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Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan study group [see comments]
... 8,12 As toxicidades mais comuns do irinotecano consistem em síndrome colinérgica aguda de náuseas; vômitos; mucosite; diarreia e rubor, que pode ser potencialmente fatal em alguns casos, e mielossupressão. 13,14 O agravamento das toxicidades pode provocar graves consequências como atrasos no ciclo de quimioterapia, redução de dose de medicamentos, internações hospitalares bem como a substituição e/ou a interrupção do tratamento vigente e risco de morte. De acordo com Common Terminology Criteria for Adverse Events (CTCAE -versão 4.0), as toxicidades provocadas pelos medicamentos antineoplásicos podem ser classificadas em cinco tipos: grau 1 -leves ou assintomáticas; grau 2moderadas; grau 3 -severas ou graves; grau 4ameaçadoras à vida; grau 5 -morte. ...
... Foram excluídos os pacientes em tratamento com protocolos de pesquisa clínica. Os protocolos analisados estão descritos no Quadro 1. O tamanho da amostra foi calculado com base na média histórica anual do número de pacientes atendidos, na instituição, diagnosticados com CCR que iniciaram o tratamento adjuvante ou paliativo com protocolo mFOLFOX6 (n= 150) ou com protocolo FOLFIRI (n= 50), e a menor incidência de toxicidades dos tipos 3 e 4 reportada na literatura (2% para mFOLFOX6 e 1% para FOLFIRI) 14,17 . Considerando um erro amostral de 5% e um intervalo de confiança de 95%, a amostra foi estimada em 26 pacientes no grupo mFOLFOX6 e 12 pacientes no grupo FOLFIRI. ...
Study design: Cohort study Objective: Analyze the adverse reactions that occurred in Brazilian patients
with colorectal cancer submitted to chemotherapy with two different protocols, in order to identify
the types and severity of those most frequent recorded. Methods: Sixty-three patients, who started
treatment from June 2014 to May 2015, were separated into two groups: mFOLFOX6 (protocol containing
oxaliplatin, folinic acid and 5-fluorouracil in bolus and continuous infusion, n= 40) and FOLFIRI
(protocol containing irinotecan, folinic acid and 5-fluorouracil in bolus and continuous infusions, n= 23).
Data related to the demographic and clinical profile of the patients were collected from the medical
record, as well as information about the treatment performed and the adverse reactions manifested.
The reactions were classified according to their severity (grades 1, 2, 3 and 4) and causality (definite,
probable, possible and doubtful). Results: A high frequency of adverse reactions was observed in both
groups, reaching 92.5% of patients with mFOLFOX6 protocol and 95.6% with FOLFIRI protocol. Gastrointestinal
and neurological toxicities were the most frequent among the groups. When comparing the
occurrence of intergroup reactions, there was difference only for gastrointestinal toxicities (p= 0.035).
In 17.5% of patients mFOLFOX6 group (n= 7) and in 8.7% of patients FOLFIRI group (n= 2), grades 3
and 4 adverse reactions were observed and classified as probable. Conclusion: The adverse reactions
were more diversified and frequent in the mFOLFOX6 group compared to the FOLFIRI group. However,
no difference was observed in the severity and causality of reactions in both groups.
... 8,12 As toxicidades mais comuns do irinotecano consistem em síndrome colinérgica aguda de náuseas; vômitos; mucosite; diarreia e rubor, que pode ser potencialmente fatal em alguns casos, e mielossupressão. 13,14 O agravamento das toxicidades pode provocar graves consequências como atrasos no ciclo de quimioterapia, redução de dose de medicamentos, internações hospitalares bem como a substituição e/ou a interrupção do tratamento vigente e risco de morte. De acordo com Common Terminology Criteria for Adverse Events (CTCAE -versão 4.0), as toxicidades provocadas pelos medicamentos antineoplásicos podem ser classificadas em cinco tipos: grau 1 -leves ou assintomáticas; grau 2moderadas; grau 3 -severas ou graves; grau 4ameaçadoras à vida; grau 5 -morte. ...
... Foram excluídos os pacientes em tratamento com protocolos de pesquisa clínica. Os protocolos analisados estão descritos no Quadro 1. O tamanho da amostra foi calculado com base na média histórica anual do número de pacientes atendidos, na instituição, diagnosticados com CCR que iniciaram o tratamento adjuvante ou paliativo com protocolo mFOLFOX6 (n= 150) ou com protocolo FOLFIRI (n= 50), e a menor incidência de toxicidades dos tipos 3 e 4 reportada na literatura (2% para mFOLFOX6 e 1% para FOLFIRI) 14,17 . Considerando um erro amostral de 5% e um intervalo de confiança de 95%, a amostra foi estimada em 26 pacientes no grupo mFOLFOX6 e 12 pacientes no grupo FOLFIRI. ...
Study design: Cohort study Objective: Analyze the adverse reactions that occurred in Brazilian patients with colorectal cancer submitted to chemotherapy with two different protocols, in order to identify the types and severity of those most frequent recorded. Methods: Sixty-three patients, who started treatment from June 2014 to May 2015, were separated into two groups: mFOLFOX6 (protocol containing oxaliplatin, folinic acid and 5-fluorouracil in bolus and continuous infusion, n= 40) and FOLFIRI (protocol containing irinotecan, folinic acid and 5-fluorouracil in bolus and continuous infusions, n= 23). Data related to the demographic and clinical profile of the patients were collected from the medical record, as well as information about the treatment performed and the adverse reactions manifested. The reactions were classified according to their severity (grades 1, 2, 3 and 4) and causality (definite, probable, possible and doubtful). Results: A high frequency of adverse reactions was observed in both groups, reaching 92.5% of patients with mFOLFOX6 protocol and 95.6% with FOLFIRI protocol. Gastrointestinal and neurological toxicities were the most frequent among the groups. When comparing the occurrence of intergroup reactions, there was difference only for gastrointestinal toxicities (p= 0.035). In 17.5% of patients mFOLFOX6 group (n= 7) and in 8.7% of patients FOLFIRI group (n= 2), grades 3 and 4 adverse reactions were observed and classified as probable. Conclusion: The adverse reactions were more diversified and frequent in the mFOLFOX6 group compared to the FOLFIRI group. However, no difference was observed in the severity and causality of reactions in both groups.
... Keywords: Irinotecan, UGT1A polymorphisms, DPYD polymorphisms, Metastatic colorectal cancer, Toxicity, Clinical response Background Irinotecan is currently one of most important drugs in the management of metastatic colorectal cancer (mCRC) [1,2]. Although the response rate and overall survival are greatly improved with the drug, about 30-50% of patients suffer severe toxicity, which particularly causes neutropenia and diarrhea [2]. ...
... Keywords: Irinotecan, UGT1A polymorphisms, DPYD polymorphisms, Metastatic colorectal cancer, Toxicity, Clinical response Background Irinotecan is currently one of most important drugs in the management of metastatic colorectal cancer (mCRC) [1,2]. Although the response rate and overall survival are greatly improved with the drug, about 30-50% of patients suffer severe toxicity, which particularly causes neutropenia and diarrhea [2]. UGT1A polymorphisms, especially UGT1A1*6 and UGT1A1*28, were previously noted to predict irinotecan-induced toxicity, but the results were inconstant [3,4]. ...
Background:
To evaluate a new UGT1A and DPYD polymorphism panel to better predict irinotecan-induced toxicity and the clinical response in Chinese patients with metastatic colorectal cancer (mCRC).
Methods:
The genotypes of UGT1A (UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A7*2, UGT1A7*3, UGT1A7*4 and UGT1A9*22) and DPYD (DPYD*5, DPYD c.1896 T > C, and DPYD*2A) were examined by direct sequencing in 661 mCRC patients receiving irinotecan-based chemotherapy. The influences of UGT1A and DPYD polymorphisms on severe irinotecan-induced toxicities and clinical outcomes were assessed.
Results:
In the cohort studied here, the incidence of UGT1A1*6, UGT1A1*28, UGT1A7*2, UGT1A7*3, UGT1A9*22, DPYD*5, and DPYD c.1896 T > C variants were 34.8%, 24.2%, 34.3%, 39.4%, 81.8%, 48.4% and 20.4%, respectively. UGT1A1*27 and DPYD*2A had low frequencies and UGT1A7*4 was not found. A total of 59 patients (8.9%) suffered severe diarrhea and 136 patients (20.6%) suffered severe neutropenia. UGT1A1*28 heterozygotes (OR = 2.263, 95%CI 1.395-3.670), UGT1A1*28 homozygotes (OR = 5.910, 95%CI 1.138-30.672) and UGT1A1*6 homozygotes (OR = 4.737, 95%CI 1.946-11.533) were independent risk factors for severe neutropenia. UGT1A polymorphisms were not found to relate to severe diarrhea. DPYD*5 was determined to be an independent risk factor for severe diarrhea (OR = 2.143, 95%CI 1.136-4.041). Neither DPYD*5 nor DPYD c.1896 T > C was found to relate to severe neutropenia. In the first-line irinotecan-based treatment, UGT1A1*28 and DPYD*5 contributed to higher response rates (P = 0.043 and P = 0.019, respectively), while DPYD*5 was found to associate with better progression-free survival (P = 0.015). UGT1A1*27 contributed to worse overall survival (P < 0.001).
