Brain metastases in adult patients with melanoma of unknown primary in the Netherlands (2011-2020).

BACKGROUND: Although patients with melanoma of unknown primary (MUP) have a better prognosis than similar-staged melanoma patients with known primary, the occurrence of brain metastases (BM) entails a serious complication. This study provides an overview of the incidence, treatment patterns, and overall survival (OS) of adult patients with BM-MUP in the Netherlands. METHODS: BM-MUP cases were retrieved from the Netherlands Cancer Registry. Patient, disease and treatment-related characteristics were summarised using descriptive statistics. Overall survival (OS) was calculated by the Kaplan-Meier method, and the impact of prognostic factors on OS was assessed using Cox proportional hazard regression analyses. RESULTS: Among 1779 MUP patients, 450 were identified as BM-MUP (25.3%). Of these patients, 381 (84.7%) presented with BM along with other metastases, while 69 (15.3%) had BM only. BM-MUP patients were predominantly male (68.2%), and had a median age of 64 years at diagnosis (interquartile range 54-71 years). Over time, the proportion of BM along other metastatic sites increased, and the occurrence of BM decreased (p = 0.01). 1-Year OS improved for the total population, from 30.0% (95% confidence interval (CI): 19.8-40.9%) in 2011-2012 to 43.6% (95%CI: 34.5-52.3%) in 2019-2020, and median OS more than doubled from 4.2 months (95%CI: 3.3-6.2 months) to 9.8 months (95%CI: 7.0-13.2 months). Patient's age, localisation of BM, presence of synchronous liver metastasis and treatment were identified as independent predictors of OS. CONCLUSION: Notwithstanding the progress made in OS for patients with BM-MUP in the past decade, their overall prognosis remains poor, and further efforts are needed to improve outcomes.

Medulloblastoma in adults: evaluation of the Dutch society for neuro-oncology treatment protocol.

PURPOSE: Medulloblastoma is a rare tumor in adults. The objective of this nationwide, multicenter study was to evaluate the toxicity and efficacy of the Dutch treatment protocol for adult medulloblastoma patients. METHODS: Adult medulloblastoma patients diagnosed between 2010 and 2018 were identified in the Dutch rare tumors registry or nationwide pathology database. Patients with intention to treat according to the national treatment protocol were included. Risk stratification was performed based on residual disease, histological subtype and extent of disease. All patients received postoperative radiotherapy [craniospinal axis 36 Gy/fossa posterior boost 19.8 Gy (14.4 Gy in case of metastases)]. High-risk patients received additional neoadjuvant (carboplatin-etoposide), concomitant (vincristine) and adjuvant chemotherapy (carboplatin-vincristine-cyclophosphamide) as far as feasible by toxicity. Methylation profiling, and additional next-generation sequencing in case of SHH-activated medulloblastomas, were performed. RESULTS: Forty-seven medulloblastoma patients were identified, of whom 32 were treated according to the protocol. Clinical information and tumor material was available for 28 and 20 patients, respectively. The histological variants were mainly classic (43%) and desmoplastic medulloblastoma (36%). Sixteen patients (57%) were considered standard-risk and 60% were SHH-activated medulloblastomas. Considerable treatment reductions and delays in treatment occurred due to especially hematological and neurotoxicity. Only one high-risk patient could complete all chemotherapy courses. 5-years progression-free survival (PFS) and overall survival (OS) for standard-risk patients appeared worse than for high-risk patients (PFS 69% vs. 90%, OS 81% vs. 90% respectively), although this wasn't statistically significant. CONCLUSION: Combined chemo-radiotherapy is a toxic regimen for adult medulloblastoma patients that may result in improved survival.

Blended online learning for oncologists to improve skills in shared decision making about palliative chemotherapy: a pre-posttest evaluation.

