Treatment Of Metastatic Colon Cancer Research Articles

CML-206 Secondary Chronic Myeloid Leukemia Following Successful Treatment of Metastatic Colon Cancer: A Case Report

CML-206 Secondary Chronic Myeloid Leukemia Following Successful Treatment of Metastatic Colon Cancer: A Case Report

A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle

BackgroundIrinotecan (CPT-11) is a classic chemotherapeutic agent that plays an important role in the clinical treatment of metastatic colon cancer and other malignant tumors. We previously designed a series of novel irinotecan derivatives. In this study, we select one representative, ZBH-01, to investigate its sophisticated antitumor mechanism in colon tumor cells.MethodsThe cytotoxic activity of ZBH-01 on colon cancer cells was evaluate by MTT or Cell Counting Kit-8 (CCK8) assay, 3D and xenograft model. The inhibitory effect of ZBH-01 on TOP1 was detected by DNA relaxation assay and Immuno Complex of Ezyme (ICE) bioassay. The molecular mechanism of ZBH-01 was explored by Next-Generation Sequencing (NGS), bioinformatics analyses, flow cytometry, qRT-PCR, and western blot etc.ResultsZBH-01 can induce obvious DNA damage and has superior antitumor activity against colon cancer cells compared to CPT-11 and SN38 (7-Ethyl-10-hydroxy camptothecin, the in vivo active form of CPT-11) both in vivo and in vitro. Its inhibitory effect on topoisomerase I (TOP1) was also comparable with these two control drugs. There are a much larger number of 842 downregulated and 927 upregulated mRNAs in ZBH-01 treatment group than that in the controls. The most significantly enriched KEGG pathways for these dysregulated mRNAs were DNA replication, the p53 signaling pathway, and the cell cycle. After constructing a protein–protein interaction (PPI) network and screening out a prominent cluster, 14 involved in the cell cycle process was identified. Consistently, ZBH-01 induced G0/G1 phase arrest in colon cancer cells, while CPT-11/SN38 caused S phase arrest. The initiation of apoptosis by ZBH-01 was also superior to CPT-11/SN38, followed by the increased expression of Bax, active caspase 3, and cleaved-PARP, and decreased expression of Bcl-2. Additionally, CCNA2 (cyclin A2), CDK2 (cyclin-dependent kinase 2), and MYBL2 (MYB proto-oncogene like 2) might be involved in the G0/G1 cell cycle arrest induced by ZBH-01.ConclusionsZBH-01 can be an antitumor candidate drug for preclinical study in the future.

P-357 Place of CEA in the evaluation of the treatment of metastatic colon cancer

P-357 Place of CEA in the evaluation of the treatment of metastatic colon cancer

Use of clinical pathways to identify patients with cancer who may benefit from serious illness conversations.

12027 Background: Treatment pathways are widely used to provide decision support and encourage guideline adherence. Pathways data may be used to identify patients for targeted interventions to improve cancer care. For example, pathways data may enable the identification of patients with poor prognoses for whom serious illness conversations (SICs) should be prioritized to ensure goal-concordant care. Methods: For patients starting new therapies at Dana-Farber, oncologists select a node in clinical pathways to indicate the line of treatment. Subspecialty oncologists identified “poor prognosis” nodes in pathways, defined as therapies for patients with expected survivals of < 12 months and for whom an SIC would be appropriate (e.g., 3rd-line treatment for metastatic colon cancer). Pathway node navigations for patients with metastatic solid tumor malignancies with poor prognosis nodes (n = 21 disease pathways) were combined with electronic medical record data to identify SIC documentation in an advance care planning module within 6 months of pathway navigation and patients’ dates of death if present. For each node, we calculated the median overall survival (OS), the proportion of patients with an SIC, and the proportion of patients who died before reaching the next node. Results: There were 10,132 navigations for 7,031 patients (median age 67 years, 52% female, 86% White) between 8/16/2019 and 1/4/2023. With each treatment line, patients’ median OS decreased and SIC rates increased (examples for 3 diseases in Table). Among patients who reached poor prognosis nodes, the median OS was 4.9 months, mean SIC rate was 43.8%, and 60.2% of patients died without reaching a subsequent node. For nodes immediately prior to poor prognosis nodes, the median OS was 7.1 months, the mean SIC rate was 25.2%, and 31.3% of patients died without reaching the next node. 46.3% of patients died without reaching a poor prognosis node. The proportion of patients having an SIC at death was 40.9% among all decedents, 50.8% for decedents reaching a poor prognosis node, and 29.3% for decedents who do not reach a poor prognosis node. Conclusions: Clinical pathways can be used as a scalable method to identify patients with metastatic solid tumors and poor prognoses. In our study, only half of patients who reached a poor prognosis node had an SIC before death and nearly half of decedents never reached a poor prognosis node, underscoring the importance of identifying this population to improve end-of-life care. A clinical trial using pathways to identify and deliver interventions to increase SICs is ongoing. [Table: see text]

