Although this retrospective multicenter study had several limitations, the results suggest that undergoing lapatinib plus capecitabine therapy after the diagnosis of brain metastasis may further improve survival compared to undergoing only trastuzumab-based therapy.

Drug interactions have been reported between 5-fluorouracil and cytochrome P450 2C9 (CYP2C9) substrates, S-warfarin and phenytoin. This study was performed to determine the influence of 5-fluorouracil on cytochrome P450 2C9 (CYP2C9) activity in colorectal cancer patients (nΩ17) receiving 5-fluorouracil. Losartan was used as a marker to assess CYP2C9 activity. Losartan and its CYP2C9 dependent metabolite, E-3174, were determined in urine. The ratios of urinary losartan/E-3174 before and after the 5-fluorouracil treatment were compared for each patient. Genotyping was performed to detect the CYP2C9*2 and CYP2C9*3. At the end of the first cycle of 5-fluorouracil, losartan/E-3174 ratio was increased by 28.0% compared to the pre-treatment values (PΩ0.15). In five patients recruited for phenotyping after three 5-fluorouracil cycles, the metabolic ratio was increased significantly by 5.3 times (PΩ0.03). The results suggest that in most patients 5-fluorouracil inhibited CYP2C9 activity. This inhibition was more pronounced when the total administered dose increased. This finding may help explain the mechanism of interaction between 5-fluorouracil and CYP2C9 substrates.5-Fluorouracil is a fluorinated pyrimidine analogue used in the treatment of a variety of solid tumours including gastrointestinal, breast, head and neck cancer (Rich et al. 2004). The cytotoxicity of 5-fluorouracil is mainly due to the formation of fluoro-deoxyuridine-monophosphate metabolite, which inhibits thymidylate synthetase and incorporates into ribonucleic acid (Rich et al. 2004). 5-Fluorouracil has a rather short elimination half-life in plasma and is mostly eliminated by dihydropyrimidine dehydrogenase (Gonzalez & Fernandez-Salguero 1995). Due to many complications during chemotherapy, many other drugs are co-administrated during treatment with 5-fluorouracil. Increasing number of drug-drug interactions between warfarin and 5-fluorouracil-based chemotherapies have been reported. These interactions result in bleeding complications due to the prolongation of prothrombin time (Brown 1997(Brown & 1999Kolesar et al. 1999). 5-Fluorouracil has also been reported to interact with phenytoin, resulting in elevated phenytoin plasma concentrations and neurotoxic side effects (Gilbar & Brodribb 2001;Konishi et al. 2002;Rosemergy & Findlay 2002;Brickell et al. 2003). Both S-warfarin and phenytoin are established CYP2C9 substrates (Lee et al. 2002). The mechanism of these interactions is unclear. Available evidence from case reports and in vitro studies in liver microAuthor for correspondence: Umit Yasar, Hacettepe University, Faculty of Medicine, Department of Pharmacology, 06100 Sihhiye, Ankara, Turkey (fax π90 312 3105312, e-mail uyasar/hacettepe.edu. tr).somes suggests that the interaction is not due to a competitive inhibition of CYP2C9 (Brown 1999;Park & Kim 2003). The effect of 5-fluorouracil on in vivo CYP2C9 activity in man has not been studied. Prospective clinical studies are needed to clarify the mechanism of the interaction between the su...

Background: The aim of this study is to determine the relationship between the survival outcomes and biological subtype in breast cancer patients with brain metastases. Methods: We retrospectively evaluated clinical data from 422 breast cancer patients with brain metastases between 2001 and 2011 from referral centers in Turkey. The study population was divided into four biological subtypes according to their hormone receptor status and HER2 expression. Results: Systemic treatment prolonged median overall survival (OS) after brain metastases in the entire group (14 vs. 3.2 months, p < 0.001). It also prolonged median OS after brain metastases in the triple negative (7.5 vs. 1.6 months, p = 0.010) and luminal A (14.3 vs. 7.1 months, p = 0.003) subgroups. The median OS for untreated patients, chemotherapy and/or hormonal therapy receiving patients, and chemotherapy and/or hormonal therapy plus targeted therapy receivers was 2, 5.8, and 17.7 months, respectively (p < 0.001), in the HER2-overexpressing subgroup. In the luminal B subgroup, it was 3.7, 5.3, and 15.4 months, respectively (p = 0.003). Conclusions: The use of systemic therapy improves OS after brain metastases in all biological subgroups. Targeted therapies also improve OS after brain metastases in HER2-positive patients. The combined use of targeted therapies and lapatinib are superior to single use and trastuzumab, respectively, in these patients.

In this study, tropisetron did not show any ventricular and atrial arrhythmogenic effect because of repolarization abnormalities. Only it may cause a slight decrease in heart rate.

