Chemotherapy-induced thymidine phosphorylase modulation in colorectal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15050-e15050
Author(s):  
G. Aprile ◽  
M. Miscoria ◽  
P. Baldin ◽  
A. Casetta ◽  
M. Pandolfi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Thymidine Phosphorylase ◽  
Active Form ◽  
Distant Metastases ◽  
Preliminary Evidence ◽  
Chemotherapeutic Agents ◽  
Immunohistochemical Expression ◽  
First Line ◽  
Nucleoside Metabolism ◽  
Positive Score

e15050 Background: Thymidine phosphorylase (TP) is an inducible enzyme responsible for nucleoside metabolism, antiapoptosis activity, and promotion of angiogenesis. In addition, conversion of the prodrug capecitabine (C) to its active form depends on TP activity. Preliminary evidence suggests that TP immunohistochemical expression may predict benefit from first-line treatment of metastatic colorectal cancer (CRC) with C plus irinotecan. Several chemotherapeutic agents have been shown to modulate TP expression. The aim of the present analysis was to verify if TP expression differs among primary and paired metastases in CRC patients, or may vary depending on patients’ exposure to chemotherapy. Methods: TP expression was evaluated by immunohistochemistry (clone p-P-GF.44C, Abcam, Cambridge, UK) in a series of 120 primary CRC and their matched distant metastases. Tsuda's scoring system was adopted, defining TP expression as negative (score 0–1) or positive (score 2–3). Results: Data on the first 57 patients are here presented. Sites of biopsied metastases were liver (n=41), lung (n=10), and peritoneum (n=6). Metastases were asynchronous in 42% of patients. Higher TP expression was observed in primary cancers than in metastases (36.8% vs. 15.8%, p=0.007). Among patients who received at least one cycle of chemotherapy before metastasis sampling (38.6%), a TP expression decrease was demonstrated in only 13% of metastatic samples. Oppositely, a significantly higher proportion of untreated patients lost TP expression in metastasis sites (36%, p=0.01). Conclusions: In advanced CRC patients, TP expression tend to decrease in metastases, particularly in those patients who did not receive chemotherapy before metastatic sampling. Although intratumoral heterogeneity and other causes of discrepancy cannot be excluded, true chemotherapy-induced modulation of TP may be hypothesized. No significant financial relationships to disclose.

Efficacy of FOLFOX4 in patients with hypoalbuminemia or immune impairment

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15141-e15141
Author(s):  
M. Shibata ◽  
N. Yumiko ◽  
T. Hirano ◽  
S. Matsuo ◽  
H. Abe ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Serum Albumin ◽  
Inverse Correlation ◽  
Chemotherapeutic Agents ◽  
Host Factors ◽  
First Line ◽  
Immunosuppressive Acidic Protein ◽  
Patients With Cancer ◽  
Nutritional Conditions ◽  
Immune Impairment

e15141 Background: The effects of chemotherapeutic agents are understood to be regulated by many factors including tumor factors such as sensitivity to drugs and host factors. Among these host factors, nutritional conditions and immune function of cancer-bearing host has been told to relate the effects of chemotherapy, however, it has not been clarified yet. Methods: We have analysed the relationships between the effects of FOLFOX4 and nutritional markers such as serum albumin concentrations and immunology markers including counts of lymphocytes and neutrophils, the ratios of these counts G/L: granulocytes/lymphocytes) and serum concentrations of immunosuppressive acidic protein (IAP) in the patients with disseminated colorectal cancer who have received FOLFOX4. All these blood examinations were performed before the first administration of FOLFOX4 as a first line chemotherapy in 18 patients with disseminated colorectal cancer. Results: Firstly serum albumin levels have shown significant correlation to lymphocyte counts and did inverse correlation to neutrophil counts and G/L ratios. The albumin levels in the patients with PD of FOLFOX outcome was significantly lower than in the patients with PR(p<0.05) and SD (p<0.05). The lymphocytes counts in the patients with PD were significantly lower than in those with PR (p<0.05) and SD (p<0.05). Neutrophil counts, on the other hand, was significantly higher in the patients with PD than in those with PR (p<0.01) and SD (p<0.05). IAP, have been recognized as a marker of immune-suppression in patients with cancer was higher in the patients with PD. Conclusions: Thus the nutritional status is closely related to the immune status in patients with cancer, and the markers of these conditions may present important informations in prediction of results of cancer chemotherapy. No significant financial relationships to disclose.

scholarly journals Liposomal Irinotecan for Treatment of Colorectal Cancer in a Preclinical Model