P-423 Place of CEA in the evaluation of the treatment of metastatic colon cancer

P-423 Place of CEA in the evaluation of the treatment of metastatic colon cancer

Abstract IA008: Biology of metastasis-competent circulating tumor cells

Abstract The characterization of circulating tumor cells (CTCs) holds promises for precision medicine because these cells are an important clinical indicator of treatment efficacy. We established the first and still only nine permanent colon CTC lines from peripheral blood samples of a patient with metastatic colon cancer collected at different time points during treatment and cancer progression. The study objectives were (i) to compare the gene expression profiles of these CTC lines, and (ii) to determine the main features acquired during treatment. The number of upregulated genes was higher in the CTC lines obtained after treatment, indicating that they acquired properties to escape treatment pressure. Among these upregulated genes, some are involved in the mTOR and PI3K/AKT signaling pathways. Moreover, cytidine deaminase expression was significantly increased in the CTC lines obtained after failure of the first- and second-line 5-fluorouracile-based treatments, suggesting that these CTCs can eliminate this specific drug and resist to therapy. Several enzymes involved in xenobiotic metabolism also were upregulated after treatment, suggesting the activation of detoxification mechanisms in response to chemotherapy. Finally, the significant higher expression of aldolase B in four of the six CTC lines obtained after treatment withdrawal and cancer progression indicated that these clones originated from liver metastases. In conclusion, these CTC lines generated at different time points during treatment of metastatic colon cancer in a single patient are characterized by the deregulation of different genes that promote (i) drug resistance, (ii) xenobiotic and energy metabolism, and (iii) stem cell properties and plasticity. Citation Format: Catherine Alix-Panabières. Biology of metastasis-competent circulating tumor cells [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA008.

Comparative analysis of the immune response to RFA and cryoablation in a colon cancer mouse model

The immune response to radiofrequency ablation (RFA) and cryoablation (CRA) was characterized and compared in a colon cancer mouse model. All studies were conducted under a research protocol approved by the National Institutes of Health, Clinical Center, Animal Care and Use Committee. BALB/cJ mice were inoculated with CT26 cells, and randomized to RFA, CRA, or sham treatment. Mice were sacrificed 3 days post-treatment, and tumor, spleen, and serum were harvested. Cell death was determined by Caspase-3 immunohistochemical and TUNEL stains. Immune response was analyzed using flow cytometry, serum cytokine assay and immunohistochemistry. Cell death, necrosis, and apoptosis induced by ablation were comparable in RFA and CRA. Decreased frequency of systemic T-regulatory cells was found in the CRA group. Both RFA and CRA reduced frequencies of several myeloid-derived suppressor cell (MDSC) subpopulations. RFA induced pro-inflammatory cytokine secretion including TNF-α and IL-12 as well as anti-inflammatory cytokines IL-5, and IL-10. CRA augmented secretion of a wider array of cytokines compared to RFA with both pro- and anti-inflammatory properties including IL-1β, IL-5, IL-6, IL-10, and KC GRO. In the tumor microenvironment, RFA reduced the number of T-regulatory cells, a finding not observed with CRA. Reduction of immune suppression via decreases in T-regulatory cells and MDSC was found to be induced by RFA or CRA. CRA augmented a wider range of cytokines than RFA, which were mainly pro-inflammatory, but also anti-inflammatory. In the tumor microenvironment, RFA demonstrated more pronounced anti-tumoral immunity. Further delineation of specific immunomodulation induced by ablation could inform drug-device development and may play a role in future hypothesis-driven immunomodulatory paradigms that combine immunotherapy drugs with tumor destruction for the treatment of metastatic colon cancer.

