Publications by authors named "Bogdan Zurawski"

12 Publications

  • Page 1 of 1

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma.

N Engl J Med 2021 03;384(9):829-841

From the Department of Medical Oncology, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston (T.K.C.); the Department of Genitourinary Oncology, Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free National Health Service Trust, London (T.P.); the Bradford Hill Clinical Research Center, Santiago, Chile (M.B.); the Department of Medical Oncology, Gustave Roussy, Villejuif, France (B.E.); the Department of Hemato-Oncology, Urologic Oncology Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City (M.T.B.), the Department of Medical Oncology, Centro Universitario contra el Cáncer, Hospital Universitario "Dr. José Eleuterio González," Universidad Autónoma de Nuevo León, Nuevo León (V.M.O.J.), and the Department of Medical Oncology, Hospital H+ Querétaro, Querétaro (J.P.F.) - all in Mexico; the Department of Outpatient Chemotherapy, Professor Franciszek Lukaszczyk Oncology Center, Bydgoszcz (B.Z.), and the Department of Clinical Oncology and Hematology, Regional Specialist Hospital, Biała Podlaska (J. Żołnierek) - both in Poland; the Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis (J.J.H.); Oncology Unit 1, Department of Oncology, Istituto Oncologico Veneto IRCCS, Padua (U.B.), the Department of Medical Oncology, Ospedale San Donato, Istituto Toscano i, Arezzo (A.H.), the Department of Internal Medicine, University of Pavia, Pavia (C.P.), and the University of Bari "A. Moro," Bari (C.P.) - all in Italy; the Department of Genitourinary Medical Oncology, M.D. Anderson Cancer Center, Houston (A.Y.S.); the Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona (C.S.); the Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston, QLD (J.C.G.), and Cabrini Monash University Department of Medical Oncology, Cabrini Health, Malvern, VIC (D.P.) - both in Australia; the Oncology Research Center, Hospital São Lucas, Porto Alegre, Brazil (C.B.); Fundacion Richardet Longo, Instituto Oncologico de Cordoba, Cordoba (M.R.), and Instituto Multidisciplinario de Oncología, Clínica Viedma, Viedma (R.K.) - both in Argentina; the Division of Medical Oncology, Department of Internal Medicine, University of Colorado School of Medicine, Aurora (E.R.K.); the Departments of Urology and Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata (Y.T.), and the Department of Urology, Keio University School of Medicine, Tokyo (R.M.) - both in Japan; the Department of Urology, Eberhard Karls University Tübingen, Tübingen, Germany (J.B.); the Departments of Clinical Research (J. Zhang.), Clinical Oncology (M.A.M.), Biostatistics (B.S.), and Health Economics and Outcomes Research (F.E.), Bristol Myers Squibb, Princeton, NJ; the Department of Clinical Oncology, Exelixis, Alameda, CA (G.M.S.); the Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (A.B.A.); and the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (R.J.M.).

Background: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.

Methods: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point.

Results: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib.

Conclusions: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER number, NCT03141177.).
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March 2021

First-Line Nivolumab Plus Ipilimumab Versus Chemotherapy in Advanced NSCLC With 1% or Greater Tumor PD-L1 Expression: Patient-Reported Outcomes From CheckMate 227 Part 1.

J Thorac Oncol 2021 04 21;16(4):665-676. Epub 2021 Jan 21.

Princess Alexandra Hospital, Woolloongabba, Australia.

Introduction: In CheckMate 227 (NCT02477826), patients with treatment-naive stage IV or recurrent NSCLC and 1% or greater tumor programmed death ligand 1 expression had significantly improved overall survival with nivolumab plus ipilimumab versus chemotherapy. We present the patient-reported outcomes (PROs).

Methods: Patients (N = 1189) were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy. PROs were exploratory. Changes in Lung Cancer Symptom Scale (LCSS) average symptom burden index, LCSS 3-item global index, EQ-5D visual analog scale (VAS), and EQ-5D utility index were analyzed descriptively. Mixed-effect model repeated measures and time-to-first deterioration and improvement analyses were conducted.