Lapatinib is the first dual tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2/neu) and epidermal growth factor receptor (EGFR). The present study evaluated the efficacy and tolerability of the combination of lapatinib and capecitabine in patients with metastatic breast cancer (MBC) who progressed after therapy with trastuzumab, a taxane and/or anthracycline. A total of 203 patients with a median age of 48 years (range: 25-82 years) were evaluated retrospectively in 11 centres between September 2007 and May 2011. All the patients had HER2-positive MBC progressing after trastuzumab and chemotherapy including an anthracycline and/or taxane. All patients were treated with the combination of lapatinib (1250 mg/day, continuously) and capecitabine (2000 mg/m(2) on days 1 through 14 of a 21-day cycle). Data on demographics, clinical outcome, and toxicity were collected for descriptive analyses. The median follow-up was 10·7 months (range: 1-40 months). An overall response rate (ORR) of 33·4% was achieved including 7 complete responses (CR, 3·4%), 61 partial responses (PR, 30·0%), and 44 stable disease (37·9%). Clinical benefit rate of 71·3% was achieved. Median progression-free survival (PFS) was 7 months (95% CI: 6-10 months), with a median overall survival (OS) of 15 months (95% CI: 12-18 months). The most common side effects were hand-foot syndrome (46·8%), nausea (42·3%), fatigue (42·2%), anorexia (38·5%), diarrhea (31·5%), and rash (29·6%). Grade 3-4 toxicities were identified as hand foot syndrome (7·9%), diarrhea (6·9%), fatigue (5·9%), and rash (5·4%). There were no symptomatic cardiac events. Lapatinib and capecitabine combination therapy is effective and well tolerated in patients with MBC who had progressive disease after trastuzumab, taxane, and/or anthracycline therapy, as evidenced by this retrospective evaluation. Toxicity was mild to moderate with low grade 3-4 toxicity.

Our objective was to determine whether oral etoposide and cisplatin combination (EoP) is superior to paclitaxel in the treatment of advanced breast cancer (ABC) patients pretreated with anthracyclines. From December 1997 to August 2003, 201 patients were randomised, 100 to EoP and 101 to paclitaxel arms. Four patients in each arm were ineligible. The doses of etoposide and cisplatin were 50 mg p.o. twice a day for 7 days and 70 mg m À2 intravenously (i.v.) on day 1, respectively, and it was 175 mg m À2 on day 1 for paclitaxel. Both treatments were repeated every 3 weeks. A median of four cycles of study treatment was given in both arms. The response rate obtained in the EoP arm was significantly higher (36.3 vs 22.2%; P ¼ 0.038). Median response duration was longer for the EoP arm (7 vs 4 months) (P ¼ 0.132). Also, time to progression was significantly in favour of the EoP arm (5.5 vs 3.9 months; P ¼ 0.003). Median overall survival was again significantly longer in the EoP arm (14 vs 9.5 months; P ¼ 0.039). Toxicity profile of both groups was similar. Two patients in each arm were lost due to febrile neutropenia. The observed activity and acceptable toxicity of EoP endorses the employment of this combination in the treatment of ABC following anthracyclines.

Keywords HER2 · Metastatic breast cancer · Lapatinib · Brain metastases SummaryBackground: We investigated the clinical outcome of patients with brain metastases (BMs) from human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) treated with lapatinib and capecitabine (LC). Patients and Methods: A total of 203 patients with HER2+ MBC, who had progressed after trastuzumab-containing chemotherapy, were retrospectively evaluated in 11 centers between September 2009 and May 2011. 85 patients who had developed BMs before the initiation of treatment with LC were included. All patients had received prior cranial radiotherapy. All patients were treated with the combination of lapatinib (1,250 mg/day continu ously) and capecitabine (2,000 mg/m 2 on days 1-14 of a 21-day cycle). Results: The median follow-up was 10.5 months (range 1-38 months). An overall response rate of 27.1% was achieved, including complete response in 2 (2.4%) and partial response in 21 (24.7%) patients. Median progression-free survival was 7 months (95% confidence interval (CI) 5-9), with a median overall survival of 13 months (95% Cl 9-17). The most common side effects were hand-foot syndrome (58.8%), nausea (55.3%), fatigue (48.9%), anorexia (45.9%), rash (36.5%), and diarrhea (35.4%). Grade 3-4 toxicities were hand-foot syndrome (9.4%), diarrhea (8.3%), fatigue (5.9%), and rash (4.7%). There were no symptomatic cardiac events. Conclusion: LC combination therapy was effective and well-tolerated in patients with HER2+ MBC with BMs, who had progressive disease after trastuzumab-containing therapy.

Background: Since multiple myeloma responds poorly to conventional chemotherapy or radiotherapy, new therapeutic approaches are needed. This study investigated the effects of dexamethasone, all-trans retinoic acid (ATRA), the active metabolite of vitamin D₃ [1,25(OH)₂D₃] and interferon-α on FO mouse myeloma cells (non-immunoglobulin-secreting myeloma cell line) in single drug or drug combination groups in vitro. Methods: Apoptosis ratio and change in cell counts in 4 single drug groups (dexamethasone, ATRA, vitamin D₃ and interferon-α) and 6 combination drug groups (dexamethasone + vitamin D_3, dexamethasone + ATRA, dexamethasone + interferon-α, vitamin D₃ + ATRA, vitamin D₃ + interferon-α, interferon-α + ATRA) were compared with the control group. Results: When treatment groups were compared with the control group, there was a significant increase in apoptosis in all, but this was most prominent in the group treated with dexamethasone alone. The apoptosis ratios were 0.10 and 6.82% in the control and dexamethasone-only groups, respectively. We also found that there was a significant decrease in cell count, particularly in the dexamethasone-only, ATRA-only, and ATRA-vitamin D₃ combination groups. Conclusion: ATRA, interferon-α, vitaminD₃ and particularly dexamethasone have significant effects on FO mouse myeloma cells resulting in a decreased cell count and an increased apoptosis ratio. This study should be repeated with human myeloma cell lines for further information.