S2202 A Rare Case of Colonic Intussusception After Self Expandable Metal Stent Placement

Introduction: Endoscopically placed colonic stenting is a palliative measure that can be used for unresectable etastatic colon cancer. It is a relatively safe procedure with a low mortality rate of about 1%. Intussusception is a rare complication of colonic stenting that occurs when the bowel telescopes about itself, possibly leading to obstruction or ischemia. Here we present a patient with intussusception 6 days after placement of a self-expandable rectosigmoid metal stent. We demonstrate successful reduction of rectosigmoid intussusception through a colonoscopy with air insufflation. Case Description/Methods: A 35-year-old female presented with 3 days of constant and progressively-worsening rectal pain, bloody rectal discharge, and thin stool. Her past medical history was significant for metastatic colon cancer treated with sigmoid colectomy and chemotherapy 2 years prior, with recurrence of disease requiring palliative self-expandable rectosigmoid metal stent placement 6 days prior to arrival. Vital signs were normal. She did not appear in acute distress and was hemodynamically stable. Pertinent examination findings included lower abdominal tenderness, normal bowel sounds, and normal rectal tone. Labs revealed WBC 12.4, Hgb 13.2, Plt 443, AST 14, ALT 8, ALP 77, total bilirubin 0.7, and a lactate of 0.9. CT scan of the abdomen and pelvis revealed intussusception at the proximal sigmoid colon without evidence of bowel obstruction. Colonoscopy revealed ball-shaped mucosa with a dusky appearance at the proximal end of the stent, consistent with intussusception and ischemic colitis. The intussusception was successfully reduced with air insufflation through colonoscopy. The patient tolerated the procedure well and was started on a diet the next day with an improvement in her rectal pain and resolution of rectal discharge (Figure). Discussion: Endoscopic colonic stenting remains a valuable palliative treatment for metastatic colon cancer. Survival rates of metastatic colon cancer do not significantly differ between palliative colonic stenting and colonic resection. However, there are fewer complications with colonic stenting than colectomy, making palliative stenting a preferred option. Intussusception is a rare complication of colonic stenting that is often treated surgically in adults. Here we demonstrate successful reduction of intussusception through colonoscopic air insufflation. We hope to bring awareness of this complication and consideration to air insufflation as first-line therapy.Figure 1.: A. A view of the distal aspect of the rectosigmoid stent revealing adequate translocation of tumor mass without evidence of obstruction. B. A view of the proximal aspect of the rectosigmoid stent revealing a dusky appearance,with thickening of the bowel. C. A view of the proximal aspect of the stent with the ball-shaped mass in a dusky appearance consistent with intussusception, as seen by arrows.

P-121 Efficacy and toxicity of biosimilar and original bevacizumab in the second-line treatment of metastatic colon cancer in routine clinical practice: Results of an observational multicenter study

A biosimilar of bevacizumab was registered in Russia in 2015 based on the results of a randomized trial in patients with NSCLC. We performed a comparison of the efficacy and tolerability of a combination of chemotherapy with the original bevacizumab from Roche and biosimilar bevacizumab from Biocad in patients with metastatic colon cancer in the second line of treatment.

Metastasectomy for Stage IVA Colon Cancer: Does the Type of Treating Institution Make a Difference?