Conclusion:
Results still showed UGT1A1*6 and UGT1A1*28 to be partially associated with irinotecan-induced toxicity and clinical response. An examination of more UGT1A loci, except for UGT1A1*6 and UGT1A1*28, was not helpful to improve the predictive value of irinotecan-based toxicity and efficacy. An examination of DPYD*5 assisted in the prediction of severe diarrhea.
... Основой терапии метастатического РТК (мРТК) до 90-х годов прошлого века являлись препараты фторпиримидинового ряда. При применении комбинации 5-фторурацила/лейковорина (5-ФУ/ЛВ), исторически служившей базовым компонентом проводимого лечения, медиана общей выживаемости (ОВ) не превышала 12,6 мес [2]. ...
... Благодаря этому подходы к лечению мРТК переместились в сторону более частого использования двойных комбинаций на основе 5ФУ/ЛВ. Сочетание 5ФУ/ЛВ и иринотекана позволило увеличить медиану ОВ до 14,8 (режим IFL) -17,4 мес (режим FOLFIRI) [2,3]. При применении режима FOLFOX/ XELOX в 1-й линии терапии метастатического колоректального рака медиана ОВ достигла 17,7 мес и 18,8 мес соответственно [4]. ...
Bevacizumab in combination with standard chemotherapy (CT) in 1st line metastatic colorectal cancer (mCRC) settings prolongs median overall survival to 20,3 months. Data of observational cohort programs suggests that bevacizumab therapy beyond disease progression, in combination with several CT regimens prolongs median overall survival till 31,8 month. Authors presents their own experience of prolonged bevacizumab therapy in mCRC patient.
... Overall, more than half (60%) of the mCRC patients received first-line combination chemotherapy with or without a targeted agent. As first-line treatment, combination chemotherapy has been associated with prolonged progression-free survival (PFS) and OS compared with single-agent chemotherapy [13][14][15][16]. Nevertheless, only a minority of the elderly patients (!75 years) received combination chemotherapy (37%), probably due to concerns on tolerability and toxicity. ...
... More studies are needed to clarify the role of anti-EGFR therapies in the population of elderly mCRC patients, especially as targeted agents may sometimes be the only therapeutic option for frail elderly patients who are unable to tolerate chemotherapy. Several phase III trials [13][14][15]31,32] and retrospective cohort studies [22,33] have demonstrated survival rates exceeding 21.5 months in mCRC patients treated with modern systemic regimens, which seems in line with the median OS of 20.2 months in patients <60 years as observed in our study. Inferior results, however, were observed in elderly mCRC patients (!75 years), with a median OS of 14 months. ...
Background:
Although the spectrum of systemic treatment for metastatic colorectal cancer (mCRC) has widened, there is a paucity of evidence for the feasibility and optimal use of these systemic agents in elderly patients. The present study provides real world data on the age-related systemic treatment and survival of CRC patients with non-resectable metachronous metastases.
Methods:
All consecutive patients with non-resectable metastases from primary resected CRC were extracted from the Eindhoven area of the Netherlands Cancer Registry (NCR). Patients receiving palliative systemic therapy were enrolled (n = 385). Systemic treatment and survival were analyzed according to age at diagnosis of metastases.
Results:
Patients aged ≥75 years more often received first-line single-agent chemotherapy than their younger counterparts (63% vs. 32%, p < .0001). First-line single-agent chemotherapy was often prescribed without additional targeted therapy (78%). Advanced age (≥75 years) was associated with a lower probability of receiving all active cytotoxic agents compared to patients aged <60 years at time of diagnosis of metastases (odds ratio (OR) 0.2, 95% CI 0.10-0.77). In a multivariable Cox regression analysis with adjustment for age and other relevant prognostic factors, the total number of received systemic agents was the only predictor of death (hazard ratio (HR) 0.7, 95% CI 0.61-0.81).
Conclusion:
The beneficial effect of treatment with all active systemic agents on survival (simultaneously or sequentially prescribed) should be taken into account when considering systemic therapy in patients with mCRC. In light of our results, future studies are warranted to clarify the role of potential targeted therapy in elderly mCRC patients, who are often not candidates for combination chemotherapy and treatment with all active cytotoxic agents.
... However, the serious issue of irinotecan in clinical practice was its dose-limiting toxicity, including severe neutropenia, regardless of any cancers. [1][2][3] Irinotecan is also a potent inhibitor of topoisomerase I, is initially hydrolyzed to its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), which is then subsequently inactivated through UGT1A1-mediated glucuronidation. [4] Irinotecan-induced neutropenia is a complex, polygenic phenotype. ...
To analyze the incidence and nongenetic risk factors of irinotecan-induced severe neutropenia in the hospital, and provide additional reference and help for clinical treatment. A retrospective analysis of patients who received irinotecan based chemotherapy from May 2014 to May 2019 in Renmin Hospital of Wuhan University was conducted. Univariate analysis and binary logistic regression analysis with the forward stepwise method were used to assess the risk factors associated with severe neutropenia induced by irinotecan. Of the 1312 patients treated with irinotecan-based regmines, only 612 patients met the inclusion criteria, and 32 patients developed irinotecan-induced severe neutropenia. In the univariate analysis, variables associated with severe neutropenia were tumor type, tumor stage, and therapeutic regimen. In the multivariate analysis, irinotecan plus lobaplatin, lung cancer or ovarian cancer, tumor stage T2, T3, and T4, were identified as risk factors that contributed independently to irinotecan-induced severe neutropenia (P < .05), respectively. The results showed that the incidence of irinotecan–induced severe neutropenia was 5.23% in the hospital. The risk factors included tumor type (lung cancer or ovarian cancer), tumor stage (T2, T3, and T4) and therapeutic regimen (irinotecan plus lobaplatin). Therefore, for patients with these risk factors, it might be advisable to actively consider optimum management to reduce the occurrence of irinotecan–induced severe neutropenia.
... Application of ½ standard deviation calibration method for overall survival to existing phase III clinical trials[25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. ...
... iRiNOTEKaN Topoizomeraz I inhibitörü olan irinotekan, çok çeşitli tümörlere karşı güçlü bir antitümör aktivite gösterir; bu nedenle en sık uygulanan kemoterapi ajanlarından biridir. 13 Birinci basamak tedavi olarak 5-FU ile kombinasyon hâlinde veya 2. basamak tedavide monoterapi olarak metastatik kolorektal kanser tedavisinde yaygın olarak kullanılmaktadır. 14 Hepatik CYP3A4 ekspresyonunda gözlemlenen bireyler arası değişkenlik çok yüksektir (>100 kat); ancak önceden tanımlanmış 43 varyant allelden hiçbirinin varlığı bu değişkenliği açıklayamaz. ...
... 1,2 Recently, new regimens combining chemotherapy and molecular targeted agents for metastatic colorectal cancer (mCRC) have been reported to improve progression-free survival (PFS) and overall survival (OS). [3][4][5][6] The standard treatment for mCRC usually consists of chemotherapy with 5-fluorouracil or capecitabine in combination with oxaliplatin or irinotecan and targeted agents such as bevacizumab, cetuximab, and panitumumab. [7][8][9][10] The most commonly used chemotherapy regimens are 5-fluorouracil with leucovorin plus oxaliplatin (FOLFOX), capecitabine plus oxaliplatin (CAPOX), and 5-fluorouracil with leucovorin plus irinotecan (FOLFIRI). ...
Objective:
Irinotecan is a useful anticancer drug for colorectal cancer treatment. UGT1A1*28 and *6 gene polymorphisms are known risk factors for irinotecan-associated toxicity. However, severe adverse effects due to irinotecan have been observed even in patients who do not harbor UGT1A1*28 or *6. We investigated gene polymorphisms in the whole exome to identify useful biomarkers for irinotecan toxicity other than UGT1A.
Methods:
A total of 178 patients with metastatic colorectal cancer (mCRC) and 87 patients with pancreatic cancer were treated with FOLFIRI, FOLFOX, FOLFOXIRI, modified FOLFIRINOX, or gemcitabine plus nab-paclitaxel. Genome-wide screening was performed using whole-exome sequencing (WES), and validation analysis was performed using qPCR with a hydrolysis probe.
Results:
Using WES after a doublet chemotherapy regimen comprising irinotecan and 5-fluorouracil (n = 15), seven single nucleotide polymorphisms (SNPs) were identified as candidate biomarkers for irinotecan-associated toxicity of neutropenia. Among the seven SNPs, an SNP in R3H domain and coiled-coil containing 1 (R3HCC1; c.919G > A, rs2272761) showed a significant association with neutropenia (>grade 3) after doublet chemotherapy. Patients receiving irinotecan including triplet chemotherapy, FOLFOXIRI for mCRC (n = 23) or modified FOLFIRINOX for pancreatic cancer (n = 40), also showed significant linear trends between R3HCC1 polymorphism and neutropenia (p = 0.017 and 0.046, respectively). No significant association was observed in patients treated with irinotecan-free regimens, FOLFOX for mCRC (n = 66), and gemcitabine plus nab-paclitaxel for pancreatic cancer (n = 47).
Conclusion:
Thus, an SNP in the R3HCC1 gene may be a useful biomarker for the toxicity of irinotecan-containing chemotherapy for mCRC and pancreatic cancer.
... [1] For patients with advanced colorectal cancer, fluoropyrimidine-based chemotherapy, either with the modified FOLFIRI regimen or 5-fluorouracil plus folinic acid plus oxaliplatin, FOLFOX-4, are recognized as first-line treatments. [4] Adding bevacizumab, the monoclonal antibody, against vascular endothelial growth factor (VEGF) to FOLFIRI or FOLFOX has revealed modest activity for metastatic colorectal cancer. [5] To the best of our knowledge, this is the first case of the use of neoadjuvant therapy to treat undifferentiated colorectal rhabdoid carcinoma. ...
