A phase I dose-escalation study of LRP5/6 antagonist BI 905677 in patients with advanced solid tumors.

Background: Aberrant Wnt pathway signaling has been implicated in the development of many cancers. Targeting of low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptors inhibits Wnt signaling and may be a novel therapy. BI 905677 is an LRP5/6 antagonist that has demonstrated preclinical antitumor activity.

International evaluation of the psychometrics of health-related quality of life questionnaires for use among long-term survivors of testicular and prostate cancer.

Background: Understanding of the physical, functional and psychosocial health problems and needs of cancer survivors requires cross-national and cross-cultural standardization of health-related quality of life (HRQoL) questionnaires that capture the full range of issues relevant to cancer survivors. To our knowledge, only one study has investigated in a comprehensive way whether a questionnaire used to evaluate HRQoL in cancer patients under active treatment is also reliable and valid when used among (long-term) cancer survivors. In this study we evaluated, in an international context, the psychometrics of HRQoL questionnaires for use among long-term, disease-free, survivors of testicular and prostate cancer.

Taxane mechanisms of action: potential implications for treatment sequencing in metastatic castration-resistant prostate cancer.

Context: In the past few years, there has been a rapid increase in the number of therapies available to treat metastatic castration-resistant prostate cancer (mCRPC). Currently, approved treatments consist of the taxane class of cytotoxic drugs and androgen-targeted therapies. The challenge for clinicians is to decide the best sequence in which to give these therapies to provide the greatest benefit to their patients.

Chemotherapy in hormone-refractory prostate cancer.

The results of the TAX 327 and SWOG 99-16 trials for the first time showed an improvement in overall survival (OS) with docetaxel-based chemotherapy in patients with metastatic hormone-refractory prostate cancer. As such, 3-weekly (q3w) docetaxel plus low-dose prednisone is widely considered to be the treatment of choice for these patients. An updated survival analysis from TAX 327 confirms that benefits observed with docetaxel are sustained at 3 years.

Is there a pharmacological basis for differences in 5-HT3-receptor antagonist efficacy in refractory patients?

5-HT3-receptor antagonists are the current antiemetic 'gold standard' for chemotherapy- and radiotherapy-induced nausea and vomiting. Interestingly, studies have shown that patients experiencing poor control of acute chemotherapy-induced nausea and vomiting with one antiemetic therapy may respond well to another agent, including a drug of the same class. This review examines pharmacological differences between the 5-HT3-receptor antagonists in order to determine potential reasons for their differing efficacy, particularly in relation to refractory emesis.

Shifting paradigms in prostate cancer; docetaxel plus low-dose prednisone - finally an effective chemotherapy.

Until now, the use of systemic chemotherapy for advanced androgen-independent prostate cancer has had very little to offer to patients. However, in 2004, two large randomised trials investigating docetaxel vs. mitoxantrone have both demonstrated survival improvements, and, in one of the trails, improvements in important secondary clinical outcome measures such as pain relief and quality of life measurements.

The oral NK(1) antagonist, aprepitant, given with standard antiemetics provides protection against nausea and vomiting over multiple cycles of cisplatin-based chemotherapy: a combined analysis of two randomised, placebo-controlled phase III clinical trials.

In early clinical trials, the NK(1) receptor antagonist, aprepitant (EMEND(R)) was shown to improve the protection provided by the best available therapy (hereafter referred to as 'standard therapy': a 5-HT(3) receptor antagonist and dexamethasone) against chemotherapy-induced nausea and vomiting over multiple cycles of cisplatin-based chemotherapy. To further study the sustainment of antiemetic efficacy of aprepitant plus standard therapy over more than one cycle of chemotherapy, we examined combined data from the multiple cycles extensions of two phase III clinical trials of oral aprepitant plus standard therapy for the prevention of chemotherapy-induced nausea and vomiting. Data were pooled from two multicentre, randomised, double-blind, placebo-controlled studies with identical design and treatment regimens.

Weekly paclitaxel as first-line chemotherapy for elderly patients with metastatic breast cancer. A multicentre phase II trial.

Paclitaxel is a cytotoxic agent with proven antitumour activity in metastatic breast cancer. Weekly administration of paclitaxel has demonstrated sustained efficacy together with a more favourable toxicity profile (e.g.

