MicroRNA Signature in Metastatic Colorectal Cancer Patients Treated With Anti-EGFR Monoclonal Antibodies

BackgroundTo investigate whether microRNAs are predictive of sensitivity to anti–epidermal growth factor receptor (EGFR) monoclonal antibodies in patients with metastatic colorectal cancer (mCRC).MethodsA total of 183 mCRC cases from 2 independent cohorts (cohort 1: 74 cases; validation cohort: 109 cases) treated with cetuximab or panitumumab were included in the study. MiRNA arrays were analyzed using Agilent's miRNA platform.ResultsThe study identified the cluster Let-7c/miR-99a/miR-125b as a signature associated with an outcome different from that of anti-EGFR therapies. In the first cohort, patients with high-intensity signatures had a significantly longer progression-free survival (PFS) (6.1 vs. 2.3 mo; P = .02) and longer overall survival (OS) ( 29.8 vs. 7.0 mo, P = .08) than patients with low-intensity signatures. In the validation cohort, patients with high signature had significantly longer PFS and OS than individuals with low-intensity signatures (PFS 7.8 vs. 4.3 mo, P = .02; OS 12.8 vs. 7.5 mo, P = .02). In the KRAS wild-type population (n = 120), high-intensity signature patients had a significantly longer PFS (7.8 vs. 4.6 mo, P = .016) and longer OS (16.1 vs. 10.9 mo, P = .09) than low-signature individuals, with no difference in KRAS mutated patients.ConclusionThe MiR-99a/Let-7c/miR-125b signature may improve the selection of patients with KRAS wild-type mCRC as good candidates for anti-EGFR therapy.     

Dermatologic Toxicity Occurring During Anti-EGFR Monoclonal Inhibitor Therapy in Patients With Metastatic Colorectal Cancer: A Systematic Review

Monoclonal antibody inhibitors of the epidermal growth factor receptor (EGFR) have been shown to improve outcomes for patients with metastatic colorectal cancer (mCRC) without RAS gene mutations. However, treatment with anti-EGFR agents can be associated with toxicities of the skin, nails, hair, and eyes. Because these dermatologic toxicities can result in treatment discontinuation and affect patient quality of life, their management is an important focus when administering anti-EGFR monoclonal antibodies. The present systematic review describes the current data reporting the nature and incidence of, and management and treatment options for, dermatologic toxicities occurring during anti-EGFR treatment of mCRC. A search of the National Library of Medicine PubMed database from January 1, 2009, to August 18, 2016, identified relevant reports discussing dermatologic toxicity management among patients with mCRC receiving anti-EGFR therapy. The studies were grouped by type and rated by level of evidence using the GRADE approach developed by the Agency for Healthcare Research and Quality. Overall, 269 reports were reviewed (nonrandomized trials, n = 120; randomized trials, n = 31; retrospective studies, n = 15; reviews, n = 39). Dermatologic toxicity of any grade occurs in most patients who receive anti-EGFR therapy; approximately 10% to 20% of patients experienced grade 3/4 toxicity. The most common dermatologic toxicities include papulopustular/acneiform rash, xerosis, and pruritus; however, nail changes, hair abnormalities, and ocular conditions also occur. Guidance for managing these toxicities includes the use of inexpensive emollient ointments and moisturizers, avoidance of sun exposure, avoidance of irritants, and the use of short showers. Several studies also found that preemptive treatment was more effective than reactive treatment at limiting the incidence and severity of skin toxicity. With appropriate treatment, the dermatologic toxicities associated with anti-EGFR monoclonal antibody therapy can be managed, minimizing patient discomfort and the need for therapy interruption and/or discontinuation. Additionally, preemptive treatment can reduce dermatologic toxicity severity, ultimately yielding better quality of life.     

