Safety and efficacy of sequential chemotherapy with carboplatin plus gemcitabine followed by weekly paclitaxel in advanced non-small cell lung cancer.

BACKGROUND: Improving survival in non-small cell lung cancer (NSCLC) will require new strategies or new drugs. Sequential administration of conventional non-cross-resistant cytotoxic drugs offers an opportunity to increase drug diversity while maintaining dose intensity. This Phase II trial was designed to assess the efficacy and feasibility of such a regimen in advanced NSCLC. METHODS: Patients with NSCLC stage IIIB or IV received as first-line treatment four cycles of carboplatin (AUC 5) (day 1) plus gemcitabine 1000 mg/m(2) (days 1 and 8) every 3 weeks. Thereafter, treatment continued with 12 weekly cycles of paclitaxel 80 mg/m(2). RESULTS: In total, 46 patients were included. Median age was 59.6 years (range 41.3-74.3 years) and 93.5 % (n = 43) had Eastern Cooperative Oncology Group performance score of 0 or 1. All but 6 had stage IV disease, and 13 (28.3 %) had squamous cell carcinomas. Thirty-six (78 %) patients completed 4 cycles of carboplatin-gemcitabine and 35 patients received at least 1 cycle of paclitaxel, of whom 16 (46 % of total) patients completed 12 cycles of paclitaxel. The overall objective response rate was 49 %. Sixteen (37 %) patients had a response to carboplatin-gemcitabine, increasing to 21 (49 %) patients after administration of paclitaxel. Of the 13 assessable patients who showed a partial response (PR) on carboplatin-gemcitabine, 12 (92 %) patients showed also a PR on paclitaxel. Of 19 assessable patients with stable disease (SD) on carboplatin-gemcitabine, 4 (21 %) had a PR and 13 (68 %) SD on paclitaxel. Toxicity was moderate: 24 % stopped because of toxicity. CONCLUSION: Sequential chemotherapy with carboplatin-gemcitabine and weekly paclitaxel is active and feasible in advanced NSCLC patients.

Signalling pathways in vasculogenic mimicry.

Solid tumour growth is dependent on the development of an adequate blood supply. For years, sprouting angiogenesis has been considered an exclusive mechanism of tumour vascularization. However, over the last years, several other mechanisms have been identified, including vessel-co-option, intussusception, recruitment of endothelial precursor cells (EPCs) and even mechanisms that do not involve endothelial cells, a process called vasculogenic mimicry (VM). The latter describes a mechanism by which highly aggressive tumour cells can form vessel-like structures themselves, by virtue of their high plasticity. VM has been observed in several tumour types and its occurrence is strongly associated with a poor prognosis. This review will focus on signalling molecules and cascades involved in VM. In addition, we will discuss the presence of VM in relation to ongoing cancer research. Finally, we describe the clinical significance of VM regarding anti-angiogenesis treatment modalities.

VHL and HIF signalling in renal cell carcinogenesis.

Hypoxia-inducible factor (HIF) plays an important role in renal tumourigenesis. In the majority of clear cell RCC (ccRCC), the most frequent and highly vascularized RCC subtype, HIF is constitutively activated by inactivation of the von Hippel-Lindau gene. Of the HIF subunits, HIF-2alpha appears to be more oncogenic than HIF-1alpha, in that HIF-2alpha activates pro-tumourigenic target genes. In addition, recent studies indicate that HIF-1alpha, more than HIF-2alpha, can undergo proteasomal degradation in VHL - /- RCC cells. A more detailed understanding of the molecular basis of hypoxia and angiogenesis in renal carcinogenesis has set the stage for the development of targeted therapies, inhibiting multiple HIF-related pathways, such as the phosphatidylinositol 3-kinase-AKT-mTOR, RAS/RAF/MAP, and VEGF signalling routes. However, despite the positive results of these targeting agents in progression-free survival, clinical resistance remains an issue. Recent pre-clinical studies have suggested new targeting approaches such as inhibition of HIF-driven key metabolic enzymes and have introduced new HIF targeting agents, such as histone deacetylase inhibitors, with successful anti-neoplastic effects. In this review, we discuss existing and novel findings about RCC carcinogenesis, with subsequent clinical implications.

