Systemic Therapy For Colorectal Cancer Research Articles

Inhibition of Aurora B kinase (AURKB) enhances the effectiveness of 5-fluorouracil chemotherapy against colorectal cancer cells

Background5-Fluorouracil (5-FU) remains a core component of systemic therapy for colorectal cancer (CRC). However, response rates remain low, and development of therapy resistance is a primary issue. Combinatorial strategies employing a second agent to augment the therapeutic effect of chemotherapy is predicted to reduce the incidence of treatment resistance and increase the durability of response to therapy.MethodsHere, we employed quantitative proteomics approaches to identify novel druggable proteins and molecular pathways that are deregulated in response to 5-FU, which might serve as targets to improve sensitivity to chemotherapy. Drug combinations were evaluated using 2D and 3D CRC cell line models and an ex vivo culture model of a patient-derived tumour.ResultsQuantitative proteomics identified upregulation of the mitosis-associated protein Aurora B (AURKB), within a network of upregulated proteins, in response to a 24 h 5-FU treatment. In CRC cell lines, AURKB inhibition with the dihydrogen phosphate prodrug AZD1152, markedly improved the potency of 5-FU in 2D and 3D in vitro CRC models. Sequential treatment with 5-FU then AZD1152 also enhanced the response of a patient-derived CRC cells to 5-FU in ex vivo cultures.ConclusionsAURKB inhibition may be a rational approach to augment the effectiveness of 5-FU chemotherapy in CRC.

Concomitant intraperitoneal and systemic chemotherapy for extensive peritoneal metastases of colorectal origin: protocol of the multicentre, open-label, phase I, dose-escalation INTERACT trial

IntroductionCytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has become standard of care for patients with peritoneal metastases of colorectal origin with a low/moderate abdominal disease load. In case of a...

Systemic Therapy for Colorectal Cancer

Colorectal cancer remains the second most common cause of cancer-related deaths in this country. Although colorectal cancer is best managed by a multidisciplinary team of surgical, radiation, and medical oncologists, cytotoxic therapy remains the backbone of treatment in the metastatic disease setting. In addition to cytotoxic therapies, vascular-targeted therapies and epidermal growth factor receptor (EGFR)–targeted therapies for selected patients with metastatic colorectal cancer improve outcomes for patients with metastatic colorectal cancer. Growing understanding of various biological subsets of colorectal cancer, including BRAF V600E mutant and mismatch repair–deficient colorectal cancers, is expanding treatment opportunities for patients and is the focus of ongoing research. This review contains 4 tables and 57 references. Key Words: chemotherapy, colorectal cancer, fluoropyrimidines, immunotherapy, metastatic, mismatch repair–deficient colorectal cancer, targeted therapy, topoisomerase inhibitors

Systemic Therapy for Colorectal Cancer

Colorectal cancer remains the second most common cause of cancer-related deaths in this country. Although colorectal cancer is best managed by a multidisciplinary team of surgical, radiation, and medical oncologists, cytotoxic therapy remains the backbone of treatment in the metastatic disease setting. In addition to cytotoxic therapies, vascular-targeted therapies and epidermal growth factor receptor (EGFR)–targeted therapies for selected patients with metastatic colorectal cancer improve outcomes for patients with metastatic colorectal cancer. Growing understanding of various biological subsets of colorectal cancer, including BRAF V600E mutant and mismatch repair–deficient colorectal cancers, is expanding treatment opportunities for patients and is the focus of ongoing research. This review contains 4 tables and 57 references. Key Words: chemotherapy, colorectal cancer, fluoropyrimidines, immunotherapy, metastatic, mismatch repair–deficient colorectal cancer, targeted therapy, topoisomerase inhibitors

Perioperative systemic therapy and cytoreductive surgery with HIPEC versus upfront cytoreductive surgery with HIPEC alone for isolated resectable colorectal peritoneal metastases: protocol of a multicentre, open-label, parallel-group, phase II-III, randomised, superiority study (CAIRO6)

