BACKGROUND: The addition of monoclonal antibodies targeting the epidermal growth factor receptor (anti-EGFR Abs) to chemotherapy for metastatic colorectal carcinoma (mCRC) is commonly delayed in the real-world clinical practice, usually because of late RAS testing results. OBJECTIVE: To determine whether delayed addition of anti-EGFR mAbs up to the fourth cycle of backbone chemotherapy adversely affected outcomes of mCRC patients treated with first-line regimens. PATIENTS AND METHODS: Clinical data of patients with histologically verified, RAS wild-type mCRC treated with first-line systemic therapy regimens containing anti-EGFR mAbs were retrospectively analysed from a national database. Patients were divided into three groups according to the timing of anti-EGFR mAbs addition to the chemotherapy backbone. Cohort A (n = 401) included patients in whom anti-EGFR mAbs were added to chemotherapy from the first cycle, cohort B (n = 71) patients with anti-EGFR mAbs added to chemotherapy from the second cycle, and cohort C (n = 101) patients who had anti-EGFR mAbs added to chemotherapy from the third or fourth cycle. RESULTS: Three hundred and thirty-six (58.6%) patients received panitumumab and 237 (41.4%) patients received cetuximab. The median progression-free survival (PFS) of the whole cohort was 12.2 months (95% confidence interval [CI] 10.9-13.5), and the median overall survival (OS) was 33.5 months (95% CI 27.6-39.4). The median PFS and OS for patients treated with anti-EGFR mAbs added to chemotherapy were 12.9 (95% CI 11.5-14.3) and 30.6 months (95% CI 25.2-36.1) for cohort A, 9.7 (95% CI 9.1-10.3) and not reached for cohort B, compared to 11.5 (95% CI 9.8-13.2) and 37.9 months (95% CI 28.6-47.3) for cohort C, respectively. CONCLUSIONS: Delayed addition of anti-EGFR mAbs to first-line chemotherapy was not associated with inferior survival or response rates.

• MeSH
• dospělí MeSH
• kolorektální nádory farmakoterapie   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• monoklonální protilátky farmakologie   terapeutické užití   MeSH
• registrace MeSH
• retrospektivní studie 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
• práce podpořená grantem MeSH
• Názvy látek
• monoklonální protilátky MeSH

The measurement of serum tumour markers is a simple and non-invasive method for assessing the response to systemic therapies in metastatic colorectal cancer (mCRC) and estimation of prognosis. The aim of our retrospective study was to evaluate the association of baseline serum levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), thymidine kinase (TK) and tissue polypeptide specific antigen (TPS) with outcome of patients with mCRC treated with combination of chemotherapy and monoclonal antibodies against epidermal growth factor receptor (anti-EGFR mAbs) in the first line. In our study, the cohort included 102 patients treated with therapy based on anti-EGFR mAbs between years 2011 and 2017 at Department of Oncology and Radiotherapy, Medical School and University Hospital in Pilsen, Czech Republic. Serum samples were collected within one month before the initiation of treatment. In multivariate Cox analysis that included serum tumour markers and clinical baseline parameters show that high baseline serum CA 19-9 was significantly associated with worse progression-free survival (HR=1.871, p=0.0330) and also overall survival (HR=3.903, p=0.0006). We have not demonstrated association of baseline levels of CEA, TK and TPS with patients' outcome. CA 19-9 is commonly used serum tumour marker which is simple and readily available and its candidate prognostic importance in the setting of anti-EGFR therapy deserves to be studied in prospective trials.