PURPOSE: To improve shared decision making (SDM) with advanced cancer patients, communication skills training for oncologists is needed. The purpose was to examine the effects of a blended online learning (i.e. e-learning and online training session) for oncologists about SDM in palliative oncological care and to compare this blended format with a more extensive, fully in-person face-to-face training format. METHODS: A one-group pre-posttest design was adopted. Before (T0) and after (T2) training, participants conducted simulated consultations (SPAs) and surveys; after the e-learning (T1), an additional survey was filled out. The primary outcome was observed SDM (OPTION12 and 4SDM). Secondary outcomes included observed SDM per stage, SPA duration and decision made as well as oncologists' self-reported knowledge, clinical behavioural intentions, satisfaction with the communication and evaluation of the training. Additionally, outcomes of the blended learning were compared with those of the face-to-face training cohort. Analyses were conducted in SPSS by linear mixed models. RESULTS: Oncologists (n = 17) showed significantly higher SDM scores after the blended online learning. The individual stages of SDM and the number of times the decision was postponed as well as oncologists' beliefs about capabilities, knowledge and satisfaction increased after the blended learning. Consultation duration was unchanged. The training was evaluated as satisfactory. When compared with the face-to-face training, the blended learning effects were smaller. CONCLUSION: Blended online SDM training for oncologists was effective. However, the effects were smaller compared to face-to-face training. The availability of different training formats provides opportunities for tailoring training to the wishes and needs of learners.

Prognostic factors among patients with brain metastases from cancer of unknown primary site.

PURPOSE: Cancers of an unknown primary site (CUPs) have a dismal prognosis, and the situation is even worse for CUPs patients with brain metastases (BM-CUPs). This study aims to give better insight into the occurrence and survival of BM-CUPs patients. METHODS: Cases were selected from the Netherlands Cancer Registry (1,430 BM-CUPs/17,140 CUPs). Baseline characteristics between CUPs patients with and without BM were tested using chi-square tests and Mann-Whitney U tests. Patients' overall survival (OS) times were estimated by the Kaplan-Meier method and prognostic factors on OS was assessed using Cox proportional hazards regression analyses. RESULTS: The proportion of BM-CUPs patients among CUPs increased from 8% in 2009-2010 to 10% in 2017-2018 (p < 0.001). Most patients presented with multiple brain lesions (53%). Survival of BM-CUPs improved over time: one-year OS increased from 10% for patients diagnosed in 2009-2010 to 17% (2017- 2018) (p < 0.01), and median survival times increased from 1.8 months to 2.2 months. Independent predictors of poor survival were multiple (HR 1.25; p < 0.01) or unknown (HR 1.48; p < 0.01) locations of BM, unknown/poorly/undifferentiated carcinoma histology (HR 1.53; p < 0.01), or clinical symptoms of BM (HR 1.74; p < 0.01), accompanying liver metastasis (HR 1.43; p < 0.01) and more than one metastatic site outside the brain compared to none (HR 1.52; p < 0.01). CONCLUSION: The incidence of patients with BM-CUPs is steadily increasing over time and overall prognosis remains dismal. Our results, however, show distinct patient subgroups that exhibit comparatively better outcomes, and more predictors may likely still be identified.

Brain tumour diagnostics using a DNA methylation-based classifier as a diagnostic support tool.

AIMS: Methylation profiling (MP) is increasingly incorporated in the diagnostic process of central nervous system (CNS) tumours at our centres in The Netherlands and Scandinavia. We aimed to identify the benefits and challenges of MP as a support tool for CNS tumour diagnostics. METHODS: About 502 CNS tumour samples were analysed using (850 k) MP. Profiles were matched with the DKFZ/Heidelberg CNS Tumour Classifier. For each case, the final pathological diagnosis was compared to the diagnosis before MP. RESULTS: In 54.4% (273/502) of all analysed cases, the suggested methylation class (calibrated score ≥0.9) corresponded with the initial pathological diagnosis. The diagnosis of 24.5% of these cases (67/273) was more refined after incorporation of the MP result. In 9.8% of cases (49/502), the MP result led to a new diagnosis, resulting in an altered WHO grade in 71.4% of these cases (35/49). In 1% of cases (5/502), the suggested class based on MP was initially disregarded/interpreted as misleading, but in retrospect, the MP result predicted the right diagnosis for three of these cases. In six cases, the suggested class was interpreted as 'discrepant but noncontributory'. The remaining 33.7% of cases (169/502) had a calibrated score <0.9, including 7.8% (39/502) for which no class indication was given at all (calibrated score <0.3). CONCLUSIONS: MP is a powerful tool to confirm and fine-tune the pathological diagnosis of CNS tumours, and to avoid misdiagnoses. However, it is crucial to interpret the results in the context of clinical, radiological, histopathological and other molecular information.

