un dato de sospecha de consumo de catinonas sintéticas, y en esos casos debería contemplarse la detección de nuevas sustancias psicoactivas de abuso.

Activity of topotecan given intravenously for 5 days every three weeks in patients with advanced non-small cell lung cancer pretreated with platinum and taxanes: a phase II study.

Topotecan, a semi-synthetic camptothecin analogue with topoisomerase I interaction, has shown to be an active agent in the treatment of advanced refractory lung cancer. This paper describes the authors' experience with this drug when used as a single agent in patients (pts) with advanced non-small cell lung cancer (NSCLC) refractory to platinum- and taxane-containing chemotherapy regimens. Thirty-five patients with NSCLC refractory to previous chemotherapy and KI ≥ 60% were included in the study. Their characteristics are as follows: median age of 52 years (range 43-69) and Karnofsky PS of 70 (60-80); 27 were male and 8 were female. Twenty-one (60%) patients had adenocarcinoma; eleven (31.4%), squamous cell, and three (8.5%), undifferentiated carcinoma. There was a median of two disease sites and two prior chemotherapy regimens. Topotecan was administered at a dose of 1.25 mg/m(2) I.V. daily for 5 days, repeated every 21 days until disease progression, maximal response, or intolerable toxicity. After 73 cycles, patients received a median of 2 treatment cycles (1-9). All patients except one were considered evaluable for toxicity; eight episodes (24%) of nausea/vomiting and two episodes (6%) of grade 1-2 asthenia, respectively, were reported. Four (12%) patients developed grade 1-2 anemia and two (6%) subjects suffered grade 3 anemia. Seven (21%) patients had grade 1-2 neutropenia and one (3%) presented grade 5 neutropenia. In 33 patients evaluable for activity of the 35 subjects included in the study; one (2.8%) presented a partial response; nine (25.7%) had stable disease, and 23 (65.7%) exhibited disease progression. Median time to progression and overall survival were 54 (12-210) and 70 (12-324) days, respectively. Intravenous topotecan at that dose and administration schedule displays scant activity in terms of response rate in individuals with advanced NSCLC previously treated with platinum and taxanes. The role and usefulness of chemotherapy in this setting warrants further investigation and confirmation through comparative studies.

Deep Brain Stimulation of the Nucleus Accumbens, Ventral Striatum, or Internal Capsule Targets for Medication-Resistant Obsessive-Compulsive Disorder: A Multicenter Study.

BACKGROUND: Deep brain stimulation of the nucleus accumbens, ventral striatum, or internal capsule region has shown a 45%-60% response rate in adults with severe treatment-refractory obsessive-compulsive disorder, regardless of which target is used. We sought to improve the effectiveness of deep brain stimulation by placing the electrode along a trajectory including these 3 targets, enabling a change of stimulation site depending on the patient's response. METHODS: This study used the medical records of 14 patients from 4 different Spanish institutions: 7 from the Hospital Universitario La Princesa, 3 from the Hospital Universitario Central de Asturias, 2 from Hospital Universitario Fundación Jiménez Díaz, and 2 from Hospital Universitari Son Espases. All patients were operated on under the same protocol. Qualitative and quantitative data were collected. RESULTS: Of 14 patients, 11 showed significant improvement in obsessive-compulsive disorder symptoms, as evident in a reduction ≥35% in Yale-Brown Obsessive Compulsive Scale scores following stimulation relative to preoperative scores. Seven patients responded to stimulation at the nucleus accumbens (the first area we set for stimulation), whereas 4 patients needed to have the active contact switched to the internal capsule to benefit from stimulation. CONCLUSIONS: Deep brain stimulation of the nucleus accumbens, internal capsule, and ventral striatum significantly benefited our cohort of patients with medication-resistant obsessive-compulsive disorder. Electrode insertion through the 3 main targets might confer additional therapeutic efficacy.

Amphetamine and methamphetamine poisonings attended in hospital emergency departments: clinical features and the usefulness of laboratory confirmation. / Intoxicaciones por anfetamina y metanfetamina atendidas en los servicios de urgencias: características clínicas y utilidad de la confirmación analítica.