Results: PRO completion rates were generally greater than 80%. On-treatment improvements from baseline in LCSS measures of symptom burden and global health status with nivolumab plus ipilimumab generally met or exceeded the minimal important difference (smallest clinically meaningful change) from weeks 24 and 30, respectively; improvements with chemotherapy generally remained below the minimal important difference. Mean on-treatment EQ-5D VAS scores for both treatments approached the U.K. population norm at week 24, remaining so throughout the treatment period. Mixed-effect model repeated measures analyses revealed numerically greater improvements from baseline with nivolumab plus ipilimumab versus chemotherapy across LCSS average symptom burden index and 3-item global index, and EQ-5D VAS and utility index. Nivolumab plus ipilimumab had delayed time-to-first deterioration (hazard ratio [95% confidence interval] 0.74 [0.56 to 0.98]) and a trend for more rapid time-to-first improvement (1.24 [0.98 to 1.59]) versus chemotherapy.

Conclusions: Nivolumab plus ipilimumab revealed delayed deterioration and numerical improvement in symptoms and health-related quality of life versus chemotherapy in patients with advanced NSCLC and 1% or greater programmed death ligand 1 expression.
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April 2021

First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial.

Lancet Oncol 2021 02 18;22(2):198-211. Epub 2021 Jan 18.

Department of Thoracic Oncology, Airway Research Center North, German Center for Lung Research, LungClinic, Grosshansdorf, Germany.

Background: First-line nivolumab plus ipilimumab has shown improved overall survival in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to investigate whether the addition of a limited course (two cycles) of chemotherapy to this combination would further enhance the clinical benefit.

Methods: This randomised, open-label, phase 3 trial was done at 103 hospitals in 19 countries. Eligible patients were aged 18 years or older with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) by an interactive web response system via permuted blocks (block size of four) to nivolumab (360 mg intravenously every 3 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) combined with histology-based, platinum doublet chemotherapy (intravenously every 3 weeks for two cycles; experimental group), or chemotherapy alone (every 3 weeks for four cycles; control group). Randomisation was stratified by tumour histology, sex, and PD-L1 expression. The primary endpoint was overall survival in all randomly assigned patients. Safety was analysed in all treated patients. Results reported here are from a pre-planned interim analysis (when the study met its primary endpoint) and an exploratory longer-term follow-up analysis. This study is active but no longer recruiting patients, and is registered with, number NCT03215706.

Findings: Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab with two cycles of chemotherapy (n=361 [50%]) or four cycles of chemotherapy alone (n=358 [50%]). At the pre-planned interim analysis (median follow-up 9·7 months [IQR 6·4-12·8]), overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14·1 months [95% CI 13·2-16·2] vs 10·7 months [9·5-12·4]; hazard ratio [HR] 0·69 [96·71% CI 0·55-0·87]; p=0·00065). With 3·5 months longer median follow-up (median 13·2 months [IQR 6·4-17·0]), median overall survival was 15·6 months (95% CI 13·9-20·0) in the experimental group versus 10·9 months (9·5-12·6) in the control group (HR 0·66 [95% CI 0·55-0·80]). The most common grade 3-4 treatment-related adverse events were neutropenia (in 24 [7%] patients in the experimental group vs 32 [9%] in the control group), anaemia (21 [6%] vs 50 [14%]), diarrhoea (14 [4%] vs two [1%]), increased lipase (22 [6%] vs three [1%]), and asthenia (tjree [1%] vs eight [2%]). Serious treatment-related adverse events of any grade occurred in 106 (30%) patients in the experimental group and 62 (18%) in the control group. Seven (2%) deaths in the experimental group (acute kidney failure, diarrhoea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia; one patient each) and six (2%) deaths in the control group (anaemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis; one patient each) were treatment related.

