FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study.

PURPOSE: In metastatic colorectal cancer, phase III studies have demonstrated the superiority of fluorouracil (FU) with leucovorin (LV) in combination with irinotecan or oxaliplatin over FU + LV alone. This phase III study investigated two sequences: folinic acid, FU, and irinotecan (FOLFIRI) followed by folinic acid, FU, and oxaliplatin (FOLFOX6; arm A), and FOLFOX6 followed by FOLFIRI (arm B). PATIENTS AND METHODS: Previously untreated patients with assessable disease were randomly assigned to receive a 2-hour infusion of l-LV 200 mg/m2 or dl-LV 400 mg/m2 followed by a FU bolus 400 mg/m2 and 46-hour infusion 2,400 to 3,000 mg/m2 every 46 hours every 2 weeks, either with irinotecan 180 mg/m2 or with oxaliplatin 100 mg/m2 as a 2-hour infusion on day 1. At progression, irinotecan was replaced by oxaliplatin (arm A), or oxaliplatin by irinotecan (arm B). RESULTS: Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI (P = .99). Median second progression-free survival (PFS) was 14.2 months in arm A versus 10.9 in arm B (P = .64). In first-line therapy, FOLFIRI achieved 56% response rate (RR) and 8.5 months median PFS, versus FOLFOX6 which achieved 54% RR and 8.0 months median PFS (P = .26). Second-line FOLFIRI achieved 4% RR and 2.5 months median PFS, versus FOLFOX6 which achieved 15% RR and 4.2 months PFS. In first-line therapy, National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis, nausea/vomiting, and grade 2 alopecia were more frequent with FOLFIRI, and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6. CONCLUSION: Both sequences achieved a prolonged survival and similar efficacy. The toxicity profiles were different.

Gastrointestinal tumors in transplantation: Two case reports and review of literature.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. As most of them harbor a KIT mutation (75%), selective kinase inhibitors are the therapeutic option and show a sustained objective response among patients with metastatic or unresectable GISTs. A well-known higher risk of neoplasm has been described among renal transplant recipients (RTRs). Nevertheless, only few cases of GIST onset among transplant patients have been reported in the literature. CASE SUMMARY: Here, we describe 2 cases of gastric GIST occurring during the follow-up of RTRs. We also review the existing literature concerning GIST occurrence in transplant patients. In total and in association with our 2 cases, 16 patients have been reported. The median age was 59.5 years and 69% were male. With a median tumor size of 45 mm, no patient displayed metastatic dissemination at diagnosis. Time from transplantation to diagnosis was highly variable between 5 mo and 21 years. Histopathological data mostly revealed high risk of progression (43%). Death increased to 29% during follow-up. Surgical treatment was systematically performed when the tumor was operable (94%). The use of adjuvant therapy was uncommon (19%). CONCLUSION: GISTs represent rare but potentially severe malignant complication among transplant patients.

Circulating tumor DNA is a prognostic marker of tumor recurrence in stage II and III colorectal cancer: multicentric, prospective cohort study (ALGECOLS).

BACKGROUND: In non-metastatic colorectal cancer (CRC), we evaluated prospectively the pertinence of longitudinal detection and quantification of circulating tumor DNA (ctDNA) as a prognostic marker of recurrence. METHOD: The presence of ctDNA was assessed from plasma collected before and after surgery for 184 patients classified as stage II or III and at each visit during 3-4 years of follow-up. The ctDNA analysis was performed by droplet-based digital polymerase chain reaction, targeting mutation and methylation markers, blindly from the clinical outcomes. Multivariate analyses were adjusted on age, gender, stage, and adjuvant chemotherapy. RESULTS: Before surgery, 27.5% of patients were positive for ctDNA detection. The rate of recurrence was 32.7% and 11.6% in patients with or without detectable ctDNA respectively (P = 0.001). Time to recurrence (TTR) was significantly shorter in patients with detectable ctDNA before (adjusted hazard ratio [HR] = 3.58, 95% confidence interval [CI] 1.71-7.47) or immediately after surgery (adjusted HR = 3.22, 95% CI 1.32-7.89). The TTR was significantly shorter in patients with detectable ctDNA during the early postoperative follow-up (1-6 months) (adjusted HR = 5, 95% CI 1.9-12.9). Beyond this period, ctDNA remained a prognostic marker with a median anticipated diagnosis of recurrence of 13.1 weeks (interquartile range 28 weeks) when compared to imaging follow-up. The rate of ctDNA+ might be underestimated knowing that consensus pre-analytical conditions were not described at initiation of the study. CONCLUSION: This prospective study confirms the relevance of ctDNA as a recurrence risk factor in stage II and III CRC before surgery and as a marker of minimal residual disease after surgery that may predict recurrence several months before imaging techniques.

