INTRODUCTION: This study aimed to better understand panitumumab use in real-life clinical practice in first- and second-line treatment of metastatic colorectal cancer in five European countries. METHODS: This is a combined analysis of two observational, non-interventional prospective cohort studies, one of which was conducted in Germany and France, the other in Bulgaria, Czech Republic, and Hungary. The studies observed patients with wild-type [Kirsten] rat sarcoma viral oncogene homolog ([K]RAS/RAS) metastatic colorectal cancer (mCRC), who had been treated with panitumumab in combination with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in the first line or with panitumumab combined with fluorouracil, leucovorin, and irinotecan (FOLFIRI) in the second line following fluoropyrimidine-based chemotherapy. The planned duration of observation was 12 months from the first dose of panitumumab. RESULTS: A total of 332 patients treated with panitumumab + FOLFOX in the first line and 94 patients treated with panitumumab + FOLFIRI in the second line were analyzed. The median number of panitumumab infusions was 10.0 in first-line FOLFOX patients and 11.5 in second-line FOLFIRI patients; the median duration of panitumumab exposure was 5.7 and 6.9 months, respectively. The unadjusted overall response rate (complete or partial response) in patients with available post-baseline response assessment (n = 290) was 51.7% in first-line FOLFOX and 44.9% in second-line FOLFIRI patients. In the first-line setting, resectability was achieved in 9.3%. Reported hospitalizations were mostly cancer-related visits such as scheduled anticancer treatment administrations, tumor assessment visits, or interventions. The majority of adverse drug reactions were skin disorders, with 75.3% in first-line FOLFOX patients and 72.3% in second-line FOLFIRI patients. CONCLUSION: Overall, the study results show that treatment patterns, clinical efficacy, and the safety profile of panitumumab in routine clinical practice were comparable to those in randomized controlled trials. The relatively low skin toxicity rate could be attributed to increasing experience in managing panitumumab-associated rash and some degree of underreporting. FUNDING: Amgen.

• Klíčová slova
• Metastatic colorectal cancer, Observational study, Panitumumab, RAS wild-type, Real-world data, Tumor location,
• MeSH
• dospělí MeSH
• fluoruracil aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• kamptothecin aplikace a dávkování   škodlivé účinky   analogy a deriváty   terapeutické užití   MeSH
• kohortové studie MeSH
• kolorektální nádory farmakoterapie   patologie   MeSH
• leukovorin aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• monoklonální protilátky terapeutické užití   MeSH
• organoplatinové sloučeniny aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• panitumumab aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• prospektivní studie MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• Ras proteiny biosyntéza   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• fluoruracil MeSH
• kamptothecin MeSH
• leukovorin MeSH
• monoklonální protilátky MeSH
• organoplatinové sloučeniny MeSH
• panitumumab MeSH
• Ras proteiny MeSH

BACKGROUND: NLRC5 is an interferon γ-inducible protein, which plays a role in immune surveillance with a potential influence on cancer survival. OBJECTIVE: We aimed to evaluate the effect of potential regulatory variants in NLRC5 on overall survival and survival after 5-fluorouracil (5-FU)-based therapy of colorectal cancer (CRC) patients. PATIENTS AND METHODS: We carried out a case-only study in a Czech population of 589 cases; 232 received 5-FU-based therapy. Eleven variants within NLRC5 were selected using in-silico tools. Associations between polymorphisms and survival were assessed by Cox regression analysis adjusting for age at diagnosis, sex, and TNM stage. Survival curves were derived using the Kaplan-Meier method. RESULTS: Two variants showed a significant association with survival. All patients and metastasis-free patients at the time of diagnosis (pM0) who were homozygous carriers of the minor allele of rs27194 had a decreased overall survival (OSall and OSpM0) and event-free survival (EFSpM0) under a recessive model (OSall P=0.003, OSpM0 P=0.005, EFSpM0 P=0.01, respectively). OS was also decreased for all patients and for pM0 patients who carried at least one minor allele of rs289747 (OSall P=0.03 and OSpM0 P=0.003, respectively). Among CRC patients, who underwent a 5-FU-based adjuvant regimen, rs12445252 was associated with OSall, OSpM0 and EFSpM0, according to the dosage of the minor allele T (OSall P=0.0004, OSpM0 P=0.0001, EFSpM0 P=0.008, respectively). CONCLUSION: Our results showed that polymorphisms in NLRC5 may be used as prognostic markers of survival of CRC patients, as well as for survival in response to 5-FU treatment.