BackgroundUpfront cytoreductive surgery with HIPEC (CRS-HIPEC) is the standard treatment for isolated resectable colorectal peritoneal metastases (PM) in the Netherlands. This study investigates whether addition of perioperative systemic therapy to CRS-HIPEC improves oncological outcomes.MethodsThis open-label, parallel-group, phase II-III, randomised, superiority study is performed in nine Dutch tertiary referral centres. Eligible patients are adults who have a good performance status, histologically or cytologically proven resectable PM of a colorectal adenocarcinoma, no systemic colorectal metastases, no systemic therapy for colorectal cancer within six months prior to enrolment, and no previous CRS-HIPEC. Eligible patients are randomised (1:1) to perioperative systemic therapy and CRS-HIPEC (experimental arm) or upfront CRS-HIPEC alone (control arm) by using central randomisation software with minimisation stratified by a peritoneal cancer index of 0–10 or 11–20, metachronous or synchronous PM, previous systemic therapy for colorectal cancer, and HIPEC with oxaliplatin or mitomycin C. At the treating physician’s discretion, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles. The first 80 patients are enrolled in a phase II study to explore the feasibility of accrual and the feasibility, safety, and tolerance of perioperative systemic therapy. If predefined criteria of feasibility and safety are met, the study continues as a phase III study with 3-year overall survival as primary endpoint. A total of 358 patients is needed to detect the hypothesised 15% increase in 3-year overall survival (control arm 50%; experimental arm 65%). Secondary endpoints are surgical characteristics, major postoperative morbidity, progression-free survival, disease-free survival, health-related quality of life, costs, major systemic therapy related toxicity, and objective radiological and histopathological response rates.DiscussionThis is the first randomised study that prospectively compares oncological outcomes of perioperative systemic therapy and CRS-HIPEC with upfront CRS-HIPEC alone for isolated resectable colorectal PM.Trial registrationClinicaltrials.gov/NCT02758951, NTR/NTR6301, ISRCTN/ISRCTN15977568, EudraCT/2016–001865-99.

Update on systemic therapy for colorectal cancer: biologics take sides.

Over the last decade, progress in the management of metastatic colorectal cancer (CRC) has focused on the development of biologic therapy in addition to the back bone of combination chemotherapy. Anti-epidermal growth factor receptor (EGFR) antibodies and agents targeting angiogenesis are widely used in the clinic, and more recently, in a subset of patients with mismatch repair (MMR) deficient cancer, immunotherapy with immune check point inhibitors have been integrated into clinical practice. The major challenge with the use of these biologic therapies is determining predictive biomarkers to optimize patient selection. In this review, we discuss the most recent updates in the use of biologic therapy in CRC. We review data on the role of primary tumor location (PTL) (sidedness) as predictive biomarker and recent advances in treatment of CRC with BRAF mutation.

Singapore Cancer Network (SCAN) Guidelines for Systemic Therapy of Colorectal Cancer

The SCAN colorectal cancer systemic therapy workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy for colorectal cancer in Singapore. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting. Five international guidelines were evaluated-those developed by the National Comprehensive Cancer Network for colon (2014) and rectal (2014) cancer, the European Society of Medical Oncology for advanced (2012) and early (2013) cancer and the National Institute of Clinical Excellence (2011). Recommendations on systemic therapy in colorectal cancer were produced. These adapted guidelines form the SCAN Guidelines 2015 for systemic therapy of colorectal cancer.

Systemic Therapy for Colorectal Cancer: Patterns of Chemotherapy and Biologic Therapy Use in Nationally Representative US Claims Database

Treatment strategies for colorectal cancer (CRC) are highly variable. The aim of this study is to examine the patterns of chemotherapy and biologic therapy use for CRC patients in a national medical claims database. A retrospective and observational analysis was performed using the i3 Innovus claims database to identify healthcare services consumed by patients aged 18years and older, diagnosed with CRC between 1 January 2005 and 30 June 2009 in commercial health plans. Of 9,876 subjects diagnosed with CRC, fluorouracil (23.5%) and capecitabine (10.0%) were the dominant first-line monotherapies, followed by bevacizumab (3.2%) and oxaliplatin (2.9%). The most common combination regimen at first line and first and second line was FOLFOX (fluorouracil, leucovorin, and oxaliplatin; more than 25%). The combinations FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab (14.2%) and FOLFOX plus bevacizumab (13.9%) were significantly more frequent in third and successivelines of CRC therapy than other regimens (χ(2)=191.2; P<0.01). Additionally, the average annualized cost of CRC treatment for all patients was $US66,452, and the adjusted analysis demonstrated that patients receiving FOLFOX-A (FOLFOX+avastin) or FOLFIRI-A (FOLFIRI+avastin) had higher costs for CRC treatment. With the exception of a sizeable portion of patients on monotherapy, the treatment patterns for CRC were largely consistent with National Comprehensive Cancer Network (NCCN) guidelines.

