Simon Van Belle

Prevention of cisplatin-induced acute and delayed emesis by the selective neurokinin-1 antagonists, L-758,298 and MK-869 - A randomized controlled trial.

Recent studies have suggested that antiemetic therapy with a triple combination of the neurokinin‐1 receptor antagonist MK‐869, a serotonin (5‐HT3) antagonist, and dexamethasone provides enhanced control of cisplatin‐induced emesis compared with standard therapy regimens. The authors compared the antiemetic activity of a dual combination of MK‐869 and dexamethasone with that of a standard dual combination of ondansetron and dexamethasone to characterize further the efficacy and tolerability profile of MK‐869.

Cancer-Related Anemia: Pathogenesis, Prevalence and Treatment

Cancer-related anemia is a cytokine-mediated disorder resulting from complex interactions between tumor cells and the immune system. Overexpression of certain inflammatory cytokines results in shortened survival of red blood cells, suppression of erythroid progenitor cells, impaired iron utilization, and inadequate erythropoietin production. Numerous other factors may also contribute to the development of anemia in cancer patients. The European Cancer Anaemia Survey (ECAS) has provided the most current, comprehensive, prospectively collected data on the incidence and prevalence of anemia among cancer patients, as well as important perspectives on anemia treatment and relationship of hemoglobin and performance status. ECAS enrolled over 15,000 treated and untreated patients with various malignancies from cancer centers in 24 European countries and followed them for up to 6 months. The initial analysis of the ECAS data revealed that 39% of the total cancer patient population was anemic (hemoglobin <12.0 g/dl) at enrollment, although the rate varied according to tumor type, disease status, and cancer treatment status. Of the patients who were not anemic at enrollment and started cancer treatment during the survey, those undergoing chemotherapy – either alone or in combination with radiotherapy – had the highest incidence of anemia (63 and 42%, respectively). Low hemoglobin levels correlated with poor performance status and only 40% of patients who were anemic at some time during the survey received treatment for their anemia. These findings are noteworthy, since a growing body of clinical evidence indicates that the treatment of anemia can significantly improve patients’ quality of life and may also improve the clinical outcome.

Effect of the Secretory Small GTPase Rab27B on Breast Cancer Growth, Invasion, and Metastasis

BACKGROUND Secretory GTPases like Rab27B control vesicle exocytosis and deliver critical proinvasive growth regulators into the tumor microenvironment. The expression and role of Rab27B in breast cancer were unknown. METHODS Expression of green fluorescent protein (GFP) fused with wild-type Rab3D, Rab27A, or Rab27B, or Rab27B point mutants defective in GTP/GDP binding or geranylgeranylation, or transient silencing RNA to the same proteins was used to study Rab27B in estrogen receptor (ER)-positive human breast cancer cell lines (MCF-7, T47D, and ZR75.1). Cell cycle progression was evaluated by flow cytometry, western blotting, and measurement of cell proliferation rates, and invasion was assessed using Matrigel and native type I collagen substrates. Orthotopic tumor growth, local invasion, and metastasis were analyzed in mouse xenograft models. Mass spectrometry identified proinvasive growth regulators that were secreted in the presence of Rab27B. Rab27B protein levels were evaluated by immunohistochemistry in 59 clinical breast cancer specimens, and Rab3D, Rab27A, and Rab27B mRNA levels were analyzed by quantitative real-time polymerase chain reaction in 20 specimens. Statistical tests were two-sided. RESULTS Increased expression of Rab27B promoted G(1) to S phase cell cycle transition, proliferation and invasiveness of cells in culture, and invasive tumor growth and hemorrhagic ascites production in a xenograft mouse model (n = 10; at 10 weeks, survival of MCF-7 GFP- vs GFP-Rab27B-injected mice was 100% vs 62.5%, hazard ratio = 0.26, 95% confidence interval = 0.08 to 0.88, P = .03). Mass spectrometric analysis of purified Rab27B-secretory vesicles identified heat-shock protein 90alpha as key proinvasive growth regulator. Heat-shock protein 90alpha secretion was Rab27B-dependent and was required for matrix metalloproteinase-2 activation. All Rab27B-mediated functional responses were GTP- and geranylgeranyl-dependent. Presence of endogenous Rab27B mRNA and protein, but not of Rab3D or Rab27A mRNA, was associated with lymph node metastasis (P < .001) and differentiation grade (P = .001) in ER-positive human breast tumors. CONCLUSIONS Rab27B regulates invasive growth and metastasis in ER-positive breast cancer cell lines, and increased expression is associated with poor prognosis in humans.