OBJECTIVES: To determine whether clinical and toxicologic findings differed between cases of amphetamine (AMP) and methamphetamine (mAMP) poisoning attended in 2 Balearic Island hospital emergency departments. MATERIAL AND METHODS: Retrospective observational study of AMP and mAMP cases with laboratory confirmation between 2013 and 2018. We compared clinical and toxicologic variables as well as clinical management between groups. RESULTS: 1) A total of 120 cases were found: 86 (71.7%) with AMP poisoning and 34 (28.3%) with mAMP poisoning. 2) Drug poisoning was confirmed by gas chromatography associated with mass spectrometry (GC-MS) in 787 urine samples found to be positive during screening. One hundred fifty-four (19.6%) were confirmed by GC-MS. Thirtyfour of them did not meet the inclusion criteria. 3) Significant differences between AMP and mAMP cases were found for age (32.3 vs 28.4 y, respectively); sex (72.1% vs 94.1% men); and Spanish nationality (64.0% vs 29.4%). Reasons for admission and clinical features also differed: the reasons were aberrant behavior (15.1% in the AMP group vs 0% in the mAMP group) and palpitations (1.2% vs 20.6%); agitation was observed in 27.9% and 8.8%, respectively. Clinical management was similar in the 2 groups. Multiple drug poisoning was detected in 76.6% patients and was more common in patients in the AMP group (82.6% vs 61.8%). The additional drugs in these cases were mainly cocaine (63.0%), cannabis (48.9%), 3,4-methylenedioxy-N-methamphetamine (MDMA) (38.0%), and alcohol (35.9%). Cannabis was detected in a significantly higher proportion in the AMP group (45.3%) than in the mAMP group (17.6%). False positives were found in 78.7% of the samples. The culprit drug was most often MDMA (71.2%). CONCLUSION: AMP poisonings were associated with age over 30 years, Spanish nationality, aberrant behavior, agitation, multiple drug findings, and the use of cannabis. Poisonings caused by mAMP abuse were associated with age under 30 years, non-Spanish nationality, palpitations, and single-drug use.

OBJETIVO: Investigar si existen diferencias clínicas y toxicológicas en pacientes intoxicados por anfetamina (ANF) y metanfetamina (MANF) atendidos en servicios de urgencias. METODO: Estudio observacional retrospectivo de intoxicaciones por ANF y MANF con confirmación analítica en Baleares (2013-2018). Se compararon variables clínicas, toxicológicas y de manejo clínico entre grupos. RESULTADOS: 1) Se incluyeron 120 pacientes, 86 (71,7%) grupo ANF y 34 (28,3%) grupo MANF. 2) La confirmación de derivados anfetamínicos se realizó por cromatografía de gases-espectrometría de masas en 787 muestras de orina previamente positivas mediante un método de cribado cualitativo. Se confirmaron 154 (19,6%) muestras. De ellas, 34 fueron excluidas. 3) Se encontraron diferencias significativas entre ANF y MANF en: edad (32,3 vs 28,4 años); sexo (72,1 vs 94,1% hombres); nacionalidad española (64,0 vs 29,4%); en motivos de admisión: alteración de conducta (15,1 vs 0%) y palpitaciones (1,2 vs 20,6%); y en características clínicas: agitación (27,9 vs 8,8%). No hubo diferencias de manejo clínico. El 76,6% de casos fueron polintoxicaciones, más comunes en ANF (82,6 vs 61,8%). En estos casos se detectó principalmente cocaína (63,0%), cannabis (48,9%), MDMA (38,0%) y alcohol (35,9%). La mayor asociación del cannabis con el grupo de ANF fue estadísticamente significativa (45,3 vs 17,6%). La causa de los falsos positivos se identificó en el 78,7% de muestras, siendo el MDMA (71,2%) la principal. CONCLUSIONES: Se observaron diferencias entre ANF y MANF en cuanto a variables demográficas y motivo de asistencia; no obstante en esta serie hubo un alto porcentaje de polintoxicaciones.

Acute extensive myelopathy after single heroin and cocaine exposure in a patient with toxicological evidence of long-term drug abstinence.

Heroin-related myelopathy is an uncommon but often devastating complication of heroin intake. It is usually reported in individuals exposed to intravenous heroin after a variable drug-free period, leading to acute and complete spinal cord injury with poor long-term outcome. We describe an original case of acute longitudinally extensive transverse myelopathy following single heroin and cocaine intravenous exposure after a long period of abstinence confirmed by toxicological hair and retrospective urine drug analysis. This case could provide new insights in the understanding of this rare neurological complication.

