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Ancukiewicz, Marek

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Ancukiewicz

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Marek

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Ancukiewicz, Marek
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    A Safety and Survival Analysis of Neoadjuvant Bevacizumab with Standard Chemoradiation in a Phase I/II Study Compared with Standard Chemoradiation in Locally Advanced Rectal Cancer
    (Alphamed Press, 2010) Willett, C. G.; Duda, Dan; Ancukiewicz, Marek; Shah, M.; Czito, B. G.; Bentley, R.; Poleski, M.; Fujita, H.; Lauwers, Gregory Y.; Carroll, M.; Tyler, D.; Mantyh, C.; Shellito, Paul; Chung, Daniel; Clark, Jeffrey; Jain, Rakesh
    Introduction. Bevacizumab is increasingly being tested with neoadjuvant regimens in patients with localized cancer, but its effects on metastasis and survival remain unknown. This study examines the long-term outcome of clinical stage II/III rectal cancer patients treated in a prospective phase II study of bevacizumab with chemoradiation and surgery. As a benchmark, we used data from an analysis of 42 patients with locally advanced rectal cancer treated with a contemporary approach of preoperative fluoropyrimidine-based radiation therapy. Materials and Methods. Outcome analyses were performed on 32 patients treated prospectively with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery as well as 42 patients treated with standard fluoropyrimidine-based chemoradiation. Results. Overall survival, disease-free survival, and local control showed favorable trends in patients treated with bevacizumab with chemoradiation followed by surgery. Acute and postoperative toxicity appeared acceptable. Conclusions. Neoadjuvant bevacizumab with standard chemoradiation and surgery shows promising long-term efficacy and safety profiles in locally advanced rectal cancer patients.
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    Plasma Soluble VEGFR-1 Is a Potential Dual Biomarker of Response and Toxicity for Bevacizumab with Chemoradiation in Locally Advanced Rectal Cancer
    (Alphamed Press, 2010) Duda, Dan; Willett, Calvin; Ancukiewicz, Marek; di Tomaso, E.; Shah, M.; Czito, B. G.; Bentley, R.; Poleski, M.; Lauwers, Gregory Y.; Carroll, M.; Tyler, D.; Mantyh, C.; Shellito, Paul; Clark, J. W.; Jain, R. K.
    We explored plasma and urinary concentrations of two members of the vascular endothelial growth factor (VEGF) family and their receptors as potential response and toxicity biomarkers of bevacizumab with neoadjuvant chemoradiation in patients with localized rectal cancer. The concentrations of VEGF, placental growth factor (PlGF), soluble VEGF receptor 1 (sVEGFR-1), and sVEGFR-2 were measured in plasma and urine at baseline and during treatment. Pretreatment values and changes over time were analyzed as potential biomarkers of pathological response to treatment as well as for acute toxicity in patients with locally advanced rectal cancer treated prospectively in 2002–2008 with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery in a phase I/II trial. Of all biomarkers, pretreatment plasma sVEGFR-1—an endogenous blocker of VEGF and PlGF, and a factor linked with “vascular normalization”—was associated with both primary tumor regression and the development of adverse events after neoadjuvant bevacizumab and chemoradiation. Based on the findings in this exploratory study, we propose that plasma sVEGFR-1 should be further studied as a potential biomarker to stratify patients in future studies of bevacizumab and/or cytotoxics in the neoadjuvant setting.