• MeSH
• časové faktory MeSH
• dospělí MeSH
• fenotyp MeSH
• fluoruracil aplikace a dávkování   škodlivé účinky   MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• genetické asociační studie MeSH
• intracelulární signální peptidy a proteiny genetika   MeSH
• jednonukleotidový polymorfismus * MeSH
• Kaplanův-Meierův odhad MeSH
• kolorektální nádory farmakoterapie   genetika   mortalita   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• přežití bez známek nemoci MeSH
• proporcionální rizikové modely MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• studie případů a kontrol MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• fluoruracil MeSH
• intracelulární signální peptidy a proteiny MeSH
• nádorové biomarkery MeSH
• NLRC5 protein, human MeSH Prohlížeč

OBJECTIVES: Aflibercept (ziv-aflibercept) significantly improves progression-free (PFS) and overall survival (OS) when added to 5-fluorouracil, leucovorin and irinotecan (FOLFIRI), compared with FOLFIRI alone, in patients with metastatic colorectal cancer previously treated with oxaliplatin-based therapy. This subset analysis of the VELOUR study investigates aflibercept plus FOLFIRI versus placebo plus FOLFIRI according to age. METHODS: Efficacy and safety were analyzed by treatment arm and age (≥ or <65years). RESULTS: Overall, 443 patients were ≥65years old (205 in aflibercept arm; 238 in placebo arm) and 783 were <65years old (407 in aflibercept arm; 376 in placebo arm). Median OS was 12.6 versus 11.3months (hazard ratio [HR]: 0.85; 95.34% CI 0.68-1.07) in patients ≥65years old and 14.5 versus 12.5months (HR: 0.80; 95.34% CI 0.67-0.95) in those patients <65years old, for patients receiving FOLFIRI plus aflibercept or placebo, respectively. There was no interaction between treatment and age. Treatment-emergent adverse events (AEs) were comparable for patients <65years and ≥65years old. The incidence of grade 3/4 AEs was higher for patients ≥65years old than for those <65years old in both the aflibercept (89.3% versus 80.5%) and placebo (67.4% versus 59.4%) arms. Interaction tests for grade 3/4 antiangiogenic agent-related AEs suggested no heterogeneity between the older and younger patient populations (p>0.1). CONCLUSION: A limited but consistent benefit on both OS and PFS was associated with the addition of aflibercept to FOLFIRI compared with placebo in patients <65 and ≥65years old, with a marked but manageable increase in the toxicity profile in older patients. TRIAL REGISTRATION: clinicaltrials.govNCT00561470.

• Klíčová slova
• Aflibercept, Elderly, Second-line, VEGF-Trap, VELOUR, mCRC,
• MeSH
• adenokarcinom farmakoterapie   MeSH
• dvojitá slepá metoda MeSH
• fluoruracil aplikace a dávkování   škodlivé účinky   MeSH
• inhibitory angiogeneze aplikace a dávkování   škodlivé účinky   MeSH
• kamptothecin aplikace a dávkování   škodlivé účinky   analogy a deriváty   MeSH
• Kaplanův-Meierův odhad MeSH
• kolorektální nádory farmakoterapie   MeSH
• leukovorin aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• přežití bez známek nemoci MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   škodlivé účinky   MeSH
• receptory vaskulárního endoteliálního růstového faktoru aplikace a dávkování   MeSH
• rekombinantní fúzní proteiny aplikace a dávkování   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• věkové faktory MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• aflibercept MeSH Prohlížeč
• fluoruracil MeSH
• inhibitory angiogeneze MeSH
• kamptothecin MeSH
• leukovorin MeSH
• receptory vaskulárního endoteliálního růstového faktoru MeSH
• rekombinantní fúzní proteiny MeSH