Chemotherapy use in end-of-life digestive cancer patients: a retrospective AGEO observational study.

BACKGROUND: The use of chemotherapy (CT) near the end-of-life (EOL) is an important issue in oncology since it could degrade quality of life. CT near EOL is still poorly studied, with no dedicated study in gastrointestinal (GI) cancer patients. AIM: To analyze in GI cancer patients the factors associated with the use of CT within 3- and 1-month before patients' death. METHODS AND PARTICIPANTS: All consecutive patients who died from a GI cancer in 10 French tertiary care hospitals during 2014 were included in this retrospective study. Clinical, demographical and biological data were collected and compared between patients receiving or not CT within 3- and 1-month before death. Variables associated with overall survival (OS) was also determined using of univariate and multivariate analyses with a Cox model. RESULTS: Four hundred and thirty-seven patients with a metastatic GI cancer were included in this study. Among them, 293 pts (67.0%) received CT within 3-months before death, and 121 pts (27.7%) received CT within 1-month before death. Patients receiving CT within 3-months before death were significantly younger (median age: 65.5 vs 72.8 years, p < 0.0001), with a better PS (PS 0 or 1: 53.9 vs 29.3%, p < 0.0001) and a higher albumin level (median: 32.8 vs 31.0 g/L, p = 0.048). Similar results were found for CT within 1 month before death. Palliative care team intervention was less frequent in patients who received CT in their last month of life (39.7% vs 51.3%, p = 0.02). In multivariate analysis, median OS from diagnosis was shorter in the group receiving CT within 1-month before death (HR = 0.59; 95% CI [0.48-0.74]). CONCLUSION: In GI-cancer patients, CT is administered within 3- and 1-month before death, in two and one third of patients, respectively. Patients receiving CT within 1-month before death, had more aggressive disease with poor OS. Palliative care team intervention was associated with less administration of CT in the last month of life. These results highlight the need to better anticipate the time to stop CT treatment in the end-of-life and the importance of an active collaboration between oncology and palliative care teams.

Reasons for chemotherapy discontinuation and end-of-life in patients with gastrointestinal cancer: A multicenter prospective AGEO study.

BACKGROUND: Previous research on chemotherapy discontinuation has mainly focused on predictive factors and outcomes. Few data are available on the reasons for chemotherapy discontinuation. The main objective was to identify the reasons for chemotherapy discontinuation in patients with gastrointestinal cancer. The secondary objectives were to describe the announcement of chemotherapy discontinuation and the time between chemotherapy discontinuation and death. METHODS: This prospective multicenter French cohort included patients with advanced gastrointestinal cancer, for whom chemotherapy was discontinued between May 2016 and January 2018. RESULTS: One hundred and fourteen patients were analyzed. The first cause of chemotherapy discontinuation was the impairment of general condition (asthenia, cachexia). Complications such as sepsis, jaundice or occlusion, were the second most frequent cause. Progression was observed at chemotherapy discontinuation in two-thirds of cases. The announcement of the chemotherapy discontinuation was made formally in 74% of cases, with a follow-up by a palliative care team initiated in 50% of cases. Sixty-nine percent of the patients received chemotherapy during the last three months of life and 26% during the last month. The median time between chemotherapy discontinuation and death was 65 days (IQR: 36.5-109): 44% of patients died at the hospital, 39% in a palliative care unit and 16% at home. CONCLUSION: Impairment of general condition was the major reason for chemotherapy discontinuation in patients with gastrointestinal cancers. Complications such as jaundice, sepsis or occlusion, were important reasons for discontinuation and could explain our shorter time between chemotherapy discontinuation and death, compared to other oncology sub-specialties.