Addition of the oral NK1 antagonist aprepitant to standard antiemetics provides protection against nausea and vomiting during multiple cycles of cisplatin-based chemotherapy.

Purpose: This analysis evaluated whether the antiemetic efficacy of the NK1 receptor antagonist aprepitant (EMEND trade mark, Merck, Whitehouse Station, NJ) plus standard antiemetics could be sustained for up to six cycles of cisplatin-based chemotherapy.

Patients And Methods: Patients receiving cisplatin > or = 70 mg/m2 were blindly assigned to receive one of the following three regimens: (1) aprepitant 375 mg 1 hour before cisplatin on day 1 and aprepitant 250 mg on days 2 to 5 (n = 35); (2) aprepitant 125 mg before cisplatin and aprepitant 80 mg on days 2 to 5 (n = 81); or (3) placebo before cisplatin on days 2 to 5 (n = 86). All groups received ondansetron 32 mg and dexamethasone 20 mg before cisplatin, and dexamethasone 8 mg on days 2 to 5.

Current position of 5HT3 antagonists and the additional value of NK1 antagonists; a new class of antiemetics.

The advent of the 5HT(3) receptor antagonists (5HT(3) antagonists) in the 1990 s and the combination with dexamethasone has resulted in acute emesis protection in 70% of patients receiving highly emetogenic chemotherapy. Despite complete protection in the acute phase, however, 40% of patients as yet have symptoms in the delayed phase. 5HT(3) antagonists and dexamethasone are only modestly effective in this delayed phase.

Overview of bladder cancer trials in the European Organization for Research and Treatment.

In the 1990s, the European Organization for Research and Treatment of Cancer Genito-Urinary (EORTC GU) Group focused on dose-intensity concepts of the methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) regimen for patents with bladder cancer. In a randomized trial in patients with advanced urothelial cell cancer, standard MVAC was compared with 2-weekly intensified MVAC plus granulocyte-colony stimulating factor (G-CSF) support. Although the dose-intensified therapy resulted in a higher overall and complete response rates, it did not result in a better median survival.

Overview of gemcitabine triplets in metastatic bladder cancer.

For more than a decade the MVAC regimen has been gold standard chemotherapy in bladder cancer, albeit that the toxicity associated with this therapy hampered its use in many of the typical elderly patients with metastatic disease. New active agents have been identified, combinations of these new agents with platinum compounds (doublets) followed, and results have become available of a phase III randomized trial of the gemcitabine and cisplatin doublet versus MVAC, that has revealed an efficacy-toxicity profile in favor of the gemcitabine-cisplatin regimen. During the conduct of this study, investigators in Spain and in the United States have incorporated both gemcitabine and paclitaxel in either cisplatin- or carboplatin based triplet regimens that, albeit thus far only in phase II studies, have indicated notable activity and favorable median survival figures, particularly in patients with visceral disease.

Phase I and pharmacokinetic studies of PNU-159548, a novel alkycycline, administered intravenously to patients with advanced solid tumours.

PNU-159548 (4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin) is the lead compound of a novel class of cytotoxic agents (alkycyclines) with a unique mechanism of action combining DNA intercalation with alkylation of guanines in the DNA major groove. The objectives of two phase I studies were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to study the pharmacokinetics (PKs) of PNU-159548 and its active metabolite PNU-169884 when administered intravenously (i.v.

Dose-dense cisplatin/paclitaxel. a well-tolerated and highly effective chemotherapeutic regimen in patients with advanced ovarian cancer.

A randomised phase I/II trial with weekly cisplatin 70 mg/m(2) (days 1, 8, 15, 29, 36, 43) in combination with escalating doses of paclitaxel either 4-weekly or weekly was conducted in 49 patients with ovarian cancer; patients were chemotherapy-nai;ve or had a first relapse after platinum-based chemotherapy. Paclitaxel could be safely escalated to 225 mg/m(2) 4-weekly or 100 mg/m(2) weekly, with fatigue as the major adverse event. Myelosuppression, renal toxicity and neurotoxicity were mild to moderate.

Pharmacology of topoisomerase I inhibitors irinotecan (CPT-11) and topotecan.