Better cosmetic results and comparable quality of life after skin-sparing mastectomy and immediate autologous breast reconstruction compared to breast conservative treatment

Preoperative chemotherapy (PCT) can be used in large primary breast cancer to facilitate breast conservative surgery (BCS). Cosmetic results of BCS are influenced by the size of the residual tumour, relative to the size of the breast. After mastectomy, immediate breast reconstruction (IBR) with autologous tissue provides excellent cosmetic outcome and has proven to be safe in breast cancer patients. Besides improving overall and disease free survival, Quality of Life (QoL), body image and cosmetic outcome are also important issues after treatment for breast cancer. In this study, Health-Related-Quality of Life (HRQL) and body image were evaluated, in patients treated with PCT, followed by BCS, or skin-sparing mastectomy (SSM) and perforator-flap breast reconstruction. Additionally, clinical observers assessed cosmetic outcome. All participants were evaluated by the Medical Outcomes Study (MOS) 36-item Short Form Health Status Survey (SF-36, 36 items) and a study-specific questionnaire. An external panel evaluated standardised photographs of the breasts. For all patients, norm-based scores of physical and mental health state are comparable with the general population, except for vitality (VT) score, which is somewhat lower. No significant differences can be observed between both groups. The majority of the patients were satisfied with the appearance of their breasts. The cosmetic results, assessed by the clinical team, were significantly better for patients having IBR, compared to BCS. The mean score was 7.5/10 for IBR, versus 6.0/10 for BCS (p<0.0001).Breast conserving treatment or mastectomy with reconstruction may yield comparable results of QoL, but cosmetic outcome is better after SSM and perforator-flap reconstruction. Patients must be offered both options, and clinicians should stress that both are equally effective.

Whole abdominopelvic radiotherapy (WAPRT) using intensity-modulated arc therapy (IMAT): First clinical experience

PURPOSE Whole abdominopelvic radiation therapy (WAPRT) is a treatment option in the palliation of patients with relapsed ovarian cancer. With conventional techniques, kidneys and liver are the dose- and homogeneity-limiting organs. We developed a planning strategy for intensity-modulated arc therapy (IMAT) and report on the treatment plans of the first 5 treated patients. METHODS AND MATERIALS Five consecutive patients with histologically proven relapsed ovarian cancer were sent to our department for WAPRT. The target volumes and organs at risk (OAR) were delineated on 0.5-cm-thick CT slices. The clinical target volume (CTV) was defined as the total peritoneal cavity. CTV and kidneys were expanded with 0.5 cm. In a preset range of 8 degrees interspaced gantry angles, machine states were generated with an anatomy-based segmentation tool. Machine states of the same class were stratified in arcs. The optimization of IMAT was done in several steps, using a biophysical objective function. These steps included weight optimization of machine states, leaf position optimization adapted to meet the maximal leaf speed constraint, and planner-interactive optimization of the start and stop angles. The final control points (machine states plus associated cumulative monitor unit counts) were calculated using a collapsed cone convolution/superposition algorithm. For comparison, two conventional plans (CONV) were made, one with two fields (CONV2), and one with four fields (CONV4). In these CONV plans, dose to the kidneys was limited by cerrobend blocks. The IMAT and the CONV plans were normalized to a median dose of 33 Gy to the planning target volume (PTV). Monomer/polymer gel dosimetry was used to assess the dosimetric accuracy of the IMAT planning and delivery method. RESULTS The median volume of the PTV was 8306 cc. The mean treatment delivery time over 4 patients was 13.8 min. A mean of 444 monitor units was needed for a fraction dose of 150 cGy. The fraction of the PTV volume receiving more than 90% of the prescribed dose (V(90)) was 9% higher for the IMAT plan than for the CONV4 plan (89.9% vs. 82.5%). Outside a build-up region of 0.8 cm and 1 cm away from both kidneys, the inhomogeneity in the PTV was 15.1% for the IMAT plans and 24.9% for the CONV4 plans (for CONV2 plans, this was 34.9%). The median dose to the kidneys in the IMAT plans was lower for all patients. The 95th percentile dose for the kidneys was significantly higher for the IMAT plans than for the CONV4 and CONV2 plans (28.2 Gy vs. 22.2 Gy and 22.6 Gy for left kidney, respectively). No relevant differences were found for liver. The gel-measured dose was within clinical planning constraints. CONCLUSION IMAT was shown to be deliverable in an acceptable time slot and to produce dose distributions that are more homogeneous than those obtained with a CONV plan, with at least equal sparing of the OARs.