• Klíčová slova
• carbohydrate antigen 19-9, cetuximab, chemotherapy, colorectal cancer, panitumumab, serum carcinoembryonic antigen, thymidine kinase, tissue polypeptide specific antigen, tumor markers,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: In Europe, treatment of metastatic colorectal cancer (mCRC) with panitumumab requires prior confirmation of RAS wild-type mutation status. Two studies - a physician survey and a medical records review (MRR) - were conducted to evaluate the use of panitumumab and awareness among prescribing oncologists of the associated RAS testing requirements in clinical practice. METHODS: Both studies enrolled participants from nine European countries and were carried out in three consecutive rounds. Rounds 1 and 2 (2012-2013) examined KRAS (exon 2) testing only; the results have been published in full previously. Round 3 (2014-2015) examined full RAS testing (exons 2, 3, 4 of KRAS and NRAS) and was initiated following a change in prescribing guidelines, from requiring KRAS alone to requiring full RAS testing. For the physician survey, telephone interviews were conducted with oncologists who had prescribed panitumumab to patients with mCRC in the previous 6 months. For the MRR, oncologists were asked to provide anonymised clinical information, extracted from their patients' records. RESULTS: In Round 3, 152 oncologists and 131 patients' records were included in the physician survey and MRR, respectively. In Round 3 of the physician survey, 95.4% (n = 145) of participants correctly identified that panitumumab should only be prescribed in RAS wild-type mCRC compared with 99.0% (n = 298) of 301 participants in Rounds 1 and 2, responding to the same question about KRAS testing. In Round 3 of the MRR, 100% (n = 131) of patients included in the study had confirmed KRAS or RAS wild-type status prior to initiation of panitumumab compared with 97.7% (n = 299) of 306 patients in Rounds 1 and 2 (KRAS only). Of those patients in Round 3, 83.2% (n = 109) had been tested for RAS status and 16.8% (n = 22) had been tested for KRAS status only. CONCLUSIONS: Physicians' adherence to prescribing guidelines has remained high over time in Europe, despite the change in indication for panitumumab treatment, from KRAS to RAS wild-type mCRC. Additionally, this study demonstrates the uptake of full RAS testing among the majority of oncologists and pathologists.

• Klíčová slova
• Medical records review, Metastatic colorectal cancer, Panitumumab, Physician survey, RAS, mCRC,
• MeSH
• chorobopisy MeSH
• dodržování směrnic MeSH
• genetické testování MeSH
• GTP-fosfohydrolasy genetika   MeSH
• kolorektální nádory farmakoterapie   genetika   MeSH
• lékaři MeSH
• lékařská praxe - způsoby provádění MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• metastázy nádorů MeSH
• monoklonální protilátky terapeutické užití   MeSH
• panitumumab MeSH
• protinádorové látky terapeutické užití   MeSH
• protoonkogenní proteiny p21(ras) genetika   MeSH
• průzkumy a dotazníky MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• přehledy MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• GTP-fosfohydrolasy MeSH
• KRAS protein, human MeSH Prohlížeč
• membránové proteiny MeSH
• monoklonální protilátky MeSH
• NRAS protein, human MeSH Prohlížeč
• panitumumab MeSH
• protinádorové látky MeSH
• protoonkogenní proteiny p21(ras) MeSH

PURPOSE: Epidermal growth factor receptor-targeted monoclonal antibodies are active as monotherapy beyond second-line treatment. Skin toxicities (STs) are common during treatment, and a positive association between ST severity and patient outcome has been reported. This study collected information on panitumumab monotherapy use in patients with KRAS exon 2 wild-type metastatic colorectal cancer in clinical practice. METHODS: This open-label, prospective, observational, noninterventional study included adult patients who had failed prior chemotherapy with 5-fluorouracil, oxaliplatin, and irinotecan. Patients received panitumumab monotherapy (6 mg/kg every 2 weeks) for ≤18 cycles. Effectiveness was assessed as disease control rate (DCR), tumor response, and freedom from progression. The incidence of ST and other adverse drug reactions (ADRs) was recorded, as were Eastern Cooperative Oncology Group performance status (ECOG PS) and quality of life. The KRAS analysis process was also evaluated. FINDINGS: The full analysis set included 632 patients (64.6% male; mean age, 62.3 years), who completed a mean of 9.6 panitumumab cycles. ST, mainly grade 1/2, occurred in 84.3% of patients, 82.7% of whom required treatment. Nonskin ADRs occurred in 3.5% of patients. By the end of treatment, the DCR was 58.9% overall, and was 53.8% and 62.7%, respectively in patients with ST grade 0/1 and grade 2/3. Significant associations were observed between maximum ST grade and best response (P=0.0009), DCR (P=0.0046), tumor response (P=0.0002), and freedom from progression (P=0.0084). At the end of the study, 67.4% of the patients had an ECOG PS of 0/1. Quality of life was rated as "very good" or "good" in 70.3% of patients. Mean time to obtain KRAS results was 18.2 days; satisfaction with different aspects of KRAS testing was "very good" or "good" in 80%-97% of patients. CONCLUSION: Panitumumab monotherapy showed adequate effectiveness and safety in patients with heavily pretreated KRAS exon 2 wild-type metastatic colorectal cancer. The most common ADR was grade 1/2 ST.