Topotecan and irinotecan (CPT-11) are both anticancer agents active in the inhibition of topoisomerase I, an enzyme involved in DNA replication and RNA transcription. During the last decades, an immense amount of research into this class of anticancer agents has been conducted, the positive results of which led to the clinical use of topotecan and CPT-11 in ovarian cancer and colorectal cancer, respectively. Here, we review the currently most important pharmacologic aspects of these drugs, including their mechanisms of action, metabolism, activity- and toxicity-profiles and mechanisms of resistance, to provide a global insight into their pharmacology.

Effects of impaired renal function on the pharmacokinetics and toxicity of i.v. ZD9331, a novel non-polyglutamated thymidylate synthase inhibitor, in adult patients with solid tumors.

ZD9331 is a potent thymidylate synthase inhibitor. Renal and hepatic clearances were found to be important routes of elimination. The objectives of this pharmacologic trial were to investigate the effect of renal impairment on the pharmacokinetics of ZD9331, to study the toxicity profile and to document any antitumor effects of ZD9331 when administered i.

Problem solving by telephone in palliative care: use of a predetermined assessment tool within a program of home care technology.

In the Rotterdam Cancer Institute, nurses from the palliative care unit take care of accessibility outside office hours for patients transferred home with technical equipment for symptoms control. The nurses use a predetermined assessment tool (PAT) for handling telephone calls. A retrospective evaluation on the registration forms used over the years 1997-1999 was performed to evaluate the telephone service.

Modulation of irinotecan metabolism by ketoconazole.

Purpose: Irinotecan (CPT-11) is a prodrug of SN-38 and has been registered for the treatment of advanced colorectal cancer. It is converted by the cytochrome P450 3A4 isozyme (CYP3A4) into several inactive metabolites, including 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC). To investigate the role of CYP3A4 in irinotecan pharmacology, we evaluated the consequences of simultaneous treatment of irinotecan with a potent enzyme inhibitor, ketoconazole, in a group of cancer patients.

Determination of the docetaxel vehicle, polysorbate 80, in patient samples by liquid chromatography-tandem mass spectrometry.

A new simple method was developed for the quantitative determination of the docetaxel (Taxotere) vehicle, polysorbate 80 (Tween 80), in human plasma. Calibration curves were constructed in the range of 1-100 microg/ml, using paclitaxel (0.01 mM) as internal standard, and were analyzed using a power fit with equal weighting.

Differential effects of fibroblast growth factors on expression of genes of the plasminogen activator and insulin-like growth factor systems by human breast fibroblasts.

In breast stroma urokinase plasminogen activator (uPA) is predominantly expressed by fibroblasts located in the near vicinity of tumor cells, and fibroblast-derived insulin-like growth factor-1 (IGF-1) may be involved in inhibiting the expression of uPA in these fibroblasts. To investigate a possible role for fibroblast growth factors (FGFs), we evaluated the expression of components of the PA system and the IGF system in normal and tumor-tissue-derived human breast fibroblasts exposed to various FGFs in vitro. mRNA analysis revealed that FGF-1, FGF-2 and FGF-4 induced the mRNA expression levels of uPA, tPA, uPAR, PAI-1 and PAI-2, and reduced those of IGF-1, IGF-1R, IGF-2R and IGFBP-4, without significantly affecting the levels of IGFBP-3, IGFBP-5 and IGFBP-6 mRNA.

Disposition of docetaxel in the presence of P-glycoprotein inhibition by intravenous administration of R101933.

Recently, a study of docetaxel in combination with the new orally administered P-glycoprotein (P-gp) inhibitor R101933 showed that this combination was feasible. However, due to the low oral bioavailability of R101933 and high interpatient variability, no further attempts to increase the level of P-gp inhibition were made. Here, we assessed the feasibility of combining docetaxel with intravenously (i.

Influence of Cremophor El on the bioavailability of intraperitoneal paclitaxel.

It has been hypothesized that the paclitaxel vehicle Cremophor EL (CrEL) is responsible for nonlinear drug disposition by micellar entrapment. To gain further insight into the role of CrEL in taxane pharmacology, we studied the pharmacokinetics of paclitaxel in the presence and absence of CrEL after i.p.