Michel Ducreux

ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.

Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1

How dying tumor cells get noticed Besides killing tumor cells directly, some chemotherapies, such as anthracyclines, also activate the immune system to kill tumors. Vacchelli et al. discovered that in mice, anthracycline-induced antitumor immunity requires immune cells to express the protein formyl peptide receptor 1 (FPR1). Dendritic cells (DCs) near tumors expressed especially high amounts of FPR1. DCs normally capture fragments of dying tumor cells and use them to activate nearby T cells to kill tumors, but DCs lacking FPR1 failed to do this effectively. Individuals with breast or colon cancer expressing a variant of FPR1 and treated with anthracyclines showed poor metastasis-free and overall survival. Thus, FPR1 may affect anti-tumor immunity in people, too. Science, this issue p. 972 Formyl peptide receptor 1 helps the immune system sense dying tumor cells. Antitumor immunity driven by intratumoral dendritic cells contributes to the efficacy of anthracycline-based chemotherapy in cancer. We identified a loss-of-function allele of the gene coding for formyl peptide receptor 1 (FPR1) that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy. The therapeutic effects of anthracyclines were abrogated in tumor-bearing Fpr1−/− mice due to impaired antitumor immunity. Fpr1-deficient dendritic cells failed to approach dying cancer cells and, as a result, could not elicit antitumor T cell immunity. Experiments performed in a microfluidic device confirmed that FPR1 and its ligand, annexin-1, promoted stable interactions between dying cancer cells and human or murine leukocytes. Altogether, these results highlight the importance of FPR1 in chemotherapy-induced anticancer immune responses.

Second St. Gallen European Organisation for Research and Treatment of Cancer Gastrointestinal Cancer Conference: consensus recommendations on controversial issues in the primary treatment of rectal cancer

Primary treatment of rectal cancer was the focus of the second St. Gallen European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Cancer Conference. In the context of the conference, a multidisciplinary international expert panel discussed and voted on controversial issues which could not be easily answered using published evidence. Main topics included optimal pretherapeutic imaging, indication and type of neoadjuvant treatment, and the treatment strategies in advanced tumours. Here we report the key recommendations and summarise the related evidence. The treatment strategy for localised rectal cancer varies from local excision in early tumours to neoadjuvant radiochemotherapy (RCT) in combination with extended surgery in locally advanced disease. Optimal pretherapeutic staging is a key to any treatment decision. The panel recommended magnetic resonance imaging (MRI) or MRI + endoscopic ultrasonography (EUS) as mandatory staging modalities, except for early T1 cancers with an option for local excision, where EUS in addition to MRI was considered to be most important because of its superior near-field resolution. Primary surgery with total mesorectal excision was recommended by most panellists for some early tumours with limited risk of recurrence (i.e. cT1-2 or cT3a N0 with clear mesorectal fascia on MRI and clearly above the levator muscles), whereas all other stages were considered for multimodal treatment. The consensus panel recommended long-course RCT over short-course radiotherapy for most clinical situations where neoadjuvant treatment is indicated, with the exception of T3a/b N0 tumours where short-course radiotherapy or even no neoadjuvant therapy were regarded to be an option. In patients with potentially resectable tumours and synchronous liver metastases, most panel members did not see an indication to start with classical fluoropyrimidine-based RCT but rather favoured preoperative short-course radiotherapy with systemic combination chemotherapy or alternatively a liver-first resection approach in resectable metastases, which both allow optimal systemic therapy for the metastatic disease. In general, proper patient selection and discussion in an experienced multidisciplinary team was considered as crucial component of care.

Leukocytosis and neutrophilia predicts outcome in anal cancer

OBJECTIVEnLeukocytosis and neutrophilia could be the tip of the iceberg in the inflammatory tumor microenvironment. We aimed to validate their prognostic significance in a cohort of patients treated with definitive chemoradiation for anal squamous cell carcinoma (SCC).nnnMATERIALS & METHODSnClinical records from all consecutive patients treated in a single institution between 2006 and 2016 with curative-intent radiotherapy were retrospectively analyzed. Leukocytosis and neutrophilia, defined as leukocyte or neutrophil count over 10,000 and 7500/mm3, respectively, were studied in terms of overall survival (OS), progression (PFS), locoregional (LFS) and distant (DFS)-free survival.nnnRESULTSnWe identified 103 non-metastatic HIV-negative patients, with concurrent chemotherapy use in 78%. Twelve and 8% displayed baseline leukocytosis and neutrophilia, respectively. Estimated 3-year OS and PFS were 88% and 67%, respectively. In univariate analysis, both leukocytosis and neutrophilia were strongly associated with inferior OS, PFS, LFS and DFS (p<0.01). In multivariate analysis, leukocytosis and neutrophilia remained strongly associated with patient outcome (p<0.01), independently from tumor T and N-stage. Anemia was an independent predictor of worse OS and PFS, while chemoradiation overall treatment time below 50days improved PFS.nnnCONCLUSIONnLeukocytosis and neutrophilia are strong prognostic factors for OS, PFS, LFS and DFS in anal cancer treated with chemoradiation. These biomarkers could help identify patients with higher risk of tumor relapse that require treatment intensification.