Cisplatin plus gemcitabine with or without vinorelbine as induction chemotherapy prior to radical locoregional treatment for patients with stage III non-small-cell lung cancer (NSCLC): results of a prospective randomized study.

To evaluate possible improvement in objective response of adding vinorelbine (V) to the combination of cisplatin/gemcitabine (CG) in induction chemotherapy for stage III NSCLC, patients (n=154) aged < or =75 years, Karnofsky index > or =70%, were stratified by stage (IIIA versus IIIB) and randomly assigned to receive: C (50mg/m(2) i.v.) plus G (1250mg/m(2) i.v.) or CG plus V (25mg/m(2) i.v.). All drugs were administered on days 1 and 8 of an every 3-week cycle. At conclusion, local treatment (LT) with surgery and/or radiotherapy was scheduled. The results indicated that, following a median of 3 cycles, the overall efficacy was 65% in the CG and 61% in the CGV group. Most patients in both groups received radiotherapy as part of their LT. Pathological complete response was confirmed by surgery in 18% in the CG and 25% in the CGV group. Median progression-free survival was 368 days in the CG and 322 days in the CGV group. There were no statistically significant differences in toxicities between groups. We conclude that the CG and CGV combinations had similar efficacy and moderate toxicity, without accruing to the triplet combination.

Irinotecan in the treatment of advanced colorectal cancer in patients pretreated with Fluorouracil-based chemotherapy: a study to determine recommendable therapeutic dosage.

Because no consensus exists regarding recommendable dose levels for irinotecan, an intrapatient dose escalation phase I-II study was initiated in previously treated patients with colorectal cancer. Survival was a secondary endpoint. Thirty-five consecutive patients with progressive disease after 5-fluorouracil-based chemotherapy were enrolled to receive irinotecan starting from 250 mg/m2/3 weeks and rising to currently used therapeutic doses. In total, 162 cycles were administered. The median tolerable dose was 250 mg/m2. Twelve patients (34%) were unable to tolerate doses greater than 250 mg/m2, 10 patients (28%) presented toxicity at 250 mg/m2 and 2 patients tolerated only 200 mg/m2. Three patients (9%) had partial response. The major adverse reactions were grade III-IV diarrhea, grade II-III nausea/vomiting, grade II-III neutropenia, and grade II-III anaemia in 28%, 48%, 11%, and 17% of the patients, respectively. Median survival time and time to progression were 8 and 3 months, respectively. The current irinotecan dose of 350 mg/m2/3 weeks appears unacceptably toxic and, hence, a lower dose needs to be considered. The response rates obtained are similar to the results observed in phase III studies, and its activity appears not to be adversely affected with this treatment scheme.

Pulmonary toxicity in patients treated with gemcitabine plus vinorelbine or docetaxel for advanced non-small cell lung cancer: outcome data on a randomized phase II study.

Studies with the gemcitabine/vinorelbine (GV) or the gemcitabine/docetaxel (GD) combinations have shown similar efficacy and less toxicity compared to platinum-based chemotherapies, in patients with advanced non-small-cell lung cancer (NSCLC). The present trial was designed to test the efficacy and safety of both, GV and GD, combinations. Chemotherapy-naïve patients (n=39)or=60% and adequate hematological, renal and hepatic function were randomly assigned to receive G 1,000 mg/m2+either V 25 mg/m2 or D 35 mg/m2 (all of which were administered i.v.) on days 1 and 8 every 21 days. Baseline characteristics were comparable in GV (n=20) and GD (n=19) groups. Results indicated objective response of 7 (35%) vs 6 (31%) patients and median time-to-treatment failure of 120 versus 90 days in the GV and GD arms, respectively. The most common non-hematological toxicities were (GV vs GD): grade 2-4 pulmonary toxicity in 1 (5%) vs 7 (37%); grade 2-3 diarrhea 0 versus 4 (21%) and edema 1 (5%) vs 3 (16%); grade 3-4 hematological toxicities occurred in 3 (15%) vs 1 (5%) patients. Our results indicate that the combination of gemcitabine/docetaxel does not have a favorable safety profile with this schedule of administration, particularly in terms of pulmonary toxicity.

Gemcitabine and vinorelbine (GV) versus cisplatin, gemcitabine and vinorelbine (CGV) as first-line treatment in advanced non small cell lung cancer: results of a prospective randomized phase II study.