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 281 ◽  
Author(s):  
Jiao-Ren Huang ◽  
Mei-Hsien Lee ◽  
Wen-Shan Li ◽  
Han-Chun Wu
Keyword(s):  
Colorectal Cancer ◽  
Active Form ◽  
Treated Group ◽  
Preclinical Model ◽  
Colonic Tissue ◽  
First Line ◽  
Tissue Samples ◽  
Clinical Benefits ◽  
Hematoxylin And Eosin ◽  
Liposomal Irinotecan

Colorectal cancer (CRC) is the most frequently diagnosed cancer and leading cause of cancer-related deaths worldwide. Because of the use of first-line CRC treatments, such as irinotecan (IRI), is hindered by dose-limiting side effects, improved drug delivery systems may have major clinical benefits for CRC treatment. In this study, we generate and characterize liposomal irinotecan (Lipo-IRI), a lipid-based nanoparticle, which shows excellent bioavailability and pharmacokinetics. Additionally, this formulation allows IRI to be maintained in active form and prolongs its half-life in circulation compared to IRI in solution. Compared with IRI statistically, the level of prostaglandin E2 (PGE2) in colonic tissue decreases, and Bifidobacterium spp. (beneficial intestinal microbiota) content increases in the Lipo-IRI-treated group. Moreover, no damage is observed by the hematoxylin and eosin staining of the normal tissue samples from the Lipo-IRI-treated group. In a xenograft mouse model, CRC tumors shrink markedly following Lipo-IRI treatment, and mice receiving a targeted combination of Lipo-IRI and liposomal doxorubicin (Lipo-Dox) extend their survival rate significantly. Overall, our results demonstrate that this formulation of Lipo-IRI shows a great potential for the treatment of colorectal cancer.

scholarly journals Tetraploidy-Associated Genetic Heterogeneity Confers Chemo-Radiotherapy Resistance to Colorectal Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1118
Author(s):  
Claudia Galofré ◽  
Öykü Gönül Geyik ◽  
Elena Asensio ◽  
Darawalee Wangsa ◽  
Daniela Hirsch ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Ionizing Radiation ◽  
Whole Genome Duplication ◽  
Genome Duplication ◽  
Chromosome Instability ◽  
Chemotherapeutic Agents ◽  
Epithelial Cell Line ◽  
Whole Genome ◽  
First Line ◽  
Radiotherapy Resistance

Tetraploidy, or whole-genome duplication, is a common phenomenon in cancer and preludes chromosome instability, which strongly correlates with disease progression, metastasis, and treatment failure. Therefore, it is reasonable to hypothesize that tetraploidization confers multidrug resistance. Nevertheless, the contribution of whole-genome duplication to chemo-radiotherapy resistance remains unclear. Here, using isogenic diploid and near-tetraploid clones from three colorectal cancer cell lines and one non-transformed human epithelial cell line, we show a consistent growth impairment but a divergent tumorigenic potential of near-tetraploid cells. Next, we assessed the effects of first-line chemotherapeutic drugs, other commonly used agents and ionizing radiation, and found that whole-genome duplication promoted increased chemotherapy resistance and also conferred protection against irradiation. When testing the activation of apoptosis, we observed that tetraploid cells were less prone to caspase 3 activation after treatment with first-line chemotherapeutic agents. Furthermore, we found that pre-treatment with ataxia telangiectasia and Rad3 related (ATR) inhibitors, which targets response to replication stress, significantly enhanced the sensitivity of tetraploid cells to first-line chemotherapeutic agents as well as to ionizing radiation. Our findings provide further insight into how tetraploidy results in greater levels of tolerance to chemo-radiotherapeutic agents and, moreover, we show that ATR inhibitors can sensitize near-tetraploid cells to commonly used chemo-radiotherapy regimens.

Expression of ABCG2 Associated with Tumor Response in Metastatic Colorectal Cancer Patients Receiving First-line FOLFOX Therapy – Preliminary Evidence

2013 ◽  
Vol 28 (2) ◽  
pp. 182-186 ◽  
Author(s):  
Pei-Ching Lin ◽  
Hung-Hsin Lin ◽  
Jen-Kou Lin ◽  
Chun-Chi Lin ◽  
Shung-Haur Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Tumor Response ◽  
Evaluation Criteria ◽  
Complete Response ◽  
Preliminary Evidence ◽  
First Line ◽  
Selective Marker ◽  
Primary Tumors ◽  
Colorectal Cancer Patients