BACKGROUND: Pegfilgrastim's role in reducing the risk of febrile neutropenia (FN) in patients with colorectal cancer (CRC) receiving chemotherapy plus bevacizumab was not previously evaluated in a prospective study. The present phase III, double-blind trial evaluated the efficacy of pegfilgrastim versus placebo in reducing the incidence of grade 3/4 FN in patients with advanced CRC receiving bevacizumab combined with first-line chemotherapy (FOLFOX [leucovorin, 5-fluorouracil, oxaliplatin] or FOLFIRI [leucovorin, 5-fluorouracil, irinotecan]). PATIENTS AND METHODS: Patients aged ≥ 18 years with locally advanced or metastatic CRC were randomized 1:1 to placebo or 6 mg of pegfilgrastim ∼24 hours after receiving chemotherapy plus bevacizumab every 14 days. The study treatment period included 4 cycles, but patients could continue treatment for ≤ 60 months. The primary endpoint was incidence of grade 3/4 FN in the first 4 cycles. The secondary endpoints included the objective response rate (ORR), overall survival, and progression-free survival, analyzed at the end of the long-term follow-up period. RESULTS: A total of 845 patients were randomized from November 2009 to January 2012 (422, pegfilgrastim; 423, placebo). Pegfilgrastim significantly reduced the incidence of grade 3/4 FN in the first 4 treatment cycles (pegfilgrastim, 2.4%; 95% confidence interval [CI], 1.1%-4.3%; placebo, 5.7%; 95% CI, 3.7%-8.3%; odds ratio [OR], 0.41; P = .014). No significant differences were observed between the 2 arms in ORR (OR, 1.15; P = .330), overall survival (hazard ratio, 0.94; P = .440), and progression-free survival (hazard ratio, 0.93; P = .300). CONCLUSION: Pegfilgrastim reduced the FN incidence in patients with advanced CRC receiving chemotherapy and bevacizumab. Administration of pegfilgrastim was tolerable and did not negatively affect the tumor response or survival in this patient population.

• Klíčová slova
• Chemotherapy, Febrile neutropenia, Objective response rate, Overall survival, Progression-free survival,
• MeSH
• bevacizumab aplikace a dávkování   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• febrilní neutropenie chemicky indukované   epidemiologie   prevence a kontrola   MeSH
• filgrastim aplikace a dávkování   MeSH
• fluoruracil aplikace a dávkování   škodlivé účinky   MeSH
• incidence MeSH
• kamptothecin aplikace a dávkování   škodlivé účinky   analogy a deriváty   MeSH
• kolorektální nádory farmakoterapie   patologie   MeSH
• leukovorin aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• míra přežití MeSH
• mladý dospělý MeSH
• následné studie MeSH
• organoplatinové sloučeniny aplikace a dávkování   škodlivé účinky   MeSH
• polyethylenglykoly aplikace a dávkování   MeSH
• přežití bez známek nemoci MeSH
• proporcionální rizikové modely MeSH
• prospektivní studie MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• vaskulární endoteliální růstový faktor A antagonisté a inhibitory   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• bevacizumab MeSH
• filgrastim MeSH
• fluoruracil MeSH
• kamptothecin MeSH
• leukovorin MeSH
• organoplatinové sloučeniny MeSH
• pegfilgrastim MeSH Prohlížeč
• polyethylenglykoly MeSH
• vaskulární endoteliální růstový faktor A MeSH

