Urogenitale Oncologie: inspirerende decennia, uitdagende toekomst

Oratie handelt over het urogenitale stelsel, in het bijzonder maligne tumoren. Dit betreft onder andere kanker van de nier, de blaas, prostaat en testis. Komen maligne tumoren van deze organen vaak voor? Inderdaad, het prostaatcarcinoom is bij de man de meest voorkomende invasieve kanker en ook het blaascarcinoom staat in de top tien op de vijfde plaats. Bij vrouwen komt blaascarcinoom minder vaak voor en staat daarmee niet in de top tien. Het niercarcinoom is bij beide seksen een betrekkelijk weinig voorkomende tumor met ongeveer 1.200 nieuwe gevallen per jaar. Ook het testiscarcinoom is een betrekkelijk zeldzame kankersoort met ongeveer 1.000 nieuwe gevallen per jaar. Het is echter wel de meest voorkomende kanker bij jonge mannen en om onbekende redenen neemt de incidentie toe en is deze in de afgelopen 20 jaar verdubbeld. In de afgelopen 2 decennia zijn er bij het testiscarcinoom, blaascarcinoom, prostaatcarcinoom en het niercelcarcinoom grote sprongen voorwaarts gemaakt. Deze ontwikkelingen zullen beschreven worden. Hierbij zal de focus liggen op de rol van het Erasmus MC en de tot stand gebrachte samenwerkingsverbanden. Tenslotte zal bij elk voor deze tumortypes een blik op de toekomst gegeven worden

Irrefutable evidence for the use of docetaxel in newly diagnosed metastatic prostate cancer: Results from the STAMPEDE and CHAARTED trials

Androgen deprivation therapy (ADT) has been used in the treatment of metastatic prostate cancer since the first description of its hormonal dependence in 1941. In 2004, docetaxel chemotherapy became the mainstay of treatment in metastatic castration-resistant prostate cancer (mCRPC), following robust, albeit modest, survival benefit in two randomized phase 3 trials. The recently published CHAARTED trial was the first to show that combining ADT with docetaxel in men with hormone-naïve (hormone-sensitive) metastatic prostate cancer (mHSPC) yielded a remarkable overall survival benefit of 13.6 months as compared with ADT alone. In the current issue of The Lancet, James et al. report results of the STAMPEDE trial in men with high-risk locally advanced or metastatic prostate cancer initiating long-term hormone therapy. The combination of six cycles of docetaxel with ADT in men commencing long-term ADT demonstrated a similar OS benefit compared with standard of care (SOC) by a median of 10 months. Based on the consistency of the data and the firmness of the benefit provided, docetaxel in addition to ADT should be considered SOC for men with newly diagnosed mHSPC

Possible lack of full cross-resistance of 5HT3 antagonists; a pilot study

We investigated the potential of cross-over to the serotonin receptor (5HT3) antagonist ondansetron after protection failure with tropisetron. Several cases of complete protection were observed. These limited data suggest that there is an indication for retreatment with a different 5HT3 antagonist after an initial failure to another and also stress the need and relevance for comparative studies between 5HT3 antagonists

The usefulness of CA15.3, mucin-like carcinoma-associated antigen and carcinoembryonic antigen in determining the clinical course in patients with metastatic breast cancer

Levels of mucin-like carcinoma-associated antigen (MCA), CA15.3 and carcinoembryonic antigen (CEA) were measured in consecutive serum samples of 40 women with metastatic breast cancer. A change in antigen level of more than 25%, either an increase or a decrease, was considered to predict progressive or responsive disease respectively. A change of less than 25% was considered to predict stable disease. MCA, CA15.3 and CEA were elevated in the serum of 68%, 76% and 48% of the patients respectively (P<0.05). The overall prediction of clinical course was similar for all three markers. A more than 25% increase of MCA, CA15.3, and CEA was observed in 61%, 54% and 36% respectively. The predictive value of a more than 25% increase was high for all three markers: 94%, 94%, 83%. Changes in marker levels were correlated with each other. Logistic regression analysis showed that combining MCA and CA15.3 did not improve the prediction further. In conclusion, these tumour markers may help in evaluating the disease course and there is no advantage in combining MCA and CA15.3

External validity of a prediction rule for residual mass histology in testicular cancer: An evaluation for good prognosis patients

We assessed the external validity of a prediction rule for nonseminomatous testicular cancer patients. The rule was developed to predict the probability of retroperitoneal metastases being benign (only necrosis/fibrosis) after chemotherapy treatment. Patients with a high probability of benign residual masses might be offered surveillance as opp

Testosterone Diminishes Cabazitaxel Efficacy and Intratumoral Accumulation in a Prostate Cancer Xenograft Model