Purpose We retrospectively analyzed ABCG2 expression levels in patients with metastatic colorectal cancer (CRC) to investigate the interaction between ABCG2 expression and the tumor response to oxaliplatin and 5-fluorouracil (FOLFOX). Methods Forty-three patients with CRC with liver metastasis who received first-line FOLFOX treatment at our institution between 2008 and 2010 were enrolled. ABCG2 expression was assessed by immunohistochemistry. Tumor response was determined using the modified Response Evaluation Criteria in Solid Tumors criteria. Results At least 50% tumor shrinkage was observed in 16/43 patients (37.2%), including a complete response in 1 patient. According to the intensity of ABCG2 expression and the percentage of tumor cells expressing ABCG2, 21 tumors displayed high ABCG2 expression. Among these tumors, only 2 (9.5%) exhibited partial responses to FOLFOX; conversely, 63.6% of tumors with low ABCG2 expression (14/22) responded to FOLFOX. Primary and corresponding metastatic samples were available for 15 patients, and 13 of the metastatic tumors had higher ABCG2 expression than the corresponding primary tumors, but only 1 of these tumors responded to FOLFOX (7.7%). Conclusions ABCG2 expression is associated with the tumor response to FOLFOX in patients with metastatic CRC. ABCG2 may be a selective marker for the efficacy of FOLFOX in treating CRC.

Systemic Therapy for Metastatic Colorectal Cancer: Current Options, Current Evidence

2005 ◽  
Vol 23 (20) ◽  
pp. 4553-4560 ◽  
Author(s):  
Hanna Kelly ◽  
Richard M. Goldberg
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Response Rate ◽  
Single Agent ◽  
Chemotherapeutic Agents ◽  
Current Data ◽  
Phase Iii ◽  
Current Evidence ◽  
First Line ◽  
Improve Response Rate

Combination chemotherapy regimens including irinotecan and oxaliplatin markedly improve response rate and prolong median survival over fluorouracil with leucovorin (FU/LV), and have supplanted FU/LV as the standard systemic approach for metastatic colorectal cancer. The recent availability of five active chemotherapeutic agents has doubled the median overall survival for metastatic colorectal cancer from 10 to 20 months, and though the optimal strategy for incorporation of all drugs is still unclear, current data support the use of chemotherapy doublets in first-line rather than sequential single-agent therapy. Multidrug regimens increase both response rate and the proportion of patients able to undergo potentially curative resection. In addition, as many as 20% to 30% of patients never receive second-line chemotherapy. When used as single agents, bolus and infusional FU/LV and capecitabine are similarly effective but have differing toxicity. Chemotherapy combinations that incorporate infusion of FU are less toxic and more effective than those using bolus FU dosing. Capecitabine is under study as an alternative dosing method for use in combination regimens; however, the optimal dose has not been defined and final safety and efficacy outcomes are being addressed in ongoing phase II and III investigations. Three combinations have shown excellent first-line efficacy in phase III trials—IFL with bevacizumab, FOLFOX, and FOLFIRI—but neither of these combinations is clearly superior. Sound clinical judgment must continue to guide treatment decisions while we await data regarding the optimal combination and sequence of fluorouracil, irinotecan, oxaliplatin, bevacizumab, and cetuximab.

scholarly journals Efficacy of second-line chemotherapy after a first-line triplet in patients with metastatic colorectal cancer

2019 ◽  
Vol 26 (1) ◽  
Author(s):  
S. Bazarbashi ◽  
A. M. Hakoun ◽  
A. M. Gad ◽  
M. A. Elshenawy ◽  
A. Aljubran ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Group Performance ◽  
Chemotherapeutic Agents ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Second Line Chemotherapy ◽  
Line Therapy ◽  
Line Chemotherapy