Interpretation: Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival versus chemotherapy alone and had a favourable risk-benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC.

Funding: Bristol Myers Squibb.
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February 2021

Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer.

N Engl J Med 2019 11 28;381(21):2020-2031. Epub 2019 Sep 28.

From the Memorial Sloan Kettering Cancer Center, New York (M.D.H.); Hospital Universitario Doce de Octubre, Centro Nacional de Investigaciones Oncológicas, Universidad Complutense, and Centro de Investigación Biomédica en Red de Cáncer, Madrid (L.P.-A.), Hospital Universitario Virgen Del Rocio, Seville (R.B.C.), and the Catalan Institute of Oncology-Germans Trias i Pujol Hospital, Badalona (E.C.C.) - all in Spain; Ambulatorium Chemioterapii, Bydgoszcz, Poland (B.Z.); the Asan Medical Center (S.-W.K.) and the Samsung Medical Center at Sungkyunkwan University School of Medicine (K.P.) - both in Seoul, South Korea; the Institute of Oncology Prof. Dr. Alexandru Trestioreanu, Bucharest, Romania (A.A.); the Hospital Italiano de Buenos Aires, Buenos Aires (L.L.); Instituto Jalisciense de Cancerologia, Guadalajara, Mexico (E.M.J.); the Saitama Cancer Center, Saitama, Japan (H.S.); Matrai Gyogyintezet, Matrahaza, Hungary (I.A.); Limoges University Hospital, Limoges (A.V.), and Aix-Marseille University, National Center for Scientific Research, INSERM, Centre de Recherche en Cancérologie de Marseille, Assistance Publique-Hôpitaux de Marseille, Marseille (F.B.) - all in France; Centre Hospitalier Universitaire Vaudois, Lausanne University, Lausanne, Switzerland (S.P.); Sotiria General Hospital, National and Kapodistrian University of Athens, Athens (K.S.); Lung Clinic Grosshansdorf, Airway Research Center North, German Center of Lung Research, Grosshansdorf, Germany (M.R.); Fox Chase Cancer Center, Philadelphia (H.B.); Johns Hopkins Kimmel Cancer Center, Baltimore (J.R.B.); Princess Alexandra Hospital, Brisbane, QLD, Australia (K.J.O.); Bristol-Myers Squibb, Princeton, NJ (W.J.G., P.B., S.K.R., R.S.K., F.E.N.); and Winship Cancer Institute, Emory University, Atlanta (S.S.R.).

Background: In an early-phase study involving patients with advanced non-small-cell lung cancer (NSCLC), the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy, particularly among patients with tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC.

Methods: In this open-label, phase 3 trial, we randomly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The patients who had a PD-L1 expression level of less than 1% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone. All the patients had received no previous chemotherapy. The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1% or more.

Results: Among the patients with a PD-L1 expression level of 1% or more, the median duration of overall survival was 17.1 months (95% confidence interval [CI], 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (P = 0.007), with 2-year overall survival rates of 40.0% and 32.8%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with nivolumab plus ipilimumab and 12.2 months (95% CI, 9.2 to 14.3) with chemotherapy. Among all the patients in the trial, the median duration of overall survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 months (95% CI, 12.2 to 15.1) with chemotherapy. The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy.

Conclusions: First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 number, NCT02477826.).
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November 2019

Detection of somatic mutations in ctDNA derived from adenocarcinoma patients - EGFR tyrosine kinase inhibitor monitoring preliminary study.

Contemp Oncol (Pozn) 2019 13;23(2):87-91. Epub 2019 Jun 13.

Department of Thoracic Surgery and Tumours, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Poland.

Aim Of The Study: The main purpose of this study was to assess detection of mutations in the epidermal growth factor receptor (EGFR) gene in circulating tumor DNA (ctDNA) as a tool for EGFR tyrosine kinase inhibitor (TKI) monitoring therapy.