Treatment of metastatic colon cancer has evolved over time. More evidence has been emerging in recent years supporting metastasectomy in selected patients. We sought to elucidate whether the type of institution-community, comprehensive community, academic/research, and integrated cancer network-would have an effect on patient outcome, specifically those colon cancer patients with isolated liver metastasis. This retrospective cohort study queried the National Cancer Database (NCDB) from 2010 to 2014 for patients who were 18years of age or older with stage IVA colon cancer with isolated liver metastasis. We then performed uni- and multivariate analyses comparing patients based on such factors as age, tumor characteristics, primary tumor location, rate of chemotherapy, and type of treating institution. Patients who came from regions of higher income, receiving chemotherapy, and presenting to an academic/research hospital were more likely to undergo metastasectomy. Median survival was longest at academic/community hospitals at 22.4months, 6 to 7months longer than the other three types of institutions. Factors positively affecting survival included receiving chemotherapy, presenting to an academic/research institution, and undergoing metastasectomy, all at P < .05. In our study, the rate of metastasectomy was more than double at academic/research institutions for those with stage IVA colon cancer with isolated liver metastasis. Prior studies have quoted a mere 4.1% synchronous colon resection and metastasectomy. Our findings suggest that we should maintain multidisciplinary approach to this complex disease process and that perhaps it is time for us to consider regionalization of care in treating metastatic colon cancer.

Danggui Buxue Decoction in the Treatment of Metastatic Colon Cancer: Network Pharmacology Analysis and Experimental Validation.

PurposeThis study aimed to reveal Danggui Buxue Decoction (DBD) candidate targets and mechanisms in the treatment of metastatic colon cancer (MCC), using network pharmacology-based analyses and experimental validation.MethodsTraditional Chinese Medicine Systems Pharmacology (TCMSP) database query and text mining were used to screen active compounds in DBD, and the Swiss target prediction platform was applied to predict compound-related target proteins. Targets likely associated with MCC were determined using GeneCards and OMIM databases. Targets common to DBD and MCC were obtained from the Venn platform; subsequently, Cytoscape was used to construct drug-compound-target-disease and protein-protein interaction networks. The hub gene was determined by R, while GO and KEGG enrichment analyses were performed on common targets to elucidate biological processes and signaling pathways involved in DBD against MCC. Finally, the metastatic colon cancer mouse model was used to detect the levels of expression of protein Bax, Bcl2, Caspase3, and Cleaved caspase3 by Western blot.ResultsA total of 28 active compounds and 61 common targets were predicted. The main compounds were quercetin, hederagenin, jaranol, methylnissolin, formononetin, calycosin, kaempferol, 3.9-di-O-methylnissolin, 24-propylcholesterol, and 7-O-methylisomucronulatol, present in Astragalus membranaceus (Huangqi, HQ). In addition, beta-sitosterol, ferulic acid, and stigmasterol, present in Angelica sinensis (Danggui, DG), were detected. JUN, PTSG2, EGFR, ESR1and, CASP3 genes were the top 5 hub genes in the PPI network. GO and KEGG enrichment analyses indicated that apoptosis played a major role in the biological processes and signaling pathways involved. Moreover, the in vivo experiment revealed that DBD inhibited MCC by up-regulating the expression of Bax, Caspase3, and Cleaved caspase3, and by down-regulating the expression of Bcl2.ConclusionThis study revealed candidate DBD targets and mechanisms in the treatment of MCC, using network pharmacology-based analyses and experimental validation. The present findings provide a reference for tumor treatment during the perioperative period.

Abstract 5296: Instability of non standard microsatellites in metastatic colorectal cancer patients treated with a bevacizumab based chemotherapy

