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Tamoxifen is a nonsteroidal anti-oestrogen with gynaecological side-effects. Only recently, ovarian cyst formation during tamoxifen treatment has been reported. The present study aimed to evaluate patient-related parameters that determine ovarian cyst formation in women using tamoxifen for breast cancer. A cross-sectional study was performed in 142 breast cancer patients using tamoxifen. Forty-five patients were also examined prior to tamoxifen treatment. Gynaecological assessment, transvaginal ultrasonography (TVU) and serum oestradiol (E[SUB2]) and follicle stimulating hormone (FSH) analysis were performed. Follow-up assessments were performed twice a year. Uni- or bilateral ovarian cysts were detected by TVU in 24 tamoxifen-using patients and in one patient before tamoxifen treatment. Multiple regression analysis showed that cyst development is related (multiple R = 0.73) to high E[SUB2] (P < 0.001), younger age (P < 0.001) and absence of high-dose chemotherapy (P = 0.007). Patients with ovarian cysts had higher serum E[SUB2] levels compared to patients without cysts (1.95 vs 0.05 nmol l[SUP-1] ;P < 0.001). All (patients after high-dose chemotherapy or older than 50 years had E[SUB2] (< 0.10 nmol l[SUP-1] and/or amenorrhoea > 1 year and did not develop ovarian cysts. Patients still having a menstrual cycle during tamoxifen had a high chance (81%) of developing ovarian cysts. Breast cancer patients receiving tamoxifen only develop ovarian cysts if their ovaries are able to respond to FSH stimulation as shown by E[SUB2] production. [ABSTRACT FROM AUTHOR]

Background In ovarian cancer, cyclooxygenase-2 (COX-2) overexpression is prognostic for poor survival. We investigated the efficacy of celecoxib (C), a selective COX-2 inhibitor, added to docetaxel (Taxotere)/carboplatin (DC) in advanced ovarian cancer. Patients and methods In a phase II, randomized study, 400 mg celecoxib b.i.d. was added to first-line DC treatment (DCC). Celecoxib was to be continued after DC termination up to 3 years. Study end points were tolerability, progression-free survival (PFS) and overall survival (OS). Results 151 of 196 eligible patients were diagnosed with stage IIIC/IV disease. Median follow-up for patients alive was 32.3 months. Celecoxib was used during a mean of 8.5 months. Twenty-three of 97 DCC patients stopped celecoxib prematurely, mainly due to skin reactions. Complete biochemical response was achieved in 51/78 DC patients (65%) versus 57/78 DCC patients (75%, not significant). In both study arms, median PFS was 14.3 months and median OS 34 months. COX-2 was expressed in 82% of 120 tumor samples retrospectively recovered. The PFS and OS of patients with intermediate/high COX-2 expression were similar to that in the other patients. Conclusion Celecoxib did not influence PFS and OS, but interpretation of results is hampered by premature celecoxib discontinuation. [ABSTRACT FROM AUTHOR]

What is already known about this subject • There are few data about the safety of paclitaxel in patients with clinically significant liver impairment. A study by Venook and colleagues (J Clin Oncol 1998; 16: 1811–19) studied paclitaxel pharmacokinetics (PK) and pharmacodynamics (PD) in patients with liver impairment. The results were mainly descriptive, as detailed PK–PD data were available for only a subgroup of patients. • Another study by Wilson and colleagues found a correlation between tumour involvement of the liver, aspartate aminotransferase and total bilirubin concentrations and reduced paclitaxel clearance in 48 patients with advanced breast cancer in an early combined Phase I/II study (J Clin Oncol 1994; 12: 1621–9). • Finally, the study by Huizing and colleagues (Ann Oncol 1995; 6: 699–704) described two advanced breast cancer patients with liver impairment who experienced higher paclitaxel AUC concentrations and more severe neuropathywhen exposed to paclitaxel 250 mg m−2 as a 3-h infusion. • Liver impairment has been studied as a covariate within population models of paclitaxel in patients with normal or mildly impaired liver function (Henningsson et al. Eur JCancer 2003; 39: 1105–14; Joerger et al. Clin Cancer Res 2006; 12: 2150–7). Both studies found a negative correlation between total bilirubin concentrations and paclitaxel elimination. What this study adds • A direct relationship between liver impairment, paclitaxel elimination and susceptibility to neutropenia/thrombopenia. • As a result of PK–PD simulations, suggestions could be made for (further) dose adaptations for patients with more severe liver impairment. Aims To assess quantitatively the safety and pharmacology of paclitaxel in patients with moderate to severe hepatic impairment. Methods Solid tumour patients were enrolled into five liver function cohorts as defined by liver transaminase and total bilirubin concentrations. Paclitaxel was administered as a 3-h intravenous infusion at doses ranging from 110 to 175 mg m−2, depending on liver impairment. Covariate and semimechanistic pharmacokinetic–pharmacodynamic (PK–PD) population modelling was used to describe the impact of liver impairment on the pharmacology and safety of paclitaxel. Results Thirty-five patients were included in the study, and PK data were assessed for 59 treatment courses. Most patients had advanced breast cancer ( n = 22). Objective responses to paclitaxel were seen in four patients (11%). Patients in higher categories of liver impairment had a significantly lower paclitaxel elimination capacity ( R2 = −0.38, P = 0.05), and total bilirubin was a significant covariate to predict decreased elimination capacity with population modelling ( P = 0.002). Total bilirubin was also a significant predictor of increased haematological toxicity within the integrated population PK–PD model ( P < 10−4). Data simulations were used to calculate safe initial paclitaxel doses, which were lower than the administered doses for liver impairment cohorts III–V. Conclusions Total bilirubin is a good predictor of paclitaxel elimination capacity and of individual susceptibility to paclitaxel-related myelosuppression in cancer patients with moderate to severe liver impairment. The proposed, adapted paclitaxel doses need validation in prospective trials. [ABSTRACT FROM AUTHOR]