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    A single-nucleotide polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene is associated with risk of radiation pneumonitis in lung cancer patients treated with thoracic radiation therapy
    (Wiley-Blackwell, 2011) Mak, Raymond; Alexander, Brian; Asomaning, Kofi; Suk Heist, Rebecca; Liu, Chen-yu; Su, Li; Zhai, Rihong; Ancukiewicz, Marek; Napolitano, Brian; Niemierko, Andrzej; Willers, Henning; Choi, Noah; Christiani, David
    Background: To study the association between functional single nucleotide polymorphisms (SNPs) in candidate genes from oxidative stress pathways, and risk of radiation pneumonitis (RP) in patients treated with thoracic radiation therapy (RT) for locally advanced lung cancer (LC). Methods: We reviewed 136 patients treated with RT for LC between 2001 and 2007, and had prior genotyping of functional SNPs in oxidative stress genes including superoxide dismutase 2 (SOD2; rs4880) and methylenetetrahydrofolate reductase (MTHFR; rs1801131, rs1801133). RP events were retrospectively scored using the Common Terminology Criteria for Adverse Events, version 4.0. Cox proportional hazard regression was performed to identify clinical variables and genotypes associated with risk of grade ≥2 and grade ≥3 RP on univariate and multivariate analysis. P-values were corrected for multiple hypothesis testing. Results: With a median follow-up of 21.4 months, the incidence of ≥grade 2 RP was 29% and ≥grade 3 RP was 14%. On multivariate analysis, after adjusting for clinical factors such as concurrent chemotherapy, and consolidation docetaxel, and lung dosimetric parameters such as V20 and mean lung dose, MTHFR genotype (rs1801131; AA versus AC/CC) was significantly associated with risk of ≥grade 2 RP (Hazard ratio [HR]: 0.37; 95% confidence interval [CI]: 0.18-0.76; p=0.006, corrected p=0.018) and ≥grade 3 RP (HR: 0.21; 95% CI: 0.06-0.70; p=0.01; corrected p=0.03). SOD2 genotype was not associated with RP. Conclusions: Our study showed an association between MTHFR genotype and risk of clinically significant RP. Further study of MTHFR-related pathways may provide insight into the mechanisms behind RP.
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    AZD2171, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma Patients
    (Elsevier BV, 2007) Batchelor, Tracy; Sorensen, Alma Gregory; di Tomaso, Emmanuelle; Zhang, Wei-Ting; Duda, Dan; Cohen, Kenneth S.; Kozak, Kevin R.; Cahill, Daniel; Chen, Poe-Jou; Zhu, Mingwang; Ancukiewicz, Marek; Mrugala, Maciej M.; Plotkin, Scott; Drappatz, Jan; Louis, David; Ivy, Percy; Scadden, David; Benner, Thomas; Loeffler, Jay; Wen, Patrick; Jain, Rakesh
    Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171—an oral tyrosine kinase inhibitor of VEGF receptors—has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1α, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.
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    Phase II Study of Cediranib, an Oral Pan–Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent Glioblastoma
    (American Society of Clinical Oncology (ASCO), 2010) Batchelor, Tracy; Duda, Dan; di Tomaso, Emmanuelle; Ancukiewicz, Marek; Plotkin, Scott; Gerstner, Elizabeth; Eichler, April; Drappatz, Jan; Hochberg, Fred H; Benner, Thomas; Louis, David; Cohen, Kenneth S.; Chea, Houng; Exarhopoulos, Alexis; Loeffler, Jay; Moses, Marsha; Ivy, Percy; Sorensen, Alma Gregory; Wen, Patrick; Jain, Rakesh
    Purpose Glioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of cediranib in patients with recurrent glioblastoma. Methods Cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points. Results Thirty-one patients with recurrent glioblastoma were accrued. APF6 after cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using two-dimensional measurements. For the 15 patients who entered the study taking corticosteroids, the dose was reduced (n = 10) or discontinued (n = 5). Toxicities were manageable. Grade 3/4 toxicities included hypertension (four of 31; 12.9%); diarrhea (two of 31; 6.4%); and fatigue (six of 31; 19.4%). Fifteen (48.4%) of 31 patients required at least one dose reduction and 15 patients required temporary drug interruptions due to toxicity. Drug interruptions were not associated with outcome. Changes in plasma placental growth factor, basic fibroblast growth factor, matrix metalloproteinase (MMP) -2, soluble VEGF receptor 1, stromal cell–derived factor-1α, and soluble Tek/Tie2 receptor and in urinary MMP-9/neutrophil gelatinase-associated lipocalin activity after cediranib were associated with radiographic response or survival. Conclusion Cediranib monotherapy for recurrent glioblastoma is associated with encouraging proportions of radiographic response, 6-month progression-free survival, and a steroid-sparing effect with manageable toxicity. We identified early changes in circulating molecules as potential biomarkers of response to cediranib. The efficacy of cediranib and the predictive value of these candidate biomarkers will be explored in prospective trials.
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    Potential of 18F-FDG PET toward personalized radiotherapy or chemoradiotherapy in lung cancer
    (Springer-Verlag, 2013) Choi, Noah; Chun, Tristen T.; Niemierko, Andrzej; Ancukiewicz, Marek; Fidias, Panos M.; Kradin, Richard; Mathisen, Douglas; Lynch, Thomas J.; Fischman, Alan J.