Genetics and epigenetics of renal cell cancer.

Renal cell carcinoma (RCC) is not a single disease, but comprises a group of tumors of renal epithelial origin, each with a different histology, displaying a different clinical course and caused by different genetic alterations. Since cure rates are inversely associated with stage and response to the available treatment regimes is limited to a subgroup of patients, diagnostic methods facilitating early detection and new therapeutic modalities are necessary. Increased knowledge of the underlying pathophysiology of RCC has resulted in the identification of genetic alterations involved in renal cell cancer carcinogenesis. Promising agents to target these pathways, especially the angiogenesis pathway, are being developed, some of which are already standard of care. In addition to genetics, knowledge on epigenetics in the process of renal tumorigenesis has been significantly increased in the last decades. Epigenetics will play an increasing role in the development of new therapeutic modalities and may deliver new prognostic and early diagnostic markers. In this review we discuss the background of RCC and the clinical applications of RCC genetics and epigenetics.

CD44 enhances tumor aggressiveness by promoting tumor cell plasticity.

Aggressive tumor cells can obtain the ability to transdifferentiate into cells with endothelial features and thus form vasculogenic networks. This phenomenon, called vasculogenic mimicry (VM), is associated with increased tumor malignancy and poor clinical outcome. To identify novel key molecules implicated in the process of vasculogenic mimicry, microarray analysis was performed to compare gene expression profiles of aggressive (VM+) and non-aggressive (VM-) cells derived from Ewing sarcoma and breast carcinoma. We identified the CD44/c-Met signaling cascade as heavily relevant for vasculogenic mimicry. CD44 was at the center of this cascade, and highly overexpressed in aggressive tumors. Both CD44 standard isoform and its splice variant CD44v6 were linked to increased aggressiveness in VM. Since VM is most abundant in Ewing sarcoma tumors functional analyses were performed in EW7 cells. Overexpression of CD44 allowed enhanced adhesion to its extracellular matrix ligand hyaluronic acid. CD44 expression also facilitated the formation of vasculogenic structures in vitro, as CD44 knockdown experiments repressed migration and vascular network formation. From these results and the observation that CD44 expression is associated with vasculogenic structures and blood lakes in human Ewing sarcoma tissues, we conclude that CD44 increases aggressiveness in tumors through the process of vasculogenic mimicry.

Promoter Methylation of CDO1 Identifies Clear-Cell Renal Cell Cancer Patients with Poor Survival Outcome.

PURPOSE: In this era of molecular diagnostics, prediction of clear-cell renal cell cancer (ccRCC) survival requires optimization, as current prognostic markers fail to determine individual patient outcome. Epigenetic events are promising molecular markers. Promoter CpG island methylation of cysteine dioxygenase type 1 (CDO1), which was identified as prognostic marker for breast cancer, is studied as a potential marker for ccRCC survival. EXPERIMENTAL DESIGN: We collected primary tissues of 365 ccRCC cases identified within the prospective Netherlands Cohort Study (NLCS). In this population-based series, CDO1 promoter methylation was observed in 124 of 324 (38.3%) patients with successful methylation-specific PCR analysis. Kaplan-Meier curves and Wilcoxon tests were used to evaluate 10-year ccRCC-specific survival. Cox regression analysis was used to obtain crude and multivariate HRs and 95% confidence intervals (CI). The relative prognostic value of multivariate models with and without CDO1 promoter methylation was compared using likelihood-ratio tests. RESULTS: Patients with CDO1 promoter methylation have a significantly poorer survival than those without (Wilcoxon P = 0.006). Differences in survival were independent of other prognostic factors, including age and sex (HR, 1.66; 95% CI, 1.12-2.45) and TNM stage, tumor size, and Fuhrman grade (HR, 1.89; 95% CI, 1.25-2.85). Multivariate models performed better with than without CDO1 promoter methylation status (likelihood-ratio P = 0.003). Survival curves were validated in an independent series of 280 ccRCC cases from The Cancer Genome Atlas (TCGA; Wilcoxon P < 0.001). CONCLUSIONS: CDO1 promoter methylation may not substitute common prognostic makers to predict ccRCC survival, but offers additional, relevant prognostic information, indicating that it might be a novel molecular marker to determine ccRCC prognosis.

