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ABSTRACT: Many cancer patients are treated with a combination of anticancer drugs. Here, we discuss the importance of drug scheduling and the need for studies that investigate the optimal timing of the various anticancer drugs. Positron emission tomography (PET) using radiolabeled anticancer drugs could be an important tool for those studies.
Cell cycle (Georgetown, Tex.) 10/2012; 11(23). · 5.36 Impact Factor
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New England Journal of Medicine 04/2012; 366(17):1637; author reply 1638-40. · 53.30 Impact Factor
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Astrid A M Van der Veldt,
Mark Lubberink,
Idris Bahce,
Maudy Walraven,
Michiel P de Boer,
Henri N J M Greuter,
N Harry Hendrikse,
Jonas Eriksson,
Albert D Windhorst,
Pieter E Postmus,
Henk M Verheul,
Erik H Serné,
Adriaan A Lammertsma,
Egbert F Smit
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ABSTRACT: Current strategies combining anti-angiogenic drugs with chemotherapy provide clinical benefit in cancer patients. It is assumed that anti-angiogenic drugs, such as bevacizumab, transiently normalize abnormal tumor vasculature and contribute to improved delivery of subsequent chemotherapy. To investigate this concept, a study was performed in non-small cell lung cancer (NSCLC) patients using positron emission tomography (PET) and radiolabeled docetaxel ([(11)C]docetaxel). In NSCLC, bevacizumab reduced both perfusion and net influx rate of [(11)C]docetaxel within 5 hr. These effects persisted after 4 days. The clinical relevance of these findings is notable, as there was no evidence for a substantial improvement in drug delivery to tumors. These findings highlight the importance of drug scheduling and advocate further studies to optimize scheduling of anti-angiogenic drugs.
Cancer cell 01/2012; 21(1):82-91. · 25.29 Impact Factor
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ABSTRACT: Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors are effective agents in the treatment of metastatic renal cell cancer (mRCC). We here investigated whether inhibition of VEGFR signalin by sunitinib causes changes in plasma proteins associated with tumor endothelium. Forty-three patients with mRCC received sunitinib 50 mg/day in a 4-weeks on 2-weeks off schedule. Sequential plasma samples were obtained before treatment (C1D1), on C1D14, on C1D28, and on C2D1 before start of cycle 2. Plasma levels were assessed for VEGF, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular cell adhesion molecule-1 (sICAM-1), von Willebrand factor (vWF), circulating angiopoietin-2 (Ang-2) and soluble Tie-2 (sTie-2). Total tumor burden was calculated at baseline and at first evaluation. Progression-free survival (PFS) and overall survival (OS) were determined. Tumor burden was positively associated with baseline circulating Ang-2 [Spearman's rho (ρ) = 0.378, p = 0.028] and vWF (ρ = 0.417, p = 0.008). During sunitinib treatment, circulating Ang-2 and sTie-2 significantly decreased (p < 0.001 for both), plasma levels of sVCAM-1 and VEGF significantly increased (p = 0.022 and p < 0.001), whereas those of sICAM-1 and vWF remained stable. These protein changes had recovered on C2D1. The reduction in circulating Ang-2 levels on C1D28 was positively correlated with the percentage decrease in tumor burden (ρ = 0.605; p = 0.002). Baseline protein levels and subsequent changes were not associated with PFS or OS. In conclusion, sunitinib-induced changes in Ang-2, sTie-2, sVCAM-1 and VEGF are related to the administration schedule, while reduction in Ang-2 is also associated with decrease in tumor burden.
International Journal of Cancer 09/2011; 131(4):E484-93. · 5.44 Impact Factor
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Astrid A M van der Veldt,
Mark Lubberink,
Henri N Greuter,
Emile F I Comans,
Gerarda J M Herder,
Maqsood Yaqub,
Robert C Schuit,
Arthur van Lingen,
S Nafees Rizvi,
Martien P J Mooijer,
Anneloes Y Rijnders,
Albert D Windhorst,
Egbert F Smit,
N Harry Hendrikse,
Adriaan A Lammertsma
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ABSTRACT: Tumor resistance to docetaxel may be associated with reduced drug concentrations in tumor tissue. Positron emission tomography (PET) allows for quantification of radiolabeled docetaxel ([(11)C]docetaxel) kinetics and might be useful for predicting response to therapy. The primary objective was to evaluate the feasibility of quantitative [(11)C]docetaxel PET scans in lung cancer patients. The secondary objective was to investigate whether [(11)C]docetaxel kinetics were associated with tumor perfusion, tumor size, and dexamethasone administration.
