Synchronous liver metastases in patients with rectal cancer:can we establish which treatment first?

Colorectal cancer (CRC) affects nearly 1.4 million new patients each year worldwide.1 The treatment algorithm for local or locally advanced colon and rectal cancer (RC), and also for patients with never-resectable metastases, is well established.2–4 However, the optimal strategy in patients with synchronous metastasis is more controversial and, especially in patients with RC, several modalities must be combined to achieve the most favorable outcome. Before the introduction of total mesorectal excision (TME) a local recurrence was frequently seen in 30–40% of patients with locally advanced RC.5 Neoadjuvant long-course chemo-radiation (LC-CRT) or short-course radiotherapy (SC-RT) followed by appropriate TME has reduced local recurrence (LR) rates to 5% or even less as shown not only in randomized trial with selected patients but also in population cohorts.6,7 However, the role and timing of neoadjuvant radiation is less well defined in patients presenting with synchronous metastasis. Randomized studies have focused on one treatment modality (e.g. preoperative LC-CRT or SC-RT in patients with resectable RC or chemotherapy in the setting of widespread nonresectable metastatic disease) but the sequence of different modalities (surgery, chemotherapy, and radiation) has not been studied in a randomized strategy trial. Based on lack of consensus regarding the optimal sequence of surgery, systemic therapy and radiotherapy for patients with stage 4 RC treated with curative intent, a ‘multidisciplinary session: synchronous liver metastases in RC: which treatment first?’ was organized by the European Society for Medical Oncology (ESMO) and presented during the ESMO 2017 conference in Madrid, Spain. Three distinct lectures focused on the radiation therapy perspective, the surgical oncology perspective, and the medical oncology perspective. The present paper is a summary of those three lectures with focus on a multidisciplinary approach and with an update on recent literature

Biweekly cetuximab and irinotecan as second-line therapy in patients with gastro-esophageal cancer previously treated with platinum

BACKGROUND: Until recently there has been no proven second-line therapy for patients with advanced gastro-esophageal cancer (GEC). Since 2004, Denmark has had a national health program where non-proven therapy can be offered to patients with advanced cancer, after approval by an expert panel appointed by the National Board of Health. This program has accelerated the introduction and implementation of new therapies in Denmark. Inspired by therapy in metastatic colorectal cancer, a combination of cetuximab and irinotecan (Cetiri) was chosen for second-line therapy in GEC patients. We report our experience with Cetiri as second-line therapy in patients with GEC. METHODS: All patients had histologically confirmed GEC and all patients had progressive disease during or after first-line platinum-containing chemotherapy. The patients received cetuximab 500 mg/m(2) on day 1 and irinotecan 180 mg/m(2) on day 1 every 2nd week until progression or unacceptable toxicity. Toxicity was prospectively evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. RESULTS: From December 2007 to February 2009, 50 consecutive patients received Cetiri as second-line therapy. Median performance status (PS) was 1. The median number of courses was seven. Seven patients (14%) had a partial response. Median progression-free survival (PFS) was 3.3 months and overall survival (OS) was 5.5 months; two patients are still alive without progressive disease. Major toxicities were: diarrhea (8%), fatigue (10%), neutropenia (16%), and febrile neutropenia (2%). CONCLUSION: Cetiri every two weeks is a convenient and well-tolerated second-line regimen in GEC patients. A promising effect was seen in patients with PS 0-1 and in patients who developed a rash

<i>mi</i>R-625-3<i>p</i> regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells

Oxaliplatin resistance in colorectal cancers (CRC) is a major medical problem, and predictive markers are urgently needed. Recently, miR-625-3p was reported as a promising predictive marker. Herein, we show that miR-625-3p functionally induces oxaliplatin resistance in CRC cells, and identify the signalling networks affected by miR-625-3p. We show that the p38 MAPK activator MAP2K6 is a direct target of miR-625-3p, and, accordingly, is downregulated in non-responder patients of oxaliplatin therapy. miR-625-3p-mediated resistance is reversed by anti-miR-625-3p treatment and ectopic expression of a miR-625-3p insensitive MAP2K6 variant. In addition, reduction of p38 signalling by using siRNAs, chemical inhibitors or expression of a dominant-negative MAP2K6 protein induces resistance to oxaliplatin. Transcriptome, proteome and phosphoproteome profiles confirm inactivation of MAP2K6-p38 signalling as one likely mechanism of oxaliplatin resistance. Our study shows that miR-625-3p induces oxaliplatin resistance by abrogating MAP2K6-p38-regulated apoptosis and cell cycle control networks, and corroborates the predictive power of miR-625-3p

Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance

Current standard treatments for metastatic colorectal cancer (CRC) are based on combination regimens with one of the two chemotherapeutic drugs, irinotecan or oxaliplatin. However, drug resistance frequently limits the clinical efficacy of these therapies. In order to gain new insights into mechanisms associated with chemoresistance, and departing from three distinct CRC cell models, we generated a panel of human colorectal cancer cell lines with acquired resistance to either oxaliplatin or irinotecan. We characterized the resistant cell line variants with regards to their drug resistance profile and transcriptome, and matched our results with datasets generated from relevant clinical material to derive putative resistance biomarkers. We found that the chemoresistant cell line variants had distinctive irinotecan- or oxaliplatin-specific resistance profiles, with non-reciprocal cross-resistance. Furthermore, we could identify several new, as well as some previously described, drug resistance-associated genes for each resistant cell line variant. Each chemoresistant cell line variant acquired a unique set of changes that may represent distinct functional subtypes of chemotherapy resistance. In addition, and given the potential implications for selection of subsequent treatment, we also performed an exploratory analysis, in relevant patient cohorts, of the predictive value of each of the specific genes identified in our cellular models