• Klíčová slova
• KRAS, metastatic colorectal cancer, observational study, panitumumab, skin toxicity,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: From 2008-2013, the European indication for panitumumab required that patients' tumor KRAS exon 2 mutation status was known prior to starting treatment. To evaluate physician awareness of panitumumab prescribing information and how physicians prescribe panitumumab in patients with metastatic colorectal cancer (mCRC), two European multi-country, cross-sectional, observational studies were initiated in 2012: a physician survey and a medical records review. The first two out of three planned rounds for each study are reported. METHODS: The primary objective in the physician survey was to estimate the prevalence of KRAS testing, and in the medical records review, it was to evaluate the effect of test results on patterns of panitumumab use. The medical records review study also included a pathologists' survey. RESULTS: In the physician survey, nearly all oncologists (299/301) were aware of the correct panitumumab indication and the need to test patients' tumor KRAS status before treatment with panitumumab. Nearly all oncologists (283/301) had in the past 6 months of clinical practice administered panitumumab correctly to mCRC patients with wild-type KRAS status. In the medical records review, 97.5% of participating oncologists (77/79) conducted a KRAS test for all of their patients prior to prescribing panitumumab. Four patients (1.3%) did not have tumor KRAS mutation status tested prior to starting panitumumab treatment. Approximately one-quarter of patients (85/306) were treated with panitumumab and concurrent oxaliplatin-containing chemotherapy; of these, 83/85 had confirmed wild-type KRAS status prior to starting panitumumab treatment. All 56 referred laboratories that participated used a Conformité Européenne-marked or otherwise validated KRAS detection method, and nearly all (55/56) participated in a quality assurance scheme. CONCLUSIONS: There was a high level of knowledge amongst oncologists around panitumumab prescribing information and the need to test and confirm patients' tumors as being wild-type KRAS prior to treatment with panitumumab, with or without concurrent oxaliplatin-containing therapy.

• MeSH
• chorobopisy * MeSH
• demografie MeSH
• exony genetika   MeSH
• kolorektální nádory farmakoterapie   sekundární   MeSH
• lékaři * MeSH
• lidé MeSH
• monoklonální protilátky terapeutické užití   MeSH
• panitumumab MeSH
• protoonkogenní proteiny p21(ras) genetika   MeSH
• senioři MeSH
• výsledek terapie MeSH
• zdravotnické přehledy * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• KRAS protein, human MeSH Prohlížeč
• monoklonální protilátky MeSH
• panitumumab MeSH
• protoonkogenní proteiny p21(ras) MeSH

AIM OF THE STUDY: The aim of this retrospective study was to determine the prognostic impact of epidermal growth factor receptor (EGFR) expression changes during neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer. MATERIAL AND METHODS: Fifty patients with locally advanced rectal cancer were evaluated. All the patients were administered the total dose of 44 Gy. Capecitabine has been concomitantly administered in the dose 825 mg/m(2) in two daily oral administrations. Surgery was indicated 4-8 weeks from the chemoradiotherapy completion. Epidermal growth factor receptor expression in the pretreatment biopsies and in the resected specimens was assessed with immunohistochemistry. RESULTS: All of 50 patients received radiotherapy without interruption up to the total planned dose. In 30 patients sphincter-saving surgery was performed, 20 patients underwent amputation of the rectum. Downstaging was described in 30 patients. Four patients have had complete pathologic remission. Twenty-six patients have had partial remission, the disease was stable in 15 patients. Progression was reported in 5 patients. The median disease-free survival was 64.9 months, median overall survival was 76.4 months. Increased EGFR expression was found in 12 patients (26.1%). A statistically significantly shorter overall survival (p < 0.0001) and disease-free survival (p < 0.0001) was found in patients with increased expression of EGFR compared with patients where no increase in the expression of EGFR during neoadjuvant chemoradiotherapy was observed. CONCLUSIONS: The overexpression of EGFR during neoadjuvant chemoradiotherapy for locally advanced rectal adenokarcinoma associated with significant shorter overall survival and disease free survival.