The role of post-traumatic stress disorder symptoms in fatigued Cambodia veterans.

Post-traumatic stress disorder (PTSD) is sometimes put forward as an explanation for unexplained somatic symptoms in military personnel who have been deployed in war or peace missions. Using a cross-sectional postal survey, we investigated whether PTSD symptoms can account for fatigue in Dutch (ex-)servicemen who returned from the peace operation United Nations Transitional Authority for Cambodia and what features distinguish veterans with and without presumptive PTSD diagnoses. Increased PTSD scores were found in 1.3% of 1,698 veterans. There was no concordance between increased PTSD scores and fatigue, as defined in previous studies. Respondents with presumptive PTSD had more often left service, had more often been exposed to severe and potentially traumatic events, and more often reported a greater impact of the mission. Furthermore, they reported more mental problems that they perceived to be service related and they held a stronger causal attribution to post-traumatic stress. In conclusion, presumptive PTSD cannot offer an explanation for fatigue in Cambodia veterans.

Chemical sensitivity in symptomatic Cambodia veterans.

Following their participation in a United Nations peacekeeping operation in Cambodia (1992-1993), Dutch veterans complained of symptoms similar to those reported by Gulf War veterans. The authors conducted a matched case-control study to evaluate 76 symptomatic and 32 matched asymptomatic Cambodia veterans on the basis of data collected by postal questionnaire. The number of symptomatic veterans who reported having used insect repellants that contained N,N,-diethyl-meta-toluamide (DEET) during the mission in Cambodia was significantly higher, compared with asymptomatic veterans. The percentage of veterans who reported feeling ill following brief exposures to chemicals such as paint or pesticides was equal in both groups, but the percentage was low compared with the results of other studies of Multiple Chemical Sensitivity Syndrome. The current study was limited by self-report and time delay (potential recall bias) between deployment to Cambodia and the time of survey. Nevertheless, the study results did not support the hypothesis that symptoms in the total group of Cambodia veterans could be related to Multiple Chemical Sensitivity Syndrome.

[Sentinel lymph node procedure in melanoma patients: a staging procedure, not a therapy]. / Schildwachtklierprocedure voor melanoom: niet therapeutisch, maar stagerend.

The definitive results of the MSLT-1 study in melanoma patients were published recently. The sentinel lymph node (SLN) procedure shows no survival benefit compared with observation. The authors reported, however, that there was a survival benefit with "biopsy management" of patients. This statement is based on subgroup analyses that we find to be incorrect for three reasons: (a) patients with a false negative SLN were incorrectly left out of consideration; (b) accelerated failure time latent subgroup analysis is an unproven statistical hypothesis, which was developed on interim data from the MSLT-1 study, and therefore cannot be used as validation; (c) there is a significant difference in terms of the percentage of patients with affected lymph nodes between the SLN group and the observation group. This excess of "prognostic false positive" patients would have incorrectly falsely improved the survival of the SLN group. We concluded that the SLN procedure does not give a survival benefit and that its role in melanoma patients should be for staging purposes and not for therapeutic purposes.

An open-label study to investigate the cardiac safety profile of cabazitaxel in patients with advanced solid tumors.

