PURPOSE: NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS: Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS: A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION: N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

• MeSH
• capecitabinum aplikace a dávkování   MeSH
• chinoliny aplikace a dávkování   MeSH
• doba přežití bez progrese choroby MeSH
• Kaplanův-Meierův odhad MeSH
• kvalita života MeSH
• lapatinib aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• nádory mozku farmakoterapie   sekundární   MeSH
• nádory prsu u mužů farmakoterapie   metabolismus   patologie   MeSH
• nádory prsu farmakoterapie   metabolismus   patologie   terapie   MeSH
• nauzea chemicky indukované   MeSH
• opakovaná terapie MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• průjem chemicky indukované   MeSH
• receptor erbB-2 metabolismus   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

• MeSH
• adjuvantní chemoterapie MeSH
• aminopyridiny farmakologie   škodlivé účinky   terapeutické užití   MeSH
• capecitabinum aplikace a dávkování   farmakologie   škodlivé účinky   MeSH
• dědičný syndrom nádoru prsu a vaječníků * farmakoterapie   chirurgie   MeSH
• indukce remise MeSH
• kognitivní poruchy chemicky indukované   MeSH
• letrozol aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• ovarektomie MeSH
• pleurální výpotek patologie   MeSH
• profylaktická mastektomie MeSH
• prognóza MeSH
• puriny škodlivé účinky   terapeutické užití   MeSH
• thorakocentéza metody   MeSH
• žilní insuficience komplikace   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

• MeSH
• adjuvantní chemoradioterapie metody   MeSH
• bevacizumab aplikace a dávkování   MeSH
• břišní absces farmakoterapie   MeSH
• capecitabinum aplikace a dávkování   MeSH
• infekce chirurgické rány MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory rekta * diagnostické zobrazování   farmakoterapie   chirurgie   MeSH
• prognóza MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• trifluridin aplikace a dávkování   MeSH
• uracil analogy a deriváty   aplikace a dávkování   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

• MeSH
• adjuvantní chemoradioterapie metody   MeSH
• adjuvantní radioterapie metody   MeSH
• capecitabinum aplikace a dávkování   farmakologie   MeSH
• dávka záření MeSH
• kolorektální nádory * chirurgie   klasifikace   radioterapie   MeSH
• lidé MeSH
• neoadjuvantní terapie metody   MeSH
• stupeň nádoru MeSH
• Check Tag
• lidé MeSH

BACKGROUND/AIM: Hepatic epithelioid haemangio-endothelioma (HEHE) is a very rare malignant tumor of vascular origin and uncertain biological behaviour that is difficult to diagnose using preoperative radiology diagnostic techniques. PATIENTS AND METHODS: The authors present here two patients with HEHE of different extent. The first patient had a generalised form of disease, with involvement of the liver, lungs and bones and was treated with a combination of bevacizumab and capecitabine. The second patient had a localised form of disease involving the liver and this was resolved using a combination of liver resection and radiofrequency ablation. In both patients, the radiology work-up before surgery was non-specific and metastases of another malignant process were considered. The definitive histological diagnosis was made by the pathologist on the basis of immunohistochemical analysis that demonstrated the presence of CD31, CD34 and calmodulin-binding transcription activator 1 (CAMTA 1). RESULTS: Both patients remain in an overall good condition 27 and 5 months respectively following treatment for HEHE. CONCLUSION: Preoperative radiological diagnosis of HEHE is difficult and immunohistochemical examination of the tumor tissue sample remains the key diagnostic tool. Radical surgical resection or liver transplantation is the method of choice in patients with localised liver involvement.