Matching genomic molecular aberrations with molecular targeted agents: Are biliary tract cancers an ideal playground?

Biliary tract cancers (BTCs) are a heterogeneous group of tumours with geographical discrepancies in terms of incidence and risk factors. However, a convergent genomic and epigenetic mutational landscape emerges from the genome-wide screens of BTCs in South East Asia, Latin America and in the Western World. Specificities are observed for some alterations and anatomical subtypes: frequent fibroblast growth factor receptor 2 (FGFR2) and isocitrate dehydrogenase 1/2 (IDH1/2) alterations are specific to intrahepatic cholangiocarcinomas (ICCs), whereas frequent ERBB2 oncogene alterations are specific to extrahepatic cholangiocarcinomas (ECCs) and gallbladder carcinomas (GBCs). Until now, the outcome of patients with BTCs treated by molecular targeted agents (MTAs) alone or in combination with conventional chemotherapy in non-biology driven trials remains poor and does not exceed the outcome of patients treated with chemotherapy alone. Encouraging reports of biology-driven therapeutic approaches should accelerate the clinical development of MTAs in BTCs. Additionally, frequent epigenetic aberrations such as IDH1/2 mutations and switch/sucrose non-fermenting (SWI/SNF) complex dysfunctions suggest that epidrugs must also be considered. In this review, we expose the rationale and feasibility to biologically drive the treatment of BTC patients.

Clinical relevance of molecular diagnostics in gastrointestinal (GI) cancer: European Society of Digestive Oncology (ESDO) expert discussion and recommendations from the 17th European Society for Medical Oncology (ESMO)/World Congress on Gastrointestinal Cancer, Barcelona

BACKGROUND AND SCOPEnIn the epoch of precision medicine and personalised oncology, which aims to deliver the right treatment to the right patient, molecular genetic biomarkers are a topic of growing interest. The aim of this expert discussion and position paper is to review the current status of various molecular tests for gastrointestinal (GI) cancers and especially considering their significance for the clinical routine use.nnnMETHODOLOGYnOpinion leaders and experts from diverse nationalities selected on scientific merit were asked to answer to a prepared set of questions about the current status of molecular diagnostics in different GI cancers. All answers were then discussed during a plenary session and reported here in providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine.nnnRESULTSnPreselected molecular genetic biomarkers that are described and disputed in the current medical literature in different GI cancers were debated, and recommendations for clinical routine practice were made whenever possible. Furthermore, the preanalytical variations were commented and proposals for quality controls of biospecimens were made.nnnCONCLUSIONnThe current article summarises the recommendations of the expert committee regarding prognostic and predictive molecular genetic biomarkers in different entities of GI cancers. The briefly and comprehensively formulated guidelines should assist clinicians in the process of decision making in daily clinical practice.

Dynamic evaluation of circulating tumour cells in patients with advanced gastric and oesogastric junction adenocarcinoma: Prognostic value and early assessment of therapeutic effects

BACKGROUNDnThe identification of dynamic biomarkers in advanced gastric and oesogastric junction adenocarcinoma (GOA) could help to tailor strategies for each patient. Enumeration of circulating tumour cells (CTCs) is approved by the US Food and Drug Administration in breast, colonxa0and prostate cancerxa0but is not in advanced GOA. Our study aims to establish the optimal threshold and the clinical significance of CTC count in advanced GOA before and during treatment.nnnMETHODSnOne hundred six patients with untreated advanced GOA were included in the ancillary study of the PRODIGE 17-ACCORD 20 trial. CTCs were detected in the peripheral blood using the CellSearchxa0system on day 0 (D0) and day 28 (D28). The prognostic value of CTCs at D0 and D28 was analysed by testing several thresholds.nnnRESULTSnAt baseline, median CTC count was 1 (range, 0-415). While CTCs ≥1, 2xa0or 3xa0at D0 were all significantly associated with worse overall survival (OS) and progression-free survival (PFS), CTCs ≥2 were the optimal threshold, on D0 or D28. CTCs ≥2xa0at D28 were also predictive of disease control. Taking into account both D0 and D28 CTC count defined 3 groups (low/low, high/low and low-high/high) with significantly different PFS (pxa0=xa00.0002) and OS (pxa0=xa00.003).nnnCONCLUSIONnQuantification of CTCs at baseline and during treatment may be a useful prognostic tool in advanced GOA, as it is associated with worse PFS and OS. A threshold ≥2 CTCs seems to have the best discriminant value. Change in CTC count between baseline and D28 could help to tailor treatment to each individual patient.