PCN47 Medical Expenditures Associated With the Use of Systemic Therapy for Colorectal Cancer in Privately Insured Adults in a Claims Database in the United States

PCN47 Medical Expenditures Associated With the Use of Systemic Therapy for Colorectal Cancer in Privately Insured Adults in a Claims Database in the United States

PCN11 Systemic Therapy for Colorectal Cancer: Patterns of Chemotherapy and Biologic Therapy Use in Nationally Representative Claims Database in the United States

PCN11 Systemic Therapy for Colorectal Cancer: Patterns of Chemotherapy and Biologic Therapy Use in Nationally Representative Claims Database in the United States

Differences in survival for advanced-stage colorectal cancer (CRC) patients by lines of therapy received in a U.S. local oncology practice.

e14106 Background: Improvements in survival for advanced-stage colorectal cancer (CRC) patients who receive chemotherapy have been reported. We compared survival rates for patients with 3+ vs. &lt;3 lines of therapy using electronic medical records of a local oncology practice in Georgia, USA. Methods: The Georgia Cancer Specialist (GCS) EMR Database (1/1/2005–07/ 31/2010) was used. The database contains data on patient demographics, cancer diagnostic information, chemotherapy and non-chemotherapy drugs administered written prescriptions, chemotherapy/radiation protocols, chemotherapy protocol changes, office visit information, and hospitalizations. Patients newly diagnosed with CRC between 01/01/05 and 06/31/10 treated with systemic therapy for CRC were identified. Patients were followed from initial CRC diagnosis to death, loss to follow-up, or end of study. Patients were categorized by number of lines of therapy received (1, 2, 3+) and original stage at diagnosis (III b/c, IV, unknown). Survival following initial line of therapy was evaluated using Cox proportional hazards models controlling forstage at diagnosis, type of 1st line treatment, and other patient characteristics. Results: The study included 704 patients with a median age of 63 years (age range 26-85 years) at diagnosis and 49% (n=345) female. 45% (n=317) and 42% (n=296) had stage IV and III b/c CRC at diagnosis, respectively. 53% (n=373) received only 1st line treatment, 27% (n=190) received 1st and 2nd line treatment and 20% (n=141) received 3rd line and beyond. The median follow up was 431 days and death was reported in 27%(n=190) of subjects. The multivariate Cox proportional hazard analysis indicated that there was no statistical difference in survival between patients who received 2nd line of therapy vs. 3 plus lines of therapy (HR=1.42; p&lt;0.067). Conclusions: A non-statistical significant association between 2nd and more than 3 total lines of therapy in survival was found in subjects diagnosed with stage III B/C and IV. However the trend towards survival was present, indicating that some patients could benefit from the addition of 3rd line but it would require additional studies to confirm this.

Recently Identified and Potential Targets for Colon Cancer Treatment

The systemic therapy for colorectal cancer has advanced from essentially a single, partially effective agent, 5-fluorouracil, to a combination of cytotoxics and antibodies offering increased survival. In addition to damage of DNA through agents, such as oxaliplatin and irinotecan, and inhibition of DNA replication, a promising approach involves modifying the control of gene expression, including epigenetic control. Modulation of invasion and metastasis should become increasingly important. Inhibition of growth-factor signaling with small-molecule drugs and antibodies can be a part of this effort. Further progress in the control of gene expression in colon cancer may be achieved with miRNAs and RNA interference if technical problems can be overcome. A number of genetic changes in colorectal cancer progression have been identified and offer targets for future therapy.

