A systematic review of the effectiveness of docetaxel and mitoxantrone for the treatment of metastatic hormone-refractory prostate cancer

A systematic review was performed to evaluate the clinical effectiveness of docetaxel in combination with prednisolone (docetaxel is licensed in the UK for use in combination with prednisone or prednisolone for the treatment of patients with metastatic hormone-refractory prostate cancer. Prednisone is not used in the UK, but it is reasonable to use docetaxel plus prednisone data in this review of docetaxel plus prednisolone) for the treatment of metastatic hormone-refractory prostate cancer. A scoping search identified a trial of docetaxel plus prednisone vs mitoxantrone plus prednisone, but did not identify any trials comparing docetaxel plus prednisolone/prednisone with any other treatments. Therefore, we considered additional indirect evidence that would enable a comparison of docetaxel plus prednisolone/prednisone with other chemotherapy regimens and active supportive care. Systematic searching (upto April 2005) identified seven randomised controlled trials. One large well-conducted trial assessed docetaxel plus prednisone vs mitoxantrone plus prednisone; this showed statistically significant improvements with 3-weekly docetaxel in terms of overall survival, quality of life, pain response and PSA decline. Two other chemotherapy regimens that included docetaxel with estramustine also showed improved outcomes in comparison with mitoxantrone plus prednisone. Three trials that compared mitoxantrone plus corticosteroids with corticosteroids alone were identified and their results for overall survival combined, which showed very little difference between the two groups. The addition of clodronate to mitoxantrone plus prednisone showed no significant differences in comparison with mitoxantrone plus prednisone alone. The evidence suggests that chemotherapy regimens containing 3-weekly docetaxel are superior to mitoxantrone or corticosteroids alone

Hybrid micro-/nanogels for optical sensing and intracellular imaging

Hybrid micro-/nanogels are playing an increasing important part in a diverse range of applications, due to their tunable dimensions, large surface area, stable interior network structure, and a very short response time. We review recent advances and challenges in the developments of hybrid micro-/nanogels toward applications for optical sensing of pH, temperature, glucose, ions, and other species as well as for intracellular imaging. Due to their unique advantages, hybrid micro-/nanogels as optical probes are attracting substantial interests for continuous monitoring of chemical parameters in complex samples such as blood and bioreactor fluids, in chemical research and industry, and in food quality control. In particular, their intracellular probing ability enables the monitoring of the biochemistry and biophysics of live cells over time and space, thus contributing to the explanation of intricate biological processes and the development of novel diagnoses. Unlike most other probes, hybrid micro-/nanogels could also combine other multiple functions into a single probe. The rational design of hybrid micro-/nanogels will not only improve the probing applications as desirable, but also implement their applications in new arenas. With ongoing rapid advances in bionanotechnology, the well-designed hybrid micro-/nanogel probes will be able to provide simultaneous sensing, imaging diagnosis, and therapy toward clinical applications

A phase II trial of docetaxel and erlotinib as first-line therapy for elderly patients with androgen-independent prostate cancer