Abstract Bevacizumab (B) is a biological agent frequently included in the treatment of metastatic colon cancer (mCRC), although at present there is no effective biomarker that can predict its efficacy. Few studies report a positive association of microsatellite instability (MSI) with the response to anti-angiogenic therapy, but the role of MSI in relation to B efficacy needs to be better understood. Elevated microsatellite alterations at selected tetranucleotides repeats (EMAST) can be observed at higher rate in mCRC patients compared to MSI. The predictive and prognostic role of EMAST has not been completely investigated so far. Moreover, it is known that angiogenesis in mCRC goes through the activation of VEGF-A, but VEGF-B can be involved in some compensatory effect during anti-VEGF-A treatments. By exploring the UCSC Genome Browser database, we found that the VEGF-B gene possesses a poly-dinucleotide microsatellite (normally 19xAG) which somatic instability has never been reported. In this study, we analyzed the status of MSI, five EMAST markers (D20S82, D20S85, D8S321, D9S242, MYCL1) and the VEGF-B microsatellite in relation to prognosis in 145 mCRC patients treated with chemotherapy alone (n=51) or chemotherapy plus B (n=94). MSI high (MSI-H) was detected in four patients (3%) out of 141 participants. Using a multivariable model and adjusting for patient characteristics, microsatellite status remains significantly associated with progression free survival (PFS) and overall survival (OS). The PFS hazard ratio (HR) for MSI-H patients was 3.18 (95% CI 1.09-9.25; p=0.034) and the OS HR was 6.45 (95% CI 2.08-19.99; p=0.001). Eleven (7.8%) patients out of 140 were positive to at least two EMAST markers. EMAST instability was associated with a general worse prognosis, trend that become significant in the group of patients treated with CT plus B in term of PFS (median survival 5 months vs 11. months, p=0.0006) and OS (median survival 6.1 months vs 29.1 months, p&amp;lt;0.0001). The interaction test showed a significant association of D20S82 (PFS p=0.004) and MYCL1(PFS p=0.029), with worse prognosis when treated with CT plus B, adding a possible predictive value in mCRC patients. The 24.2% of patients (29 out of 120) showed a VEGF-B-poly-AG instability. Amplification of the poly-AG is associated with worse outcome in PSF (7.0 month of median survival vs 28.0 months for patients with shortened poly-AG; p=0.005) in patients treated with CT alone, suggesting that an extended microsatellite in VEGF-B might have a role in the resistance to chemotherapy. In conclusion, MSI, EMAST and VEGF-B poly-AG instability are associated with prognosis in mCRC patients treated with CT or CT plus B. MSI and EMAST instability are associated with worse prognosis in CT+B patients, while VEGF-B microsatellite instability is linked to worse prognosis in CT patients. Further investigations are needed but we can hypothesize that MSI, EMAST and VEGF-B poly-AG instability can have some relevance for the clinical outcome of the disease. Citation Format: Francesca Pirini, Luigi Pasini, Sara Ravaioli, Gianluca Tedaldi, Emanuela Scarpi, Giorgia Marisi, Chiara Molinari, Daniele Calistri, Alessandro Passardi, Paola Ulivi. Instability of non standard microsatellites in metastatic colorectal cancer patients treated with a bevacizumab based chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5296.

Identification and clinical validation of metastasis-associated biomarkers based on large-scale samples in colon-adenocarcinoma

AimDistant metastasis is the main cause of death in patients with colon-adenocarcinoma(COAD). Due to the lack of effective molecular markers and treatment, the prognosis of patients with metastatic colon cancer is still rather poor. MethodsMetastatic related signature (MRS) of stage I and stage IV in colon cancer were identified from different cohorts. Univariate cox regression is used to analyze the relationship between MRS and the overall survival. L1000FWD and DGIdb databases are used to identify molecular drugs. Expression and functional experimental validation of the hub MRS were carried out. Results16 MRS were identified, of which 14 MRS was significantly correlated with overall survival. Further functional enrichment analysis showed that MRS was significantly involved with important biological functions such as cell migration, and apoptosis. As important metastatic related genes, GSR, FAS and CYP1B1 have significant interaction with drug molecules. Further studies have confirmed that the expression of FAS and GSR is low, and inhibition of its expression can promote the metastasis of COAD. CYP1B1 expression is highly expressed, and inhibition of its expression can attenuate the malignant biological behavior of colon cancer. ConclusionOur research could increase the understanding of the mechanism of colon cancer metastasis and provide theoretical basis for the treatment of metastatic colon cancer.