Integration of elicited expert information via a power prior in Bayesian variable selection: Application to colon cancer data.

BACKGROUND: Building tools to support personalized medicine needs to model medical decision-making. For this purpose, both expert and real world data provide a rich source of information. Currently, machine learning techniques are developing to select relevant variables for decision-making. Rather than using data-driven analysis alone, eliciting prior information from physicians related to their medical decision-making processes can be useful in variable selection. Our framework is electronic health records data on repeated dose adjustment of Irinotecan for the treatment of metastatic colorectal cancer. We propose a method that incorporates elicited expert weights associated with variables involved in dose reduction decisions into the Stochastic Search Variable Selection (SSVS), a Bayesian variable selection method, by using a power prior. METHODS: Clinician experts were first asked to provide numerical clinical relevance weights to express their beliefs about the importance of each variable in their medical decision making. Then, we modeled the link between repeated dose reduction, patient characteristics, and toxicities by assuming a logistic mixed-effects model. Simulated data were generated based on the elicited weights and combined with the observed dose reduction data via a power prior. We compared the Bayesian power prior-based SSVS performance to the usual SSVS in our case study, including a sensitivity analysis using the power prior parameter. RESULTS: The selected variables differ when using only expert knowledge, only the usual SSVS, or combining both. Our method enables one to select rare variables that may be missed using only the observed data and to discard variables that appear to be relevant based on the data but not relevant from the expert perspective. CONCLUSION: We introduce an innovative Bayesian variable selection method that adaptively combines elicited expert information and real world data. The method selects a set of variables relevant to model medical decision process.

Gastrointestinal stromal tumours (GISTs): French Intergroup Clinical Practice Guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO).

BACKGROUND: This document is a summary of the French Intergroup guidelines regarding the management of gastrointestinal stromal tumours (GISTs) updated in December 2018. DESIGN: This collaborative work summarizes clinical practice recommendations (guidelines) on the management of GISTs. It is based on recent literature review, ESMO recommendations and expert opinions. RESULTS: The diagnosis of GIST is based on histological examination and immunohistochemistry with markers KIT and DOG-1. Each case must be discussed within a multidisciplinary team. Complete surgical resection tumour, avoiding peroperative perforation, is the potentially curative treatment of localized GISTs. The estimation of the recurrence risk is essential, or adjuvant treatment,and follow-up adaptation. Genotyping (KIT and PDGFRA) of all but very low-risk GISTs is recommended. The nature of mutation has a prognostic value and predictive influence on drug efficacy. Imatinib, a tyrosine-kinase inhibitor, is the standard adjuvant treatment after R0 resection of a GIST with a high risk of recurrence, and the first line therapy for advanced GISTs. Suninitib and regorafenib are respectively the second- and third-line standard treatments for advanced GISTs. CONCLUSION: Guidelines for management of GISTs are continuously evolving and need to be regularly updated. This constant progress is made possible through clinical and translational research.

Pharmaceutical interventions to improve safety of chemotherapy-treated cancer patients: A cross-sectional study.

PURPOSE: Cancer chemotherapy is a high-risk process. To improve patient safety, a systematic pharmaceutical analysis of chemotherapy prescriptions is performed in our institution. The aim of this study was to assess the impact of pharmaceutical interventions (PIs) on the safety of patient chemotherapy prescriptions. METHODS: This prospective cross-sectional study was conducted in an 800-bed university hospital with oncology departments. All chemotherapy prescriptions were included and PIs were collected prospectively during one month. The clinical impact of PIs was scored by an expert panel of oncologists and pharmacists, using the Hatoum scale. Univariate and multivariate analysis were conducted to identify factors associated with a higher frequency of PIs. RESULTS: Of 1346 prescriptions included, 129 required a PI (9.6% (95% CI: 8.1-11.4)). Most PIs were scored as having at least a significant impact for patient safety (69.8% (95% CI: 60.4-76.9)). The frequency of PIs was significantly associated with tumour site (p = 0.04) and weekday of prescription (p = 0.005). Multivariate analysis identified factors independently associated with PI performance, including pancreas and biliary tract cancers (odds ratio = 2.8 (95% CI: 1.4-5.3)), ovary cancers (odds ratio = 2.4 (95% CI: 1.2-4.8)) and head and neck cancers (odds ratio = 2.4 (95% CI: 1.1-5.1)) and the day 1 of the protocol with a cytotoxic agent (odds ratio = 3.7 (95% CI: 1.1-11.1)). CONCLUSIONS: Oncology pharmacists have a critical role in the safety of chemotherapy prescriptions. The coordination between healthcare professionals and access to patient data seem essential to improve the PIs' relevance and their clinical impact on patient safety.