... Patients with stage II CRC are often cured with surgery alone, but 15%-20% of patients have a recurrence and eventually succumb to their disease [3]. Owing to the wide use of 5-fluorouracil (5-FU)-based adjuvant chemotherapy, reduced relapses have been observed in patients with stage III CRC [4][5][6]. However, the application of adjuvant chemotherapy to patients with stage II CRC remains controversial because of its minimal benefit that is usually considered to be not worth the toxic effects of the drugs [7][8][9]. ...
Background:
For stage II colorectal cancer (CRC), the efficacy of adjuvant chemotherapy remains controversial. Consensus molecular subtype (CMS) have been validated to be a prognostic tool for CRCs. In this study, CMS status was investigated as prognostic biomarkers for the efficacy of adjuvant chemotherapy for stage II colorectal cancer.
Materials and methods:
The tissue microarray (TMA) was retrospectively constructed of 165 non-consecutive, primary, and sporadic stage II CRCs. CMS status was determined by immunohistochemistry staining of CDX2, HTR2B, FRMD6, and ZEB1, combining with MSI testing. The prognostic for adjuvant chemotherapy efficacy of CMS status was calculated by Kaplan-Meier curves and Cox regression analysis. Subgroup analyses were conducted according to tumor location.
Results:
Kaplan-Meier curves indicated that CMS was associated with overall survival (OS) and disease-free survival (DFS) for stage II CRCs. Cox regression analysis showed that CMS was an independent risk factor for OS. Among high-risk clinicopathological factors, patients with CMS2/3 (HR: 0.445, 95%CI: 0.227-0.875), left-sided tumors (HR: 0.488, 95%CI:0.247-0.968) or less than 12 lymph nodes examined (HR: 0.307, 95%CI: 0.097-0.974) had survival benefit from adjuvant chemotherapy. Subgroup analysis showed that adjuvant chemotherapy only improved OS for patients with left-sided tumors of CMS2/3 subtype. Regardless of CMS, right-sided tumors had no benefit from adjuvant chemotherapy.
Conclusion:
CMS is a better prognostic factor for adjuvant chemotherapy for stage II CRCs. Together with tumor location, CMS classification will aid in personalized treatment for stage II CRCs.
Implications for practice:
For stage II colorectal cancer, the efficacy of adjuvant chemotherapy remains controversial, for that its minimal benefit (no more than 5% on average) is considered not worth the toxic effects of the drugs. There is still no effective prognostic and predictive biomarkers. Our study showed that Consensus Molecular Subtypes (CMS) status is a predictive marker for adjuvant chemotherapy efficacy. Patients with left-sided tumors of CMS2/3 subtype have survival benefit by receiving adjuvant chemotherapy, which will aid in personalized treatment for stage II CRCs. Moreover, this test of CMS based on IHC is cheap, not time consuming, and easily conducted in the laboratories of most hospitals.
... 18 In the last 20 years, however, new chemotherapy regimens were developed and have increased response rates to approximately 50%. 19,20 The most commonly used CRLM chemotherapy regimens include oxaliplatin with 5-FU and leucovorin, known as FOLFOX, and irinotecan plus 5-FU and leucovorin, known as FOLFIRI. Previous studies have shown that the type of liver injury is regimen specific. ...
Patients with colorectal cancer (CRC) have benefited significantly from advances in multimodal treatment with significant improvements in long-term survival. More patients are currently being treated with surgical resection or ablation following neoadjuvant or adjuvant chemotherapy. However, several cytotoxic agents that are administered routinely have been linked to liver toxicities that impair liver function and regeneration. Recognition of chemotherapy-related liver toxicity emphasizes the importance of multidisciplinary planning to optimize care. This review aims to summarize current data on multimodal treatment concepts for CRC, provide an overview of liver damage caused by commonly administered chemotherapeutic agents, and evaluate currently suggested protective agents.
... FOLFIRI (irinotecan, bolus and continuous-infusion fluorouracil, leucovorin) represents one of the key regimens for the treatment of metastatic colorectal cancer (mCRC) due to the significant survival advantage reported by clinical trials as both pre-treated mCRC and first-line therapy (1,2). Furthermore, the more recent combination of FOLFIRI with molecularly targeted anticancer agents, such as the anti-angiogenic bevacizumab or aflibercept (3,4) and anti-EGFR agents cetuximab or panitumumab (5,6), has further improved the efficacy of mCRC therapy. ...
Nuclear receptors act as mediators of cancer-related inflammation and gene expression. They have a regulatory effect on genes encoding proteins related to drug adsorption, distribution, metabolism, and excretion. The aim of the present study was to highlight novel prognostic markers among polymorphisms in genes encoding for nuclear receptor proteins and inflammation-related cytokines in patients treated with a FOLFIRI regimen. This study included two independent cohorts comprising a total of 337 mCRC patients homogeneously treated with first-line FOLFIRI. Genotyping of 246 haplotype-tagging polymorphisms in 22 genes was performed using bead array technology. The NR1I2 (PXR)-rs1054190 and VDR-rs7299460 polymorphisms were significantly associated with patient overall survival (OS). A detrimental effect of the NR1I2 rs1054190-TT genotype on OS was observed in both the discovery and replication cohorts (HR = 6.84, P = 0.0021, q-value = 0.1278 and HR = 3.56, P = 0.0414, respectively). Patients harboring the NR1I2 rs1054190-TT genotype had a median OS of 9 months vs. 21 months in patients with C-allele (P < 0.0001 log-rank test). VDR rs7299460-T was consistently associated with a longer OS in both cohorts (discovery: HR = 0.61, P = 0.0075, q-value = 0.1535; replication: HR = 0.57, P = 0.0477). Patients with the VDR rs7299460-T allele had a median OS of 23 months compared to 18 months in those with the CC genotype (P = 0.0489, log-rank test). The NR1I2-rs1054190 polymorphism also had an effect on the duration of progression-free survival, consistent with the effect observed on OS. Two novel prognostic markers for mCRC treated with FOLFIRI were described and, if validated by prospective trials, have a potential application in the management of these patients.
... Patients with metastatic colorectal cancer with liver or lung metastases have a 5-year overall survival rate of 30-50% (24). Conventional chemotherapy for metastatic colorectal cancer with leucovorin and fluorouracil may extend the progressionfree survival and overall survival, regardless of the use of oxaliplatin or irinotecan (25); however, the long-term results are not satisfactory. Therapeutic chemotherapy treatment for colon cancer with liver metastases is not currently possible. ...
Background/aim:
Colon cancer is prone to distant metastases to other sites and the risk of recurrence is relatively high. Therefore, the identification of liver metastasis-related factors is important for the diagnosis or treatment of colon cancer. The aim of this study was to identify the metastasis-related factors that are differentially expressed in synchronous solitary liver metastasis compared to primary colon cancer.
Materials and methods:
Tissues of primary colon cancer and associated with liver metastases of five patients were used for mass spectrometry. Identified proteins were validated by western blotting. The in silico analysis was performed using the STRING database and GeneMANIA.
Results:
We identified 58 differentially expressed proteins (DEPs), including 51 under-expressed and 7 over-expressed proteins among a total of 164 identified proteins. Major hubs of protein-protein networks were ACTC1, PRDX6, TPI1, and ALDH1A1. DEPs were located in the extracellular region and cytoplasm and were involved in the regulation of enzymatic activity. The metabolic process was significantly enriched in biological processes and an involvement in the KEGG pathway.
Conclusion:
These DEPs can potentially be used as biomarkers for the diagnosis of liver metastasis and they may provide a new strategy for developing anti-metastatic liver drugs in colon cancer patients.
... The antitumor efficacy, as well as the cytotoxicity of 5-FU administered as an intravenous bolus was demonstrated to be potentiated by the addition of the reduced folate leucovorin (LV; 5-formyl tetrahydrofolate [THF]) [83][84][85]. The topoisomerase I inhibitor irinotecan (IRI) plus the intravenous bolus 5-FU/LV (IFL regimen) was considered the standard of care in 2000 [86,87]. However, the undesired toxicity profile of the IFL regimen led to the development of the IFL infusion or FOLFIRI regimen (IRI plus infusional 5-FU/LV) [88,89], especially as a second-line chemotherapy for patients with good status and organ function [90,91]. ...
Colorectal cancer (CRC) is among the five most commonly diagnosed cancers worldwide, constituting 6% of all cancers and the third leading cause of cancer death. CRC is the third and second most frequent cancer in men and women worldwide, accounting for 14% and 13% of all cancer incidence rates, respectively. CRC incidence is decreasing in older populations, but it has been significantly rising worldwide in adolescents and adults younger than 50 years old. Significant advances in the screening methods and surgical procedures have been underlying the reduction of the CRC incidence rate in older populations. However, there is an urgent demand for the development of alternative effective therapeutic options to overcome advanced metastatic CRC, while preventing disease recurrence. This review addresses the immune and CRC biology, summarizing the recent advances on the immune and/or therapeutic regimens currently in clinical use. We will focus on the emerging role of nanotechnology in the development of combinational therapies targeting and thereby regulating the function of the major players in CRC progression and immune evasion.