Inactivation of the androgen receptor (AR) pathway by androgen deprivation therapy (ADT) is the mainstay of (metastatic) prostate cancer therapy. Ultimately, the AR pathway will be re-activated despite castrate levels of circulating androgens. Thereby, maintaining its role even in castration resistant prostate cancer (CRPC). The recent STAMPEDE and CHAARTED trials showed that docetaxel in combination with ADT increased survival in hormone sensitive prostate cancer patients, suggesting cross-talk between AR signaling and chemotherapy efficacy. We hypothesized that a similar interaction may also apply for CRPC that is treated with cabazitaxel. We studied the impact of androgen status on the efficacy, pharmacodynamics and -kinetics of cabazitaxel in a unique and clinically relevant patient derived xenograft model of castration resistant disease. We found that cabazitaxel is highly effective in a castrate setting with strongly reduced AR activation, while tumor growth inhibition by cabazitaxel was completely abolished in the presence of high AR pathway activity. Moreover, additional experiments showed that intratumoral cabazitaxel levels were 3.5 times higher in tumors from castrated mice as compared to tumors from androgen-supplemented animals. We confirmed that cabazitaxel pharmacokinetics were not affected by testosterone, suggesting that androgen status might influence cabazitaxel tumor uptake directly. This study reveals the impact of androgen status on cabazitaxel efficacy and supports the potential of combination of taxane chemotherapeutics with AR axis targeting agents

Flux Compactifications of M-Theory on Twisted Tori

We find the bosonic sector of the gauged supergravities that are obtained from 11-dimensional supergravity by Scherk-Schwarz dimensional reduction with flux to any dimension D. We show that, if certain obstructions are absent, the Scherk-Schwarz ansatz for a finite set of D-dimensional fields can be extended to a full compactification of M-theory, including an infinite tower of Kaluza-Klein fields. The internal space is obtained from a group manifold (which may be non-compact) by a discrete identification. We discuss the symmetry algebra and the symmetry breaking patterns and illustrate these with particular examples. We discuss the action of U-duality on these theories in terms of symmetries of the D-dimensional supergravity, and argue that in general it will take geometric flux compactifications to M-theory on non-geometric backgrounds, such as U-folds with U-duality transition functions.Comment: Latex, 47 page

Weekly high-dose cisplatin is a feasible treatment option: Analysis on prognostic factors for toxicity in 400 patients

In the present study we describe the toxicity of weekly high-dose (70-85 mg m-2) cisplatin in 400 patients (203 men, 197 women; median age 54 years) with advanced solid tumours treated in the period 1990-2001 who took part in phase I/II trials, investigating the feasibility and efficacy of weekly cisplatin alone, or in combination with paclitaxel or etoposide. Cisplatin was administered in 250 ml NaCl 3% over 3 h, for six intended administrations. The mean number of administrations was 53 (range, 1-6 administrations). Reasons not to complete six cycles were disease progression (7.5%), haematological toxicity (9%), nephrotoxicity (7%), ototoxicity (2.5%), neurotoxicity (1%), gastrointestinal toxicity (1%), cardiovascular complications (0.5%) or a combination of reasons including noncompliance and patient's request (5.5%). Logistic regression analysis was used to evaluate baseline parameters for prognostic value regarding toxicity. Leukopenia correlated with etoposide cotreatment, and thrombocytopenia with cisplatin dose and prior (platinum-based) chemotherapy. Risk factors for nephrotoxicity were older age, female gender, smoking, hypoalbuminaemia and paclitaxel coadministration. Neurotoxicity >grade I (11% of patients) was associated with prior chemotherapy and paclitaxel coadministration. Symptomatic hearing loss occurred in 15% with anaemia as the predisposing factor. We conclude that weekly high-dose cisplatin administered in hypertonic saline is a feasible treatment regimen

The influence of single-nucleotide polymorphisms on overall survival and toxicity in cabazitaxel-treated patients with metastatic castration-resistant prostate cancer

Purpose: Cabazitaxel, used in patients with metastatic castration-resistant prostate cancer (mCRPC), is associated with adverse events which may require dose reductions or discontinuation of treatment. We investigated the potential association of single-nucleotide polymorphisms (SNPs) in genes encoding drug transporters and drug-metabolizing enzymes with cabazitaxel toxicity, overall survival (OS) and pharmacokinetics (PK). Methods: A total of 128 cabazitaxel-treated mCRPC patients, of whom prospectively collected data on toxicity and OS were available and 24 mCRPC patients with available cabazitaxel PK measurements, were genotyped using genomic DNA obtained from EDTA blood. The SLCO1B1 (388A > G; *1B; rs2306283 and 521 T > C; *5; rs4149056 and haplotype SLCO1B1*15), SLCO1B3 (334 T > G; rs4149117), CYP3A4 (*22; rs35599367), CYP3A5 (*3; rs776746), ABCB1 (3435C > T; rs1045642), and TUBB1 (57 + 87A > C; rs463312) SNPs were tested for their association with clinical and PK parameters by univariate/multivariate logistic regression, log-rank test, or Kruskal–Wallis test. Results: The SLCO1B1*15 haplotype was significantly associated with a lower incidence of leukopenia and neutropenia (p = 0.020 and p = 0.028, respectively). Patients harboring a homozygous variant for SLCO1B1*1B experienced higher rate ≥ grade 3 (p = 0.042). None of the SNPs were associated with pharmacokinetics or OS. Conclusions: In this study, SLCO1B1 (SLCO1B1*15 and SLCO1B1*1B) was associated with cabazitaxel-induced adverse events in mCRPC patients. As the associations were opposite to previous studies in other drugs and contradicted an underlying pharmacokinetic rationale, these findings are likely to be false-positive and would ideally be validated with even larger (pharmacokinetic) cohorts