5-FU or mitomycin C hepatic arterial infusion after failure of arterial oxaliplatin in patients with colorectal cancer unresectable liver metastases.

INTRODUCTION: Hepatic arterial infusion (HAI) chemotherapy with oxaliplatin is an accepted option in the management of colorectal cancer (CRC) with dominant liver metastases (LM). However, despite prolonged control, some patients experience disease progression. On the other hand, oxaliplatin leads to dose-limiting toxicity. In these cases, the use of a second-line HAI with an alternative drug has never been reported to date. We evaluated treatment outcomes in patients receiving second-line HAI with 5-FU or mitomycin C, after first-line HAI of oxaliplatin in heavily pretreated patients. MATERIAL AND METHODS: Between March 2010 and June 2016, this observational study included 24 patients with unresectable CRC LM and treated with HAI of 5-FU (17 patients) or mitomycin C (7 patients), after HAI of oxaliplatin. RESULTS: Mean age was 61.7 years. Forty-two percent of patients (10/24) had extra-hepatic metastases and 75% (18/24) at least 8 liver metastases. Including HAI of oxaliplatin, all patients had previously received at least 2 lines of chemotherapy±targeted agents (100%) and 96% (23/24) received concomitant systemic therapies together with HAI of 5-FU or mitomycin C. The overall objective response rate and disease control rate were, respectively, 42% (10/24) and 71% (17/24). Median progression-free survival and overall survival (OS) were, respectively, 5.6 and 25.8 months; hepatic progression-free survival was 8.5months. Thirteen percent (3/24) of the patients received further curative intent treatment after HAI 5-FU and mitomycin C. No toxic death occurred and the toxicity profile was acceptable. CONCLUSIONS: HAI of 5-FU or mitomycin C is an alternative option in patients with predominant CRC LM, when they experience disease progression or do not tolerate HAI of oxaliplatin.

NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients.

Despite effective targeted therapy acting on KIT and PDGFRA tyrosine kinases, gastrointestinal stromal tumors (GIST) escape treatment by acquiring mutations conveying resistance to imatinib mesylate (IM). Following the identification of NKp30-based immunosurveillance of GIST and the off-target effects of IM on NK cell functions, we investigated the predictive value of NKp30 isoforms and NKp30 soluble ligands in blood for the clinical response to IM. The relative expression and the proportions of NKp30 isoforms markedly impacted both event-free and overall survival, in two independent cohorts of metastatic GIST. Phenotypes based on disbalanced NKp30B/NKp30C ratio (ΔBClow) and low expression levels of NKp30A were identified in one third of patients with dismal prognosis across molecular subtypes. This ΔBClow blood phenotype was associated with a pro-inflammatory and immunosuppressive tumor microenvironment. In addition, detectable levels of the NKp30 ligand sB7-H6 predicted a worse prognosis in metastatic GIST. Soluble BAG6, an alternate ligand for NKp30 was associated with low NKp30 transcription and had additional predictive value in GIST patients with high NKp30 expression. Such GIST microenvironments could be rescued by therapy based on rIFN-α and anti-TRAIL mAb which reinstated innate immunity.

Advances in management of adjuvant chemotherapy in rectal cancer: Consequences for clinical practice.