• Klíčová slova
• chemotherapy, epidermal growth factor receptor, neoadjuvant treatment, radiotherapy, rectal adenocarcinoma,
• Publikační typ
• časopisecké články MeSH

While 5-fluorouracil used as single agent in patients with metastatic colorectal cancer has an objective response rate around 20%, the administration of combinations of irinotecan with 5-fluorouracil/folinic acid or oxaliplatin with 5-fluorouracil/folinic acid results in significantly increased response rates and improved survival. However, the side effects of systemic therapy such as myelotoxicity, neurotoxicity or gastrointestinal toxicity may lead to life-threatening complications and have a major impact on the quality of life of the patients. Therefore, biomarkers that would be instrumental in the choice of optimal type, combination and dose of drugs for an individual patient are urgently needed. The efficacy and toxicity of anticancer drugs in tumor cells is determined by the effective concentration in tumor cells, healthy tissues and by the presence and quantity of the drug targets. Enzymes active in drug metabolism and transport represent important determinants of the therapeutic outcome. The aim of this review was to summarize published data on associations of gene and protein expression, and genetic variability of putative biomarkers with response to therapy of colorectal cancer to 5-fluorouracil/leucovorin/oxaliplatin and 5-fluorouracil/leukovorin/irinotecan regimens. Gaps in the knowledge identified by this review may aid the design of future research and clinical trials.

• Klíčová slova
• 5-Fluorouracil, Chemotherapy, Colorectal cancer, Irinotecan, Oxaliplatin,
• MeSH
• biotransformace genetika   MeSH
• chemorezistence genetika   MeSH
• farmakogenetika * MeSH
• fenotyp MeSH
• fluoruracil aplikace a dávkování   MeSH
• individualizovaná medicína * MeSH
• irinotekan MeSH
• kamptothecin aplikace a dávkování   analogy a deriváty   MeSH
• kolorektální nádory farmakoterapie   genetika   MeSH
• leukovorin aplikace a dávkování   MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• organoplatinové sloučeniny aplikace a dávkování   MeSH
• oxaliplatin MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• fluoruracil MeSH
• irinotekan MeSH
• kamptothecin MeSH
• leukovorin MeSH
• nádorové biomarkery MeSH
• organoplatinové sloučeniny MeSH
• oxaliplatin MeSH

PURPOSE: The aim of the present study was to examine the effect of neoadjuvant chemoradiation on tumor epidermal growth factor receptor (EGFR) expression in patients with locally advanced rectal adenocarcinoma. PATIENTS AND METHODS: A total of 53 patients with rectal adenocarcinoma (clinical stages II and III) were studied. Neoadjuvant treatment consisted of 50.4 Gy/28 fractions external radiation with concomitant continuous 5-fluorouracil. Surgical resection was performed 4-6 weeks after the chemoradiation. EGFR expression in the pretreatment biopsies and in the resected specimens was assessed with immunohistochemistry. RESULTS: Patients with an increase of EGFR expression during chemoradiation had significantly shorter disease-free survival (DFS; p = 0.003) and overall survival (OS; p = 0.005) compared to patients with either no change or decrease in EGFR expression. The 5-year DFS in patients with increased EGFR expression was only 29% compared to 61% in patients without an increase of EGFR expression. Similarly, the 5-year OS of the patients with increased EGFR expression was 29% compared to 66% in patients without an increase of EGFR expression. All recurrences in patients who had an increase of EGFR expression occurred within the first 2 years after the treatment. The increase in EGFR expression was the only significant predictor of DFS (p = 0.007) and OS (p = 0.04) using multivariate Cox regression analysis. CONCLUSION: An increase of EGFR expression during chemoradiation may be associated with significantly shorter DFS and OS. The increase of EGFR could identify a population of patients in whom the effect of the treatment with anti-EGFR therapy should be studied.

• MeSH
• adenokarcinom diagnóza   metabolismus   terapie   MeSH
• adjuvantní chemoradioterapie * MeSH
• dospělí MeSH
• erbB receptory metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery metabolismus   MeSH
• nádorové proteiny metabolismus   MeSH
• nádory rekta diagnóza   metabolismus   terapie   MeSH
• neoadjuvantní terapie MeSH
• prognóza MeSH
• reprodukovatelnost výsledků MeSH
• senzitivita a specificita MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• erbB receptory MeSH
• nádorové biomarkery MeSH
• nádorové proteiny MeSH