A randomized phase II study to compare oxaliplatin plus 5-fluorouracil and leucovorin (FOLFOX4) versus oxaliplatin plus raltitrexed (TOMOX) as first-line chemotherapy for advanced colorectal cancer

INTRODUCTION: The aim of this study was to compare TOMOX versus FOLFOX4 as first-line treatment of advanced colorectal cancer (CRC). MATERIALS AND METHODS: 191 chemotherapy-naïve patients were randomized to receive TOMOX or FOLFOX4. Patients were evaluated every 3 months and chemotherapy was continued until disease progression or unacceptable toxicity. Overall response rate was the primary endpoint. RESULTS: 183 patients were included in the intent-to-treat analysis (92 TOMOX and 91 FOLFOX4). Overall response rate was 45.6 and 36.3 % (p = 0.003) for TOMOX and FOLFOX4, respectively. No statistically significant differences were observed in overall survival (15.6 and 17.2 months; p = 0.475); progression-free survival (7.7 and 8.7 months; p = 0.292), and response duration (6.4 and 7.6 months; p = 0.372) for TOMOX and FOLFOX4, respectively. Grades 3 and 4 neutropenia (p < 0.0001) and leukopenia (p = 0.028) were more common with the FOLFOX4 regimen, while hepatic disorders and asthenia were higher in TOMOX group (p = ns). There were two treatment-related deaths in the FOLFOX4 arm and one in the TOMOX arm. Quality of life analysis based on the SF-36 revealed differences between the two regimens for physical and mental composite scores after 6 weeks, and for body pain and emotional role functioning after 6 and 12 weeks; all of these favored the FOLFOX4 arm (p ≤ 0.05). CONCLUSIONS: TOMOX and FOLFOX4 seem to have similar efficacy and are well tolerated in the first-line treatment for advanced CRC with different profiles of toxicity. The convenient TOMOX regimen may offer an alternative to fluoropyrimidine-based regimens (AU)

Epidermal growth factor receptor (EGFR) mutations in a series of non-small-cell lung cancer (NSCLC) patients and response rate to EGFR-specific tyrosine kinase inhibitors (TKIs)

INTRODUCTION Epidermal growth factor receptor (EGFR) mutation related to tyrosine kinase inhibitors' (TKIs) responsiveness in non-small cell lung cancer (NSCLC) has become an important issue for therapeutic decision-making in NSCLC patients. MATERIAL AND METHODS Sixty-nine Caucasian NSCLC patients were screened for mutations in the tyrosine kinase (TK) domain of EGFR by direct sequencing from December 2005 to September 2010. RESULTS Activating mutations in the EGFR TK domain were found in 8 of 69 (11.6%) (7 deletions in exon 19 and one L858R mutation in exon 21). Seven of those mutations were found in adenocarcinoma and one mutation in bronchiolo-alveolar carcinoma; five of them in females (one smoker) and three of them in males (one smoker). All patients carrying activating mutations in the TK domain of EGFR were treated with TKIs. Ten patients not carrying an activating mutation in EGFR, who progressed after chemotherapy, were also treated with compassionate use of EGFR-specific TKIs (gefitinib or erlotinib). An objective response (partial response) was observed in all patients carrying an activating mutation in EGFR that received TKIs. Median overall survival for these patients has not been reached, however mean survival has been estimated at 39.5 months (95% CI, 22-57). CONCLUSIONS As previously reported, EGFR TK mutational analysis was a predictive test for response to targeted therapy with EGFR TKIs. The early identification of these patients consistently attains disease response and clearly improves outcomes (AU)

Response to erlotinib in recurrent glioblastoma multiforme showing coexpression of EGFRvIII and PTEN

Glioblastoma multiforme (GBM) is the most aggressive brain tumour in adults and remains incurable despite multimodal intensive treatment regimens. We present a patient with a recurrent glioblastoma who showed coexpression of the epidermal growth factor receptor mutant variant III (EGFRvIII) and the tumour-suppressor protein PTEN. She was treated with the tyrosine kinase inhibitor erlotinib for four months, achieving a partial response with improvement of neurologic symptoms. A review of the pertinent literature supporting the future use of therapies against epidermal growth factor receptor (EGFR) in highgrade gliomas is also provided (AU)