More than half the patients with rectal cancer present with locally advanced rectal disease at diagnosis with a high risk of recurrence. Preoperative chemoradiotherapy and standardized radical surgery with total mesorectal excision have been established as the 'gold standard' for treating these patients. Pathological staging using the ypTNM classification system to decide on adjuvant chemotherapy (ACT) is widely used in clinical practice, but the delivery of ACT is still controversial, as many discrepancies persist in the conclusions of different trials, due to heterogeneity of the inclusion criteria between studies, lack of statistical power, and variations in preoperative and adjuvant regimens. In 2014, a meta-analysis of four randomized phase-III trials (EORTC 22921, I-CNR-RT, PROCTOR-SCRIPT, CHRONICLE) failed to demonstrate any statistical efficacy of fluorouracil (5FU)-based ACT. Three recent randomized trials aimed to compare 5FU with 5FU plus oxaliplatin-based chemotherapy. Two of them (ADORE, CAO/ARO/AIO-04) appeared to find a disease-free survival benefit for patients treated with the combination therapy. Thus, while awaiting new data, it can be said that, as of 2015, patients with yp stage I tumors or histological complete response derived no benefit from adjuvant therapy. On the other hand, the FOLFOX chemotherapy regimen should be proposed for yp stage III patients, and may be considered for yp stage II tumors in fit patients with high-risk factors. Nevertheless, well-designed and sufficiently powered clinical trials dedicated to adjuvant treatments for rectal cancer remain justified in future to achieve a high level of proof in keeping with evidence-based medical standards.

Prognostic value of health-related quality of life in patients with metastatic pancreatic adenocarcinoma: a random forest methodology.

PURPOSE: Eastern Cooperative Oncology Group Performance Status (ECOG-PS) is currently an important parameter in the choice of treatment strategy for metastatic pancreatic adenocarcinoma (mPA) patients. However, previous research has shown that patients' self-reported health-related quality of life (HRQOL) scales provided additional prognostic information in homogeneous groups of patients with respect to ECOG-PS. The aim of this study was to identify HRQOL scales with independent prognostic value in mPA and to propose prognostic groups for these patients. METHODS: We analysed data from 98 chemotherapy-naive patients with histologically proven mPA recruited from 2007 to 2011 in the FIRGEM phase II study which aimed to compare the effectiveness of two chemotherapy regimen. HRQOL data were assessed with the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. A random survival forest methodology was used to impute missing data and to identify major prognostic factors for overall survival. RESULTS: Baseline HRQOL assessment was completed by 60 % of patients (59/98). Twelve prognostic variables were identified. The three most important prognostic variables were fatigue, appetite loss, and role functioning, followed by three laboratory variables. The model's discriminative power assessed by Harrell's C statistic was 0.65. Fatigue score explained almost all the survival variability. CONCLUSION: HRQOL scores have prognostic value for mPA patients with good ECOG-PS. Moreover, the patient's fatigue, appetite loss, and self-perception of daily activities were more reliable prognostic indicators than clinical and laboratory variables. These HRQOL scores, especially the fatigue symptom, should be urgently included for prognostic assessment of mPA patients (with good ECOG-PS).

Safety and efficacy of palliative systemic chemotherapy combined with colorectal self-expandable metallic stents in advanced colorectal cancer: A multicenter study.

PURPOSE: Self-expandable metallic stent (SEMS) placement is an accepted palliative therapy for management of acute malignant bowel obstruction in advanced colorectal cancer. Nevertheless, data are lacking on the effects of systemic chemotherapy combined with colorectal SEMS. The aim of this study was to investigate the safety and efficacy of palliative chemotherapy for advanced colorectal cancer combined with colorectal SEMS placement. PATIENTS AND METHODS: This multicentre retrospective study included all consecutive advanced colorectal cancer patients who received first-line palliative chemotherapy combined with endoscopic stenting for colorectal cancer with obstruction. We analyzed the number of cycles and the type of combination used. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, response rate, grade 3-4 toxicity and the outcomes of SEMS for malignant colorectal obstruction. RESULTS: A total of 38 patients were included. Among them, 25 patients received oxaliplatin and 5-fluorouracil combination chemotherapy. Objective response and stabilization occurred in 38 and 24% of patients, respectively. The median overall survival and progression-free survival from the start of chemotherapy were 18 and 5months, respectively. The objective response rate and overall disease control rate were 38 and 62%, respectively. Toxicity was generally acceptable. Major complications related to stenting included perforation (8%), stent migration (5%), and reobstruction secondary to tumor ingrowths (13%). CONCLUSIONS: Chemotherapy combined with colonic stenting as a first-line treatment seems to be a valid option in advanced colorectal cancer patients with malignant colorectal obstruction.