Thirty-four lung cancer patients underwent dynamic PET-computed tomography (CT) scans using [(11)C]docetaxel. Blood flow was measured using oxygen-15 labeled water. The first 24 patients were premedicated with dexamethasone. For quantification of [(11)C]docetaxel kinetics, the optimal tracer kinetic model was developed and a noninvasive procedure was validated.
Reproducible quantification of [(11)C]docetaxel kinetics in tumors was possible using a noninvasive approach (image derived input function). Thirty-two lesions (size ≥4 cm(3)) were identified, having a variable net influx rate of [(11)C]docetaxel (range, 0.0023-0.0229 mL·cm(-3)·min(-1)). [(11)C]docetaxel uptake was highly related to tumor perfusion (Spearman's ρ = 0.815;P < 0.001), but not to tumor size (Spearman's ρ = -0.140; P = 0.446). Patients pretreated with dexamethasone showed lower [(11)C]docetaxel uptake in tumors (P = 0.013). Finally, in a subgroup of patients who subsequently received docetaxel therapy, relative high [(11)C]docetaxel uptake was related with improved tumor response.
Quantification of [(11)C]docetaxel kinetics in lung cancer was feasible in a clinical setting. Variable [(11)C]docetaxel kinetics in tumors may reflect differential sensitivity to docetaxel therapy. Our findings warrant further studies investigating the predictive value of [(11)C]docetaxel uptake and the effects of comedication on [(11)C]docetaxel kinetics in tumors.
Clinical Cancer Research 07/2011; 17(14):4814-24. · 7.74 Impact Factor
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European Radiology 06/2011; 21(10):2148-9; author reply 2150. · 3.22 Impact Factor
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New England Journal of Medicine 05/2011; 364(19):1873; author reply 1873-5. · 53.30 Impact Factor
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ABSTRACT: The objective of this study was to identify genetic polymorphisms related to the pharmacokinetics and pharmacodynamics of sunitinib that are associated with a prolonged progression-free survival (PFS) and/or overall survival (OS) in patients with clear-cell metastatic renal cell cancer (mRCC) treated with sunitinib.
A retrospective multicenter pharmacogenetic association study was performed in 136 clear-cell mRCC patients treated with sunitinib. A total of 30 polymorphisms in 11 candidate genes, together with clinical characteristics were tested univariately for association with PFS as primary and OS as secondary outcome. Candidate variables with P < 0.1 were analyzed in a multivariate Cox regression model.
Multivariate analysis showed that PFS was significantly improved when an A-allele was present in CYP3A5 6986A/G [hazard ratio (HR), 0.27; P = 0.032], a CAT copy was absent in the NR1I3 haplotype (5719C/T, 7738A/C, 7837T/G; HR, 1.76; P = 0.017) and a TCG copy was present in the ABCB1 haplotype (3435C/T, 1236C/T, 2677G/T; HR, 0.52; P = 0.033). Carriers with a favorable genetic profile (n = 95) had an improved PFS and OS as compared with noncarriers (median PFS and OS: 13.1 versus 7.5 months and 19.9 versus 12.3 months). Next to the genetic variants, the Memorial Sloan-Kettering Cancer Center prognostic criteria were associated with PFS and OS (HR, 1.99 and 2.27; P < 0.001).
This exploratory study shows that genetic polymorphisms in three genes involved in sunitinib pharmacokinetics are associated with PFS in mRCC patients treated with this drug. These findings advocate prospective validation and further elucidation of these genetic determinants in relation to sunitinib exposure and efficacy.