Anti-EGFR and Anti-VEGF Agents in First-Line Therapy for Advanced Colorectal Cancer

Outcomes for metastatic colorectal cancer have improved progressively with the incorporation of new drugs into standard treatment regimens. Most recently, targeted therapies against VEGF and EGFR have improved upon the prior standard for first-line therapy with FOLFOX or FOLFIRI. As attempts to combine anti-VEGF and anti-EGFR drugs have been unsuccessful, it is necessary to choose between them when beginning first-line therapy. This review summarizes the existing literature to best inform this decision. To date, three head-to-head trials have compared anti-EGFR and anti-VEGF therapy in RAS wild-type patients: PEAK, FIRE-3, and CALGB/SWOG 80405. PEAK and FIRE-3 suggested a survival advantage for anti-EGFR therapy over anti-VEGF therapy, though CALGB/SWOG 80405 did not. Results have emerged recently to suggest that tumors arising from the right colon are resistant to anti-EGFR therapy, and that any advantage of anti-EGFR therapy over anti-VEGF therapy may be limited to left-sided tumors.     

Management of Toxicity Induced by Anti-EGFR Therapy in Metastatic Colorectal Cancer

Use of anti-epidermal growth factor receptor (anti-EGFR) agents has yielded significant advances in the treatment of patients with metastatic colorectal cancer. In fact these drugs, which include the monoclonal antibodies cetuximab and panitumumab, can be delivered both as a single agent and in combination with chemotherapy, achieving better survival and quality of life and in some cases also resectability of metastases. However, these agents can result in the development of toxicities that are usually different from those observed with chemotherapy alone. For the management of these adverse effects, proper knowledge is mandatory. Skin toxicity is the most frequent adverse effect. Other toxicities can be observed, such as hypomagnesemia, gastrointestinal toxicity, and thromboembolic events. Severe infusion reactions can be life-threatening. For these reasons a review of anti-EGFR-drug-related toxicity is useful for clinical practice.     

First-Line Mono-Chemotherapy in Frail Elderly Patients with Metastatic Colorectal Cancer

Background: Unlike for fit elderly metastatic colorectal cancer (mCRC) patients, general approaches to initialtreatment for the frail older mCRC patients are not clear. Our aim was to evaluate the efficiency and safetyof first-line single-agent treatment in one such group. Materials and Methods: We retrospectively evaluatedmCRC patients aged 70 or older with an Eastern Cooperative Oncology Group performance score of 2. Theyhad no prior treatment and underwent first-line single-agent capecitabine or other monotherapies until diseaseprogression or unacceptable toxicity. Results: Thirty-six patients were included. Most (n:28, 77.8%) weretreated with capecitabine. One patient achieved a complete response and 5 patients had a partial response foran overall response rate of 16.6%. Twelve patients (33.3%) remained stable. Median progression free survivalwas 5 months (confidence interval (CI), %; 3.59-6.40) and median overall survival was 10 months (95 CI%;8.1-11.8). Grade 3-4 toxicity was found in 6 patients (16.6%). Febrile neutropenia was not observed and therewere no toxicity-associated deaths. Conclusions: Capecitabine is a safe chemotherapeutic agent with moderateactivity for first-line treatment of older metastatic colorectal cancer patients with limited performance status.     

Prognostic Factors in First-Line Chemotherapy Treated Metastatic Gastric Cancer Patients: A Retrospective Study

Background: The majority of patients with gastric cancer in developing countries present with advanceddisease. Systemic chemotherapy therefore has limited impact on overall survival. Patients eligible for chemotherapyshould be selected carefully. The aim of this study was to analyze prognostic factors for survival in advancedgastric cancer patients undergoing first-line palliative chemotherapy. Methods: We retrospectively reviewed107 locally advanced or metastatic gastric cancer patients who were treated with docetaxel and cisplatin plusfluorouracil (DCF) as first-line treatment between June 2007 and August 2011. Twenty-eight potential prognosticvariables were chosen for univariate and multivariate analyses. Results: Among the 28 variables of univariateanalysis, nine variables were identified to have prognostic significance: performance status, histology, locationof primary tumor, lung metastasis, peritoneum metastasis, ascites, hemoglobin, albumin, weight loss and bonemetastasis. Multivariate analysis by Cox proportional hazard model, including nine prognostic significancefactors evident in univariate analysis, revealed weight loss, histology, peritoneum metastasis, ascites and serumhemoglobin level to be independent variables. Conclusion: Performance status, weight loss, histology, peritoneummetastasis, ascites and serum hemoglobin level were identified as important prognostic factors in advancedgastric cancer patients. These findings may facilitate pretreatment prediction of survival and can be used forselecting patients for treatment.     