Material And Methods: The study was conducted using 20 samples from 7 adenocarcinoma patients treated with TKIs. Blood samples for ctDNA analysis were collected in 2015-2016. ctDNA was isolated using the QIAamp Circulating Nucleic Acid Kit (Qiagen) and analyzed using the ctEGFR Mutation Detection Kit (EntroGen).

Results: The most common exon 19 deletion and p.Leu858Arg mutation in exon 21 of the EGFR gene were detected. We observed a correlation between stabilization of patient condition and the lack of p.Thr790Met mutation detection in ctEGFR during TKI treatment (2 out of 7 patients). We also observed a correlation between progression of the disease and p.Thr790Met mutation detection in ctEGFR (3 out of 7 cases). We did not detect ctDNA p.Thr790Metp in two patients in whom progression occurred shortly thereafter. Last but not least, we noticed that good organization during plasma collection and transportation (average time of 6 minutes and 30 seconds) allows to use K2EDTA tubes.

Conclusions: When tissue is limited or insufficient, analysis of the ctEGFR mutational status can be considered as an alternative tool for qualifying patients with non-small cell lung cancer (NSCLC) for TKI therapy, also as a potential monitoring tool. The plasma p.Thr790Met-negative result needs to be verified for the presence of p.Thr790Met-positive tumor tissue.
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June 2019

A systemic literature review of neuroimaging studies in women with breast cancer treated with adjuvant chemotherapy.

Contemp Oncol (Pozn) 2017 22;21(1):6-15. Epub 2017 Mar 22.

The Franciszek Lukaszczyk Oncology Center, Bydgoszcz, Poland.

Chemotherapy-induced cognitive deficits in patients with breast cancer, predominantly in attention and verbal memory, have been observed in numerous studies. These neuropsychological findings are corroborated by the results of neuroimaging studies. The aim of this paper was to survey the reports on cerebral structural and functional alterations in women with breast cancer treated with chemotherapy (CTx). First, we discuss the host-related and disease-related mechanisms underlying cognitive impairment after CTx. We point out the direct and indirect neurotoxic effect of cytostatics, which may cause: a damage to neurons or glial cells, changes in neurotransmitter levels, deregulation of the immune system and/or cytokine release. Second, we focus on the results of neuroimaging studies on brain structure and function that revealed decreased: density of grey matter, integrity of white matter and volume of multiple brain regions, as well as their lower activation during cognitive task performance. Finally, we concentrate on compensatory mechanisms, which activate additional brain areas or neural connection to reach the premorbid cognitive efficiency.
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March 2017

Potential Role of Methylation Marker in Glioma Supporting Clinical Decisions.

Int J Mol Sci 2016 Nov 10;17(11). Epub 2016 Nov 10.

Molecular Oncology and Genetics Department, The F. Lukaszczyk Oncology Center, 85-796 Bydgoszcz, Poland.

The /2 gene mutations, loss/mutation, 1p/19q status, and promoter methylation are increasingly used as prognostic or predictive biomarkers of gliomas. However, the effect of their combination on radiation therapy outcome is discussable. Previously, we demonstrated that the c.G395A; p.R132H mutation was associated with longer survival in grade II astrocytoma and GBM (Glioblastoma). Here we analyzed the promoter methylation status in patients with a known mutation status in codon 132 of , followed by clinical and genetic data analysis based on the two statuses. After a subtotal tumor resection, the patients were treated using IMRT (Intensity-Modulated Radiation Therapy) with 6 MeV photons. The total dose was: 54 Gy for astrocytoma II, 60 Gy for astrocytoma III, 60 Gy for glioblastoma, 2 Gy per day, with 24 h intervals, five days per week. The patients with promoter methylation and somatic mutation (OS = 40 months) had a better prognosis than those with methylation alone (OS = 18 months). In patients with astrocytoma anaplasticum ( = 7) with the p.R132H mutation and hypermethylated , the prognosis was particularly favorable (median OS = 47 months). In patients with astrocytoma II meeting the above criteria, the prognosis was also better than in those not meeting those criteria. The mutation appears more relevant for the prognosis than methylation. The p.R132H mutation combined with hypermethylation seems to be the most advantageous for treatment success. Patients not meeting those criteria may require more aggressive treatments.
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November 2016

Verbal fluency in breast cancer patients treated with chemotherapy.