Results of surgical treatment of patients with stage IV colon cancer of older age groups and ways to improve them

The effectiveness of cytoreductive operations in geriatric patients with stage IV colon cancer was assessed. A comparative analysis of the results of surgical treatment of metastatic colon cancer in patients of various age groups was carried out. The molecular biological properties of colon adenocarcinoma in patients with metastatic colorectal cancer were studied. The clinical significance of immunohistochemical markers as the proliferative index of stem cancer cells (ALDH+Ki-67+) and the chemokine receptor CXCR4 was determined for predicting the long-term results of surgical treatment of patients with stage IV colon cancer has been determined. It was found that the survival rates of elderly and senile patients are not inferior to those in patients under 60 years of age. A comparative analysis of the immediate and long-term results of treatment indicates the effectiveness of cytoreductive interventions in elderly and senile patients suffering from stage IV colon cancer. It was found that the expression level of the receptor for CXCR4 chemokines and the proliferative activity of stem cancer cells correlate with the life expectancy of patients after cytoreductive interventions and can be used to clarify the indications for their implementation.

The role of fibroblast growth factor receptor 4 (FGFR4) signaling in anti-EGFR resistance in colon cancer.

4060 Background: Anti-EGFR therapy has been used as a standard treatment for metastatic colon cancer, but the innate resistance is still issues of increasing significance. Fibroblast growth factor receptor 4 (FGFR4) plays an important role in cell proliferation, invasion and anti-apoptosis, through the pathway of MAPK-ERK and PI3K-AKT. We investigated potential crosstalk between FGFR4 and EGFR signaling to identify new resistant mechanism of anti-EGFR therapy and how to overcome it in colon cancer. Methods: RNA-Seq was used to identify the associated signal pathway and down targets induced by FGFR4. Molecular studies including RTK array, RT-qPCR, western blotting were performed to validate the interaction between FGFR4 and EGFR signaling in vitro and in vivo. Next, the effect of FGFR4 in cetuximab resistance was investigated in vitro and in colon cancer patients. Results: FGFR4 overexpression in colon cancer cells activates downstream signaling, such as, PI3K/Akt and RAS/RAF/Erk pathway. Gene Ontology (GO) analysis from RNA-seq revealed that differentially expressed genes (DEGs) altered by expression of FGFR4 were related to biological functions, including cell proliferation, epidermal growth factor receptor signaling, NIK/NF-kB signaling, interferon-gamma signaling, wound healing. RT–qRCR showed that FGFR4 promotes the EGFR and ErbB3 by inducing the expression of EGFR ligands such as AREG, BTC, EREG, HBEGF. In vivo tumorigenesis, we found that FGFR4 promotes tumor growth and high expression of AREG in xenograft tumors. FGFR4 expression reduced the sensitivity to cetuximab in colon cancer cells and synergistic effect was shown when treated with FGFR4 inhibitor with cetuximab. A positive correlation between FGFR4 and AREG expression was observed in cancer, but not in normal tissues and high FGFR4 or AREG expression showed significantly inferior overall survival than low expression in patients treated with cetuximab for metastatic colon cancer. Conclusions: We demonstrated a pivotal mechanism of FGFR4 in colon cancer progression and cetuximab resistance through inducing AREG. Our data point to FGFR4 as a new biomarker to predict cetuximab response and dual targeting of FGFR4 and EGFR may be a promising treatment modality for colon cancer.

Targeting RICTOR Sensitizes SMAD4-Negative Colon Cancer to Irinotecan.

Deciphering molecular targets to enhance sensitivity to chemotherapy is becoming a priority for effectively treating cancers. Loss of function mutations of SMAD4 in colon cancer are associated with metastatic progression and resistance to 5-fluorouracil (5-FU), the most extensively used drug of almost all chemotherapy combinations used in the treatment of metastatic colon cancer. Here, we report that SMAD4 deficiency also confers resistance to irinotecan, another common chemotherapeutic frequently used alone or in combination with 5-FU against colon cancer. Mechanistically, we find that SMAD4 interacts with and inhibits RICTOR, a component of the mTORC2 complex, resulting in suppression of downstream effector phosphorylation of AKT at Serine 473. In silico meta-analysis of publicly available gene expression datasets derived from tumors indicates that lower levels of SMAD4 or higher levels of RICTOR/AKT, irrespective of the SMAD4 status, correlate with poor survival, suggesting them as strong prognostic biomarkers and targets for therapeutic intervention. Moreover, we find that overexpression of SMAD4 or depletion of RICTOR suppresses AKT signaling and increases sensitivity to irinotecan in SMAD4-deficient colon cancer cells. Consistent with these observations, pharmacologic inhibition of AKT sensitizes SMAD4-negative colon cancer cells to irinotecan in vitro and in vivo. Overall, our study suggests that hyperactivation of the mTORC2 pathway is a therapeutic vulnerability that could be exploited to sensitize SMAD4-negative colon cancer to irinotecan. IMPLICATIONS: Hyperactivation of the mTORC2 pathway in SMAD4-negative colon cancer provides a mechanistic rationale for targeted inhibition of mTORC2 or AKT as a distinctive combinatorial therapeutic opportunity with chemotherapy for colon cancer.