Background Exposing patients with metastatic colorectal cancer (mcrc) to all three active chemotherapeutic agents (oxaliplatin, irinotecan, fluorouracil) has improved survival. The benefit of second-line chemotherapy after a first-line triplet is not clearly defined. We evaluated the efficacy of second-line chemotherapy in patients who had received first-line triplet therapy.Methods The medical records of patients treated on a prospective trial of first-line triplet therapy were reviewed for second-line treatment. Univariate and multivariate analyses were performed to establish factors of prognostic significance.Results Of the 53 patients who received first-line triplet therapy, 28 (53%) received second-line chemotherapy [13 men; 8 with a colon primary; mutant KRAS in 10, wild-type in 15, and unknown status in 3; Eastern Cooperative Oncology Group performance status (ps) of 1 in 16 patients, ps 2 in 3, ps 3 in 2, and unknown in 7; involved organs: liver in 17 patients, lung in 16, and peritoneum in 8]. Second-line chemotherapy consisted of xelox or folfox in 13 patients, xeliri or folfiri in 12, and single-agent irinotecan in 3. Concurrent bevacizumab was given in 16 patients (57%), and cetuximab, in 2 (7%). Median survival was 28.0 months [95% confidence interval (ci): 22.8 months to 33.2 months] for patients receiving second-line therapy and 23.0 months (95% ci: 13.2 months to 32.8 months) for those not receiving it. Best response was partial in 6 patients (21%), stable disease in 11 (39%), and progressive disease in 11 (39%). Median progression-free survival was 4.8 months (95% ci: 2.4 months to 9.6 months), and overall survival was 15 months (95% ci: 9.6 months to 20.4 months).Conclusions Second-line chemotherapy after first-line triplet therapy in mcrc is feasible and suggests efficacy comparable to that reported for second-line therapy after a doublet, regardless of the agent used.by research evidence.

scholarly journals Intercostal Artery Pseudoaneurysm Formation after Irinotecan Transarterial Chemoembolization of a Spinal Metastasis from Colorectal Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Natanel Jourabchi ◽  
Steven Sauk ◽  
Cheryl Hoffman ◽  
Edward Wolfgang Lee ◽  
Stephen Thomas Kee
Keyword(s):  
Colorectal Cancer ◽  
Adverse Effects ◽  
Transarterial Chemoembolization ◽  
Spinal Metastasis ◽  
Chemotherapeutic Agents ◽  
Intercostal Artery ◽  
First Line ◽  
Artery Pseudoaneurysm ◽  
Pseudoaneurysm Formation ◽  
The Past

Over the past decade, irinotecan has become one of the first-line chemotherapeutic agents used in the treatment of metastatic colorectal cancer. Recently, irinotecan has been administered transarterially in order to perform chemoembolization in the liver. In the limited number of reports available to date using this approach, serious adverse effects have not yet been reported. In this paper, we describe the formation of an intercostal artery pseudoaneurysm after transarterial chemoembolization with irinotecan-eluting beads in a patient with spinal metastasis from colorectal cancer.

scholarly journals Network Meta-analysis of First-Line Systemic Treatment for Patients With Metastatic Colorectal Cancer

2021 ◽  
Vol 28 ◽  
pp. 107327482110334
Author(s):  
Shan Xu ◽  
Ali Sak ◽  
Yasin Bahadir Erol
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Metastatic Colorectal Cancer ◽  
Meta Analysis ◽  
Random Effect Model ◽  
Treatment Strategies ◽  
Chemotherapeutic Agents ◽  
Controlled Trials ◽  
First Line ◽  
Central Registry

Purpose To assess the relative efficacy and safety of first-line systemic therapies in patients with metastatic colorectal cancer. Experimental Design A comprehensive literature review was conducted including MEDLINE, Embase, and the Cochrane Central Registry of Controlled Trials for phase II or III randomized controlled trials (RCTs) published up to and including July 15, 2019. We included RCTs in which at least 1 intervention was either chemotherapeutic agents (such as fluorouracil, irinotecan, or oxaliplatin) or antibodies targeting angiogenesis (such as bevacizumab) or agents that act on the epidermal growth factor receptor pathway (such as cetuximab and panitumumab) or studies reported at least one of the following outcomes: overall survival (OS), progression-free survival (PFS), and/or Grade 3 + adverse events (AEs). Using a random effect model, we performed a Bayesian network meta-analysis to analyze the probability of optimal therapeutic regime obtained from direct comparisons with indirect evidences. We estimated hazard ratios for OS and PFS. Results A total of 30 RCTs comprising 12,146 mCRC patients with 25 different treatment strategies were included. The triple combination FOLFOXIRI [fluorouracil, leucovorin, oxaliplatin, and irinotecan] plus bevacizumab provided significant survival benefits with improved OS over all other treatments. The network meta-analysis also indicated a significant advantage of using FOLFOXIRI plus bevacizumab in comparison to other treatment strategies for PFS. Besides, FOLFOXIRI plus bevacizumab was associated with the well-tolerated adverse events. Conclusions Our study supported the use of FOLFOXIRI plus bevacizumab as the best first-line regimen and potentially effective and safe strategy for the management of patients with mCRC.

Sign in / Sign up

Export Citation Format

Share Document