This population-based study aimed to analyse variations in surgical treatment and guideline compliance with respect to the application of radiotherapy and axillary lymph node dissection (ALND), for early breast cancer, before and after the sentinel node biopsy (SNB) introduction. The study included 13 532 consecutive surgically treated stage I-IIIA breast cancer patients diagnosed in 1989-2002. Hospitals showed large variation in breast-conserving surgery (BCS) rates, ranging between 27 and 72% for T1 and 14 and 42% for T2 tumours. In multivariate analysis marked inter-hospital and time-dependent variation in the BCS rate remained after correction for case-mix. The guideline adherence was markedly lower for elderly patients. In 25.2% of the patients aged > or = 75 years either ALND or radiotherapy were omitted. The proportion of patients with no ALND after an SNB increased from 1.8% in 1999 to 37.8% in 2002. However, in 2002 also 12.2% of the patients with a positive SNB did not have an ALND. Guideline compliance for BCS, with respect to radiotherapy and ALND, fell since the SNB introduction, from 96.1% before 2000 to 91.4% in 2002 (P < 0.001). Noncompliance may however reflect patient-tailored medicine, as for elderly patients with small, radically resected primary tumours. The considerable variation in BCS-rates is more consistent with variations in surgeon preferences than patient's choice. [ABSTRACT FROM AUTHOR]

Rationale: In patients suffering from metastatic carcinoid tumors, chronic disturbances of serotonergic metabolism are frequently present. Serotonin is supposed to influence a range of cognitive functions. Objectives: The present study evaluated the cognitive performance of carcinoid patients. Methods: In 14 patients with proven carcinoid syndrome, neuropsychological functioning was studied. Visual search, sustained attention, set shifting ability and spatial working memory were assessed using tests from the CANTAB neuropsychological battery. This was compared with the performance of matched healthy controls. Results: Plasma tryptophan levels were lower than controls. Patients showed an enhanced ability to learn new stimulus-response associations. Sustained visual attention, however, was impaired. Conclusion: Cognitive patterns were different from those found in depressive patients and partly mimicked those found in tryptophan depletion experiments. Further investigation has to point out the role of serotonergic changes in the accomplishment of affective states. [ABSTRACT FROM AUTHOR]

Objective. The purpose of this study was to determine the efficacy, tolerability, and pharmacokinetics of intraperitoneal (ip) paclitaxel combined with intravenous (iv) carboplatin and cyclophosphamide.Patients and methods. Twenty-five newly diagnosed patients with Stage IC–IV epithelial ovarian cancer received ip paclitaxel with iv carboplatin and cyclophosphamide as a first-line treatment. Paclitaxel pharmacokinetics was determined during the first cycle on day 1 or 8.Results. This regimen was well tolerated, as abdominal pain and hematological toxicities were minor, while neurotoxicity grade I/II was reported in only 20% and myalgia in 24% of patients and were fully reversible. After treatment 13 of 18 (72%) of the patients had no evidence of disease. At a median follow-up of 30 months patients with residual disease after surgery (n = 10) had a median progression-free survival (PSF) of 13 months; for the optimally debulked group (n = 15) the actuarial PFS was 60% at 48 months. The elimination of paclitaxel from the peritoneal cavity and plasma followed first-order kinetics and was not influenced by adding carboplatin with cyclophosphamide.Conclusion. This regimen was well tolerated, with minimal hematologic or neurotoxicity, and allowed the application of a triple-drug schedule without compromising dose intensity. To judge its efficacy, comparison with a standard iv paclitaxel-based schedule should be performed in a formal phase III study. [Copyright &y& Elsevier]