PURPOSE: This study assessed the cardiovascular safety of cabazitaxel, based on thorough evaluation of QT and non-QT variables, and the relationship between pharmacokinetic and pharmacodynamic electrocardiographic (ECG) profiles and the occurrence of Grade ≥3 cardiovascular adverse events. METHODS: Patients with advanced solid tumors were treated with cabazitaxel 25 mg/m(2) every 3 weeks. Digital ECG recordings were obtained during Cycle 1 over 24 h after dosing. The primary end point was effect of cabazitaxel on QT interval corrected by the Fridericia formula (QTcF). Secondary end points were additional ECG parameters (QT, PR and QRS intervals, and heart rate), plasma pharmacokinetics of cabazitaxel and overall clinical safety. RESULTS: The pharmacodynamic (ECG) population included 94 patients. In 63 patients with a full 24-h ECG evaluation, the maximum upper bound of 90 % confidence interval (CI) for mean QTcF change from baseline was 7.46 ms (mean 4.8 ms), occurring at 1 h 30 min post-infusion. The slope of QTcF change from baseline versus cabazitaxel concentration was slightly negative (-0.012 [95 % CI -0.017; -0.008], equivalent to a 1.2 ms decrease per 100 ng/mL increase in cabazitaxel concentration). For non-QT variables, no effect was noted. No Grade ≥3 cardiac adverse events were observed; Grade ≥3 hypotension and lymphocele occurred in two patients and one patient, respectively. CONCLUSION: These results suggest that cabazitaxel has no clinically significant cardiovascular adverse effects in patients with advanced solid tumors.

[The Dutch guideline 'Renal cell carcinoma']. / Nederlandse richtlijn 'Niercelcarcinoom'.

The Dutch guideline 'Renal Cell Carcinoma' has been revised on the basis of new literature. With the assistance of the Netherlands Cancer Registry an assessment was made of the current care for patients with renal cell carcinoma. Renal cell carcinoma is a type of cancer for which knowledge of the genetic basis of the different histological subtypes has led to the development of new targeted therapies. By the introduction of these systemic therapies, histological subtyping of renal cell carcinoma has become more important. Although in the previous guideline cytological or histological diagnosis was recommended to determine the nature of the tumourous process in the kidney, in the revision it is advised to use histological needle biopsies to determine the histological subtype and therefore to provide evidence for the choice of systemic therapy. With modern diagnostic techniques, more patients with smaller tumours are identified. For these tumours, less invasive therapies are recommended in order to preserve as much renal tissue as possible.

A phase I, open-label, randomized crossover study to assess the effect of dosing of the MEK 1/2 inhibitor Selumetinib (AZD6244; ARRY-142866) in the presence and absence of food in patients with advanced solid tumors.

PURPOSE: This Phase I study assessed whether food influences the rate and extent of selumetinib absorption in patients with advanced solid malignancies and determined the safety, tolerability, and pharmacokinetic (PK) profile of selumetinib and its active metabolite N-desmethyl-selumetinib in fed and fasted states. METHODS: A single dose of 75 mg selumetinib was to be taken with food on Day 1 followed by a single dose of 75 mg after fasting for at least 10 h on Day 8, or vice versa, followed by twice daily dosing of 75 mg selumetinib from Day 10. Plasma concentrations and PK parameters were determined on Days 1 and 8. Patients could continue to receive selumetinib for as long as they benefitted from treatment. RESULTS: In total, 31 patients were randomized to receive selumetinib; 15 to fed/fasted sequence and 16 to fasted/fed sequence. Comprehensive PK sampling was performed on 11 and 10 patients, respectively. The geometric least-squares means of C(max) and AUC for selumetinib were reduced by 62% (ratio 0.38 90% CI 0.29, 0.50) and 19% (ratio 0.81 90% CI 0.74, 0.88), respectively, under fed compared with fasting conditions. The rate of absorption (t(max)) of selumetinib (fed) was delayed by approximately 2.5 h (median). The food effect was also observed for the active metabolite N-desmethyl-selumetinib. Selumetinib was well tolerated. CONCLUSIONS: The presence of food decreased the extent of absorption of selumetinib. It is recommended that for further clinical studies, selumetinib be taken on an empty stomach. Selumetinib demonstrated an acceptable safety profile in the advanced cancer population.