Background: Docetaxel is the standard first-line agent for the treatment of androgen-independent prostate cancer (AIPC). The combination of docetaxel with molecularly targeted therapies may offer the potential to increase the efficacy and decrease the toxicity of cytotoxic chemotherapy for prostate cancer. Previous studies demonstrate activation of the human epidermal growth factor receptor (EGFR) in prostate cancer. Erlotinib is a specific inhibitor of the tyrosine-kinase activity of EGFR. The goal of this study is to determine the anti-cancer activity docetaxel combined with erlotinib for the treatment of elderly subjects with AIPC. Methods: This is a multi-institutional Phase II study in patients with histologically confirmed adenocarcinoma of the prostate and age [greater than or equal to] 65 years. Patients were requred to have progressive disease despite androgen-deprivation therapy as determined by: (1) measurable lesions on cross-sectional imaging; (2) metastatic disease by radionucleotide bone imaging; or (3) elevated prostate specific antigen (PSA). Treatment cycles consisted of docetaxel 60 mg/m2 IV on day 1 and erlotinib 150 mg PO days 1-21. Patients with responding or stable disease after 9 cycles were eligible to continue on erlotinib alone as maintenance therapy. Results: Characteristics of 22 patients enrolled included: median age 73.5 years (range, 65-80); median Karnofsky Performance Status 90 (range 70-100); median hemoglobin 12.1 g/dl (range, 10.0-14.3); median PSA 218.3 ng/ml (range, 9-5754). A median of 6 treatment cycles were delivered per patient (range 1-17). No objective responses were observed in 8 patients with measurable lesions (0%, 95% CI 0-31%). Bone scan improvement and PSA decline was seen in 1 patient (5%, 95% CI 0.1-25%). Five of 22 patients experienced [greater than or equal to] 50% decline in PSA (23%, 95% CI 8-45%). Hematologic toxicity included grade 3 neutropenia in 9 patients and neutropenic fever in 2 patients. Common non-hematologic toxicities ([greater than or equal to] grade 3) included fatigue, anorexia, and diarrhea. Conclusion: Docetaxel/erlotinib can be delivered safely in elderly patients with AIPC. Anti-cancer disease activity appears generally comparable to docetaxel when used as monotherapy. Hematologic and nonhematologic toxicity may be increased over docetaxel monotherapy. Prospective randomized studies would be required to determine if the toxicity of docetaxel and erlotinib justifies its use in this setting.This study was supported by NIH Prostate SPORE P50 CA92131 to DBA. Phase One Foundation to MEG and DBA

A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol

From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License.London NHS Trust sponsored this stud

A lactate shuttle system between tumour and stromal cells is associated with poor prognosis in prostate cancer

Background In a malignant tumour, cancer cells are embedded in stromal cells, namely cancer-associated fibroblasts (CAFs). These CAFs are now accepted as important players in cancer dynamics, being involved in tumour growth and progression. Although there are various reports on the interaction between tumour and stromal cells, the clinico-pathological significance of this cross-talk is still largely unknown. In this study, we aimed to characterise the expression of key metabolic proteins involved in glucose transport, pyruvate/lactate shuttle system, glycolytic metabolism and fatty acid oxidation in CAFs and tumour cells in different stages of malignant transformation. We further aimed to contextualise the clinico-pathological significance of these protein expression profiles with reference to known prognostic indicators, including biochemical recurrence in pT stage. Methods Prostate tissues were obtained from 480 patients with a median age of 64 years following radical prostatectomy with no previous hormonal therapy. Tissues were analysed for the expression of several key metabolism-related proteins in glands and surrounding fibroblasts by immunohistochemistry. Reliable markers of prognosis such as pT stage and biochemical recurrence were assessed for each case. Results We observed that prostate cancer cells did not rely mainly on glycolytic metabolism, while there was a high expression of MCT4 and CAIX - in CAFs. This corroborates the hypothesis of the "Reverse Warburg effect" in prostate cancer, in which fibroblasts are under oxidative stress and express CAIX, an established hypoxia marker. We found that alterations in the expression of metabolism-related proteins were already evident in the early stages of malignant transformation, suggesting the continuing alteration of CAFs from an early stage. Additionally, and for the first time, we show that cases showing high MCT4 expression in CAFs with concomitant strong MCT1 expression in prostate cancer (PCa) cells are associated with poor clinical outcome, namely pT3 stage of the tumour. Conclusions In summary, this work demonstrates for the first time the clinico-pathological significance of the lactate shuttle in prostate cancer. It also suggests that other alterations in CAFs may be useful prognostic factors, and further supports the use of MCT1/MCT4 as targets for PCa therapy.NPG received a fellowship from the Portuguese Foundation for Science and Technology (FCT), refs. SFRH/BD/61027/2009. This work was supported by the FCT grant ref. PTDC/SAUMET/113415/2009, under the scope of "Programa Operacional Tematico Factores de Competitividade" (COMPETE) of "Quadro Comunitario de Apoio III" and co-financed by Fundo Comunitario Europeu FEDER. JA was supported by a Boehringer Ingelheim Fonds fellowship