Can curcumin along with chemotherapeutic drug and lipid provide an effective treatment of metastatic colon cancer and alter multidrug resistance?

Cancer is one of the most deadly diseases spreading all over the world and a major cause of fear in the society. Colon cancer is the 4th most common cancer causing death in both male and female equally, mainly caused due to the improper diet plans, consumption of the red meat and lack of exercise. Although the design of the chemotherapeutic drugs is well advanced, many of them developed resistance towards the cancer cells. The major reason behind the drug resistance in the colon cancer cells is due to the action exhibited by P-gp, which belongs to a member of ABC transporter family. P-glycoprotein (P-gp) effluxes the drug from its entry into the cancer cells, by treating it as a foreign body and hence decreases the therapeutic concentration of chemotherapeutic drugs inside the cancer cells. For overcoming this scenario, we posit the use of the curcumin (as a flavonoid) along with the lipid and the chemotherapeutic drug to provide an effective therapy and to overcome the possible issues associated with the failure in the therapy. Curcumin possesses dual mode of actions as a chemosensitizing agent and also as a chemotherapeutic drug. It generally acts as a chemosensitizer which can alter or inhibit the efflux pump exhibited by P-gp and provide a pathway for the entry of the chemotherapeutic drug into the cancer cells. Lipids have the potential to overcome the Multidrug resistance (MDR) and related issues; in addition, lipids are used for targeting colon cancer cells and also can act during the metastatic condition of the cancer which is hypothesised to be proven by using various studies. If our hypothesis is proven, the use of curcumin with lipids and the chemotherapeutic drug in a novel combination will reduces the majority of the issues related to the multidrug resistance, the recurrence and the spread of cancer could be overcome in a safe and effective manner.

Use of Bevacizumab for Elderly Patients With Stage IV Colon Cancer: Analysis of SEER-Medicare Data

BackgroundBevacizumab is used for the treatment of metastatic colon cancer in conjunction with first-line chemotherapy. In this study, we examined receipt of first-line bevacizumab and predictors of its use among older patients with stage IV colon cancer. Materials and MethodsWe used data from the Surveillance, Epidemiology, and End Results-Medicare dataset to identify patients with stage IV colon cancer diagnosed from 2005 to 2013 who received FOLFOX (5-fluorouracil/leucovorin/oxaliplatin) or FOLFIRI (5-fluorouracil/leucovorin/irinotecan) as first-line therapy. We used multivariable regression analysis to determine demographic and clinical factors associated with use of concomitant bevacizumab. ResultsWe identified 3785 patients with stage IV colon cancer who met our eligibility criteria. Of these, 2352 (62.1%) received bevacizumab. Bevacizumab use has decreased over time from 68.2% in 2005 to 57.6% in 2013 (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.91-0.97). Patients were less likely to receive bevacizumab if they were older (compared with 65-69 years, ≥ 80 years: OR, 0.64; 95% CI, 0.52-0.80), or had multiple comorbidities (compared with comorbidity score of 0, score of 1: OR, 0.73; 95% CI, 0.60-0.89). ConclusionOver one-half of elderly patients received bevacizumab as part of their first-line therapy for stage IV colon cancer. Bevacizumab use has been slowly decreasing since 2005. Newer anti-epidermal growth factor receptor treatments have not been supplanting bevacizumab, as first-line biologic use in general has also decreased during this time period.