A randomized controlled trial of a skills training for oncologists and a communication aid for patients to stimulate shared decision making about palliative systemic treatment (CHOICE): study protocol.

BACKGROUND: Systemic treatment for advanced cancer offers uncertain and sometimes little benefit while the burden can be high. Hence, treatment decisions require Shared Decision Making (SDM). The CHOICE trial examines the separate and combined effect of oncologist training and a patient communication aid on SDM in consultations about palliative systemic treatment. METHODS: A RCT design with four parallel arms will be adopted. Patients with metastatic or irresectable cancer with a median life expectancy <12 months who meet with a medical oncologist to discuss the start or continuation of palliative systemic treatment are eligible. A total of 24 oncologists (in training) and 192 patients will be recruited. The oncologist training consists of a reader, two group sessions (3.5 h; including modelling videos and role play), a booster feedback session (1 h) and a consultation room tool. The patient communication aid consists of a home-sent question prompt list and a value clarification exercise to prepare patients for SDM in the consultation. The control condition consists of care as usual. The primary outcome is observed SDM in audio-recorded consultations. Secondary outcomes include patient and oncologist evaluation of communication and decision-making, the decision made, quality of life, potential adverse outcomes such as anxiety and hopelessness, and consultation duration. Patients fill out questionnaires at baseline (T0), before (T1) and after the consultation (T2) and at 3 and 6 months (T3 and T4). All oncologists participate in two standardized patient assessments (before-after training) prior to the start of patient inclusion. They will fill out a questionnaire before and after these assessments, as well as after each of the recorded consultations in clinical practice. DISCUSSION: The CHOICE trial will enable evidence-based choices regarding the investment in SDM interventions targeting either oncologists, patients or both in the advanced cancer setting. The trial takes into account the immediate effect of the interventions on observed communication, but also on more distal and potential adverse patient outcomes. Also, the trial provides evidence regarding the assumption that SDM about palliative cancer treatment results in less aggressive treatment and more quality of life in the final period of life. TRIAL REGISTRATION: Netherlands Trial Registry number NTR5489 (prospective; 15 Sep 2015).

A phase I, dose escalation, pharmacodynamic, pharmacokinetic, and food-effect study of α2 integrin inhibitor E7820 in patients with advanced solid tumors.

UNLABELLED: Introduction E7820 is an orally administered sulfonamide that inhibits alfa-2-integrin mRNA expression. Pre-clinically E7820 showed tumor anti-angiogenic effects in various tumor cell lines and xenograft mouse models. Human daily dosing of 100 mg QD had previously been shown to be safe and tolerable. Methods The study consisted of two parts: Part A (food effect) and Part B (determination of maximum tolerated dose (MTD) for bi-daily (BID) dosing). E7820 dosing started at 50 mg BID with planned escalation to 60, 80 and 100 mg BID every 28 days. Results Fifteen patients were enrolled in Part A and 26 in Part B. The most frequent adverse events of all grades were constipation, diarrhea, nausea, and fatigue while anemia, neutropenia, and fatigue were most frequent grade ≥3 toxicities. At dose-level 60 mg BID, two patients experienced dose-limiting toxicities (grade 3 neutropenic sepsis and grade 4 neutropenia). Therefore the recommended dose (RD) was 50 mg BID. Food had no effect on E7820 exposure. E7820 exposure following twice daily administration was dose-proportional. Expression of platelet integrin-α2 measured as a response biomarker in Part B, generally decreased by a median 7.7 % from baseline following treatment with 50 mg BID E7820. Reduction was most pronounced within 1-week post treatment. The median duration of treatment was median 54, range 20-111 days. The best overall response in any treatment group was stable disease (SD): 23.1 % in Part A (100 mg QD); at the RD 66.7 % (12 of 18 patients) and 40 % in the 60 mg BID group in Part B. CONCLUSIONS: Food had no effect on E7820 exposure. A dose of 50 mg BID was considered the MTD. Treatment with E7820 is safe and tolerable with 2/3 of patients (66.7 %) at MTD having SD as their best response.