Pulmonary Metastasectomy: A Moving Target

For at least 60 years, surgical resection has been a widely used approach to the management of patients with lung metastases from a variety of solid tumors. For many of these patients, surgical resection has provided the only potentially curative treatment. Analyses of numerous retrospective series have led to well-accepted surgical selection criteria: a primary tumor that has been definitively controlled, metastases limited to the lung that can be completely resected, ability of the patient to tolerate the planned operation, and lack of a better alternative treatment. The number of lung metastases, the disease-free interval since treatment of the primary tumor, the tumor doubling time, the presence of lymph node metastases, the histology of the primary tumor, and in some instances, elevated serum markers such as carcinoembryonic antigen are known to influence outcome and may be incorporated into the decision of whether to offer surgery to the patient. However, there remain many controversial aspects to

Overview of systemic therapy for colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and second leading cause of death from cancer in North America. The authors provide an overview of the indications for both chemotherapy and targeted therapy, as well as discuss the efficacy and toxicity of systemic therapy. They highlight the key studies that lead to the initial historical use of fluorouracil (5FU) based chemotherapy in the adjuvant and metastatic setting, the recent adoption of 5FU plus leucovorin (LV) and oxaliplatin (FOLFOX) chemotherapy over 5FU when treating adjuvant patients, and the use of FOLFOX or 5FU plus LV and irinotecan (FOLFIRI) in metastatic patients. They also review the role of chemotherapy in treating rectal cancer and resectable liver metastatic disease. Future areas of research focus for systemic therapy of colorectal cancer are highlighted.

The Role of Molecular Markers in Predicting Response to Therapy in Patients with Colorectal Cancer

Advances in systemic therapy for colorectal cancer have dramatically improved prognosis. While disease stage has traditionally been the main determinant of disease course, several molecular characteristics of tumor specimens have recently been shown to have prognostic significance. Although to date no molecular characteristics have emerged as consistent predictors of response to therapy, retrospective studies have investigated the role of a variety of biomarkers, including microsatellite instability, loss of heterozygosity of 18q, type II transforming growth factor beta receptor, thymidylate synthase, epidermal growth factor receptor, and Kirsten-ras (KRAS). This paper reviews the current literature, ongoing prospective studies evaluating the role of these markers, and novel techniques such as gene profiling, which may help to uncover the more complex molecular interactions that will predict response to chemotherapy in patients with colorectal cancer.

Systemic Therapy for Colorectal Cancer

Colorectal cancer is one of the most commonly diagnosed malignant diseases, with an estimated 1,023,000 new cases and 529,000 deaths worldwide each year. This review considers recently developed cytotoxic chemotherapies and biologic agents that are effective against colorectal cancer and assesses their use as treatments for metastatic disease and as components of adjuvant therapy.

Die systemische Therapie des Kolonkarzinoms 2004

This article reviews the available data regarding the acticity of postoperative adjuvant systemic therapy for colorectal cancer as first and second-line treatment in metastatic disease. The efficacy of adjuvant treatment of patients with stage III colorectal cancer is well established. 5-fluorouracil (5-FU) and folic acid over 6 months (still) represent todays standard and should serve as comparison in randomized studies. The risk of relapse is low in stage II colon carcinoma and consequently the efficacy is relatively small compared to stage III. New investigation indicate, Capecitabene has the potential to replace 5-FU/FS as standard treatment for patients with colon cancer. Efficacy results are expected to be available in 2004. In metastatic disease combination of 5-FU/folic acid plus CPT-11 or OXA are treatment of choice for the first-line therapy of metastatic colorectal carcinoma. FOLFOX is high-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second- line therapy for metastatic colorectal cancer. It resulted in prolongation of the median progress free survival from 6,8 to 8,8 months and increased the survival for 4,5 months. New perspectives are novel chemotherapeutic and targeted agents in metastatic colorectal cancer: For the first time, there has been a targeted therapy shown convincingly to prolong survival for patients with unresectable metastatic colorectal cancer in a well-performed Phase III trial. This agent is bevacizumab, a humanised monoclonal antibody targeting the circulating proangiogenic growth factor vascular endothelial growth factor. Results with bevacizumab should lead to rapid expansion of the number of strategies targeting tumour neovasculature. Additionally, an antibody against the epidermal growth factor, cetuximab, has been shown to have both single-agent activity and the potential ability to partially reverse resistance to a chemotherapy drug. These advancements, as well as data on other novel treatment agents that have been studied specifically in patients with colorectal neoplasms, are discussed in detail.