Clinical Cancer Research 02/2011; 17(3):620-9. · 7.74 Impact Factor
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ABSTRACT: In the past 5 years, the introduction of targeted therapy has dramatically changed the outcome of patients with metastatic renal cell cancer (mRCC). In particular, drugs that inhibit signaling of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) have significantly improved the perspectives of patients with this chemoresistant disease. Here, we review the currently approved targeted drugs for the treatment of mRCC. We describe the anti-VEGF monoclonal antibody bevacizumab, the receptor tyrosine kinase inhibitors sunitinib, sorafenib and pazopanib as well as the mTOR inhibitors temsirolimus and everolimus and discuss their role in the contemporary management of patients with mRCC.
Discovery medicine 11/2010; 10(54):394-405.
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ABSTRACT: The purpose of this study was to evaluate the correlation between dynamic-contrast-enhanced computed tomography (DCE-CT) and first-pass dynamic-contrast-enhanced ultrasound (DCE-US) of normal appearing liver parenchyma and of colorectal cancer liver metastases. Thirty patients with hepatic metastases from colorectal cancer underwent DCE-CT and DCE-US. To obtain DCE-US reproducibility measurements, double contrast-passages (2 × 2.4 mL SonoVue intravenous) were acquired. From several DCE-US-derived perfusion indices, the slope-value scored best with a reproducibility concordance correlation coefficient ranging from 0.75-0.93 and overall highest correlation to DCE-CT-derived variables (r = 0.52 to 0.73). The DCE-US-based tumor-to-liver perfusion gradient also showed a low test-retest variability and moderately correlated to DCE-CT (concordance correlation coefficient 0.87-0.92; r = 0.57 to 0.59). To conclude, DCE-US-based slope-value and tumor-to-liver perfusion gradient correlate best with DCE-CT perfusion values. However, both techniques cannot be used interchangeably. DCE-US should be restricted for studies in which a considerable change in perfusion is expected and for patients with a relatively high tumor blood flow at baseline.
Ultrasound in medicine & biology 10/2010; 36(10):1626-36. · 2.02 Impact Factor
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ABSTRACT: Docetaxel is an important chemotherapeutic agent used for the treatment of several cancer types. As radiolabelled anticancer agents provide a potential means for personalized treatment planning, docetaxel was labelled with the positron emitter (11)C. Non-invasive measurements of [(11)C]docetaxel uptake in organs and tumours may provide additional information on pharmacokinetics and pharmacodynamics of the drug docetaxel. The purpose of the present study was to determine the biodistribution and radiation absorbed dose of [(11)C]docetaxel in humans.
Biodistribution of [(11)C]docetaxel was measured in seven patients (five men and two women) with solid tumours using PET/CT. Venous blood samples were collected to measure activity in blood and plasma. Regions of interest (ROI) for various source organs were defined on PET (high [(11)C]docetaxel uptake) or CT (low [(11)C]docetaxel uptake). ROI data were used to generate time-activity curves and to calculate percentage injected dose and residence times. Radiation absorbed doses were calculated according to the MIRD method using OLINDA/EXM 1.0 software.
Gall bladder and liver demonstrated high [(11)C]docetaxel uptake, whilst uptake in brain and normal lung was low. The percentage injected dose at 1 h in the liver was 47 +/- 9%. [(11)C]docetaxel was rapidly cleared from plasma and no radiolabelled metabolites were detected. [(11)C]docetaxel uptake in tumours was moderate and highly variable between tumours.
The effective dose of [(11)C]docetaxel was 4.7 microSv/MBq. As uptake in normal lung is low, [(11)C]docetaxel may be a promising tracer for tumours in the thoracic region.
European Journal of Nuclear Medicine 10/2010; 37(10):1950-8. · 4.53 Impact Factor
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ABSTRACT: Quantification of tumor perfusion using radioactive water (H(2)(15)O) and PET is a promising method for monitoring treatment with antiangiogenic agents. However, use of dynamic H(2)(15)O scans together with a fully 3-dimensional clinical PET/CT scanner needs to be validated. The purpose of the present study was to assess validity and reproducibility of dynamic H(2)(15)O PET/CT scans for measuring tumor perfusion and validate the quantitative accuracy of parametric perfusion images.