Prognostic value and kinetics of circulating endothelial cells in patients with recurrent glioblastoma randomised to bevacizumab plus lomustine, bevacizumab single agent or lomustine single agent. A report from the Dutch Neuro-Oncology Group BELOB trial.

BACKGROUND: Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma. METHODS: In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated. RESULTS: The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log10CEC hazard ratio (HR) 0.41, 95% CI 0.18-0.91) and 6 weeks (log10CEC HR 0.16, 95% CI 0.05-0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated with OS. CONCLUSION: CEC numbers increased during treatment with bevacizumab plus lomustine but not during treatment with either agent alone, suggesting that this combination induced the greatest vascular damage. Although the absolute number of CECs was not associated with OS in patients treated with bevacizumab either alone or in combination, they could serve as a marker in glioblastoma patients receiving lomustine single agent.

In vivo toxicity and bioavailability of Taxol and a paclitaxel/beta-cyclodextrin formulation in a rat model during HIPEC.

BACKGROUND: Peritoneal carcinomatosis (PC) remains a dreaded clinical syndrome and a common evolution of gastrointestinal and ovarian cancers. In recent years, hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery has emerged as a promising strategy in the management of PC. In this study, a novel paclitaxel (Pac) formulation was investigated for its toxicity and bioavailability during HIPEC compared with Taxol. MATERIALS AND METHODS: The maximum tolerated dose (MTD) after HIPEC of both formulations (Taxol and Pac/RAME-beta-CD) was determined. MTD was defined as the highest nonlethal dose with a reduction in body weight of < or = 10% over 2 weeks. Blood parameters (red blood cell and white blood cell count, creatinine, ALT, and GGT) were evaluated over 20 days. Bioavailability of both Pac formulations after HIPEC was determined under normothermic (37 degrees C) and hyperthermic (41 degrees C) conditions for 90 min. RESULTS: Following HIPEC, both formulations had a similar MTD: 0.24 mg paclitaxel per ml. Red blood cell count decreased to a minimum after 10 days and was not fully recovered after 20 days for both formulations. White blood cell monitoring showed a significant increase in neutrocytes at day 10 and 15 for the Pac/RAME-beta-CD formulation. Liver and kidney parameters did not change significantly. Bioavailability data of Pac/RAME-beta-CD showed a 40-fold increase of the area under the curve (AUC) of plasma concentrations compared with Taxol. Hyperthermia yielded no significant differences in bioavailability data. CONCLUSION: These results showed that both formulations had a similar toxicity profile but differed significantly in bioavailability.

Effect of cyclosporin A administration on the biodistribution and multipinhole muSPECT imaging of [123I]R91150 in rodent brain.

PURPOSE: P-glycoprotein (Pgp) is an efflux protein found amongst other locations in the blood-brain barrier. It is important to investigate the effect of Pgp modulation on clinically used brain tracers, because brain uptake of the tracer can be altered by blocking of the Pgp efflux transporter. The function of Pgp can be blocked with cyclosporin A. METHODS: We investigated the effect of cyclosporin A administration on the biodistribution of [(123)I]R91150 in rodents, and the effect of Pgp blocking on the quality of multipinhole muSPECT imaging with [(123)I]R91150. The influence of increasing doses of cyclosporin A on the brain uptake of [(123)I]R91150 was investigated in NMRI mice. A biodistribution study with [(123)I]R91150 was performed in male Sprague-Dawley rats pretreated with cyclosporin A and not pretreated. Brain uptake of [(123)I]R91150 after cyclosporin A injection was compared to the brain uptake in untreated animals, and a displacement study with ketanserin was performed in both groups. A multipinhole muSPECT brain imaging study was also performed using a Milabs U-SPECT-II camera in male Sprague-Dawley rats. To exclude the effect of possible metabolites, a metabolite study was also performed. RESULTS: At the highest cyclosporin A dose (50 mg/kg), a sevenfold increase in brain radioactivity concentration was observed in NMRI mice. Also, a dose-response relationship was established between the dose of cyclosporin A and the brain uptake of [(123)I]R91150 in mice. Compared to the control group, a five-fold increase in [(123)I]R91150 radioactivity concentration was observed in the brain of Sprague-Dawley rats after cyclosporin A treatment (50 mg/kg). Radioactivity concentration in the frontal cortex increased from 0.24+/-0.0092 to 1.58+/-0.097% injected dose per gram of tissue after treatment with cyclosporin A (at the 1-h time-point). Blood radioactivity concentrations did not increase to the same extent. The cortical activity was displaced by administration of ketanserin. A metabolite study confirmed that there was no increased metabolism of [(123)I]R91150 due to cyclosporin A. The visual quality of multipinhole muSPECT images with [(123)I]R91150 in Sprague-Dawley rats improved markedly after cyclosporin A pretreatment. CONCLUSION: From the results obtained in the biodistribution studies, it can be concluded that [(123)I]R91150 is a substrate for Pgp in rodents. A relationship between the administered dose of cyclosporin A and the increase in [(123)I]R91150 brain radioactivity concentration was established. The overall quality of our multipinhole muSPECT images with [(123)I]R91150 in rats improved markedly after pretreatment of the animals with cyclosporin A.