Clinical relevance of KRAS-mutated subclones detected with picodroplet digital PCR in advanced colorectal cancer treated with anti-EGFR therapy.

PURPOSE: KRAS mutations are predictive of nonresponse to anti-EGFR therapies in metastatic colorectal cancer (mCRC). However, only 50% of nonmutated patients benefit from them. KRAS-mutated subclonal populations nondetectable by conventional methods have been suggested as the cause of early progression. Molecular analysis technology with high sensitivity and precision is required to test this hypothesis. EXPERIMENTAL DESIGN: From two cohorts of patients with mCRC, 136 KRAS, NRAS, and BRAF wild-type tumors with sufficient tumor material to perform highly sensitive picodroplet digital PCR (dPCR) and 41 KRAS-mutated tumors were selected. All these patients were treated by anti-EGFR therapy. dPCR was used for KRAS or BRAF mutation screening and compared with qPCR. Progression-free survival (PFS) and overall survival (OS) were analyzed according to the KRAS-mutated allele fraction. RESULTS: In addition to the confirmation of the 41 patients with KRAS-mutated tumors, dPCR also identified KRAS mutations in 22 samples considered as KRAS wild-type by qPCR. The fraction of KRAS-mutated allele quantified by dPCR was inversely correlated with anti-EGFR therapy response rate (P < 0.001). In a Cox model, the fraction of KRAS-mutated allele was associated with worse PFS and OS. Patients with less than 1% of mutant KRAS allele have similar PFS and OS than those with wild-type KRAS tumors. CONCLUSIONS: This study suggests that patients with mCRC with KRAS-mutated subclones (at least those with a KRAS-mutated subclones fraction lower or equal to 1%) had a benefit from anti-EGFR therapies.

Fixed-dose rate gemcitabine alone or alternating with FOLFIRI.3 (irinotecan, leucovorin and fluorouracil) in the first-line treatment of patients with metastatic pancreatic adenocarcinoma: an AGEO randomised phase II study (FIRGEM).

BACKGROUND: Fluorouracil and irinotecan-based, and gemcitabine-based regimens, are the standard of care in the first-line treatment of patients with metastatic pancreatic cancer. New approaches are needed to improve survival and quality of life. Whether a sequential approach alternating irinotecan, fluorouracil and gemcitabine may be effective and tolerable in patients with metastatic pancreatic cancer is unknown. METHODS: In this randomised, multicentre, open-label, phase 2 trial, patients with metastatic pancreatic adenocarcinoma, World Health Organisation (WHO) performance status 0-1, and bilirubin levels <1.5 upper limit of normal values (ULN) were randomised 1:1 to receive as first-line treatment either FOLFIRI.3 (irinotecan, leucovorin and fluorouracil) alternating with fixed-dose rate gemcitabine as 2-month periods (FIRGEM, arm A), or fixed-dose rate gemcitabine alone (arm B). Treatment was continued until disease progression or limiting toxicity. The primary end-point was the crude progression-free survival (PFS) rate at 6 months. The study is registered with EudraCT (N° 2006-005703-34). RESULTS: Between October 2007 and March 2011, 98 patients were enroled. The observed 6-month PFS rate was 43.5% (95% confidence interval (CI), [28.6-58.4%]) in arm A reaching the Fleming decision rules criteria to reject H0 and 26.1% (95% CI [12.9-39.3%]) in arm B. Objective response rates were 37% (23-51%) in arm A and 10% (1-19%) in arm B. Median PFS (5.0 versus 3.4 months, hazard ratio (HR)=0.59 [0.38-0.90]) and overall survival (11.0 versus 8.2 months, HR=0.71 [0.46-1.10]) were higher in arm A compared to arm B. The most frequent grade 3-4 toxicities were neutropenia (49%/24%; febrile neutropenia, 4%/0% in arms A/B), diarrhoea (arm A, 12% and arm B, 0%), and nausea/vomiting (8%/4%). No toxic deaths occurred. CONCLUSION: The FIRGEM strategy appears to be effective and feasible in patients with metastatic pancreatic cancer.