The objective of this study was to assess whether adding cisplatin to gemcitabine/vinorelbine combination improves the clinical outcome in patients with non-small-cell lung cancer (NSCLC). Chemotherapy-naïve patients with advanced NSCLC; age < or = 75 years: Karnofsky performance status > or = 60%, and with adequate hematological, renal and hepatic function, were randomized into 2 treatment groups to receive Gemcitabine 1250 mg/m2 + vinorelbine 30 mg/m2 (GV group), or cisplatin 50 mg/m2 + gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 (CGV group). All drugs were administered on days 1 and 8 every three weeks: From September 1999 to March 2003, 114 patients were enrolled. No statistically significant difference was observed in GV vs CGV group in objective response (37 versus 47%, respectively; P = 0.5), median time to progression (5 versus 5.8 months; P = 0.6), overall survival (9 versus 10 months; P = 0.9) and 1-year survival (26 versus 28%; P = 0.9). Conversely, toxicities were significantly higher for CGV, including grade 3-4 neutropenia (24 versus 45%); neutropenic fever (4 versus 14%, including one toxic death); grade 3-4 thrombocytopenia (2 versus 14%); and grade 3-4 emesis (2 versus 14%). Our results suggest that the combination of gemcitabine and vinorelbine is less toxic than three-drug combination with cisplatin while showing similar efficacy.

Activity of carboplatin in patients with advanced non-small cell lung cancer pre-treated with a non-platinum combination.

To assess the efficacy of carboplatin when used as a single agent in patients with advanced non small cell lung cancer (NSCLC) and who are refractory to chemotherapy with a non-platinum combination, we recruited patients (n=40) NSCLC patients, 36 of whom were males, with an overall median age of 59 years (range 39-79) and Karnofsky Performance Status of 70% (range 60-90%). At baseline, the patients had a median of one disease site (range 1-3) and had received a median of one prior regimen (range 1-2). Carboplatin was administered (i.v.; AUC=6) every 3 weeks until disease progression or non-acceptable toxicity was reached. In total 169 cycles were administered (median 4 cycles/patient; range 1-8). Main toxicities were grade 2-3 anemia and grade 4 thrombocytopenia (22.5% of patients). Overall clinical response rate was 10% (4 partial responses); 26 patients (65%) had stable disease and 8 (20%) had disease progression. Median time to progression and median survival time were 90 and 187 days, respectively. One year survival rate was 13%. We conclude that carboplatin shows minimal toxicity with a discrete anti-tumor activity in patients with NSCLC and who are refractory to non-platinum combinations.

Combination of docetaxel, epirubicin and vinorelbine administered every 2 weeks as first-line therapy in patients with metastatic breast cancer: a dose-finding study.

AIMS: To assess efficacy and optimum combination dosage of intravenous docetaxel (T), epirubicin (E) and vinorelbine (N) administered every 2 weeks and without colony stimulating factor (CSF) support in patients with metastatic breast cancer (MBC). PATIENTS AND METHOD: Patients (n = 5 1) with MBC were consecutively assigned to four different dose levels (DL) to receive (in mg/m2): Level I = T35 + E30 + N25; Level II = T30 + E30 + N25; Level III = T30 + E25 + N25; and Level IV = T25 + E25 + N25. Consecutive cycles were delayed if absolute neutrophil and/or platelet counts fell below 1.5 x 10(9) and 100 x 10(9) l(-1), respectively. Treatment at a given dose level was suspended if 33% or more of patients included in a given cohort had unacceptable toxicity. RESULTS: The patients evaluable for toxicity (n = 48) received 448 cycles (median 9; range 1-23). There was neutropenia G 3-4 in 30 patients (63%) with fever in 3 (6%). The G 2-3 non-hematological toxicities were alopecia in 39 patients (81%), mucositis in 11 (23%), and nausea/vomiting in 8 (17%). There were no toxic deaths. Treatment delay or dose reduction after first cycle occurred in > or = 30% of patients treated in all DLs, except the fourth. Objective response was achieved in 29 of the 47 evaluable patients (58%; 95% CI: 50-66). The median duration of response, time-to-progression and overall survival were 13, 11 (range 8-14) and 20 (range 16-24) months, respectively. CONCLUSION: The combination of docetaxel, epirubicin and vinorelbine without CSF support ought not to exceed 25 mg/m2 every 2 weeks. The efficacy is no greater than other existing regimens for first-line treatment of MBC.