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Clinical-molecular factors predicting response and survival for tyrosine-kinase inhibitors

The development of drugs with special mechanisms of action, such as tyrosine kinase inhibitors (TKIs), means that new clinical-molecular questions are being examined and this will help us to better select from the treatments available. In this study we review questions of survival and response to TKIs, attempting to distinguish prediction-and prognosis-related factors, at both the clinical and molecular levels. The evidence available today allows us to affirm that the benefits of TKI treatment occur regardless of the patient's status as a smoker, his/her gender or histological sub-type. Interestingly, in a subset analysis of ever-smokers, men with squamous cell histology derived a statistically significant survival benefit from erlotinib, a population that was previously thought not to benefit. The question of who should receive TKIs is still not completely resolved. Therefore, there should be an international effort to achieve a prognostic index, as has been done for lymphomas, that combines molecular and clinical factors. Such an index would classify patients into several sub-groups, defining the likelihood of non-response to TKIs (AU)

mTOR inhibitors and the anti-diabetic biguanide metformin: new insights into the molecular management of breast cancer resistance to the HER2 tyrosine kinase inhibitor lapatinib (Tykerb)

The small molecule HER2 tyrosine kinase inhibitor (TKI) lapatinib (Tykerb) is approved for the therapy of patients with HER2-positive breast carcinomas who have progressed on trastuzumab (Herceptin). Unfortunately, the efficacy of this HER2 TKI is limited by both primary (inherent) and acquired resistance, the latter typically occurring within 12 months of starting therapy. One of the key factors limiting our understanding of the mechanisms involved in lapatinib resistance is the lack of published preclinical models. We herein review lapatinib-refractory models recently developed at the bench and the survival pathways discovered. As hyperactivation of the pharmacologically targetable PI3K/mTOR/p70S6K1 axis appears to be central to the occurrence of lapatinib resistance, preclinical data showing enhanced antitumour effects when combining lapatinib with mTOR inhibitors (e.g., rapamycin analogues and NVP-BEZ235) highlight the importance of translational work to yield clinically useful regimens capable of delaying or treating lapatinib resistance. The unexpected ability of the anti-type II diabetes drug metformin to inactivate mTOR and decrease p70S6K1 activity further reveals that this biguanide, generally considered non-toxic and remarkably inexpensive, might be considered for new combinatorial lapatinib-based protocols in HER2-overexpressing breast cancer patients (AU)

A novel EGFR nonsense mutation in a non-small-cell lung cancer (NSCLC) patient who did not derive any clinical benefit with combination chemotherapy and erlotinib

Most of the somatic epidermal growth factor receptor (EGFR) mutations described to date in non-smallcell lung cancer (NSCLC) patients are located in the kinase domain and are considered activating mutations. Some of these mutations are associated with response to specific EGFR tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib. Here we report a case of a previously undescribed EGFR nonsense mutation in a lung adenocarcinoma patient who did not derive any clinical benefit with combination chemotherapy and erlotinib. To the best of our knowledge this is the second report in the literature describing an EGFR nonsense mutation in lung cancer patients (AU)

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Phase I/II study of gefitinib and capecitabine in patients with colorectal cancer