PURPOSE: Tivozanib, a selective inhibitor of VEGFR-1, -2, and -3, plus mFOLFOX6 in an advanced gastrointestinal cancer phase Ib study had encouraging antineoplastic activity and a tolerable safety profile. This randomized, open-label, phase II trial of tivozanib/mFOLFOX6 versus bevacizumab/mFOLFOX6 in patients with previously untreated metastatic colorectal cancer (mCRC) evaluated tivozanib activity versus bevacizumab. EXPERIMENTAL DESIGN: Treatment-naïve patients received mFOLFOX6 every 2 weeks of each 28-day cycle plus either tivozanib orally 1.5 mg once daily for 21 days or bevacizumab intravenously 5 mg/kg every 2 weeks. Investigator-assessed progression-free survival (PFS) was the primary endpoint; some secondary endpoints included safety, overall survival, overall response rate (ORR), duration of response, time to treatment failure, and biomarker subgroup analyses. RESULTS: A prespecified interim futility analysis demonstrated that the futility boundary for superiority of tivozanib/mFOLFOX6 over bevacizumab/mFOLFOX6 for PFS in the intent-to-treat population was crossed; median PFS was 9.4 versus 10.7 months [HR = 1.091; confidence interval (CI), 0.693-1.718; P = 0.706]. Tivozanib/mFOLFOX6 resulted in PFS and ORR comparable with bevacizumab/mFOLFOX6; interim analyses biomarker results revealed no significant PFS association. Post hoc final analyses demonstrated a potential difference in tivozanib-specific PFS in patients with low neuropilin-1 (NRP-1), but not in patients with high NRP-1. Tivozanib/mFOLFOX6 was tolerable and adverse events were comparable with both bevacizumab/mFOLFOX6 and previous tivozanib studies. CONCLUSIONS: The efficacy of tivozanib/mFOLFOX6 was comparable with but not superior to bevacizumab/mFOLFOX6 in patients with previously untreated mCRC. Since data from the prespecified interim analysis did not demonstrate superiority, this resulted in discontinuation of the study. The safety and tolerability profile of tivozanib/mFOLFOX6 was consistent with other tivozanib trials. NRP-1 is a potential predictive biomarker for tivozanib activity, but these results require further validation. Clin Cancer Res; 22(20); 5058-67. ©2016 AACR.

• MeSH
• bevacizumab škodlivé účinky   terapeutické užití   MeSH
• chinoliny škodlivé účinky   terapeutické užití   MeSH
• fenylmočovinové sloučeniny škodlivé účinky   terapeutické užití   MeSH
• fluoruracil škodlivé účinky   terapeutické užití   MeSH
• inhibitory angiogeneze terapeutické užití   MeSH
• kolorektální nádory farmakoterapie   patologie   MeSH
• leukovorin škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery krev   MeSH
• neuropilin-1 krev   MeSH
• organoplatinové sloučeniny škodlivé účinky   terapeutické užití   MeSH
• přežití bez známek nemoci MeSH
• progrese nemoci MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• receptory vaskulárního endoteliálního růstového faktoru antagonisté a inhibitory   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• bevacizumab MeSH
• chinoliny MeSH
• fenylmočovinové sloučeniny MeSH
• fluoruracil MeSH
• inhibitory angiogeneze MeSH
• leukovorin MeSH
• nádorové biomarkery MeSH
• neuropilin-1 MeSH
• organoplatinové sloučeniny MeSH
• receptory vaskulárního endoteliálního růstového faktoru MeSH
• tivozanib MeSH Prohlížeč

BACKGROUND: The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD (DPYD), including DPYD*2A and c.2846A>T. Three other variants-DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A-have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity. METHODS: We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade ≥3) fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0·0167 (Bonferroni correction). FINDINGS: 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08-9·30, p<0·0001), as was c.1236G>A/HapB3 (1·59, 1·29-1·97, p<0·0001). The association between c.1601G>A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86-2·70, p=0·15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5·72, 95% CI 1·40-23·33, p=0·015; and 2·04, 1·49-2·78, p<0·0001, respectively) and haematological toxicity (adjusted RR 9·76, 95% CI 3·03-31·48, p=0·00014; and 2·07, 1·17-3·68, p=0·013, respectively), but not with hand-foot syndrome. DPYD*2A and c.2846A>T were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75-4·62, p<0·0001; and 3·02, 2·22-4·10, p<0·0001, respectively). INTERPRETATION: DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD*2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines. FUNDING: None.