... The clinically administered SN38 prodrug, CPT-11, causes diarrhea in up to 70% of treated patients, and incidence of grade 3 or 4 diarrhea has been observed in 31% of the patients [68]. Several strategies, including the removal of GI bacteria [69] and the use of selective inhibitors of β-glucuronidase [70], have been employed to alleviate CPT-11-induced toxicity. ...
Nanomedicines have been extensively explored for cancer treatment, and their efficacies have arguably been proven in various cancer cell-derived xenograft (CDX) mouse models. However, they generally fail to show such therapeutic advantages in patients because of the huge pathological differences between human tumors and CDX models.
Methods: In this study, we fabricated colloidal ultrastable nanomedicines from polymeric prodrugs and compared the therapeutic efficacies in hepatocellular carcinoma (HCC) CDX and clinically relevant patient-derived xenograft (PDX) mouse models, which closely mimic human tumor pathological properties. Working towards this goal, we esterified a highly potent SN38 (7-ethyl-10-hydroxycamptothecin) agent using oligo- or polylactide (oLA or PLA) segments with varying molecular weights.
Results: The resulting SN38 conjugates assembled with polyethylene glycol-block-polylactic acid to form systemically injectable nanomedicines. With increasing PLA chain length, the SN38 conjugates showed extended retention in the nanoparticles and superior antitumor activity, completely eradicating xenografted tumors in both mouse models. Our data implicate that these small-sized and ultrastable nanomedicines might also efficaciously treat cancer in patients. More interestingly, the systemically delivered nanomedicines notably alleviated the incidence of bloody diarrhea.
Conclusion: Our studies demonstrate that the appropriate molecular editing of anticancer drugs enables the generation of better tolerated cytotoxic nanotherapy for cancer, which represents a potentially useful scaffold for further clinical translation.
... In a study of patients with hepatic metastatic disease from CRC who underwent liver resection, Fong et al. [6] tumor burden and the incidence of complications associated with surgery, including incomplete excision, metastasis, and tumor-cell shedding. [11][12][13] The chemotherapy regimens folinic acid + 5fluorouracil (5-FU) + oxaliplatin (FOLFOX) [14][15][16] and folinic acid + 5FU + irinotecan (FOLFIRI) [17][18][19][20] have both been reported to achieve a longer median survival time of up to 31.5 months in patients with mCRC or advanced CRC. ...
Aim:
The aim of this is study is to assess the efficacy and safety of conversion capecitabine plus oxaliplatin (XELOX) in Chinese patients with potentially resectable colorectal liver metastases (CLMs).
Patients and methods:
Thirty patients (median age 57.5 years) with potentially resectable CLMs were treated with XELOX in a single-arm, open-label, nonrandomized, multicenter clinical trial.
Results:
The objective response rate in the 30 patients was 40% (95% confidence interval: 22.7%-59.4%), and the rate of conversion to resectable CLMs was 43.3%. Patients who underwent liver resection (n = 11) had a longer median progression-free survival and overall survival than those who did not. XELOX showed an acceptable safety profile.
Conclusion:
XELOX may effectively convert potentially resectable CLM into resectable CLM, providing survival benefits with a favorable safety profile.
Clinical trials.gov identifier:
NCT 00997685.
... On the other hand, CPT revealed ruthless and erratic side effects in clinical trials [25], but extensive studies led to the development of CPT derivatives in large numbers, and only topotecan (TPT; 9-dimethyl amino-10-hydroxy CPT) (Fig. 3b) and irinotecan (CPT-11; 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) (Fig. 3c) received the Food and Drug Administration (FDA) approval for clinical use, in 1996, and were marketed by GlaxoSmithKline and Pharmacia (now Pfizer), respectively; at present, they are used for prescription of ovarian and colon cancers [26,27]. ...
The World Health Organization reports that approximately 80% population from developing countries are facing complications from synthetic drugs used in maintaining their primary health-care needs. The chemotherapeutic strategies are very striking and have earned serious concern as potential means of controlling the incidence of this dreadful disease. However, the major problem in cancer is the long lasting toxicity of the well reputable chemical drugs. Since ancient times, medicinal plants have attracted enormous attention, to fight against various diseases with their broad-spectrum biological and therapeutic properties. Although plants, phytochemicals and their analogues have been confirmed to be safe and effective, having strong anticancer properties. A number of pharmaceutical agents with diverse chemical structures of natural origin from plants have been discovered as anticancer agents such as vincristine, vinblastine, podophyllotoxin, camptothecin, taxol, resveratrol, withaferin A, quercetin, and curcumin. Further modifications of these phytochemicals led to the development of numerous outstanding molecules such as drugs like topotecan, irinotecan, taxotere, etoposide, and teniposide. In this in-depth review, we meticulously investigated the selected medicinal plants for their anticancer properties. In particular, novel compounds from plants have beneficial effects on human health. Our observations suggest the preventive and therapeutic use of phytochemicals in managing various human malignancies.
... 21,22 Studies also showed that treatment with irinotecan, fluorouracil, and leucovorin resulted in significantly longer PFS and longer overall survival, as compared with treatment with fluorouracil and leucovorin. 23 In some multicenter randomized trials, the response rate and overall survival were significantly higher in patients in the irinotecan group than in those in the no-irinotecan group; time to progression was also significantly longer in the irinotecan group than in the no-irinotecan one. 24 These results suggest the effective role of irinotecan in the treatment for mCRC. ...
Topoisomerase 1 (TOPO-1) and carboxylesterase 2 (CES-2) are found to play crucial roles in the pathogenesis of various cancers. The prognostic role of TOPO-1 and CES-2 in patients with metastatic colorectal cancer (mCRC) who underwent irinotecan chemotherapy was largely unknown. In the current study, we assessed the expression of TOPO-1 and CES-2 in mCRC and analyzed its potential relevance to irinotecan based therapy. A total of 98 patients with mCRC were included in this study. The expression of TOPO-1 and CES-2 in mCRC tissues was evaluated by immunohistochemistry. For TOPO-1, 46 patients showed high expression and 52 patients showed low expression. For CES-2, 53 patients showed high expression and 45 patients showed low expression. The correlation between TOPO-1 or CES-2 expression and clinicopathological characteristics of mCRC patients was analyzed. Neither TOPO-1 nor CES-2 had significant correlation with age, gender, tumor site, tumor grade and metastatic sites in mCRC patients. However, high expression of CES-2 but not TOP-1 was positively correlated with better curative effect. Kaplan-Meier and log-rank test were applied to assess the correlation between progression-free survival (PFS)/overall survival (OS) and TOPO-1 or CES-2 expression in mCRC patients. High expression of TOPO-1 and CES-2 are correlated with longer PFS and OS. In summary, our findings suggest that TOPO-1 and CES-2 may play important roles irinotecan sensitivity in mCRC patients. Evaluation of expression of TOPO-1 and CES-2 may provide preliminary clinical evidence for the management of irinotecan-based therapy in mCRC patients.
... Although the survival rate of patients with CRC has improved, it is lower than that for patient with other types of cancer [1,2]. Furthermore, although the use of oxaliplatin and irinotecan with 5-fluorouracil has increased the overall survival rate of patients with CRC, this treatment regimen is highly toxic with high rates of side effects [3]. Therefore, alternative therapies including natural compounds have been recommended for cancer therapy [4]. ...
Genipin, a major component of Gardenia jasminoides Ellis fruit, has been shown to inhibit the growth of gastric, prostate, and breast cancers. However, the anti-proliferative activity of genipin in colorectal cancer (CRC) has not been characterized. Herein, we demonstrated that genipin inhibits the proliferation of CRC cells and that genipin suppressed the Hedgehog pathway. Further investigation showed that p53 and NOXA protein levels were increased during inhibition of Hedgehog pathway-mediated apoptosis in CRC cells. We also showed that p53 modulated the expression of NOXA during genipin-induced apoptosis, and suppression via SMO also played a role in this process. Subsequently, GLI1 was ubiquitinated by the E3 ligase PCAF. In a xenograft tumor model, genipin suppressed tumor growth, which was also associated with Hedgehog inactivation. Taken together, these results suggest that genipin induces apoptosis through the Hedgehog signaling pathway by suppressing p53. These findings reveal a novel regulatory mechanism involving Hedgehog/p53/NOXA signaling in the modulation of CRC cell apoptosis and tumor-forming defects.
... A very similar compound, purvalanol A, potently suppresses the anchorageindependent growth of c-Src-transformed cells as well as HT-29 and SW48 human colon cancer cells [40]. Moreover, irinotecan, an exclusive repurposed drug that was found in the case of colorectal cancer, in combination with fluorouracil and leucovorin benefits patients with metastatic colorectal cancer [41]. From the rectum analysis, mitoxantrone is one out of six exclusive drugs that were found. ...
Background
Systemic approaches offer a different point of view on the analysis of several types of molecular associations as well as on the identification of specific gene communities in several cancer types. However, due to lack of sufficient data needed to construct networks based on experimental evidence, statistical gene co-expression networks are widely used instead. Many efforts have been made to exploit the information hidden in these networks. However, these approaches still need to capitalize comprehensively the prior knowledge encrypted into molecular pathway associations and improve their efficiency regarding the discovery of both exclusive subnetworks as candidate biomarkers and conserved subnetworks that may uncover common origins of several cancer types.