    Purpose We investigated the metabolic response of lung cancer to radiotherapy or chemoradiotherapy by 18F-FDG PET and its utility in guiding timely supplementary therapy. Methods: Glucose metabolic rate (MRglc) was measured in primary lung cancers during the 3 weeks before, and 10–12 days (S2), 3 months (S3), 6 months (S4), and 12 months (S5) after radiotherapy or chemoradiotherapy. The association between the lowest residual MRglc representing the maximum metabolic response (MRglc-MMR) and tumor control probability (TCP) at 12 months was modeled using logistic regression. Results: We accrued 106 patients, of whom 61 completed the serial 18F-FDG PET scans. The median values of MRglc at S2, S3 and S4 determined using a simplified kinetic method (SKM) were, respectively, 0.05, 0.06 and 0.07 μmol/min/g for tumors with local control and 0.12, 0.16 and 0.19 μmol/min/g for tumors with local failure, and the maximum standard uptake values (SUVmax) were 1.16, 1.33 and 1.45 for tumors with local control and 2.74, 2.74 and 4.07 for tumors with local failure (p < 0.0001). MRglc-MMR was realized at S2 (MRglc-S2) and the values corresponding to TCP 95 %, 90 % and 50 % were 0.036, 0.050 and 0.134 μmol/min/g using the SKM and 0.70, 0.91 and 1.95 using SUVmax, respectively. Probability cut-off values were generated for a given level of MRglc-S2 based on its predicted TCP, sensitivity and specificity, and MRglc ≤0.071 μmol/min/g and SUVmax ≤1.45 were determined as the optimum cut-off values for predicted TCP 80 %, sensitivity 100 % and specificity 63 %. Conclusion: The cut-off values (MRglc ≤0.071 μmol/min/g using the SKM and SUVmax ≤1.45) need to be tested for their utility in identifying patients with a high risk of residual cancer after standard dose radiotherapy or chemoradiotherapy and in guiding a timely supplementary dose of radiation or other means of salvage therapy. Electronic supplementary material The online version of this article (doi:10.1007/s00259-013-2348-4) contains supplementary material, which is available to authorized users.
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    Effects of Sorafenib on Intra-Tumoral Interstitial Fluid Pressure and Circulating Biomarkers in Patients with Refractory Sarcomas (NCI Protocol 6948)
    (Public Library of Science, 2012) Raut, Chandrajit; Boucher, Yves; Duda, Dan; Morgan, Jeffrey; Quek, Richard; Ancukiewicz, Marek; Lahdenranta, Johanna; Eder, Joseph Paul; Demetri, George; Jain, Rakesh
    Purpose: Jain Sorafenib is a multi-targeted tyrosine kinase inhibitor with therapeutic efficacy in several malignancies. Sorafenib may exert its anti-neoplastic effect in part by altering vascular permeability and reducing intra-tumoral interstitial hypertension. As correlative science with a phase II study in patients with advanced soft-tissue sarcomas (STS), we evaluated the impact of this agent on intra-tumor interstitial fluid pressure (IFP), serum circulating biomarkers, and vascular density. Patients and Methods: Patients with advanced STS with measurable disease and at least one superficial lesion amenable to biopsy received sorafenib 400 mg twice daily. Intratumoral IFP and plasma and circulating cell biomarkers were measured before and after 1–2 months of sorafenib administration. Results were analyzed in the context of the primary clinical endpoint of time-to-progression (TTP). Results: In 15 patients accrued, the median TTP was 45 days (range 14–228). Intra-tumoral IFP measurements obtained in 6 patients at baseline showed a direct correlation with tumor size. Two patients with stable disease at two months had post-sorafenib IFP evaluations and demonstrated a decline in IFP and vascular density. Sorafenib significantly increased plasma VEGF, PlGF, and SDF1\(\alpha\) and decreased sVEGFR-2 levels. Increased plasma SDF1\(\alpha\) and decreased sVEGFR-2 levels on day 28 correlated with disease progression. Conclusions: Pretreatment intra-tumoral IFP correlated with tumor size and decreased in two evaluable patients with SD on sorafenib. Sorafenib also induced changes in circulating biomarkers consistent with expected VEGF pathway blockade, despite the lack of more striking clinical activity in this small series.