Comparison of proposed diagnostic criteria with FACT-F and VAS for cancer-related fatigue: Proposal for use as a screening tool

The objective was to validate the use of the proposed International Statistical Classification of Diseases and Related Health Problems (10th revision) (ICD-10) criteria for fatigue (P-ICD10) through comparison with the Functional Assessment of Cancer Therapy Fatigue (FACT-F) subscale and three visual analogue scale (VAS) qualities in cancer patients thought to be fatigued. Fatigue was assessed in 834 cancer patients at three clinical centres in Belgium, using P-ICD10, FACT-F, and VAS to assess: level of energy (VAS1), quality of life (VAS2), and ability to perform daily activities (VAS3). Of the 834 interviewed cancer patients, 54% were classified as fatigued by the P-ICD10 criteria. Internal consistency of P-ICD10 was very good (alpha coefficient 0.82). The principal component analysis corroborated good internal consistency with all variables included in the first component; a second component was used to identify psychological fatigue (concentration and short-term memory disabilities). An abridged set of screening tools based on the first three general symptoms of the P-ICD10 is proposed with 100% specificity and 86% specificity, respectively. There was a marked decrease in FACT-F and VAS1 scores in patients diagnosed as fatigued by the P-ICD10 (mean±SD, FACT-F 20±9 vs 39±8, VAS1 34±21 vs 61±21). A logistic regression model between P-ICD10 criteria diagnosis and FACT-F (VAS1) identified a score of 34 (61) on the FACT-F scale as a proposed cut-off point for the diagnosis of fatigue. The ICD-10 criteria can be recommended as a diagnostic tool, whereas the FACT-F scale and the level of energy 100-mm VAS assess the intensity of fatigue, and are more suitable for follow-up of cancer-related fatigue.

Combined karyotyping, CGH and M-fish analysis allows detailed characterization of unidentified chromosomal rearrangements in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine tumor of the skin. Cytogenetic studies have indicated that deletions and unbalanced translocations involving chromosome 1 short arm material occur in 40% of the investigated cases. Recurrent chromosomal imbalances detected by comparative genomic hybridization (CGH) analysis were loss of 3p, 10q, 13q and 17p and gains of 1q, 3q, 5p and 8q. In order to study genomic aberrations occurring in MCC in further detail, we combined karyotyping, CGH and multiplex‐fluorescence in situ hybridization (M‐FISH), a strategy that proved to be successful in the analysis of other malignancies. Analysis of 6 MCC cell lines and 1 MCC tumor revealed mostly near‐diploid karyotypes with an average of 5 chromosomal rearrangements. The observed karyotypic changes were heterogeneous, with 3–27 breakpoints per case, leading to imbalance of the involved chromosomal regions that was confirmed by CGH. Chromosomal rearrangements involving the short arm of chromosome 1, the long arm of chromosome 3 and gain of 5p material were the most frequently observed abnormalities in our study. In keeping with previous observations, this series of MCCs showed no evidence for high‐level amplification. We provid a detailed description of chromosomal translocations occurring in MCC that could be useful to direct future intensive investigation of these chromosomal regions.