Efficacy and safety of nab-paclitaxel in patients with previously treated metastatic colorectal cancer: a phase II COLO-001 trial.

PurposeThis single-arm, phase II trial evaluated nab-paclitaxel monotherapy in pretreated patients with metastatic colorectal cancer (mCRC).MethodsPatients with mCRC (RAS wild-type and RAS mutant cohorts) received nab-paclitaxel 125xa0mg/m2 days 1, 8, and 15 (28-day cycle). The primary endpoint was investigator-assessed progression-free survival (PFS) rate at week 8; secondary endpoints included overall survival, overall response rate, and safety. Stage 1 planned enrollment was 15 patients per cohort per Simon 2-stage design. Stage 2 enrollment was to continue unlessxa0≤8 of the first 15 patients per cohort achieved PFS at 8xa0weeks.ResultsStage 1 enrolled 41 patients (RAS wild type: nxa0=xa018; RAS mutant: nxa0=xa023). In both RAS cohorts, 3 of 15 patients initially enrolled were progression-free at week 8 (20%; 95% CI 4.0–48.0). Median PFS was 8.1xa0weeks (95% CI 7.7–8.6) and 7.9xa0weeks (95% CI 7.6–8.0) for RAS wild-type and RAS mutant cohorts, respectively. There were no complete or partial responses. The overall disease control rate was 16% (95% CI 6.0–32.0), and rates were similar in the RAS wild-type and RAS mutant cohorts (18 and 15%, respectively). No new safety signals were reported; the most common gradexa0≥3 adverse events included neutropenia, asthenia, and peripheral neuropathy. This study did not progress to stage 2 per the preplanned statistical stopping rule.ConclusionsIn patients with heavily pretreated mCRC, nab-paclitaxel did not demonstrate promising antitumor activity; further assessment of nab-paclitaxel monotherapy in this population of patients is not supported.Trial registrationNCT02103062.

Carcinoid syndrome in neuroendocrine tumors: a prognostic effect?

Carcinoid syndrome has been known for more than 75 years. However, it was regarded for a long time as merely a syndrome linked to diagnosis of neuroendocrine tumours (NETs), without any other relevance in treatment of the disease. The proportion of patients presenting with carcinoid syndrome varies from 3% to 21%; one review stated a quite reliable percentage of 18%. In The Lancet Oncology, Daniel Halperin and colleagues present a large population-based study of nearly 10 000 patients with NETs, providing an unbiased estimate of the number of patients presenting with carcinoid syndrome at diagnosis (1786 [19%] of 9512 patients with NETs). However, NETs, especially grade 1 NETs of the ileum, are quite indolent, and the number of patients who will develop carcinoid syndrome months or years after diagnosis of a primary tumour remains unknown because the occurrence of carcinoid syndrome during very long follow-up of patients with metastatic disease was not taken into account in the study. The detrimental prognostic eff ect of carcinoid syndrome at diagnosis of NETs has to be considered in clinical practice. These patients are given somatostatin analogues when the diagnosis of NET is made and the presence of carcinoid syndrome is identifi ed. However, in clinical practice, minor symptoms of carcinoid syndrome, especially mild cutaneous fl ushing, diarrhoea with only two or three bowel movements per day, and abdominal pain, are not so easy to recognise, and oncologists have to be vigilant. Somatostatin analogues have an anti-tumoural eff ect in progressive and nonprogressive tumours, suggesting that treatment should begin as soon as possible in these patients without a watch and wait period. This immediate treatment could be particularly recommended in patients with symptomatic carcinoid syndrome. An accurate dose of somatostatin analogues to obtain perfect control of carcinoid syndrome and a rapid switch to second-line treatment of carcinoid syndrome, such as transarterial chemoembolisation, must also be recommended. The reasons for the prognostic eff ect of carcinoid syndrome are unclear. Carcinoid heart disease as a consequence of carcinoid syndrome could substantially impair survival. However, the data presented by Halperin and colleagues came from a population-based registry, with limitations on the details of variables recorded. As a consequence, the variables related to tumour burden were impossible to include in the multivariate model. Appearance of carcinoid syndrome could be the consequence of a large tumoural mass, which itself confers poor prognosis. In the study population, patients with carcinoid syndrome were more likely to receive chemotherapy than were those without. However, almost all consensus guidelines on treatment of NETs recommend that chemotherapy is not an option for treatment of this kind of tumour. The clinical treatment profi le of patients in this database with carcinoid syndrome is therefore more aggressive than that of those without, suggesting potential overuse of chemotherapy. For 30 years, only a few drugs were available to treat carcinoid syndrome (octreotide and lanreotide). Approval of these drugs has clearly changed the treatment and quality of life of patients. Transarterial chemoembolisation is another way to control the secretion of the disease. The same is possibly true for everolimus, which has already been shown to control secretion in pancreatic NETs such as insulinoma, even if no data have been published assessing its role in control of carcinoid syndrome. But, fi ndings from two trials have shown promising data in this fi eld. The fi rst assessed metabolic radiotherapy, which has been shown to prolong progression-free survival in patients with NETs arising from the midgut compared with octreotide. This eff ect is seen in functional NETs because metabolic radiotherapy also has an eff ect on the tumoural mass and it could help to control the symptoms. Furthermore, the effi cacy of a specifi c treatment of carcinoid syndrome has been reported. This compound, telotristat etiprate, specifi cally inhibits tryptophan hydroxylase whose main role is to convert tryptophan into 5-hydroxy-tryptophan. Findings from the TELESTAR study have shown that this new compound is active in refractory carcinoid syndrome after failure of somatostatin analogues, and combination of both agents (somatostatin analogues Sc ie nc e Ph ot o Li br ar y