Methods
In this study we present the development of the Informed Walks model based on random walks that incorporate information from molecular pathways to mine candidate genes and gene-gene links. The proposed model has been applied to TCGA (The Cancer Genome Atlas) datasets from seven different cancer types, exploring the reconstructed co-expression networks of the whole set of genes and driving to highlighted sub-networks for each cancer type. In the sequel, we elucidated the impact of each subnetwork on the indication of underlying exclusive and common molecular mechanisms as well as on the short-listing of drugs that have the potential to suppress the corresponding cancer type through a drug-repurposing pipeline.
Conclusions
We have developed a method of gene subnetwork highlighting based on prior knowledge, capable to give fruitful insights regarding the underlying molecular mechanisms and valuable input to drug-repurposing pipelines for a variety of cancer types.
Electronic supplementary material
The online version of this article (10.1186/s12918-017-0473-6) contains supplementary material, which is available to authorized users.
... The first-line treatments for patients with metastatic colorectal cancer (mCRC) usually involves combination chemotherapies that include infusional 5-fluorouracil and leucovorin plus either irinotecan or oxaliplatin [1,2]. Capecitabine, an oral fluoropyrimidine anticancer agent, in combination with oxaliplatin (CapeOX), had similar efficacy to regimens based on infusional 5-furuorouracil in combination with oxaliplatin used in previous studies [3][4][5]. ...
Background
The aim of this study was to evaluate the efficacy and safety of CapeOX plus bevacizumab with a planned oxaliplatin stop-and-go strategy in Japanese patients with metastatic colorectal cancer (mCRC). Methods
Patients with untreated mCRC were treated with 4 cycles of CapeOX plus bevacizumab therapy, followed by capecitabine plus bevacizumab maintenance therapy. Reintroduction of oxaliplatin was scheduled after 8 cycles of maintenance therapy or upon tumor progression. The primary endpoint was progression-free survival (PFS), and secondary end points included overall survival (OS), objective response rate to each treatment, reintroduction rate of oxaliplatin, frequency of peripheral sensory neuropathy (PSN), and safety. ResultsThe 52 patients who received the protocol treatment were included in the evaluation of efficacy and safety. Median PFS and OS were 12.4 months (95% confidence interval [CI], 10.0–14.8) and 30.6 months (95% CI, 27.6–33.5), respectively. The objective response rates were 55.8% for the initial CapeOX plus bevacizumab therapy, 17.8% for capecitabine plus bevacizumab maintenance therapy, and 31.0% for reintroduced CapeOX plus bevacizumab therapy. The frequency of PSN was 63.5%, including 3.8% of patients with grade 3 PSN. No patients required treatment discontinuation because of PSN during the induction or maintenance therapy. Conclusions
CapeOX plus bevacizumab therapy with a planned oxaliplatin stop-and-go strategy is a feasible first-line treatment for Japanese patients with mCRC. Trial registrationThis trial is registered with the University Hospital Medical Information Network in 15 March 2010 (UMIN000006478).
... An extract of the Pacific yew tree, Taxus brevifolia was discovered to possess excellent anticancer properties and effective against ovarian cancer (Devoti ,2006 ;Gurab-Fakim,2006).) .Jacoby ,(2005) published their findings as well as the structure of the active component, Paclitaxel irreversibly binds to β-tubulin, thus promoting microtubule stabilization ( Devoti ,2006).This tubulin-microtubule equilibrium is essential for cell multiplication, and its stabilization causes programmed cell death ( Wilson and Jordan,1995) Camptothecin , discovered from the deciduous tree Camptotheca acuminata, is also an anticancer agent which has a unique mechanism of action used to treatment of ovarian and colon cancers (Saltz et al.,2000;Gore et al.,2001). Camptothecin and its derivatives are topoisomerase-I inhibitors, and soluble cause cell death by DNA damage ( Staker et al., 2002) .However, camptothecin itself is too insoluble to be used as a drug but its several water-analogs, namely, topotecan and irinotecan have been developed as effective drugs ( Oberlies and Kroll,2004). ...
Plant plays an important role as a source of many anticancer drugs with minimal side effects , for this purpose this study was designed to evaluate the cytotoxic effects of crude and pure extracts of Convolvulus arvensis plant on cancer and transformed cell lines in vitro .This book also included the effect of these extracts on mitotic index on cancer cell line and lymphocytes. The book was demonstrated that the pure extract significantly inhibits the treated cancer cell line proliferation and cause apoptosis. Different methods have been used for detection of apoptosis: light microscope, fluorescent microscope and DNA electrophoresis.
... Complete resection is essential for the cure of CRC. However, metastatic CRC (mCRC) cannot be cured by surgical resection alone, and the prognosis of such patients is poor [2,3]. ...
Purpose:
This study investigated the efficacy and safety of cetuximab-based treatment in patients with chemotherapy-resistant refractory mCRC with KRAS G13D mutation.
Patients and methods:
An assessment of the efficacy and safety of cetuximab-based treatment was performed in an observation-enriched randomized controlled study comparing the cetuximab alone group (Cet group) and the combination of cetuximab and irinotecan group (CetI group) for KRAS G13D-mutated mCRC in Japan. In this study, the patients received a biweekly (500 mg/m(2) on day 1) or weekly (250 mg/m(2)) intravenous infusion of cetuximab in Cet group, or a biweekly (500 mg/m(2) on day 1) or weekly (250 mg/m(2)) intravenous infusion of cetuximab followed by irinotecan (150 mg/m(2)) in CetI group. Propensity score adjustment was used to achieve balance in the observational arm.
Results:
Data from a total of 29 patients (10 in Cet group, 19 in CetI group) were analyzed. Crude median progression-free survival time was 2.9 months in the Cet group and 2.5 months in the CetI group. Crude disease control rates were 55.6% in the Cet group and 47.4% in the CetI group. After a median follow-up of 43 months, the crude median overall survival was 8.0 months in the Cet group and 7.6 months in the CetI group. Cetuximab-based treatment did not markedly increase any characteristic toxicity and was generally well tolerated. Propensity score analyses adjusted for performance status and number of metastases showed comparable results with the crude results.
Conclusion:
Cetuximab-based treatment seemed to benefit patients with chemotherapy-resistant, refractory KRAS G13D-mutated mCRC. Our results might support the administration of cetuximab-based treatment for KRAS-mutant mCRC and would be able to provide treatment flexibility in this setting.
... Several transporters are involved in IRT transport: SLCO1B1, ABCB1, ABCC1, ABCC2 and ABCG2 [2,311]. Much like with other chemotherapeutics, overexposure of IRT can lead to ADRs such as myelosuppression, diarrhea and neutropenia [3,312]. Both UGT1A1 and CYP3A5 are well expressed in children and attain the adult level activity within 3–6 months post birth, hence genetic variants might predict the inter-individual variability to a large extent among children [313]. ...
During the 3rd congress of the European Society of Pharmacogenomics and Personalised Therapy (ESPT) in Budapest in 2015, a preliminary meeting was held aimed at establishing a pediatric individualized treatment in oncology and hematology committees. The main purpose was to facilitate the transfer and harmonization of pharmacogenetic testing from research into clinics, to bring together basic and translational research and to educate health professionals throughout Europe. The objective of this review was to provide the attendees of the meeting as well as the larger scientific community an insight into the compiled evidence regarding current pharmacogenomics knowledge in pediatric oncology. This preliminary evaluation will help steer the committee's work and should give the reader an idea at which stage researchers and clinicians are, in terms of personalizing medicine for children with cancer. From the evidence presented here, future recommendations to achieve this goal will also be suggested.
... Theoretically , failure of PRO data to have an impact on clinical practice may stem from problems that start with the trial design and conduct, compounded by poor reporting and separate PRO and clinical publications. Further research is now needed to investigate whether improved reporting will have the desired effect of informing patient-centred care, clinical decision Author [citation] PRO rationale Level of detail* Interpretation of PRO in relation to clinical findings Level of detail † Saltz [62] No PRO rationale Absent " the [intervention] was associated with higher rates of tumor regression, progression-free survival, and overall survival without compromising the quality of life. " General Sobrero [63] No PRO rationale Absent " .. Progression free survival was significantly longer in experimental. . ...
Purpose:
The CONSORT extension for patient reported outcomes (PROs) aims to improve reporting, but guidance on the optimal integration with clinical data is lacking. This study examines in detail the reporting of PROs and clinical data from randomized controlled trials (RCTs) in gastro-intestinal cancer to inform design and reporting of combined PRO and clinical data from trials to improve the 'take home' message for clinicians to use in practice.
Materials and methods:
The case study was undertaken in gastro-intestinal cancer trials. Well-conducted RCTs reporting PROs with validated instruments were identified and categorized into those combining PRO and clinical data in a single paper, or those separating data into linked primary and supplemental papers. Qualitative methods were developed to examine reporting of the critical interpretation of the trial results (trial exegesis) in the papers in relation of the PRO and clinical outcomes and applied to each publication category. Results were used to inform recommendations for practice.
Results:
From 1917 screened abstracts, 49 high quality RCTs were identified reported in 36 combined and 15 linked primary and supplemental papers. In-depth analysis of manuscript text identified three categories for understanding trial exegesis: where authors reported a "detailed", "general", or absent PRO rationale and integrated interpretation of clinical and PRO results. A total of 11 (30%) and 6 (16%) combined papers reported "detailed" PRO rationale and integrated interpretation of results although only 2 (14%) and 1 (7%) primary papers achieved the same standard respectively. Supplemental papers provide better information with 11 (73%) and 3 (20%) achieving "detailed" rationale and integrated interpretation of results. Supplemental papers, however, were published a median of 20 months after the primary RCT data in lower impact factor journals (median 16.8 versus 5.2).