Independent Risk Factors for Anemia in Cancer Patients Receiving Chemotherapy: Results from the European Cancer Anaemia Survey

Objectives: To develop a hitherto unavailable risk factor model for accurately predicting anemia development in cancer patients before chemotherapy (CT) administration. Methods: 2,070 nonanemic patients from the European Cancer Anaemia Survey (ECAS) with hemoglobin (Hb) ≧12 g/dl at enrollment who received their first CT during ECAS and underwent at least two CT cycles were divided randomly into split half (SH) 1 and SH2 (n = 1,035 each). The model was developed on SH1 using logistic regression to simultaneously evaluate predictive factors, and was validated using SH2 and an additional similar subpopulation of 5,901 ECAS patients. Anemia risk values were assigned to the predictive factors and the sum of the predictive factors gave the total anemia risk score; lower-, higher-, and highest-risk cutoff points of the total anemia risk score were determined. Results: Variables ultimately identified as significant predictive factors for anemia were: lower initial Hb (≤12.9 g/dl in females, and ≤13.4 g/dl in males); having lung or gynecologic cancer versus gastrointestinal (GI)/colorectal cancer; cancer at any other site versus GI/colorectal cancer; treatment with platinum CT, and female gender. Conclusion: Using this evidence-based risk model, nonanemic patients who are at the highest risk of develop ing anemia prior to receiving CT can be identified clinically, allowing appropriate anemia management to be planned.

Cancer-Related Anemia: Biological Findings, Clinical Implications and Impact on Quality of Life

Anemia is a common symptom in cancer patients. The relationship among anemia, cancer progression and clinical outcomes of cancer treatment is complex and much remains to be elucidated. One hypothesis for an etiological link is that anemia contributes to the development of tumor hypoxia, which in turn has been shown to induce proteomic and genomic changes within the tumor cells that ultimately favor malignant progression and treatment resistance. A substantial body of clinical data indicates that anemia can be a significant independent prognostic factor for treatment response and survival in cancer patients treated with chemotherapy or radiotherapy. In addition, studies have shown a correlation between anemia and decline in quality of life (QOL) in cancer patients. Of the many factors that impact cancer patients’ QOL, fatigue has emerged as the most prevalent, troubling, under-recognized and under-treated of all symptoms experienced by anemic cancer patients. Systematic correction of anemia with appropriate supportive therapies prior to or during chemotherapy or radiotherapy may enhance patients’ QOL.

A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer

Purpose: This dedicated QTc phase I study, conducted in advanced-stage cancer patients, assessed the effect of a single supratherapeutic dose (800 mg) of vorinostat on the QTc interval. Experimental Design: A randomized, partially blind, placebo-controlled, two-period, crossover study was conducted. Patients (n = 25) received single doses of 800 mg vorinostat and placebo in the fasted state. Holter electrocardiogram monitoring was done before each treatment and for 24 h postdose. Blood samples for vorinostat concentration were collected through 24 h postdose following vorinostat treatment only. Prescribed electrocardiogram and blood sampling times were designed to capture the expected Cmax of vorinostat. Results: Twenty-four of the 25 patients enrolled in the study were included in the QTc analysis. The upper bound of the two-sided 90 confidence interval for the QTcF interval for the placebo-adjusted mean change from baseline of vorinostat was <10 ms at every time point. No patient had a QTcF change from baseline value >30 ms. One patient had QTcF values >450 ms (seen after both vorinostat and placebo administration) and none had values >480 ms. Mean AUC0- and Cmax values attained were on the order of 1.93- and 1.41-fold higher, respectively, compared with the 400 mg clinical dose. Based on assessment of clinical and laboratory adverse experiences, single doses of 800 mg vorinostat were generally well tolerated. Conclusions: Administration of a single supratherapeutic dose of the histone deacetylase inhibitor vorinostat is not associated with prolongation of the QTc interval. A dedicated QTc study in advanced cancer patients is a robust means for assessing risk for ventricular repolarization prolongation. (Clin Cancer Res 2009;15(22):707784)