Hsa-miR-31-3p expression is linked to progression-free survival in patients with KRAS wild-type metastatic colorectal cancer treated with anti-EGFR therapy.

PURPOSE: To identify microRNAs (miRNA) that predict response to anti-EGFR antibodies in patients with wild-type KRAS metastatic colorectal cancer (mCRC). EXPERIMENTAL DESIGN: miRNA profiling was performed in a training set of 87 patients with mCRC refractory to chemotherapy treated with anti-EGFR antibodies. This included 33 fresh-frozen (FF) and 35 formalin-fixed paraffin-embedded (FFPE) samples retrospectively collected and 19 prospectively collected FF samples. An independent validation cohort consisting of 19 FF and 26 FFPE prospectively collected samples from patients with mCRC treated with anti-EGFR antibodies was used to confirm our findings. RESULTS: After screening the expression of 1,145 miRNAs in FF samples from the training set, we identified that hsa-miR-31-3p expression level was significantly associated with progression-free survival (PFS). Statistical models based on miRNA expression discriminated between high and low risk of progression for both FF and FFPE samples. These models were confirmed in the validation cohort for both FF [HR, 4.1; 95% confidence interval (CI), 1.1-15.3; P < 0.04] and FFPE samples (HR, 2.44; 95% CI, 1.1-5.4; P = 0.028). The percentage of variation of RECIST criteria in the validation series was significantly associated with the expression level of hsa-miR-31-3p (r(2) = 0.49; P = 0.0035) and risk status determined by hsa-miR-31-3p expression level (P = 0.02, Kruskal-Wallis rank test). Nomograms were built and validated to predict PFS-depending on hsa-miR-31-3p expression level. Following in vitro studies, we identified 47 genes regulated by hsa-miR-31-3p. CONCLUSION: Hsa-miR-31-3p seems to be a new mCRC biomarker whose expression level allows for the identification of patients with wild-type KRAS mCRC who are more likely to respond to anti-EGFR therapy.

Sustained response with gemcitabine plus Nab-paclitaxel after folfirinox failure in metastatic pancreatic cancer: report of an effective new strategy.

INTRODUCTION: Folfirinox has shown a benefit in terms of survival and quality of life in first line treatment of metastatic pancreatic cancer. However, efficacy of second line chemotherapy after folfirinox is still limited. Gemcitabine plus Nab-paclitaxel have been recently validated as first line treatment with an increased overall survival compared to gemcitabine. This combination has never been studied as second-line after folfirinox. CASE REPORT: A metastatic pancreatic cancer was diagnosed in a 60-year-old patient with a performance status of 0. After 10 cycles of folfirinox, and an initial objective response, we objectively noted progressive disease according to the RECIST 1.1 criteria together with an increased carbohydrate antigen 19-9. The multidisciplinary team decided to use gemcitabine plus Nab-paclitaxel as second line palliative chemotherapy. After 2 months, we obtained an objective response. After 6 months, this response was maintained with an acceptable tolerability. CONCLUSION: Gemcitabine plus Nab-paclitaxel, as second line palliative chemotherapy, after failure of folfirinox, could be a good strategy for patients with a performance status of 0 and 1. Obviously, this data has to be confirmed in larger patients series and in future comparative clinical studies.

Chemotherapy versus self-expanding metal stent as primary treatment of severe dysphagia from unresectable oesophageal or gastro-oesophageal junction cancer.

OBJECTIVE: To compare chemotherapy first (group 1) versus self-expanding metal stent first (group 2) for the management of malignant dysphagia in unresectable oesophageal or gastro-oesophageal junction cancer. METHODS: Patients from two university hospitals with severe malignant dysphagia (dysphagia score ≥ 2) uneligible for surgery or radiochemotherapy were evaluated retrospectively. RESULTS: Forty-two patients were included in group 1, and 29 in group 2. After 4 weeks, dysphagia scores improved by at least 1 point in 67% of patients in group 1 versus 93% in group 2 (p=0.01); 48% of patients in group 1 were able to eat solid food versus 68% in group 2 (p=0.054). In group 1, a self-expanding metal stent was secondarily placed in 18 patients (42.9%), whereas in group 2 dysphagia required a second self-expanding metal stent placement in 33.3% of patients. CONCLUSION: Chemotherapy as the first treatment may be a valid option, avoiding self-expanding metal stent insertion in half of the patients.