Eleven patients with non-small cell lung cancer were included in this study. Patients underwent 2 dynamic H(2)(15)O (370 MBq) PET scans on the same day. During the first scan, arterial blood was withdrawn continuously. Input functions were derived from blood sampler data and the ascending aorta as seen in the images themselves (image-derived input function [IDIF]). Parametric perfusion images were computed using a basis function implementation of the standard single-tissue-compartment model. Volumes of interest (VOIs) were delineated on low-dose CT (LD-CT) and parametric perfusion images.
VOIs could be accurately delineated on both LD-CT and parametric perfusion images. These parametric perfusion images had excellent image quality and quantitative accuracy when compared with perfusion values determined by nonlinear regression. Good correlation between perfusion values derived from the blood sampler input function and IDIF was found (Pearson correlation coefficient, r = 0.964; P < 0.001). Test-retest variability of tumor perfusion was 16% and 20% when delineated on LD-CT and parametric perfusion images, respectively.
The use of ascending aorta IDIFs is an accurate alternative to arterial blood sampling for quantification of tumor perfusion. Image quality obtained with a clinical PET/CT scanner enables generation of accurate parametric perfusion images. VOIs delineated on LD-CT have the highest reproducibility, and changes of more than 16% in tumor perfusion are likely to represent treatment effects.
Journal of Nuclear Medicine 10/2010; 51(11):1684-90. · 6.38 Impact Factor
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ABSTRACT: Targeted therapy has significantly improved the perspectives of patients with metastatic renal cell cancer (mRCC). Frequently, these new molecules cause disease stabilization rather than substantial tumor regression. As treatment options expand with the growing number of targeted agents, there is an increasing need for surrogate markers to early assess tumor response. Here, we review the currently available imaging techniques and response evaluation criteria for the assessment of tumor response in mRCC patients. For computed tomography (CT), different criteria are discussed including the Response Evaluation Criteria in Solid Tumors (RECIST), the Choi criteria, the modified Choi criteria, and the size and attenuation CT (SACT) criteria. Functional imaging modalities are discussed, such as dynamic contrast-enhanced CT (DCE-CT), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), dynamic contrast-enhanced ultrasonography (DCE-US), and positron emission tomography (PET).
Targeted Oncology 06/2010; 5(2):95-112. · 3.61 Impact Factor
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Acta oncologica (Stockholm, Sweden) 05/2010; 49(4):520-3. · 2.27 Impact Factor
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ABSTRACT: Hypertension is a common side effect in cancer patients treated with inhibitors of vascular endothelial growth factor/vascular endothelial growth factor receptor-2 signaling and may represent a marker of clinical benefit. Functional rarefaction (a decrease in perfused microvessels) or structural rarefaction (a reduction in anatomic capillary density) may play an important role in the development of hypertension. We investigated whether sunitinib caused impairment of microvascular function and/or reduction of capillary density in patients with metastatic renal cell cancer (mRCC). Sixteen mRCC patients were treated with sunitinib (50 mg/day). Assessments of 24-h ambulatory blood pressure, microvascular endothelial function by laser Doppler fluxmetry, and capillary density by capillary microscopy were performed at baseline and days 14 and 28. Median blood pressure had increased on day 14 (systolic 10 mmHg, P<0.01 and diastolic blood pressure 8 mmHg, P<0.01). Capillary density had decreased from 69 to 61 capillaries/mm (P<0.01). This decrease was related to the increase in systolic and diastolic blood pressure (r=-0.57, P<0.05 and r=-0.68, P<0.01, respectively). A more pronounced decrease in capillary density was associated with increased visibility of the subpapillary plexus (P=0.041). Preliminary findings indicated that median progression-free survival was significantly prolonged in patients with a greater than 6 capillaries/mm decrease in density as compared with patients with a less pronounced decrease (P=0.044). In conclusion, reduction in skin capillary density is associated with a rise in blood pressure during sunitinib therapy and, by itself, might be useful as a predictive marker of clinical outcome.