Clinical Relevance of Alternative Endpoints in Colorectal Cancer First-Line Therapy With Bevacizumab: A Retrospective Study

Background

We studied the relationship between intermediate criteria and overall survival (OS) in metastatic colorectal cancer (mCRC) patients who received first-line chemotherapy with bevacizumab.

Impact of the Specific Mutation in KRAS Codon 12 Mutated Tumors on Treatment Efficacy in Patients with Metastatic Colorectal Cancer Receiving Cetuximab-Based First-Line Therapy: A Pooled Analysis of Three Trials

Purpose: This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras (KRAS) gene on treatment efficacy in patients with metastatic colorectal cancer (mCRC). Patients: Overall, 119 patients bearing a KRAS mutation in codon 12 were evaluated. All patients received cetuximab-based first-line chemotherapy within the Central European Cooperative Oncology Group (CECOG), AIO KRK-0104 or AIO KRK-0306 trials. Results: Patients with KRAS codon 12 mutant mCRC showed a broad range of outcome when treated with cetuximab-based first-line regimens. Patients with tumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations (overall survival 23.3 vs. 14-18 months; hazard ratio 0.66, range 0.43-1.03). An interaction model illustrated that KRAS p.G12C was associated with unfavorable outcome when treated with oxaliplatin plus cetuximab. Conclusion: The present analysis suggests that KRAS codon 12 mutation may not represent a homogeneous entity in mCRC when treated with cetuximab-based first-line therapy.     

Treatment and Survival Outcome of BRAF-Mutated Metastatic Colorectal Cancer: A Retrospective Matched Case-Control Study

Background

Somatic v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation, present in approximately 10% of metastatic colorectal cancer (mCRC) cases, is associated with poor prognosis. Patient outcome outside of clinical trials has only been reported in small series. We report real-world data on treatment and survival for BRAF-mutated (MT) patients at a single tertiary center, compared with a matched BRAF wild type (WT) control group.

Chemotherapy-Induced Neutropenia and Outcome in Patients With Metastatic Castration-Resistant Prostate Cancer Treated With First-Line Docetaxel

Background

Neutropenia is a common side effect associated with docetaxel use. We retrospectively investigated the association between chemotherapy-induced neutropenia and survival in metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line docetaxel.

First-Line Treatment of Patients with Metastatic Colorectal Cancer: An Overview of Recent Data on Chemotherapy plus Targeted Agents

Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Advances in therapies over the past decade have led to improved outcomes for many patients. In addition to cytotoxic chemotherapy, advances in our understanding of tumor biology have led to the development of agents targeted against molecular pathways. The addition of these so-called targeted agents has been shown to add further to the activity of chemotherapy combinations and, in some cases, to offer modest survival advantages. However, these agents are not without substantial potential for toxicity. This review will discuss the available therapies and the data to justify the appropriate use and nonuse of targeted therapies in patients with metastatic CRC.     

Effectiveness of Cetuximab as First-Line Therapy for Patients With Wild-Type KRAS and Unresectable Metastatic Colorectal Cancer in Real-Life Practice: Results of the EREBUS Cohort

Introduction

Few real-life data are available on cetuximab benefit. The EREBUS cohort was performed to assess metastases resection rate, use, safety, and survival outcomes in wild-type KRAS (Kirsten rat sarcoma viral oncogene) patients with initially unresectable metastatic colorectal cancer (mCRC) treated by cetuximab in real practice.