Breast Cancer 2017 May 19;24(3):376-383. Epub 2016 Jul 19.

Institute of Psychology, Kazimierz Wielki University, Staffa 1, 85-867, Bydgoszcz, Poland.

Background: Cognitive decline caused by chemotherapy used in the treatment of malignant diseases was reported in several studies. ICCTF recommends the diagnosis of cognitive function in patient treated with chemotherapy. One of the suggested method is Verbal Fluency Test (VFT).

Methods: Study was carried out on a group of 30 women with early breast cancer treated with adjuvant chemotherapy and 29 healthy controls. The patients underwent neuropsychological assessment using VFT at three time points: T1: before chemotherapy, T2: mid-chemotherapy and T3: post-chemotherapy. The examination in healthy controls was conducted at the same time intervals.

Results: In phonetic fluency task patients produced more words at T2 compared to T1 (Z = 2.02; p < 0.05) and at T3 compared to T1, both patients (Z = 2.36; p < 0.05) and controls (Z = 2.57; p < 0.01). The patients scored lower than controls (Z = -2.04; p < 0.05) as well as on average cluster size in the same task (Z = -2.38; p < 0.05) at T3, while they scored higher on the number of phonetic switches at T2 compared to T1 (Z = 2.62; p < 0.01) and at T3 compared to T1 (Z = 2.50; p < 0.01). In semantic task controls produced more words at T3 than at T1 (Z = 2.62; p < 0.01) and at T3 compared to T2 (Z = 2.89; p < 0.01) and semantic clusters at T3 compared to T2 (Z = 2.43; p < 0.05). In patients, number of clusters was smaller at T3 compared to T2 (Z = -2.85; p < 0.05), while number of semantic switches was higher at T3 than at T2 (Z = 3.05; p < 0.01). Patients scored also lower than controls on number of semantic switches at T2 (Z = -2.05; p < 0.05).

Conclusions: Chemotherapy does not decrease verbal fluency, but it has a negative impact on semantic memory.
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May 2017

CEREBEL (EGF111438): A Phase III, Randomized, Open-Label Study of Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer.

J Clin Oncol 2015 May 20;33(14):1564-73. Epub 2015 Jan 20.

Xavier Pivot, Centre Hospitalier Universitaire, Hôpital Jean Minjoz, Besançon, France; Alexey Manikhas, St Petersburg City Oncology Dispensary; Vladimir Semiglazov, Petrov Research Institute of Oncology, St Petersburg, Russian Federation; Bogdan Żurawski, Franciszek Lukaszczyk Oncology Center, Bydgoszcz; Ewa Chmielowska, Centrum Onkologii im. Prof Franciszka Lukaszczyka Oddzial Kliniczny Onkologii, Bydgoszcz, and Uniwersytet Mikolaja Kopernika Torun, Torun; Boguslawa Karaszewska, Przychodnia Lekarska KOMED, ul Wojska Polskiego 6, Konin, Poland; Rozenn Allerton, The Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Stephen Chan, Nottingham University Hospital, Nottingham; Roma Parikh and Fareha Nagi, GlaxoSmithKline, Uxbridge, United Kingdom; Alessandra Fabi, "Regina Elena" National Cancer Institute, Rome; Paolo Bidoli, Azienda Ospedaliera San Gerardo di Monza U.O. Oncologia Medica, Monza, Lombardia; Stefania Gori, Azienda Ospedaliera di Perugia, Ospedale S. Maria della Misericordia, Struttura Complessa di Oncologia Medica, Perugia, Umbria, and Azienda Ospedaliera Sacro Cuore-Don Calabria-Negrar, Negrar, Verona, Italy; Eva Ciruelos, Hospital Universitario 12 de Octubre, Madrid, Spain; Magdolna Dank, SE Radiológiai és Onkoterápiás Klinika; Lajos Hornyak, Veszprém Megyei Csolnoky Ferenc Kórház, Onkológiai Osztály, Budapest, Hungary; Sara Margolin, Karolinska University Hospital, Stockholm, Sweden; Arnd Nusch, Gem Praxis Drs Nusch, Kalhori und Langer, Friedrichstr, Velbert, Germany; and Michelle DeSilvio, Sergio Santillana, and Ramona F. Swaby, GlaxoSmithKline, Collegeville, PA.