Biweekly docetaxel, fluorouracil, leucovorin, oxaliplatin (TEF) as first-line treatment for advanced gastric cancer and adenocarcinoma of the gastroesophageal junction: safety and efficacy in a multicenter cohort.

BACKGROUND: Docetaxel-cisplatin-5-FU chemotherapy is superior to 5-FU-cisplatin in terms of response rate and survival in advanced gastric cancer (AGC), but is more toxic. Oxaliplatin is better tolerated than cisplatin, which it can effectively replace in this setting. We hypothesize that incorporating docetaxel into a simplified FOLFOX regimen should be a tolerable and effective option in first-line treatment of AGC. METHODS: Data were collected at six French centers from patients with metastatic or local AGC who received docetaxel, fluorouracil, leucovorin, or oxaliplatin (TEF) as first-line treatment. TEF was administered as follows: docetaxel (50 mg/m(2)), oxaliplatin (85 mg/m(2)), and leucovorin (40 mg/m(2)) on day 1, and 5-FU continuous infusion for 48 h (2400 mg/m(2)) every 2 weeks. RESULTS: Forty-one patients were enrolled. Performance status was grade 0 and 1 in respectively 27 and 58 % of patients; 17 patients had adenocarcinoma of the gastroesophageal junction; 37 patients had metastatic disease, 22 had a poorly differentiated or diffuse type. Objective response rate was 66 %, with a complete response in two patients (5 %). Median progression-free survival and overall survival were respectively 6.3 and 12.1 months. Tolerability was acceptable with no treatment-related deaths. The most frequent grade 3-4 toxicities were neutropenia (30 %) and neuropathy (12.5 %). Curative intent surgery after response to TEF was performed in seven patients (17 %). CONCLUSION: TEF is an effective first-line treatment with an acceptable toxicity profile for patients with AGC. It may allow curative resection in initially unresectable patients. TEF should now be evaluated in prospective randomized trials.

Multiplex picodroplet digital PCR to detect KRAS mutations in circulating DNA from the plasma of colorectal cancer patients.

BACKGROUND: Multiplex digital PCR (dPCR) enables noninvasive and sensitive detection of circulating tumor DNA with performance unachievable by current molecular-detection approaches. Furthermore, picodroplet dPCR facilitates simultaneous screening for multiple mutations from the same sample. METHODS: We investigated the utility of multiplex dPCR to screen for the 7 most common mutations in codons 12 and 13 of the KRAS (Kirsten rat sarcoma viral oncogene homolog) oncogene from plasma samples of patients with metastatic colorectal cancer. Fifty plasma samples were tested from patients for whom the primary tumor biopsy tissue DNA had been characterized by quantitative PCR. RESULTS: Tumor characterization revealed that 19 patient tumors had KRAS mutations. Multiplex dPCR analysis of the plasma DNA prepared from these samples identified 14 samples that matched the mutation identified in the tumor, 1 sample contained a different KRAS mutation, and 4 samples had no detectable mutation. Among the tumor samples that were wild type for KRAS, 2 KRAS mutations were identified in the corresponding plasma samples. Duplex dPCR (i.e., wild-type and single-mutation assay) was also used to analyze plasma samples from patients with KRAS-mutated tumors and 5 samples expected to contain the BRAF (v-raf murine sarcoma viral oncogene homolog B) V600E mutation. The results for the duplex analysis matched those for the multiplex analysis for KRAS-mutated samples and, owing to its higher sensitivity, enabled detection of 2 additional samples with low levels of KRAS-mutated DNA. All 5 samples with BRAF mutations were detected. CONCLUSIONS: This work demonstrates the clinical utility of multiplex dPCR to screen for multiple mutations simultaneously with a sensitivity sufficient to detect mutations in circulating DNA obtained by noninvasive blood collection.