Synthesis, radiosynthesis and in vivo evaluation of [I]-4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(4-iodobenzyl)piperidine as a selective tracer for imaging the dopamine transporter.

Dopamine transporter (DAT) neuroimaging is a useful tool in Parkinson's disease diagnosis, staging and follow-up providing information on the integrity of the dopaminergic neurotransmitter system in vivo. 4-(2-(Bis(4-fluorophenyl)-methoxy)ethyl)-1-(4-iodobenzyl)piperidine (7) has nanomolar affinity for DAT and better selectivity over the other monoamine transporters compared with the existing SPECT radioligands for DAT. The aim of this study was to synthesize and evaluate [(123)I]-7 as an in vivo tracer for DAT.The tributylstannyl precursor was synthesized with an overall yield of 25%. [(123)I]-7 was synthesized by electrophilic destannylation with a yield of 40±10%. Radiochemical purity appeared to be >98%, whereas specific activity was at least 667 GBq/µmol. Biodistribution studies in mice showed brain uptake of 0.96±0.53%ID/g at 30 s post injection (p.i.) and 0.26±0.02%ID/g at 3 h p.i. High blood activity was observed at all time points. Pretreatment with Cyclosporin A raised brain uptake indicating that [(123)I]-7 is transported by P-glycoprotein (P-gp) pumps. In rats, regional brain distribution of [(123)I]-7 was not in agreement with DAT distribution. These results indicate that [(123)I]-7 is not suitable for mapping DAT in vivo but could be a useful tracer for the P-gp transporter.

Cortical motor threshold determination in dogs.

In humans, determining the cortical motor threshold (CMT) is a critical step in successfully applying a transcranial magnetic stimulation (TMS) treatment. Stimulus intensity, safety and efficacy of a TMS treatment are dependent of the correct assessment of the CMT. Given that TMS in dogs could serve as a natural animal model, an accurate and reliable technique for the measurement of the CMT should be available for dogs. Using a visual descending staircase paradigm (Rossini paradigm), the CMT repeatability was assessed and compared to the electromyographic (EMG) variant. The influence of a HF-rTMS treatment on the CMT was examined. Subsequently, the CMT was measured under sedation and general anaesthesia. Finally, the coil-cortex distance was associated with the CMT, weight, age and gender. During one year the CMT was measured three times, during which it remained constant, although a higher CMT was measured (40% higher machine output) when using EMG (P-value < .001) and under general anaesthesia (P-value = .005). On average, a 40% and 12% higher machine output were registered. An aHF-rTMS protocol does not influence the CMT. Males have on average a 5.2 mm larger coil cortex distance and an 11.81% higher CMT. The CMT was positively linearly associated (P-value < .05) with the weight and age of the animals. Only within female subjects, a positive linear association was found between the CMT and the coil-cortex distance (P-value = .02). Using the visual Rossini paradigm, the CMT can be reliably used over time and during a TMS treatment. It has to be kept in mind that when using EMG or assessing the CMT under general anaesthesia, a higher CMT is to be expected. As in humans, every parameter that influences the coil-cortex distance may also influence the CMT.