Purpose: CEREBEL compared the incidence of CNS metastases as first site of relapse in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer receiving lapatinib-capecitabine or trastuzumab-capecitabine.

Patients And Methods: Patients without baseline CNS metastases were randomly assigned (1:1) to receive lapatinib-capecitabine (lapatinib 1,250 mg per day; capecitabine 2,000 mg/m(2) per day on days 1 to 14 every 21 days) or trastuzumab-capecitabine (trastuzumab loading dose of 8 mg/kg followed by an infusion of 6 mg/kg every 3 weeks; capecitabine 2,500 mg/m(2) per day on days 1 to 14 every 21 days). The primary end point was incidence of CNS metastases as first site of relapse. Secondary end points included progression-free survival (PFS) and overall survival (OS).

Results: The study was terminated early with 540 enrolled patients (271 received lapatinib-capecitabine, and 269 received trastuzumab-capecitabine). Incidence of CNS metastases as first site of relapse was 3% (eight of 251 patients) for lapatinib-capecitabine and 5% (12 of 250 patients) for trastuzumab-capecitabine (treatment differences, -1.6%; 95% CI, -2% to 5%; P = .360). PFS and OS were longer with trastuzumab-capecitabine versus lapatinib-capecitabine (hazard ratio [HR] for PFS, 1.30; 95% CI, 1.04 to 1.64; HR for OS, 1.34; 95% CI, 0.95 to 1.64). Serious adverse events were reported in 13% (34 of 269 patients) and 17% (45 of 267 patients) of patients in the lapatinib-capecitabine and trastuzumab-capecitabine arms, respectively.

Conclusion: CEREBEL is inconclusive for the primary end point, and no difference was detected between lapatinb-capecitabine and trastuzumab-capecitabine for the incidence of CNS metastases. A better outcome was observed with trastuzumab-capecitabine in the overall population. However, lapatinib-capecitabine efficacy may have been affected by previous exposure to a trastuzumab regimen and/or when treatment was given as first- or second-line therapy in the metastatic setting.
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May 2015

Impact of specific KRAS mutation in exon 2 on clinical outcome of chemotherapy- and radiotherapy-treated colorectal adenocarcinoma patients.

Mol Diagn Ther 2014 Oct;18(5):559-66

Department of Radiotherapy, The F. Lukaszczyk Oncology Center, Bydgoszcz, Poland,

Background And Objectives: Knowledge obtained via high-throughput technologies, used for tumor genome sequencing or identifying gene expression and methylation signatures, is clinically applicable thanks to molecular characterization in the context of tumor development and progression. This study was conducted to assess the impact of specific KRAS mutation in codons 12 and 13 on clinical outcome of chemotherapy and radiotherapy in colorectal cancer patients.

Methods: A total of 239 samples of colorectal adenocarcinoma underwent histological evaluation and DNA isolation.