Conclusion:
It is recommended that single papers, with detailed PRO rationale and integrated PRO and clinical data are published to optimize trial exegesis. Further work to examine whether this improves the use of PRO data to inform practice is needed.
... Capecitabine , another oral fluoropyrimidine, is currently recommended as an alternative for the treatment of these patients since its similar efficacy to 5-FU was demonstrated in randomized studies [10]. Subsequently, two other cytotoxic drugs (irinotecan and oxaliplatin) had their efficacy confirmed in the treatment of mCRC, thus becoming part of treatment protocols since 1999 [7,[11][12][13]. Lately, the eyes of the medical community around the world have been turned to targeted molecular therapies. ...
Background
Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of neoplasm-related death in the United States. Several studies analyzed the efficacy of bevacizumab combined with different chemotherapy regimens consisting on drugs such as 5-FU, capecitabine, irinotecan and oxaliplatin. This systematic review aims to evaluate the effectiveness and safety of chemotherapy plus bevacizumab versus chemotherapy alone in patients with previously untreated advanced or metastatic colorectal cancer (mCRC). Methods
Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoints were overall survival and progression-free survival. Data extracted from the studies were combined by using hazard ratio (HR) or risk ratio (RR) with their corresponding 95 % confidence intervals (95 % CI). ResultsThe final analysis included 9 trials comprising 3,914 patients. Patients who received the combined treatment (chemotherapy + bevacizumab) had higher response rates (RR = 0.89; 95 % CI: 0.82 to 0.96; p = 0.003) with heterogeneity, higher progression-free survival (HR = 0.69; 95 % CI: 0.63 to 0.75; p < 0.00001) and also higher overall survival rates (HR = 0.87; 95 % CI: 0.80 to 0.95; p = 0.002) with moderate heterogeneity. Regarding adverse events and severe toxicities (grade ≥ 3), the group receiving the combined therapy had higher rates of hypertension (RR = 3.56 95 % CI: 2.58 to 4.92; p < 0.00001), proteinuria (RR = 1.89; 95 % CI: 1.26 to 2.84; p = 0.002), gastrointestinal perforation (RR = 3.63; 95 % CI: 1.31 to 10.09; p = 0.01), any thromboembolic events (RR = 1.44; 95 % CI: 1.20 to 1.73; p = 0.0001), and bleeding (RR = 1.81; 95 % CI: 1.22 to 2.67; p = 0.003). Conclusion
The combination of chemotherapy with bevacizumab increased the response rate, progression-free survival and overall survival of patients with mCRC without prior chemotherapy. The results of progression-free survival (PFS) and overall survival (OS) were comparatively higher in those subgroups of patients receiving bolus 5-FU or capecitabine-based chemotherapy plus bevacizumab, when compared to patients treated with infusional %-FU plus bevacizumab (no difference in PFS and OS). Regarding the type of cytotoxic scheme, regimens containing irinotecan and fluoropyrimidine monotherapy showed superior efficacy results when combined to bevacizumab.
... Numerous studies have recently made remarkable advances in the search for a cure for metastatic CRC. For instance, the addition of irinotecan and oxaliplatin to 5-fluorouracil (5-FU) increased the median overall survival of 1 year [2]. Median overall survival was also increased by nearly a factor of two to 20 months when monoclonal antibody therapies such as cetuximab and bevacizumab were used [3][4][5]. ...
Metformin is an anti-diabetic drug with a promising anti-cancer potential. In this study, we show that subtoxic doses of metformin effectively sensitize human colorectal cancer (CRC) cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which induces apoptosis. Metformin alone did not induce apoptosis, but significantly potentiated TRAIL-induced apoptosis in CRC cells. CRC cells treated with metformin and TRAIL showed activation of the intrinsic and extrinsic pathways of caspase activation. We attempted to elucidate the underlying mechanism, and found that metformin significantly reduced the protein levels of myeloid cell leukemia 1 (Mcl-1) in CRC cells and, the overexpression of Mcl-1 inhibited cell death induced by metformin and/or TRAIL. Further experiments revealed that metformin did not affect mRNA levels, but increased proteasomal degradation and protein stability of Mcl-1. Knockdown of Mule triggered a significant decrease of Mcl-1 polyubiquitination. Metformin caused the dissociation of Noxa from Mcl-1, which allowed the binding of the BH3-containing ubiquitin ligase Mule followed by Mcl-1ubiquitination and degradation. The metformin-induced degradation of Mcl-1 required E3 ligase Mule, which is responsible for the polyubiquitination of Mcl-1. Our study is the first report indicating that metformin enhances TRAIL-induced apoptosis through Noxa and favors the interaction between Mcl-1 and Mule, which consequently affects Mcl-1 ubiquitination.
... In recent times there has been a marked increase in the incidence of mortality from CRC in Japan (3,4). At present, cytotoxic agents, including irinotecan, oxaliplatin and fluoropyrimidines, have extended the median survival times (MSTs) of patients with advanced CRC (5)(6)(7)(8)(9)(10)(11)(12). Despite these advances, advanced CRC remains incurable in the majority of patients. ...
Colorectal cancer (CRC) is one of the most commonly occurring cancers worldwide. A burgeoning number of studies have demonstrated that the addition of cetuximab to another standard first-line regimen markedly improves the outcome of CRC treatment. However, at present, the efficacy and safety of cetuximab-based combination chemotherapy has not been well described in Japan. The aim of the present study was to evaluate the efficacy and safety of first-line chemotherapies that included cetuximab for patients with advanced or metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type CRC in Japan. This prospective multicenter observational study was conducted at 13 affiliated medical institutions. A total of 64 patients were enrolled between 2010 and 2013. The patients met the following criteria for eligibility: i) histologically confirmed, advanced or metastatic KRAS wild-type CRC; and ii) cetuximab-based chemotherapies administered as a first-line treatment. First-line cetuximab-based treatments were administered as follows: 29 patients (45.3%) received a combination of infusional fluorouracil, leucovorin and oxaliplatin; 14 patients (21.9%) received a combination of capecitabine and oxaliplatin; and 10 patients (15.6%) received a combination of infusional fluorouracil, leucovorin and irinotecan. The overall response rate (including complete plus partial responses) was 50% (32/64 patients). Initially, 48 lesions were diagnosed as unresectable. Among those, 13 lesions (27.1%) were converted to a resectable status following cetuximab-based combination chemotherapy treatments. The median overall survival time and the progression-free survival time were 1,189 and 359 days, respectively. The most frequent grade 3/4 adverse event was neutropenia, which occurred in 20.3% of the patients. The incidence of grade 3/4 skin toxicity was 17.2% (11/64 patients). Cetuximab-based therapies may represent a promising first-line regimen for patients with advanced or metastatic KRAS wild-type CRC in Japan. In addition, this combination was associated with a low incidence of serious toxicities.
... Over the past 10 years, various combinations of chemotherapy were investigated for the treatment of metastatic CRC (mCRC) (Jackson et al., 2009 ). Chemotherapy combinations recommended usually contain fluorouracil (5-FU) or capecitabine , associated with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) (Colucci et al., 2005; Schmoll et al., 2007; Fuchs et al., 2007; Van Cutsem et al., 2001; de Gramont et al., 2000; Douillard et al., 2000; Saltz et al., 2000). Recently, molecular targeted therapies have had special attention from the medical community worldwide. ...
Hepatotoxicity is an expanding field in hepatology and implies chemical-driven liver damage. This includes toxicity notably related to conventional drug medications, as well as illicit drugs, herbal medicine, and dietary supplements. Drug-induced liver injury is responsible for 5% of all hospital admissions and 50% of all acute liver failures. Patients with advanced colorectal cancer have largely gained these last decades in long-term survival rate from advances in multimodal treatment and standardized multidisciplinary approaches. However, as a drawback, several modern systemic chemotherapy-based treatments cause liver injury. These are qualified under the term chemotherapy-associated liver injury (CALI). Steatosis, steatohepatitis and sinusoidal obstruction syndrome develop following chemotherapy for colorectal cancer.
Overview
The role of dose and schedule have always and continue to play a critical role in clinical cancer drug treatment. Dose is a significant determinant of the antitumor activity and toxicology for the established cytotoxic chemotherapeutic agents and newly developed targeted agents. The relationship for dose, or more correctly exposure, is quite consistent for the effect on normal tissues, most clearly seen in the deoxyribonucleic acid (DNA) damaging agents and mitotic tubule inhibitors. The effect of dose for biologically therapeutic agents such as the interferons, interleukins, monoclonal antibodies, hormones, and for molecularly targeted tyrosine kinase inhibitors is complicated, and there is not the same unequivocal evidence for a dose–response effect with these agents. Contemporary targeted agents have a much more specific relationship to the extent of target interaction. The schedule of drug administration may be important to the therapeutic index independent of dose. Cytokinetic studies related to drug schedule have led to the improved use of agents such as cytosine arabinoside (cytarabine, ara‐C) in both experimental and clinical leukemia. Most of the molecularly targeted agents, whether small molecules or monoclonal antibodies, are dosed to provide a continuous effect, which markedly changes the clinical toxicity profile but has come for reconsideration as a general approach.
The intrinsic tumor cell sensitivity, the tumor burden, and the presence of resistance determine the outcome of therapy as much as exposure, which does correlate well with host factors and toxicity, particularly the pharmacokinetics of drug clearance and kinetics of sensitive host cell targets. Bone marrow transplantation and hematopoietic growth factors have permitted the use of increased doses of alkylating agents to improve results and increase cures in several settings.