• MeSH
• capecitabinum škodlivé účinky   farmakokinetika   MeSH
• dihydrouracildehydrogenasa (NADP) genetika   metabolismus   MeSH
• farmakogenetika MeSH
• fenotyp MeSH
• fluoruracil škodlivé účinky   farmakokinetika   MeSH
• ftorafur škodlivé účinky   farmakokinetika   MeSH
• gastrointestinální nemoci chemicky indukované   diagnóza   genetika   MeSH
• genetická predispozice k nemoci MeSH
• hodnocení rizik MeSH
• krevní nemoci chemicky indukované   diagnóza   genetika   MeSH
• lidé MeSH
• multivariační analýza MeSH
• nádory diagnóza   farmakoterapie   genetika   MeSH
• odds ratio MeSH
• polymorfismus genetický * MeSH
• protinádorové antimetabolity škodlivé účinky   farmakokinetika   MeSH
• rizikové faktory MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH
• Názvy látek
• capecitabinum MeSH
• dihydrouracildehydrogenasa (NADP) MeSH
• fluoruracil MeSH
• ftorafur MeSH
• protinádorové antimetabolity MeSH

BACKGROUND AND PURPOSE: This study estimated patients' early response following neoadjuvant chemoradiotherapy (CHRT) of locally advanced rectal cancer based on 5-fluorouracil (5-FU). The target was to achieve pathological complete response (pCR; residual disease-free stage) and toxicities of grade ≤2, using individual dosing predicted according to the steady-state plasma concentration (C ss) and pharmacokinetic parameters of 5-FU: the area under the time-concentration curve at steady state (AUC) and clearance (CL). PATIENTS AND METHODS: This open-label prospective study enrolled 33 adult patients treated with 5-FU administered as a continuous intravenous infusion over 4-5 weeks, as follows: in Group 1a (N = 6), the patients received a standard dose of 300 mg/m(2)/24 h. In Group 1b (N = 7), the patients were treated with an escalated dose of 400-1,000 mg/m(2)/24 h. In Group 2 (N = 20), the patients were given dosing kinetically guided in order to reach the target range of 5-FU C ss 50-100 µg/L. Tolerability was tested according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Radiotherapy was delivered with 10-15 MV photon beams at 1.8 Gy/fraction up to 50.4 Gy in 28 daily fractions for 5 days a week. Surgery followed 4-6 weeks after the completion of CHRT and clinical restaging. The pCR and residual tumour stage were evaluated using preoperative tumour downstaging in magnetic resonance, postoperative histopathological staging and tumour regression rate (residual disease). RESULTS AND CONCLUSION: The cumulative AUC of 5-FU (total exposure to the drug) correlated with cumulative 5-FU dose (r = 0.61; p < 0.001) and residual disease (r s = -0.53; p < 0.005). A higher target pCR rate was reached in patients individually treated (Group 2) who finished the whole 5-week CHRT. The individual daily dose needed to reach the target C ss should be >350 mg/m(2) (up to 600 mg/m(2)) provided that 5-FU metabolic ratio is within the range of 2.5-6 and the cumulative AUC5wks is within 50-100 mg·h/L.