Changes in canine cerebral perfusion after accelerated high frequency repetitive transcranial magnetic stimulation (HF-rTMS): A proof of concept study.

Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a treatment for several neuropsychiatric disorders in human beings, but the neurobiological effects of rTMS in dogs have not been investigated to date. A proof of concept study was designed to evaluate the effect of rTMS on cerebral perfusion, measured with single photon emission computed tomography (SPECT), in dogs. An accelerated high frequency (aHF)-rTMS (20Hz) protocol was applied to the canine left frontal cortex. To accurately target this area, eight dogs underwent a 3 Tesla magnetic resonance imaging (MRI) scan before stimulation. The left frontal cortex was subjected to five consecutive aHF-rTMS sessions with a figure-of-eight coil designed for human beings at an intensity of 110% of the motor threshold. The dogs underwent 99mTc-d,1 hexamethylpropylene amine oxime (HMPAO) SPECT scans 1 week prior to and 1day after the stimulations. Perfusion indices (PIs) were determined semi-quantitatively; aHF-rTMS resulted in significantly increased PIs in the left frontal cortex and the subcortical region, whereas no significant differences were noted for the other regions. Behaviour was not influenced by the stimulation sessions. As has been observed in human beings, aHF-rTMS applied to the left frontal cortex alters regional cerebral perfusion in dogs.

Biodistribution and tolerance of intravenous iodine-131-labelled hypericin in healthy dogs.

Hypericin (Hyp) is a necrosis-avid compound that can be efficiently labelled with radioiodine for both diagnostic and therapeutic purposes. Before 131 I-Hyp can be considered as a clinically useful drug in a combination therapy for canine cancer patients, evaluation of its toxicity is necessary. The aim of this study was to investigate the biodistribution and tolerance of a single dose administration of 131 I-Hyp. Three healthy dogs were included. 131 I-Hyp at a dose of 0.2 mg/kg and an activity of 185 MBq was intravenously injected. The effects on physical, haematological and biochemical parameters were characterized and the biodistribution and elimination pattern, the effective half-life and dose rate were assessed. Drug-related adverse events were limited to mild gastrointestinal signs, resolving within 48 hours. No significant differences were found in blood haematology and serum biochemistry before and after treatment. Following administration, highest percentage of injected dose (%ID ± SD) was found in the liver (5.5 ± 0.33), the lungs (4.17 ± 0.14) and the heart (3.11 ± 0.78). After 24 hours, highest %ID was found in colon (4.25 ± 1.45) and liver (3.45 ± 0.60). Clearance from all organs was effective within 7 days. Effective half-life was established at 80 hours, and the dose rate fell below <20 µSv/h at 1 m within 1 day. The current study reveals that single dose treatment with 131 I-Hyp at the described dose is well tolerated by healthy dogs and supports the use of radioiodinated hypericin in a combination therapy for canine cancer patients.

[The portfolio will increase the quality of specialist education]. / Het portfolio zal de kwaliteit van de speciajistenopleiding vergroten.

The portfolio gives the doctor who is undergoing training to become a specialist (Dutch abbreviation aios) a tool to help describe his or her own progress and the future targets in the training programme, and assists the trainer to obtain a more detailed insight into the educational goals that should receive more emphasis. The self-critical attitude of the aios that this helps to develop is a good guarantee for society of the thoroughness of medical specialist training.

Successful treatment of leptomeningeally metastasised pituitary carcinoma with temozolomide.

A 69-year-old man presented with leptomeningeally metastasised pituitary carcinoma, rapidly progressing despite previous treatment with resection, radiotherapy and cabergoline. The patient received temozolomide chemotherapy, resulting in a complete clinical, radiological and biochemical response after 14 cycles, which has been maintained since then. This case lends further support to the role of temozolomide in refractory pituitary tumours.

Phase I study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with 5-fluorouracil and leucovorin: a safe combination.