• MeSH
• bevacizumab aplikace a dávkování   MeSH
• capecitabinum aplikace a dávkování   MeSH
• dospělí MeSH
• epiteloidní hemangioendoteliom diagnóza   farmakoterapie   patologie   chirurgie   MeSH
• hepatektomie MeSH
• játra patologie   chirurgie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory jater diagnóza   farmakoterapie   patologie   chirurgie   MeSH
• nádory kostí diagnóza   farmakoterapie   patologie   sekundární   MeSH
• nádory plic diagnóza   farmakoterapie   patologie   sekundární   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• PEGPH20,
• MeSH
• adenokarcinom * MeSH
• capecitabinum aplikace a dávkování   terapeutické užití   MeSH
• deoxycytidin aplikace a dávkování   terapeutické užití   MeSH
• extracelulární matrix chemie   MeSH
• hyaluronoglukosaminidasa terapeutické užití   MeSH
• klinické zkoušky jako téma MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• nádory slinivky břišní * terapie   MeSH
• protinádorové antimetabolity MeSH
• randomizované kontrolované studie jako téma MeSH
• Check Tag
• lidé MeSH

BACKGROUND: The randomised phase 3 TURANDOT trial compared two approved bevacizumab-containing regimens for HER2-negative metastatic breast cancer in terms of efficacy, safety, and quality of life. The interim analysis did not confirm non-inferior overall survival (stratified hazard ratio [HR] 1·04; 97·5% repeated CI [RCI] -∞ to 1·69). Here we report final results of our study aiming to show non-inferior overall survival with first-line bevacizumab plus capecitabine versus bevacizumab plus paclitaxel for locally recurrent or metastatic breast cancer. METHODS: In this multinational, open-label, randomised phase 3 TURANDOT trial, patients aged 18 years or older who had an Eastern Cooperative Oncology Group performance status 0-2 and measurable or non-measurable HER2-negative locally recurrent or metastatic breast cancer who had received no previous chemotherapy for locally recurrent or metastatic breast cancer were stratified and randomly assigned (1:1) using permuted blocks of size six to either bevacizumab plus paclitaxel (bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 4 weeks) or bevacizumab plus capecitabine (bevacizumab 15 mg/kg on day 1 plus capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors were oestrogen or progesterone receptor status, country, and menopausal status. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel in the per-protocol population by rejecting the null hypothesis of inferiority (HR ≥1·33) using a stratified Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00600340. FINDINGS: Between Sept 10, 2008, and Aug 30, 2010, 564 patients were randomised, representing the intent-to-treat population. The per-protocol population comprised 531 patients (266 in the bevacizumab plus paclitaxel group and 265 in the bevacizumab plus capecitabine group). At the final overall survival analysis after 183 deaths (69%) in 266 patients receiving bevacizumab plus paclitaxel and 201 (76%) in 265 receiving bevacizumab plus capecitabine in the per-protocol population, median overall survival was 30·2 months (95% CI 25·6-32·6 months) versus 26·1 months (22·3-29·0), respectively. The stratified HR was 1·02 (97·5% RCI -∞ to 1·26; repeated p=0·0070), indicating non-inferiority. The unstratified Cox model (HR 1·13 [97·5% RCI -∞ to 1·39]; repeated p=0·061) did not support the primary analysis. Intent-to-treat analyses were consistent with the per-protocol results. The most common grade 3 or worse adverse events were neutropenia (54 [19%] of 284 patients in the bevacizumab plus paclitaxel group vs 5 [2%] of 277 patients in the bevacizumab plus capecitabine group), hand-foot syndrome (1 [<1%] vs 43 [16%]), peripheral neuropathy (39 [14%] vs 1 [<1%]), leucopenia (20 [7%] vs 1 [<1%]), and hypertension (12 [4%] vs 16 [6%]). Serious adverse events were reported in 65 (23%) of 284 patients receiving bevacizumab plus paclitaxel and 68 (25%) of 277 receiving bevacizumab plus capecitabine. Deaths in two (1%) of 284 patients in the bevacizumab plus paclitaxel group were deemed by the investigator to be treatment-related. No treatment-related deaths occurred in the bevacizumab plus capecitabine group. INTERPRETATION: Bevacizumab plus capecitabine represents a valid first-line treatment option for HER2-negative locally recurrent or metastatic breast cancer, offering good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel. Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel, we suggest that physicians should consider possible predictive risk factors for overall survival, individual's treatment priorities, and the differing safety profiles. FUNDING: Roche.