613TiPA PROSPECTIVE, OBSERVATIONAL TRIAL TO FURTHER ASSESS SAFETY AND EFFICACY OF REGORAFENIB IN PATIENTS WITH METASTATIC COLORECTAL CANCER (MCRC) IN ROUTINE CLINICAL PRACTICE (CORRELATE)

ABSTRACT Background: The oral multikinase inhibitor regorafenib significantly improved overall survival vs placebo (HR 0.77, p = 0.0052) in patients with mCRC that progressed on available treatments in the randomized, double-blind, placebo-controlled CORRECT trial (Grothey, Van Cutsem et al. Lancet 2013). CORRELATE will characterize the safety and efficacy of regorafenib in real-world clinical practice. Trial design: This prospective, observational, multicenter trial (ClinicalTrials.gov identifier NCT02042144) will be conducted in routine clinical practice settings in more than 25 countries in Europe, Latin America, and the Asia-Pacific region. The trial will recruit 3,000 patients with mCRC previously treated with other approved therapies and for whom a decision has been made to treat with regorafenib. Patients will receive oral regorafenib 160u2003mg once daily for weeks 1–3 of each 4-week cycle. Dose interruptions and reductions will be permitted for the management of adverse events. The primary endpoint is the incidence of treatment-emergent adverse events, assessed using National Cancer Institute Common Terminology Criteria for Adverse Events. Secondary endpoints are overall survival, progression-free survival, disease control rate, health-related quality of life (assessed using the EQ-5D questionnaire), and healthcare resource use. Data sources will include medical records, routine measurements, and patient-reported outcome questionnaires. All patients receiving ≥1 dose of regorafenib will be included in the overall analysis. Two planned interim assessments will occur after 1,000 and 2,000 patients have been observed for ≥3 months. The final analysis will be performed when all patients have been followed for ≥18 months from the time they discontinue regorafenib (unless they withdrew from the trial early because of death, consent withdrawal, or patient/investigator decision to stop). Recruitment is under way, with the first patient enrolled in April 2014; the estimated primary completion date is July 2017. Disclosure: M.P. Ducreux: has the following financial disclosures: Advisory board: Merck, Roche, Bohringer, Amgen, Novartis, Sanofi Corporate sponsored research: Roche, Pfizer Employment (wife): Sandoz; A. Falcone: Advisory Boards for Amgen, Bayer, Roche, Merck Serono, Sanofi and Corporate Sponsored Research for Amgen, Bayer, Roche, Merck Serono, Sanofi; C.J.A. Punt: has the following financial disclosures: Advisory board: Roche, Amgen, Sanofi, Nordic Pharma, Bayer; J. Thaler: has the following financial disclosures: Advisory board: Bayer, Merck . All other authors have declared no conflicts of interest.