We performed a phase I study with the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 combined with 5-fluorouracil and leucovorin (5-FU/LV) to determine safety profile and assess pharmacokinetic interactions. Patients with advanced solid malignancies received LV 20 mg/m(2) followed by 5-FU 425 mg/m(2) both administered intravenously in 15 min daily for 5 days every 4 weeks. ABT-510 was administered subcutaneously twice daily continuously from day 2 onwards. Blood and urine samples for pharmacokinetic analyses were collected at days 1, 5 and 22. Twelve patients received a total of 45 cycles of 5-FU/LV combined with ABT-510. ABT-510 dose levels studied were 50 and 100 mg. The combination was well tolerated, with a toxicity profile comparable to that of 5-FU/LV alone. At the dose levels studied no significant pharmacokinetic interactions were observed. These data indicate that ABT-510 administered twice daily subcutaneously can be safely combined with 5-FU/LV administered daily for 5 days, every 4 weeks.

A phase I study of intraperitoneal topotecan in combination with intravenous carboplatin and paclitaxel in advanced ovarian cancer.

The aim of this study was to determine the maximum tolerated dose (MTD) of intraperitoneal (i.p.) topotecan combined with standard doses of intravenous (i.v.) carboplatin and paclitaxel and to investigate its pharmacokinetics. Women with primary ovarian cancer stage IIb - IV received six cycles of i.v. carboplatin and paclitaxel with escalating topotecan doses i.p. of 10, 15, 20 and 25 mg/m(2). Twenty-one patients entered this trial. Febrile neutropenia, thrombocytopenia requiring platelet transfusion and fatigue grade 3 were dose-limiting toxicities (DLT) at 25 mg/m(2) i.p. and 20 mg/m(2) i.p. of topotecan was considered to be the MTD. The mean plasma t(1/2) was 3.8 +/- 2.3 h for total topotecan and 4.4 +/- 3.9 h for active lactone. The area under the curve (AUC) was proportional with dose, R = 0.54, p < 0.05 for total topotecan and the peritoneal / plasma AUC ratio was 46 +/- 30. Fifteen patients who completed treatment had a median progression-free survival (PFS) of 27 months. In this setting the MTD of topotecan is 20 mg/m(2) i.p. The efficacy of this regimen should be explored further in a formal phase III study.

Endothelial cell effects of cytotoxics: balance between desired and unwanted effects.

Since Folkman defined angiogenesis more than 25 years ago as the most important process in tumour growth and metastasis, specific anti-angiogenic agents have been developed. One obvious route to block this process was until recently overlooked, however. Tumour endothelial cells are different from normal endothelial cells and may respond differently to conventional cytotoxics. Chemotherapeutic-induced vascular toxicity has been observed in various clinical studies and seems to be based on endothelial cell damage as seen in vitro in human umbilical vein endothelial cells (HUVEC) models with protracted low-dose cytostatic exposure. Translated into the clinical setting, such "metronomically" administered chemotherapy could lead to anti-angiogenesis enhancing anti-tumour efficacy of cytostatic drugs. This paper reviews the desired anti-tumour endothelial activity versus the unwanted general vascular toxicity of cytostatic drugs. Several ways to enhance the anti-tumour activity and to circumvent the unwanted vascular toxicity of these "accidental" anti-angiogenic drugs will be discussed.

Long-term survivors of ovarian malignancies after cisplatin-based chemotherapy; cardiovascular risk factors and signs of vascular damage.

Male germ cell tumour patients treated with cisplatin-based chemotherapy frequently develop cardiovascular risk factors and disease, but sparse information is available about long-term complications of this type of chemotherapy in women. We investigated the prevalence of cardiovascular risk factors and vascular damage in 21 women (median age 39 years; range 26-57 years) with an epithelial or germ cell tumour of the ovary cured by cisplatin-based chemotherapy after a median follow-up of 14 years (range 3-21 years). Hypercholesterolaemia was present in 62%, obesity in 24%, hypertension in 14%, insulin resistance in 14%, and microalbuminuria in 24% of patients. Microalbuminuria was more frequent in long-term cancer survivors than in a female background population with a similar age (23.8 versus 3.2%; P<0.05). A substantial portion of young female patients cured by cisplatin-based chemotherapy are likely to develop cardiovascular risk factors and signs of endothelial damage at an early stage.