Plasma Dynamics of RAS/RAF Mutations in Patients With Metastatic Colorectal Cancer Receiving Chemotherapy and Anti-EGFR Treatment

Background

RAS and RAF mutations in colorectal cancer (CRC) hold value in precision medicine. Liquid biopsy is an alternative to tumor tissue biopsy, and circulating tumor DNA (ctDNA) has been intensively investigated, but the clinical relevance of RAS and RAF mutations in plasma is yet to be determined. This study aimed to investigate the clinical aspects of RAS/RAF mutations during combination treatment.

Haematologic Parameters in Metastatic Colorectal Cancer Patients Treated with Capecitabine Combination Therapy

Background: The standard treatment in the metastatic colorectal cancer consists of 5-FU based infusionalregimens. However, with oral fluoropyrimidines, equal tumor responses may be obtained. Capecitabine causesmacrocytosis of the cells by inhibition of DNA synthesis. In this context, a relationship was found between meancorpuscular volume (MCV) and response to therapy in breast cancer patients treated with Capecitabine, butwhether this relationship also pertains in colorectal cancer has not been established. Materials and Methods: Atotal of 102 metastatic colorectal cancer patients treated with a oxaliplatin (XELOX)±Bevacizumab combinationwere retrospectively evaluated. Patients were randomized into three groups. Hematological parameters (MCV,MPV, PCT, PLT, NLR) were recorded retrospectively, before treatment and after 3 cycles of chemotherapy.Results: After three cycles of therapy, 20 (19.6%) patients had progressive disease (PD), 41 (40.1%) hadstable disease (SD), and 41 (40.1%) demonstrated a partial response (PR). In 62 (60.7%) treatment was withcapesitabin plus XELOX therapy, and in 40 (39.2%) it was XELOX-Bevacizumab combination therapy. Therewas no difference among three groups before the treatment in terms of MCV, MPV, PCT, PLT, and NLR.MCV showed significant increase in chemotherapy response groups (PR and SD). In addition, a significantdecrease was observed for platelet count in chemotherapy response groups. While NLR decrease was seen inonly a PR group, PCT decrease was observed in all three groups. PCT and PLT values were higher in patientsreceiving Bevacizumab. Conclusions: PLT, PCT, MPV, and NLR values were decreased due to Capecitabinebasedchemotherapy, however MCV was increased. PCT and PLT values were higher in patients who receivedBevacizumab than those who did not. MCV, PLT, and NLR can be considered as important factors in predictingresponse to colorectal carcinoma treatment.     

The Evolving Role of Monoclonal Antibodies in Colorectal Cancer: Early Presumptions and Impact on Clinical Trial Development

Targeted biologic agents have an established role in treating metastatic colorectal cancer (mCRC). Bevacizumab, a recombinant monoclonal antibody against the vascular endothelial growth factor ligand is approved by the U.S. Food and Drug Administration (FDA) for bevacizumab‐naïve patients. Cetuximab, a chimeric monoclonal antibody (mAb) against the epidermal growth factor receptor (EGFR) is FDA approved as a single agent, or in combination with irinotecan, in both irinotecan‐naïve and refractory patients, and has additional efficacy in combination with oxaliplatin. Panitumumab, a fully human EGFR mAb, is FDA approved as a single agent in refractory patients but has additional efficacy in combination with chemotherapy. After reaching a temporary therapeutic plateau of FDA‐approved agents for the treatment of mCRC, pivotal results have developed that critically affect the care for these patients. Correlative data from randomized trials of EGFR inhibitors across disease settings have demonstrated higher response rates, specifically for patients with wild‐type K‐RAS tumors. The interpretation of the B‐RAF mutation and other molecular markers may further define the appropriateness of anti‐EGFR therapy. Recent literature revealed that the first‐line use of combined anti‐EGFR therapy plus bevacizumab resulted in inferior outcomes and additional toxicities. Furthermore, the role of biologic agents for locally advanced colon cancer cannot be advocated at this time. With impending changes in the health care system, the economic impact of mAbs will continue to be scrutinized. Hence, as the significance of molecular markers continues to develop, their role as it pertains to the appropriate use of biologic agents in the treatment of mCRC will continue to evolve.     