Phase II study of sequential chemotherapy with docetaxel–estramustine followed by mitoxantrone–prednisone in patients with advanced hormone-refractory prostate cancer

Sequential chemotherapy may improve treatment efficacy avoiding the additive toxicity associated with concomitant polichemotherapy in hormone-refractory prostate cancer (HRPC). Forty patients received docetaxel 30 mg m−2 intravenous (i.v.), weekly, plus estramustine 280 mg twice daily for 12 weeks. After 2 weeks rest, patients with a decline or stable PSA were treated with mitoxantrone 12 mg m−2 i.v. every 3 weeks plus prednisone 5 mg twice daily for 12 cycles. Forty patients were assessable for toxicity after docetaxel/estramustine. Main toxicities were grade 3–4 AST/ALT or bilirubin increase in seven patients (17.5%) and deep venous thrombosis (DVT) in four patients (10%). Twenty-seven patients received mitoxantrone/prednisone. Main toxicities included DVT in one patient (3.7%) and congestive heart failure in two patients (7%). Thirty-nine patients were assessable for PSA response. Twenty-nine patients (72.5%; 95% CI 63–82%) obtained a ⩾50% PSA decline with 15 patients (37.5%; 95% CI 20–50%) that demonstrated a ⩾90% decrease. Median progression-free and overall survival were respectively 7.0 (95% CI 5.8–8.2 months) and 19.2 months (95% CI 13.9–24.3 months). In conclusion, although this regimen demonstrated a favourable toxicity profile, sequential administration of mitoxantrone is not able to improve docetaxel activity in patients with HRPC

Development and characterization of a microfluidic model of the tumour microenvironment

The physical microenvironment of tumours is characterized by heterotypic cell interactions and physiological gradients of nutrients, waste products and oxygen. This tumour microenvironment has a major impact on the biology of cancer cells and their response to chemotherapeutic agents. Despite this, most in vitro cancer research still relies primarily on cells grown in 2D and in isolation in nutrient- and oxygen-rich conditions. Here, a microfluidic device is presented that is easy to use and enables modelling and study of the tumour microenvironment in real-time. The versatility of this microfluidic platform allows for different aspects of the microenvironment to be monitored and dissected. This is exemplified here by real-time profiling of oxygen and glucose concentrations inside the device as well as effects on cell proliferation and growth, ROS generation and apoptosis. Heterotypic cell interactions were also studied. The device provides a live ‘window’ into the microenvironment and could be used to study cancer cells for which it is difficult to generate tumour spheroids. Another major application of the device is the study of effects of the microenvironment on cellular drug responses. Some data is presented for this indicating the device’s potential to enable more physiological in vitro drug screening

On the probability of cost-effectiveness using data from randomized clinical trials

BACKGROUND: Acceptability curves have been proposed for quantifying the probability that a treatment under investigation in a clinical trial is cost-effective. Various definitions and estimation methods have been proposed. Loosely speaking, all the definitions, Bayesian or otherwise, relate to the probability that the treatment under consideration is cost-effective as a function of the value placed on a unit of effectiveness. These definitions are, in fact, expressions of the certainty with which the current evidence would lead us to believe that the treatment under consideration is cost-effective, and are dependent on the amount of evidence (i.e. sample size). METHODS: An alternative for quantifying the probability that the treatment under consideration is cost-effective, which is independent of sample size, is proposed. RESULTS: Non-parametric methods are given for point and interval estimation. In addition, these methods provide a non-parametric estimator and confidence interval for the incremental cost-effectiveness ratio. An example is provided. CONCLUSIONS: The proposed parameter for quantifying the probability that a new therapy is cost-effective is superior to the acceptability curve because it is not sample size dependent and because it can be interpreted as the proportion of patients who would benefit if given the new therapy. Non-parametric methods are used to estimate the parameter and its variance, providing the appropriate confidence intervals and test of hypothesis