• MeSH
• chemoradioterapie MeSH
• fluoruracil aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• intravenózní infuze MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory rekta farmakoterapie   metabolismus   patologie   radioterapie   MeSH
• následné studie MeSH
• neoadjuvantní terapie MeSH
• prospektivní studie MeSH
• protinádorové antimetabolity aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• senioři MeSH
• staging nádorů metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fluoruracil MeSH
• protinádorové antimetabolity MeSH

BACKGROUND: Therapy with 5-fluorouracil (5-FU) and capecitabine is often complicated by skin toxicity (hand-foot syndrome, HFS). Topical application of uridine ointment is beneficial for alleviating HFS and other pyrimidine nucleosides have been described as 5-FU toxicity modulators. We tested pyrimidine nucleosides and their combinations to find the best combination for topical therapy of HFS. MATERIALS AND METHODS: Cellular viability was measured by the real-time cell analyser and methyl thiazol tetrazolium (MTT) assay in order to evaluate the effect of pyrimidine nucleosides on HaCaT keratinocytes treated with 5-FU. The results were confirmed by evaluation of the cellular colonization by microphotography. RESULTS: Cytidine and uridine protected keratinocytes to the same extent. Thymidine enhanced the protective effect when added to cytidine or uridine. Deoxycytidine did not have any protective effect. CONCLUSION: Our findings support the rationale for using uridine or cytidine in combination with thymidine in ointment for HFS treatment.

• Klíčová slova
• 5-FU, Hand-foot syndrome, cytidine, deoxycytidine, keratinocytes, thymidine, uridine,
• MeSH
• dihydrouracildehydrogenasa (NADP) fyziologie   MeSH
• fluoruracil škodlivé účinky   MeSH
• keratinocyty účinky léků   MeSH
• kultivované buňky MeSH
• lidé MeSH
• protinádorové antimetabolity škodlivé účinky   MeSH
• pyrimidinové nukleosidy farmakologie   MeSH
• tetrazoliové soli MeSH
• thiazoly MeSH
• thymidylátsynthasa antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dihydrouracildehydrogenasa (NADP) MeSH
• fluoruracil MeSH
• protinádorové antimetabolity MeSH
• pyrimidinové nukleosidy MeSH
• tetrazoliové soli MeSH
• thiazoly MeSH
• thiazolyl blue MeSH Prohlížeč
• thymidylátsynthasa MeSH

BACKGROUND: Patients with metastatic colorectal cancer (mCRC) previously-treated with oxaliplatin benefit significantly from the addition of aflibercept to FOLFIRI in relation to overall survival, progression-free survival and response rate. PATIENTS AND METHODS: The results for efficacy and safety over the time course of the VEGF Trap (aflibercept) with irinotecan in colorectal cancer after failure of oxaliplatin regimen trial were analysed based on data from 1226 patients randomised to receive FOLFIRI plus either aflibercept (n=612) or placebo (n=614). Hazard ratios (HR) by 6-month time period were estimated using a piecewise Cox proportional hazard model. Severity of adverse events (AEs) was graded using National Cancer Institute Common Terminology Criteria, version 3.0. RESULTS: The estimated probabilities of survival were 38.5% versus 30.9% at 18 months, 28.0% versus 18.7% at 24 months and 22.3% versus 12.0% at 30 months, for the aflibercept- and placebo-treated arms, respectively. The proportional improvement in the HR over time was consistent with the survival probability results; survival at 24 months was improved by 50% and almost doubled at 30 months. The majority of worst-grade AEs occurred within the first four cycles of treatment and in a small percent of treatment cycles and were mostly reversible. Common chemotherapy- and anti-vascular epithelial growth factor (VEGF)-associated AEs occurred rarely and in a small proportion of cycles with the majority being of single occurrence. CONCLUSIONS: The addition of aflibercept to FOLFIRI showed a continued and persistent improvement in overall survival over time in patients with mCRC. Although grade 3-4 AEs were more frequent in the aflibercept arm, they occurred in early treatment cycles and decreased sharply following initial presentation.