Systemic therapy for colorectal cancer: focus on newer chemotherapy and novel agents

Systemic therapy for metastatic colorectal cancer is evolving rapidly after many years without significant change. Standard adjuvant therapy for rectal cancer, on the other hand, remains much the same as it has been since the early 1990s. Recent additions to the colorectal cancer armamentarium include capecitabine, irinotecan, and oxaliplatin. Use of these agents in metastatic colorectal cancer and potential for use in localized rectal cancer are discussed. In addition to these “classical” chemotherapeutic agents, there are a number of exciting therapies designed to target specific molecular features of malignant cells. These agents are now being tested in colorectal cancer in addition to chemotherapy and to radiotherapy, with the hope that improvements in outcome will be made without substantial increases in treatment toxicity. The focus of the section on newer classes of agents will be on agents that are in phase II and III trials, with brief mention of other exciting treatment strategies.

Systemic therapy for colorectal cancer

Colorectal cancer alone accounts for around 200,000 deaths in Europe and represents a significant health problem. Although about fifty percent of patients are cured by surgery alone, the other half will eventually die due to metastatic disease, which includes approximately 25% of patients who have evidence of metastases at the time of diagnosis. Surgical resection of the primary tumor and regional lymph nodes is the only curative therapy for colorectal cancer. However, adjuvant chemotherapy in stage III for colon cancer following curative resection has been shown to reduce the risk of recurrence by 19-40% and of death by 16-33%. Today, 5-fluoroUracil and Leucovorin given for six months may represent the best adjuvant treatment available The contribution of levamisole to adjuvant treatment seems to be marginal, if any. The benefit of adjuvant chemotherapy for the patients with Dukes B colon cancer is less clear. A meta-analysis of 1,381 patients with advanced colorectal cancer showed a significant increase in response rate with the bolus 5-fluoroUracil and Leucovorin versus 5-fluoroUracil alone but no significant difference in median survival. Continuous infusion allows higher doses of 5-FU than rapid bolus infusion and improves response rate survival and time to progression. Oral fluoropyrimidines (capecitabine and Uracil/Tegafur [UFT]) are as active as intravenous fluoropyrimidines. Compared to intravenous 5FU, oral fluoropyrimidines have safety advantages clinical benefits, and are more convenient for patients. Phase III randomized clinical trials in patients with metastatic colorectal cancer demonstrate the significant superiority of combining irinotecan with 5-fluoroUracil and Leucovorin or oxaliplatin with 5-fluoroUracil and Leucovorin over the same 5-fluoroUracil and Leucovorin alone. Several phase II studies have shown that the combination of the oral fluoropyrimidines plus irinotecan or oxaliplatin is very active in metastatic colorectal cancer. Trials with agents acting on novel targets in colorectal cancer are progressing rapidly, including doxifluridine, new inhibitors of thymidylate synthase (ZD9331), oral camptothecins (Rubitecan), multitarget antifolate antimetabolite (Premetrexet), inhibitors of epidermal growth factor receptor (Cetuximab), COX-2 inhibitors (celecoxib) and farnesyltransferaze inhibitors (Zarnestra). However, a few randomized trials failed to show a survival advantage compared with placebo in patients with advanced refractory colorectal cancer.

Oral fluoropyrimidines in the treatment of colorectal cancer.

5-Fluorouracil (5-FU) has been the mainstay of systemic therapy for colorectal cancer since its initial development 40 years ago. Efforts to improve the therapeutic index of 5-FU have included alteration of schedule and addition of biochemical modulators. An understanding of 5-FU mechanisms of action has resulted in major therapeutic advances in the past 10 years; however, a plateau has been reached in the efficacy of 5-FU, mandating a paradigm shift for those involved in colorectal cancer drug development. One direction vigorously pursued is the development of orally administered fluoropyrimidines that maintain or improve upon the effectiveness of intravenous 5-FU. In this paper the preclinical and clinical development of oral fluoropyrimidines and their modulators is reviewed, including UFT, capecitabine, ethynyluracil and S-1.