Purpose: To evaluate the feasibility and pharmacology of intraperitoneal (IP) topotecan. Patients and methods: Fifteen patients with recurrent ovarian cancer in a phase I trial were treated with escalating IP topotecan doses (5-30 mg/m[SUP2]) for pharmacokinetic analysis. Results: Dose limiting toxicity (DLT) was acute hypotension, chills and fever at the 30 mg/m[SUP2] dose level. Haematological toxicity and abdominal pain were mild for all dose levels studied. Pharmacokinetics: Peak plasma levels of total topotecan were reached at 2.7 ± 1.1 h after IP instillation. The apparent V[SUBss] was 69.9 ± 25.4 L/m[SUP2], plasma clearance 13.4 ± 2.5 L/h/m[SUP2] and plasma T1/2 3.7 ± 1.3 h. The plasma AUC was correlated with the dose (R = 0.95, P < 0.01). The plasma AUC ratio of lactone versus total topotecan (lactone + carboxy-forms) increased with the dose from 16% to 55%, (R = 0.84, P < 0.01). Peritoneal total topotecan was cleared from the peritoneal cavity at 0.4 ± 0.3 L/h.m[SUP2] with a T1/2 = 2.7 ± 1.7 h. The mean peritoneal/plasma AUC ratio for total topotecan was 54 ± 34. Conclusion: A substantial dose of topotecan can be delivered by the IP route, achieving cytotoxic plasma levels of topotecan, with acceptable toxicity. The recommended dose for further phase II trials is 20 mg/m[SUP2] IP, which enables combination with active doses of other cytotoxic drugs, in view of its limited myelotoxicity when given by this route. [ABSTRACT FROM AUTHOR]

Long-term peripheral blood counts and factors influencing long-term trilineage haematological recovery of consecutive patients in a single institution treated with high-dose chemotherapy (HDC) and ABMT or PSCT for solid tumours were examined. Patients with a relapse-free survival of <1 year were included in the analysis (n = 131). Peripheral blood counts were examined 6 months and yearly following transplantation. Median follow-up was 4.1 years (range 1–10+ years). Three years after transplantation 91% of patients had normal white blood counts (WBC), 94% normal haemoglobin (Hb) and 75% normal platelets. Trilineage recovery was complete in 70% (n = 83) at 3 years and 85% (n = 50) at 5 years. Recovery of Hb occurred before WBC and platelet recovery. Approximately 25% of patients displayed an elevated MCV throughout the follow-up period. These long-term results were independent of age, high-dose regimen, number of reinfused stem cells and stem cell source. Double (n = 12) vs single (n = 119) transplantations showed significantly slower trilineage recovery and higher MCV. No secondary graft failure, myelodysplasia or leukaemia was encountered. In conclusion, complete trilineage recovery after HDC followed by ABMT or PSCT occurs slowly. PSCT and ABMT are capable of maintaining long-term haematopoiesis. Slower recovery is seen after double transplantations. The results suggest lasting implications for bone marrow function after autologous transplantation. Bone Marrow Transplantation (2001) 27, 959–966. [ABSTRACT FROM AUTHOR]

Our aim was to study the feasibility of an intensified intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) schedule with the aim to escalate dose intensity (DI). Twenty-three premenopausal breast cancer patients received 6 cycles of adjuvant CMF intravenously on days 1 and 8 every 3 weeks and granulocyte colony-stimulating factor days 9-18. Endpoints were DI and toxicity. Twenty-one out of 23 patients (91%) received the projected total dose and reached ≥ 85% of the projected DI. Compared to 'classical' CMF, all patients reached ≥ 111% DI. Nine patients received the planned schedule without delay. Thirteen patients (57%) were treated for infection and four patients (17%) were hospitalized for febrile neutropenia. Twelve patients received red blood cell transfusions (52%). Radiation therapy (n = 6) had no adverse impact on dose intensity or haematological toxicity. This dose-intensified CMF schedule was accompanied by enhanced haematological toxicity with clinical sequelae, namely fever, intravenous antibiotics and red blood cell transfusions, but allows a high dose intensity in a majority of patients. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented describing a case report of a 55-year-old woman who experienced severe and disabling tendinopathy during treatment with the aromatase inhibitor anastrozole.