Impact of Radioimmunoscintigraphy on the Management of Colorectal and Ovarian Cancer Patients: A Retrospective Study

Noninvasive differentiation of benign from malignant disease has emerged as an important diagnostic challenge in the current age of health-care cost containment. Most physicians today acknowledge that early and accurate detection of cancer is important in successful treatment. Antibodies have been developed, labeled with radioactive isotopes, and used to detect and treat malignant tumors. During the past few years, several radiolabeled antibodies have received approval from the U.S. Food and Drug Administration for imaging colorectal, lung, ovarian, and prostate carcinomas, thus expanding and improving the physician's ability to detect and follow cancer in patients. At present, there is ample evidence in the literature to suggest that imaging with the ^IIIIn-labeled monoclonal antibody B72.3 is clinically useful for detecting primary/recurrent colorectal and recurrent ovarian carcinomas. In this article, we present a retrospective review of 136 patients from 10 moderate-sized hospitals who underwent a study with radioimmunoscintigraphy (R1S), using the ^IIIIn B72.3 antibody and standard diagnostic examinations for the detection of recurrent colorectal or ovarian carcinoma. The resulting data were analyzed in an effort to determine if (and how) information obtained from this radioimmunoscinti-graphic procedure is being used by referring physicians. Our findings suggest a gradually increasing use of scan findings with the ^IIIIn B72.3 antibody in making patient-management decisions.     

Results of a Phase II Trial of Cetuximab plus Capecitabine/Irinotecan as First-Line Therapy for Patients with Advanced and/or Metastatic Colorectal Cancer

BackgroundXELIRI (capecitabine/irinotecan) is effective and well tolerated in metastatic colorectal cancer (mCRC). Cetuximab is active in mCRC alone or with chemotherapy. This study evaluated cetuximab plus XELIRI in first-line treatment of mCRC.Patients and MethodsSubjects had histologically confirmed unresectable colorectal adenocarcinoma (with T4 lesions) after preoperative chemoradiation and/or metastases. Treatment was capecitabine 1700 mg/m² (850 mg/m² orally twice a day on days 1-14 for 3 weeks), irinotecan 200 mg/m² intravenously (I.V.) on day 1 every 3 weeks, and weekly cetuximab (initially 400 mg/m² I.V. [120 minutes], subsequently 250 mg/m² [30 minutes]).ResultsBaseline characteristics (N = 70): 43 men (61%); median age, 61.5 years; Eastern Cooperative Oncology Group performance status 0/1 = 66%/34%; 94% adenocarcinoma. Previous therapy: surgery (91%), chemotherapy (14%), or radiation therapy (7%). Responses (patients completing ≥ 2 cycles): complete response (5.7%), partial response (37.7%), stable disease (43.4%), and progressive disease (PD; 13.2%); 16 patients discontinued early (n = 4 allergic reaction, n = 2 withdrew consent, n = 2 death, and n = 8 other adverse events [AEs]). The overall per-protocol response rate was 43.4% (34% intent to treat [ITT]; disease control rate, 86.8%; 69% ITT). The median time to progression was 8.1 months (range, < 1-27.0 months), and the median time to response was 1.6 months (range, 1.1-8.4 months). The median survival was 20.5 months, and 45.7% of patients remain alive. Of the 38 deaths, 84% were because of PD. No death was treatment related. The most frequent grade 3/4 treatment-related AEs included diarrhea, neutropenia, and nausea/vomiting; 32% of patients required dose reductions. All patients are off the study primarily because of PD (34.3%) or AEs (40.0%).ConclusionIn summary, XELIRI plus cetuximab is a promising regimen that merits further study for first-line mCRC.