Efficacy of continuing anti-angiogenic agents in the second-line treatment for metastatic colon cancer depending on the KRAS mutation status: a meta-analysis

Objective: to assess the efficacy of anti-angiogenic agents incorporated into second-line chemotherapeutic regimens for metastatic colon cancer depending on the KRAS gene mutation status.Materials and methods. We selected completed prospective randomized controlled phase III clinical trials evaluating the efficacy of antiangiogenic agents (bevacizumab, ramucirumab and aflibercept) added to second-line chemotherapy for metastatic colon cancer with subanalysis of treatment efficacy depending on the KRAS gene mutation status. Meta-analysis was performed using the ReviewManager (RevMan) v. 5.3 (The Cochrane Collaboration, Denmark).Results. Three studies (ML18147, RAISE, VELOUR) involving 2165 patients (1137 with KRAS wild-type tumors and 1028 with KRAS-mutant tumors) met the inclusion criteria and were included into this meta-analysis. The majority of patients (84 %) received bevacizumab in the first-line treatment. The results of our meta-analysis suggest that adding an anti-angiogenic drug to chemotherapy in patients with KRAS wildtype colon cancer significantly improved both progression-free survival (hazard ratio (HR) 0.71; 95 % confidence interval (CI) 0.62–0.80; р&lt;0.00001; I2 = 22 %, p = 0.21) and overall survival (HR 0.76; 95 % CI 0.66–0.88; р= 0.0001; I2 = 0, p = 0.59). In patients with KRASmutant colon cancer, incorporation of an anti-angiogenic drug into the treatment regimen was not associated with better overall survival (ОР0.9; 95 % CI 0.79–1.03; р= 0.11; I2 = 0, p = 0.98), although improved progression-free survival (HR 0.78; 95 % CI 0.68–0.89; р= 0.0002; I2 = 0, p = 0.46). Conclusion. Continuation of anti-angiogenic therapy in the second-line treatment for metastatic colon cancer is most effective in patients with KRAS wild-type tumors. In individuals with KRAS-mutant tumors, continuation of bevacizumab or switch to another anti-angiogenic agent in the second-line treatment improves progression-free survival and has a statistically insignificant effect on overall survival.

Regorafenib tolerance and outcomes in inner-city minority colorectal cancer population.

722 Background: Regorafenib (REG) is an oral multikinase inhibitor used for treatment of metastatic colon cancer after progression on fluorouracil, oxaliplatin and irinotecan therapy. The FDA approval was based on CORRECT trial showing improvements in progression-free survival (PFS) and overall survival (OS). Another trial (CONCUR) showed similar results. However, these trials included predominantly Whites and Asians. Our study aimed to evaluate treatment outcomes in the underserved, mainly African Americans and Hispanics. Methods: Cook County hospital is the 3rd largest public hospital in the US. All patients with an order for REG were identified from our pharmacy database. Charts were retrospectively reviewed for cancer stage, age, ethnicity, previous treatments, PFS and OS. Patients with non-colorectal cancer, incomplete data, no evidence of REG usage were excluded. Statistical analysis was done by t-test on subgroups. Results: A total of 42 patients were screened and 30 were included in the study. A comparison of outcomes with CORRECT and CONCUR trials is presented in Table 1. Our study patients, despite being less heavily pre-treated, had a worse OS compared to the clinical trials, with similar PFS. There was a trend towards better PFS and OS in women in our study of 4.3 and 4.8 months compared to men with 1.9 and 3.3 months respectively (p = NS). Six (20%) patients discontinued REG due to intolerance within a median of 1.2 months. The intolerant patients had a significantly higher median BMI of 31 compared to 24.9 for patients who continued the medication to progression (p = 0.019). Conclusions: Compared to CORRECT and CONCUR trials, population of predominantly AA and Hispanics showed a trend towards worse OS despite being less heavily pre-treated indicating worse outcomes in minorities treated with REG. Women showed better PFS and OS compared to men in our study. Patients unable to tolerate REG had significantly higher BMI, indicating a need to study dosing in this subgroup. [Table: see text]