Anti-cancer drugs 04/2010; 21(4):439-46. · 2.23 Impact Factor
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ABSTRACT: Hypertension is a common side effect in cancer patients treated with inhibitors of vascular endothelial growth factor/vascular endothelial growth factor receptor-2 signaling and may represent a marker of clinical benefit. Functional rarefaction (a decrease in perfused microvessels) or structural rarefaction (a reduction in anatomic capillary density) may play an important role in the development of hypertension. We investigated whether sunitinib caused impairment of microvascular function and/or reduction of capillary density in patients with metastatic renal cell cancer (mRCC). Sixteen mRCC patients were treated with sunitinib (50 mg/day). Assessments of 24-h ambulatory blood pressure, microvascular endothelial function by laser Doppler fluxmetry, and capillary density by capillary microscopy were performed at baseline and days 14 and 28. Median blood pressure had increased on day 14 (systolic 10 mmHg, P<0.01 and diastolic blood pressure 8 mmHg, P<0.01). Capillary density had decreased from 69 to 61 capillaries/mm2 (P<0.01). This decrease was related to the increase in systolic and diastolic blood pressure (r=−0.57, P<0.05 and r=−0.68, P<0.01, respectively). A more pronounced decrease in capillary density was associated with increased visibility of the subpapillary plexus (P=0.041). Preliminary findings indicated that median progression-free survival was significantly prolonged in patients with a greater than 6 capillaries/mm2 decrease in density as compared with patients with a less pronounced decrease (P=0.044). In conclusion, reduction in skin capillary density is associated with a rise in blood pressure during sunitinib therapy and, by itself, might be useful as a predictive marker of clinical outcome.
Anti-Cancer Drugs 03/2010; 21(4):439-446. · 2.41 Impact Factor
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The Journal of urology 02/2010; 183(4):1646-7; author reply 1647. · 4.02 Impact Factor
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JAMA The Journal of the American Medical Association 04/2009; 301(12):1227; author reply 1227. · 30.03 Impact Factor
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Journal of Clinical Oncology 03/2009; 27(8):1339-40; author reply 1340-2. · 18.37 Impact Factor
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ABSTRACT: Clarifying the diagnosis of clinically suspected recurrence of cervical cancer can be challenging. The aim of this study was to investigate the clinical value of (18)F-FDG PET in this context.
The medical records of a cohort of 40 (18)F-FDG PET referrals in whom recurrence of cervical cancer was clinically suspected were reviewed. Two expert gynecologic oncologists assessed the level of pre-PET clinical doubt, quality of pre-PET work-up, and impact of (18)F-FDG PET on diagnostic understanding and management using questionnaires.
In patients with clinically equivocal recurrence, (18)F-FDG PET had a sensitivity of 92% and a specificity of 93% (prevalence, 65%). Before (18)F-FDG PET, there was high disagreement about the adequacy of the conventional work-up (intraclass correlation coefficient [ICC], 0.25) and the presence of recurrence (ICC, 0.24). (18)F-FDG PET increased experts' confidence (median increase, 14% and 25%; P < 0.0001) and diagnostic agreement (from 68% to 98%; ICC, from 0.24 to 0.95). When (18)F-FDG PET was positive for recurrence, the median overall survival was 13 mo. For patients with negative (18)F-FDG PET findings, the median survival was not reached (log rank, 15.50, P = 0.0001). When the treatment plan was categorized as local therapy, systemic therapy, and expectative management, (18)F-FDG PET changed the treatment plan in half of all cases. The 2 experts reported that (18)F-FDG PET led to a better diagnosis and a beneficial change in management in, respectively, 60% and 65% of cases.
(18)F-FDG PET can help to clarify the diagnosis of clinically suspected recurrence of cervical cancer. In this patient population, (18)F-FDG PET had significant value in diagnostic understanding and management of recurrent cervical cancer, facilitating decision making and treatment planning. Therefore, (18)F-FDG PET should be part of the diagnostic work-up in detection of recurrent cervical cancer. The high positive predictive value of (18)F-FDG PET in these patients suggests that inclusion in intervention trials might be based on a positive (18)F-FDG PET scan.
Journal of Nuclear Medicine 11/2008; 49(12):1936-43. · 6.38 Impact Factor