For most chemotherapeutic agents that directly or indirectly target DNA or the mitotic spindle used alone or in combination, intermittent courses (e.g., four 5‐day courses every 3–4 weeks) are generally superior to other schedules such as continuous dosing to permit normal tissue recovery and maximize dose. Cytarabine in acute myeloid leukemia (AML) and 5‐fluorouracil (5‐FU) in gastrointestinal (GI) cancers are notable exceptions, driven in short by the extremely rapid plasma clearance due to metabolism.
Continuous oral administration of many new targeted therapies, particularly kinase inhibitors is the current clinical schedule for reasons related to the mechanism of action. The continued suppression of proliferative growth factor signals and interruption of survival pathway signals in tumor cells or the repair of DNA appears necessary in the clinic and in preclinical models. This is the case for the poly (ADP‐ribose) polymerase (PARP) inhibitor rucaparib. Monoclonal antibodies produced with contemporary means, whether alone or as a drug antibody conjugate, have predictable clearance/half‐lives equivalent to native immunoglobulin G (IgG) proteins (half‐life 21–23 days).
The most compelling rationale for combination chemotherapy is tumor cell heterogeneity and its implication for drug resistance, and the success of combination chemotherapy in the clinic. In practical clinical terms, the selection of specific combinations in particular types of cancer depends on the individual activity of the agents in the target cancer type and the absence of overlapping toxicities. The agents with the highest single‐agent activity are preferred, particularly agents that produce complete responses (if any such agents exist), with different mechanisms of action to address the theoretical heterogeneity issue.
The vast majority of cancers are treated successfully only with combinations of agents chosen for the highest possible individual activity against a specific type of cancer. Empiricism was an essential component in the development of contemporary cancer therapy, but rational drug discovery, analog development, preclinical modeling, precise pathologic diagnosis, careful staging of disease, and clinical trial design are the foundation for the measure of success known today. The breakthroughs in molecular biology have presented the oncologist with enormous opportunities and challenges. Based on these breakthroughs, a molecular diagnosis will be able not only to determine where and how cancer originates but also the processes that are essential to its survival.
Irinotecan (CPT-11) is an anticancer agent widely used in the treatment of a variety of adult solid tumors. The objective of this study was to develop an optimal sampling strategy model that accurately estimates pharmacokinetic parameters of CPT-11 and its active metabolite, SN-38. This study included 221 patients with advanced solid tumors or lymphoma receiving CPT-11 single or combination therapy with 5-fluorouracil (5-FU)/leucovorin (LV) (FOLFIRI) plus bevacizumab from 4 separate clinical trials. Population pharmacokinetic analysis of CPT-11 and SN-38 was performed by non-linear mixed effects modeling. The optimal sampling strategy model was developed using D-optimality with expected distribution approach. The pharmacokinetic profiles of CPT-11 and SN-38 were best described by a 3- and 2-compartment model, respectively, with first-order elimination. Body surface area and co-administration with 5-FU/LV plus bevacizumab were significant covariates (p < 0.01) for volumes of the central compartment of CPT-11 and SN-38, and clearance of CPT-11. Pre-treatment total bilirubin and co-administration with 5-FU/LV and bevacizumab were significant covariates (p < 0.01) for clearance of SN-38. Accurate and precise predictive performance (r2 > 0.99, -2 < bias (%ME) < 0, precision (% RMSE) < 12) of both CPT-11 and SN-38 was achieved using: (i) 6 fixed sampling times collected at 1.5, 3.5, 4, 5.75, 22, 23.5 hours post-infusion; or (ii) 1 fixed time and 2 sampling windows collected at 1.5, [3-5.75], [22-23.5] hours post-infusion. The present study demonstrates that an optimal sampling design with three blood samples achieves accurate and precise pharmacokinetic parameter estimates for both CPT-11 and SN-38.
Cancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display inherent resistance to standard therapies and give rise to metastases. Despite accruing evidence establishing a link between deregulation of epitranscriptome-related players and tumorigenic process, the role of messenger RNA (mRNA) modifications dynamic in the regulation of CSC properties remains poorly understood. Here, we show that the cytoplasmic pool of fat mass and obesity-associated protein (FTO) impedes CSC abilities in colorectal cancer through its m6Am (N6,2'-O-dimethyladenosine) demethylase activity. While m6Am is strategically located next to the m7G-mRNA cap, its biological function is not well understood and has not been addressed in cancer. Low FTO expression in patient-derived cell lines elevates m6Am level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear m6Am methyltransferase, PCIF1/CAPAM, partially reverses this phenotype. FTO-mediated regulation of m6Am marking constitutes a novel, reversible pathway controlling CSC abilities that does not involve transcriptome remodeling, but could fine-tune translation efficiency of selected m6Am marked transcripts. Altogether, our findings bring to light the first biological function of the m6Am modification and its potential adverse consequences for colorectal cancer management.
Angiogenesis has been identified as a hallmark of cancer. Thus, anti-angiogenic targeting has been evaluated in cancer. Colorectal cancer is one of the entities where this therapeutic principal has been most successfully introduced into the daily care of patients. Today, several anti-angiogenic drugs are approved in all lines of metastasized colorectal cancer (mCRC). In adjuvant settings, anti-angiogenic treatment did not show any benefit. In summary, still overall the benefit from anti-angiogenic treatment is modest and the identification of specific patient subgroups benefiting from this treatment is missing. Several new drugs are in development to further improve the treatment of patients with mCRC. In addition, large efforts were made to identify predictive biomarker, but so far, none of these has entered the clinical routine. Here we present the current status of anti-angiogenic drugs in mCRC and the new drugs in development for this clinical entity.
Colorectal cancer is the third most commonly diagnosed cancer in the United States. While screening methods strive to improve rates of early stage detection, 25% of patients have metastatic disease at the time of diagnosis, with the most common sites being the liver, lung, and peritoneum. While once perceived as hopeless, the last two decades have seen substantial strides in the medical, surgical, and regional therapies to treat metastatic disease offering significant improvements in survival.
Modern chemotherapy agents transformed standard care for metastatic colorectal cancer (mCRC) but raised concerns about the financial burden of the disease. We studied comparative effectiveness of treatment plans that involve up to three lines of therapies and impact of treatment sequencing on health and cost outcomes. We employed a Markov model to represent the dynamically changing health status of mCRC patients and used Monte-Carlo simulation to evaluate various treatment plans consistent with existing guidelines. We calibrated our model by a meta-analysis of published data from an extensive list of clinical trials and measured the effectiveness of each plan in terms of cost per quality-adjusted life year. We examined the sensitivity of our model and results with respect to key parameters in two scenarios serving as base case and worst case for patients’ overall and progression-free survivals. The derived efficient frontiers included seven and five treatment plans in base case and worst case, respectively. The incremental cost-effectiveness ratio (ICER) ranged between $26,260 and $152,530 when the treatment plans on the efficient frontiers were compared against the least costly efficient plan in the base case, and between $21,256 and $60,040 in the worst case. All efficient plans were expected to lead to fewer than 2.5 adverse effects and on average successive adverse effects were spaced more than 9 weeks apart from each other in the base case. Based on ICER, all efficient treatment plans exhibit at least 87% chance of being efficient. Sensitivity analyses show that the ICERs were most dependent on drug acquisition cost, distributions of progression-free and overall survivals, and health utilities. We conclude that improvements in health outcomes may come at high incremental costs and are highly dependent in the order treatments are administered.
Metastatic liver disease is a major cause of cancer-related morbidity and mortality. Surgical resection is considered the only curative treatment, yet only a minority is eligible. Patients who present with unresectable disease are treated with systemic agents and/or locoregional therapies. The latter include thermal ablation and catheter-based transarterial interventions. Thermal ablation is reserved for those with limited tumor burden. It is used to downstage the disease to enable curative surgical resection, as an adjunct to surgery, or in select patients it is potentially curative. Transarterial therapies are indicated in those with more diffuse disease. The goals of care are to palliate symptoms and prolong survival. The indications and supporting data for thermal ablation and transarterial interventions are reviewed, technical and tumor factors that need to be considered prior to intervention are outlined, and finally several cases are presented.
Das kolorektale Karzinom ist weltweit eine der häufigsten malignen Erkrankungen, wobei die Inzidenz in den einzelnen Ländern der Erde sehr stark schwankt: Das Erkrankungsrisiko ist in Südafrika, Asien und Südamerika deutlich geringer als in den USA, Australien und Westeuropa. Für das Jahr 1998 wird die Zahl der in Deutschland neu an einem kolorektalen Karzinom Erkrankten auf 51.700 Menschen geschätzt (Kolonkarzinom: 34.346, Rektumkarzinom: 22.662). Dies entspricht einer Inzidenz für das Kolonkarzinom von etwa 34/100.000 bei Männern und von 27,4/1.000.000 bei Frauen. Beim Rektumkarzinom beträgt die geschätzte Inzidenz 26,9/100.000 für Männer und 16,7/100.000 für Frauen. Das Risiko, ein kolorektales Karzinom zu entwickeln, beträgt in der westlichen Welt bei Geburt 5,8–6,4%, das Risiko, daran zu versterben, 2,7–2,8%.