OBJECTIVE: The objectives of this phase I/II study were to determine the maximum tolerated dose (MTD), characterise the principal toxicities in the phase I part and assess the efficacy in the phase II part of gefitinib, an oral selective inhibitor of the epidermal growth factor receptor, in combination with capecitabine in patients with advanced colorectal cancer (CRC). METHODS AND PATIENTS: Patients with advanced CRC were treated with gefitinib administered daily for 21 days and capecitabine administered twice daily for 14 days of a 21-day cycle. The dose levels of gefitinib (mg) and capecitabine (mg/m(2) bid) assessed were 250/1000 and 250/ 1250. An expanded cohort was enrolled at the MTD to better characterise toxicity and efficacy. A total of 32 previously treated patients were accrued. In the phase I part 10 subjects were treated, with one dose-limiting toxicity. Overall 26 patients were treated at the MTD of the combination, which was gefitinib 250 mg/day and capecitabine 1250 mg/m(2) twice daily. RESULTS: The most frequent treatment-related adverse events included asthenia, diarrhoea, nausea, rash and anorexia. The incidence profile was very similar in phases I and II. No objective responses were documented but 53% of the patients achieved stable disease as best response to therapy. CONCLUSIONS: Capecitabine 1250 mg/m(2) twice daily 14 of 21 days and gefitinib at 250 mg/day can be safely administered in combination. The combination is relatively well tolerated. There were no objective responses, although an interesting stabilisation rate was documented, in previously treated advanced CRC patients (AU)

Hipertrofia benigna de próstata: revisión de la eficacia, tolerancia e impacto en la calidad de vida del tratamiento prolongado con alfuzosina / Bening prostatic hypertrophy: review of the efficacy, tolerance and quality of life impact of the long-term treatment with alfuzosin

OBJETIVO PRINCIPAL: Evaluar la efectividad de Alfuzosina, en términos de rapidez de efecto y duración del mismo, en pacientes con HPB. Objetivos secundarios: Analizar la efectividad según el observador, el cumplimiento del tratamiento y la tolerancia a Alfuzosina, indagando concretamente sobre las reacciones adversas de tipo cardiovascular y sexual. Simultáneamente, definir el perfil clínico del paciente con síntomas de prostatismo que busca espontáneamente tratamiento médico en España. DISEÑO DEL ESTUDIO: Estudio observacional, descriptivo, multicéntrico y retrospectivo a 6 meses. FUENTE Y RECOGIDA DE DATOS: De las historias clínicas de pacientes con HPB tratados con Alfuzosina durante más de 6 meses se extrajeron, además de los datos habituales anamnésicos y de exploración física (edad, sintomatología, tensión arterial, comorbilidad, etc.) los relacionados con la respuesta al tratamiento seguido en cuanto a efectividad, cumplimiento y tolerancia durante el primer y segundo trimestre desde la iniciación del mismo. Los datos de 1635 individuos a quienes se instauró tratamiento con Alfuzosina fueron utilizados para definir el perfil clínico de esta población. Sólo los 911 pacientes que mantuvieron el tratamiento durante seis meses fueron considerados para el análisis de efectividad y tolerancia. RESULTADOS: A los seis meses de tratamiento se observó una mejora en la intensidad media de cada uno de los síntomas urinarios estadísticamente significativa (p<0,005). Así mismo, la puntuación media de cada una de las variables analizadas en el cuestionario así como del I-PSS global se redujo significativamente (p<0,005). La efectividad apreciada por el observador fue buena o muy buena para el 88,5 por ciento a los 6 meses de tratamiento. El cumplimiento, fue considerado excelente ya que de los 914 individuos controlados en la última fase el 96,4 por ciento seguía con el tratamiento prescrito en la fase inicial. Sólo se reconocieron reacciones adversas en 16 pacientes (3 por ciento) que motivaron modificaciones de dosis o suspensión de la medicación (dos casos). El estudio específico de reacciones adversas de tipo cardiovascular mostró una ligera disminución de la tensión arterial sistólica (142,9 mmHg versus 137,86 mmHg) y diastólica (83,53 mmHg versus 80,72 mmHg) y de la frecuencia cardiaca (76,80 l/m versus 76,04 l/m). La puntuación media obtenida de la vida sexual mostró una mejora en todos ellos si bien mínima. CONCLUSIONES: Se confirma la utilidad, efectividad y aceptación de la Alfuzosina en pacientes con HPB en tratamientos prolongados, considerándose esta medicación como una primera opción en pacientes con el perfil clínico que se define en esta serie (AU)