• Klíčová slova
• Aflibercept, Colorectal cancer, Efficacy, PlGF, Safety, VEGF-A, VEGF-B,
• MeSH
• biomarkery farmakologické MeSH
• fluoruracil škodlivé účinky   farmakologie   terapeutické užití   MeSH
• irinotekan MeSH
• kamptothecin škodlivé účinky   analogy a deriváty   farmakologie   terapeutické užití   MeSH
• kolorektální nádory patologie   MeSH
• leukovorin škodlivé účinky   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• metastázy nádorů MeSH
• organoplatinové sloučeniny terapeutické užití   MeSH
• oxaliplatin MeSH
• přežití bez známek nemoci MeSH
• progrese nemoci MeSH
• proporcionální rizikové modely MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   farmakologie   terapeutické užití   MeSH
• receptory vaskulárního endoteliálního růstového faktoru škodlivé účinky   farmakologie   terapeutické užití   MeSH
• rekombinantní fúzní proteiny škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• aflibercept MeSH Prohlížeč
• biomarkery farmakologické MeSH
• fluoruracil MeSH
• irinotekan MeSH
• kamptothecin MeSH
• leukovorin MeSH
• organoplatinové sloučeniny MeSH
• oxaliplatin MeSH
• receptory vaskulárního endoteliálního růstového faktoru MeSH
• rekombinantní fúzní proteiny MeSH

BACKGROUND: The Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy (PRIME) demonstrated that panitumumab-FOLFOX4 significantly improved progression-free survival (PFS) versus FOLFOX4 as first-line treatment of wild-type (WT) KRAS metastatic colorectal cancer (mCRC), the primary end point of the study. PATIENTS AND METHODS: Patients were randomized 1:1 to panitumumab 6.0 mg/kg every 2 weeks + FOLFOX4 (arm 1) or FOLFOX4 (arm 2). This prespecified final descriptive analysis of efficacy and safety was planned for 30 months after the last patient was enrolled. RESULTS: A total of 1183 patients were randomized. Median PFS for WT KRAS mCRC was 10.0 months [95% confidence interval (CI) 9.3-11.4 months] for arm 1 and 8.6 months (95% CI 7.5-9.5 months) for arm 2; hazard ratio (HR) = 0.80; 95% CI 0.67-0.95; P = 0.01. Median overall survival (OS) for WT KRAS mCRC was 23.9 months (95% CI 20.3-27.7 months) for arm 1 and 19.7 months (95% CI 17.6-22.7 months) for arm 2; HR = 0.88; 95% CI 0.73-1.06; P = 0.17 (68% OS events). An exploratory analysis of updated survival (>80% OS events) was carried out which demonstrated improvement in OS; HR = 0.83; 95% CI 0.70-0.98; P = 0.03 for WT KRAS mCRC. The adverse event profile was consistent with the primary analysis. CONCLUSIONS: In WT KRAS mCRC, PFS was improved, objective response was higher, and there was a trend toward improved OS with panitumumab-FOLFOX4, with significant improvement in OS observed in an updated analysis of survival in patients with WT KRAS mCRC treated with panitumumab + FOLFOX4 versus FOLFOX4 alone (P = 0.03). These data support a positive benefit-risk profile for panitumumab-FOLFOX4 for patients with previously untreated WT KRAS mCRC. KRAS testing is critical to select appropriate patients for treatment with panitumumab.

• Klíčová slova
• FOLFOX, antibody, chemotherapy, metastatic colorectal cancer, panitumumab,
• MeSH
• dospělí MeSH
• fluoruracil aplikace a dávkování   škodlivé účinky   MeSH
• geny ras MeSH
• kolorektální nádory farmakoterapie   genetika   patologie   MeSH
• kvalita života MeSH
• leukovorin aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• organoplatinové sloučeniny aplikace a dávkování   škodlivé účinky   MeSH
• panitumumab MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• fluoruracil MeSH
• leukovorin MeSH
• monoklonální protilátky MeSH
• organoplatinové sloučeniny MeSH
• panitumumab MeSH