• MeSH
• bevacizumab aplikace a dávkování   MeSH
• capecitabinum aplikace a dávkování   MeSH
• kvalita života * MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   metabolismus   patologie   MeSH
• metastázy nádorů MeSH
• míra přežití MeSH
• nádory prsu farmakoterapie   metabolismus   patologie   MeSH
• následné studie MeSH
• paclitaxel aplikace a dávkování   MeSH
• prognóza MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• receptor erbB-2 metabolismus   MeSH
• senioři MeSH
• staging nádorů MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

PURPOSE: To describe concentration versus time profiles of capecitabine and its metabolites 5'-DFUR, 5'-DFCR and 5-FU, depending on tablet formulation and on frequent and/or relevant genetic polymorphisms of cytidine deaminase, dihydropyrimidine dehydrogenase, thymidylate synthase and methylenetetrahydrofolate reductase (MTHFR). METHODS: In 46 cancer patients on chronic capecitabine treatment, who voluntarily participated in the study, individual therapeutic doses were replaced on four consecutive mornings by the study medication. The appropriate number of 500 mg test (T) or reference (R) capecitabine tablets was given in randomly allocated sequences TRTR or RTRT (replicate design). Average bioavailability was assessed by ANOVA. RESULTS: Thirty female and 16 male patients suffering from gastrointestinal or breast cancer (mean age 53.4 years; mean dose 1739 mg) were included. The T/R ratios for AUC0-t(last) and C max were 96.7 % (98 % CI 90.7-103.2 %) and 87.2 % (98 % CI 74.9-101.5 %), respectively. Within-subject variability for AUC0-t(last) and C max (coefficient of variation for R) was 16.5 and 30.2 %, respectively. Similar results were seen for all metabolites. No serious adverse events occurred. For the MTHFR C677T (rs1801133) genotype, an increasing number of 677C alleles showed borderline correlation with an increasing elimination half-life of capecitabine (p = 0.043). CONCLUSIONS: The extent of absorption was similar for T and R, but the rate of absorption was slightly lower for T. While such differences are not considered as clinically relevant, formal bioequivalence criteria were missed. A possible, probably indirect role of the MTHFR genotype in pharmacokinetics of capecitabine and/or 5-FU should be investigated in further studies.

• MeSH
• alely MeSH
• aplikace orální MeSH
• capecitabinum aplikace a dávkování   farmakokinetika   MeSH
• cytidindeaminasa genetika   metabolismus   MeSH
• deoxycytidin analogy a deriváty   metabolismus   MeSH
• dihydrouracildehydrogenasa (NADP) genetika   metabolismus   MeSH
• dospělí MeSH
• floxuridin metabolismus   MeSH
• fluoruracil metabolismus   MeSH
• genotyp MeSH
• játra enzymologie   MeSH
• jednonukleotidový polymorfismus MeSH
• karboxylesterasa metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolická aktivace genetika   MeSH
• methylentetrahydrofolátreduktasa (NADPH2) genetika   metabolismus   MeSH
• nádorové proteiny metabolismus   MeSH
• plocha pod křivkou MeSH
• prekurzory léčiv aplikace a dávkování   farmakokinetika   MeSH
• protinádorové antimetabolity aplikace a dávkování   farmakokinetika   MeSH
• senioři MeSH
• tablety MeSH
• terapeutická ekvivalence MeSH
• thymidinfosforylasa metabolismus   MeSH
• thymidylátsynthasa genetika   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

• MeSH
• capecitabinum aplikace a dávkování   MeSH
• chinazoliny aplikace a dávkování   MeSH
• lidé MeSH
• maytansin aplikace a dávkování   MeSH
• míra přežití MeSH
• nádory prsu * farmakoterapie   patologie   MeSH
• receptor erbB-2 antagonisté a inhibitory   MeSH
• trastuzumab aplikace a dávkování   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• klinické zkoušky MeSH

• MeSH
• capecitabinum aplikace a dávkování   farmakologie   MeSH
• chinazoliny aplikace a dávkování   MeSH
• lidé MeSH
• míra přežití MeSH
• nádory prsu * farmakoterapie   patologie   MeSH
• přežití bez známek nemoci MeSH
• protokoly protinádorové kombinované chemoterapie MeSH
• receptor erbB-2 * antagonisté a inhibitory   MeSH
• trastuzumab aplikace a dávkování   farmakologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• klinické zkoušky MeSH