Results And Conclusions: Patients with a mutation in KRAS codon 13 experienced worse outcome than those with a mutation in KRAS codon 12. Moreover, the cases of mutations in KRAS codons 12 or 13 were associated with a significantly higher mortality than the cases of wild-type KRAS, and some patients with KRAS mutated in codon 12 had an exceptionally long overall survival. Finally, primary preoperative radiation therapy followed by surgery significantly increased overall survival more efficiently than surgery followed by chemotherapy. This should be investigated in further studies. The fact that all patients treated with radiotherapy + surgery were alive, again focused our attention on the effect of preoperative radiation therapy on the prognosis for colorectal cancer patients. However, the number of patients in this subgroup is too small to allow any specific explanation for this observation. We should, rather, point out a problem for further investigation.
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October 2014

KRAS and BRAF mutation analysis in colorectal adenocarcinoma specimens with a low percentage of tumor cells.

Mol Diagn Ther 2013 Jun;17(3):193-203

Molecular Oncology and Genetics Unit, Department of Tumor Pathology and Pathomorphology, Franciszek Lukaszczyk Oncology Center, ul. dr I. Romanowskiej 2, 85-796, Bydgoszcz, Poland.

Background And Objective: The rapid development of molecular biology techniques allows for the introduction of real-time polymerase chain reaction (PCR) methods with a limit of mutation detection at 1% in a background of wild-type DNA. Analysis of KRAS mutations in codons 12, 13, and 61, together with analysis of BRAF mutations in codon 600, are predictive biomarkers for anti-epidermal growth factor receptor (EGFR) treatment in colorectal cancer. Our aim was to compare PCR methods for KRAS mutations and BRAF mutation analysis using DNA isolated from tissue samples previously evaluated for presence of tumor cells using a quantitative scale and the percentage of tumor cells (PTC) scale. We addressed the question of whether a low number of tumor cells can be qualified for somatic mutation testing.

Results: Our study showed that PTC as low as 10% was good enough to detect KRAS G12D, G13D, and Q61L mutations in formalin-fixed paraffin-embedded (FFPE) material. Furthermore, our results indicate that up to 20% of colorectal cancer may carry mutations in the KRAS codon 61 and BRAF codon 600, which suggests the value of these mutation analyses because patients carrying them are unlikely to respond to cetuximab or panitumumab. A low level of KRAS somatic mutation detection has not been studied in depth in the context of clinical outcomes in patients; therefore, we compared new PCR methods, (KRBR-RT 50 Entrogen; ViennaLab StripAssay) and re-evaluated KRAS and BRAF status in patients with relapse after targeted therapy.

Conclusions: The importance of molecular results was confirmed by clinical observation of a patient with relapse who had qualified for targeted therapy with KRAS WT status (but was diagnosed by less sensitive single-stranded conformation polymorphisms method). Interestingly, during anti-EGFR treatment, it came to the selection of cells with KRAS G12C mutation which were present from the beginning in the tumor but at a low level (detected by PCR methods) only and led consequently to the metastasis. Taking into consideration the limit of detection, labor time, and assay cost, the real-time PCR method seems to be very promising especially for FFPE material with the PTC below 15%.
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June 2013

[The assessment of temperament, quality of life and intensity of depressive symptoms in patients with Hodgkin's disease in different stages of the illness].

Psychiatr Pol 2005 Jul-Aug;39(4):679-90

Centrum Onkologii w Bydgoszczy.

Hodgkin's disease is an oncology illness of unknown aetiology connected with high risk of psychological disturbances, depressive symptoms and poorer quality of life. The aim of this study was to assess temperamental factors, intensity of depression and quality of life in patients with Hodgkin's disease in the diagnostic period, active oncology treatment and in remission. In this study 50 subjects with a diagnosis of Hodgkin's disease participated, all aged 20-65 years. Temperament was assessed using the Zawadzki and Strelau Temperament Scale, quality of life was measured using the WHO QL scale. The intensity of depressive symptoms was evaluated by the 17-item Hamilton Depression Rating Scale. The results obtained suggested a possibility of changes in temperamental factors of patients with Hodgkin's disease in different stages of the illness, a significant increase of depressive symptoms and the association between intensity of depression and quality of life as well as intensity of temperamental changes. The differences between the results obtained in male and female subjects with Hodgkin's disease indicate different coping mechanisms in male and female patients.
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December 2005