Eine gastroösophageale Refluxkrankheit (GERD) liegt vor, wenn ein Risiko für organische Komplikationen durch einen gesteigerten gastroösophagealen Reflux (GER) und/oder eine signifikante Störung der Lebensqualität infolge der Refluxbeschwerden besteht (C). Unter GERD werden die verschiedenen Manifestationen NERD („non erosive reflux disease“), erosive Ösophagitis (ERD), Barrett-Ösophagus und extraösophageale Manifestationen subsumiert (C).
The balance between acetylation and deacetylation of histone proteins plays a critical role in the regulation of genomic functions. Aberrations in global levels of histone modifications are linked to carcinogenesis and are currently the focus of intense scrutiny and translational research investments to develop new therapies, which can modify complex disease pathophysiology through epigenetic control. However, despite significant progress in our understanding of the molecular mechanisms of epigenetic machinery in various genomic contexts and cell types, the links between epigenetic modifications and cellular phenotypes are far from being clear. For example, enzymes controlling histone modifications utilize key cellular metabolites associated with intra- and extracellular feedback loops, adding a further layer of complexity to this process. Meanwhile, it has become increasingly evident that new assay technologies which provide robust and precise measurement of global histone modifications are required, for at least two pressing reasons: firstly, many approved drugs are known to influence histone modifications and new cancer therapies are increasingly being developed towards targeting histone deacetylases (HDACs) and other epigenetic readers and writers. Therefore, robust assays for fingerprinting the global effects of such drugs on preclinical cell, organoid and in vivo models is required; and secondly, robust histone-fingerprinting assays applicable to patient samples may afford the development of next-generation diagnostic and prognostic tools. In our study, we have used a panel of monoclonal antibodies to determine the relative changes in the global abundance of post-translational modifications on histones purified from cancer cell lines treated with HDAC inhibitors using a novel technique, called epigenetic reverse phase protein array. We observed a robust increase in acetylation levels within 2–24 h after inhibition of HDACs in different cancer cell lines. Moreover, when these cells were treated with N-acetylated amino acids in addition to HDACs, we detected a further increase in histone acetylation, demonstrating that these molecules could be utilized as donors of the acetyl moiety for protein acetylation. Consequently, this study not only offers a novel assay for diagnostics and drug screening but also warrants further research of the novel class of inexpensive, non-toxic natural compounds that could potentiate the effects of HDAC inhibitors and is therefore of interest for cancer therapeutics.
Irinotecan-induced severe neutropenia and diarrhea, which remain unpredictable, has restrained the dose and clinical efficiency of irinotecan administration. In the present study, a total of 70 irinotecan-treated patients with histologically confirmed metastatic gastrointestinal cancer were enrolled. Despite genotyping well-reported alleles, direct sequencing was specifically adopted to avoid ethnic heterogeneity and to identify novel variations. The promoter (-1000 bp) and exon 1 regions of UDP glucuronosyltransferase family 1 member A complex locus (UGT1A1) gene family members UGT1A1, UGT1A7 and UGT1A9 were sequenced, and comprehensive analysis of their genetic polymorphisms was performed to determine the association between inherited genetic variations and irinotecan-induced toxicity. A total of 23 different genetic variants were detected in the present study, including 2 novel polymorphisms. The results of the present study revealed that UGT1A1*6 and UGT1A7*3 are risk factors for irinotecan-induced severe neutropenia, and UGT1A9*1b is associated with severe diarrhea. These results may provide biomarkers for the selection of the optimal chemotherapy for Chinese patients with metastatic gastrointestinal cancer.
Introduction: Aflibercept in combination with FOLFIRI has been shown to improve overall survival in the pivotal VELOUR study. Aflibercept has not yet been marketed in India. Sanofi has made available this drug for Indian patients under a program called Named Patient Access Program (NPP). We present a limited clinical experience with the use of aflibercept at our center. Materials and Methods: We analyzed the data of the patients who received aflibercept under NPP. Aflibercept was given in combination with FOLFIRI as second-line for patients who progressed on oxaliplatin based therapy. Aflibercept was given at 4 mg/kg intravenous (IV) every 15 days. Chemotoxicities were assessed as per CTCAE. Response evaluation was done every four cycles. Results: Five patients were enrolled. The median age was 34 years. The median number of aflibercept cycles administered was 12. Common grade 2/3 toxicities were mucositis, diarrhea, neutropenia thrombocytopenia, and hypertension seen in three (60%), three (60%), two (40%), two (40%), and one patient respectively. After four cycles, the response was assessed as: One complete remission (CR), three partial remissions (PR), and one progressive disease (PD). Three patients completed 12 cycles of chemotherapy and aflibercept. At the end of 12 cycles, one patient still in CR and two patients were in PR. Four patients were alive till date. Conclusion: As we had very less number of patients, it was very difficult to compare it with VELOUR data. It is one of option as second-line in metastatic colorectal cancer (mCRC) who progressed on oxaliplatin chemotherapy. Mucositis, diarrhea, and hematological toxicity were the most common toxicity in our patient.
This is the protocol for a review and there is no abstract. The objectives are as follows:
The aim of this systematic review is to compare efficacy and safety of two chemotherapeutic regimens, irinotecan monotherapy or irinotecan in combination with fluoropyrimidines, for patients with advanced colorectal cancer when administered in the first or second-line setting.
Objective:
To explore the inhibitory effect of bevacizumab, a vascular endothelial growth factor antibody, on angiogenesis in human osteosarcoma of nude mice.
Methods:
Twenty-one nude mice were inoculated with red fluorescent protein (RFP)-labeled human osteosarcoma cell line 143B-RFP, that is, clones that expressed RFP in the cytoplasm, and randomly assigned to one of three groups: G1 (Control group, injected with saline solution); G2 (intraperitoneal bevacizumab 2 mg/kg twice per week) and G3 (intraperitoneal bevacizumab 5 mg/kg, twice per week). The tumor-bearing mice were examined in a fluorescence light box that was illuminated periodically. The primary tumors were measured by fluorescence imaging weekly and their volumes calculated.
Results:
The mean tumor volumes were significantly smaller in the G3 (186.4 ± 100.8 mm(3) ) than the control group (587.0 ± 406.8 mm(3) ) (P < 0.05) on Day 31, and again significantly smaller in the G3 (677.3 ± 461.9 mm(3) ) than the control group (3162.6 ± 1529.2 mm(3) ) on Day 38 (P < 0.01). The average tumor volume in the G2 group was 493.5 ± 425.4 mm(3) on Day 31 and 1870.1 ± 1524.8 mm(3) on Day 38. The effect on tumor volume was greater in the G3 than the G2 group. Three mice in the G2 group, four in the G3 group and four in the control group developed lung metastases that were confirmed by pathological examination; these differences were not statistically significant (P < 0.05).
Conclusions:
Bevacizumab exhibits strong antiangiogenesis activity in experimental osteosarcoma in a nude mouse model but does not influence the incidence of lung metastasis. Our findings may have considerable potential for the treatment of osteosarcoma.
Controversy exists over whether aggressive surgical resection of the primary tumor without metastasectomy first or chemotherapy first in stage IV colon cancer with unresectable synchronous liver-only-metastases (CLM) improves patients. Materials and Methods: We retrospectively reviewed the outcome of 156 patients initially diagnosed with unresectable synchronous CLM who were under treatment in our institution from January 2004 to December 2012. Patients with extrahepatic diseases or previous hepatic resection were excluded. All patients with a follow-up of at least 3 months were included. Progression-free survival (PFS) and 5-year overall survival (OS) curves were calculated using the Kaplan–Meier method. Results: Among the 156 patients with CLM, 43 (27.56%) received aggressive surgical resection of the primary tumor without metastasectomy first, 113 (72.43%) received systemic chemotherapy first. At 5 years, the adjusted PFS and OS in stage IV colon cancer with inoperable metastases were 24.2% and 20.4%, respectively, in the surgical resection of the primary tumor first group and 46.0% and 16.9% in the chemotherapy first group (P = 0.515 and P = 0.742, respectively). In multivariate analysis, there was no statistical difference in the PFS and 5-year OS between the surgical resection of the primary tumor first group and chemotherapy first. Conclusion: Surgical resection of the primary tumor without metastasectomy first in CLM is not associated with improved survival as compared with chemotherapy first. Additional research is necessary to determine which patients may benefit from this intervention.
The use of adjuvant chemotherapy has improved survival in early-stage colon cancer. Ongoing adjuvant clinical trials are evaluating the addition of targeted therapies to standard chemotherapy regimen. Preliminary results with bevacizumab were disappointing. Also, cetuximab added to chemotherapy does not seem to be better than chemotherapy alone, even in selected wild-type KRAS populations. A better understanding of mechanisms of action of drugs, tumor biology, and predictive biomarkers are needed to design future adjuvant trials.
Manojkumar Bupathi, Daniel H Ahn, Tanios Bekaii-Saab Department of Medical Oncology, Richard Solove Research Institute and James Cancer Hospital, The Ohio State University Wexner Medical Center, Columbus, OH, USAAbstract: Metastatic colorectal cancer (mCRC) is a prevalent disease for which combination cytotoxic chemotherapy is the mainstay of treatment. With the use of targeted therapy, including anti-angiogenic agents, there have been significant improvements in overall outcome of patients with mCRC. Bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor ligand A, is approved for use in mCRC patients in both the first and second lines of therapy. With a better understanding of the disease through molecular profiling, identification of prognostic biomarkers may lead to better patient selection with improved outcomes for those affected by this disease. Keywords: VEGF, colon, rectum, cancer
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