D. Malka

Prognostic factors influencing survival from metastatic (stage IV) gastroenteropancreatic well-differentiated endocrine carcinoma

Survival of metastatic gastroenteropancreatic well-differentiated endocrine carcinoma (GEP WDEC) is not well characterized. We evaluated the long-term outcome and prognostic factors for survival in 118 patients with distant metastases from GEP WDEC. Inclusion criteria were 1) pathological review by a single pathologist according to the present WHO criteria, 2) absence of previous therapy apart from surgery, 3) complete morphological evaluation within 3 months including somatostatin receptor scintigraphy, and 4) follow-up at Gustave-Roussy Institute until death or studys end. Clinical, biological marker, and pathological parameters were analyzed in univariate and multivariate statistical models. Survival after the first complete imaging work-up of the metastatic disease was determined using Kaplan-Meier method. Overall, survival for 5 years after the diagnosis of metastatic disease was 54%. In multivariate analysis, age (hazard ratio (HR): 1.05, 95% confidence interval (CI): 1.01-1.08, P = 0.01), the number of liver metastases (HR: 3.4, 95% CI: 1.4-8.3, P = 0.01), tumor slope (HR: 1.1, 95% CI: 1.0-1.1, P = 0.001), and initial surgery (HR: 0.3, 95% CI: 0.1-0.8, P = 0.01) were predictive of survival. Five-year survival was 100%, 91% (95% CI, 51-98%), 62% (95% CI, 37-83%), and 9% (95% CI, 6-32%) when patients had 0, 1, 2, 3 or more poor prognostic features respectively. This study enables the stratification of metastatic GEP WDEC patients into distinct risk groups. These risk categories can be used to tailor therapeutic approaches and also to design and interpret clinical trials.

Small bowel adenocarcinoma phenotyping, a clinicobiological prognostic study

Background:Small bowel adenocarcinoma (SBA) is a rare tumour with a poor prognosis. Molecular biology data on SBA carcinogenesis are lacking.Methods:Expression of HER2, β-catenin, p53 and mismatch repair (MMR) protein was assessed by immunohistochemistry. KRAS, V600E BRAF mutations and microsatellite instability were investigated.Results:We obtained samples from 63 SBA patients (tumour stages: I–II: 30%; III: 35%; IV: 32%; locally advanced: 3%). HER2 overexpression (3+) was observed in 2 out of 62 patients, overexpression of p53 in 26 out of 62, abnormal expression of β-catenin in 12 out of 61, KRAS mutation in 21 out of 49, BRAF V600E mutation in 1 out of 40 patients, MMR deficiency (dMMR) in 14 out of 61 and was consistent with Lynch syndrome in 9 out of 14 patients. All of the dMMR tumours were in the duodenum or jejunum and only one was stage IV. Median overall survival (OS) was 36.6 months (95% CI, 26.9–72.2). For all patients, in univariate analysis, stages I–II (P<0.001), WHO PS 0–1 (P=0.01) and dMMR phenotype (P=0.02) were significantly associated with longer OS. In multivariate analysis, disease stage (P=0.01) and WHO PS 0–1 (P=0.001) independently predicted longer OS. For stage IV patients, median OS was 20.5 months (95% CI: 14.6; 36.6 months). In multivariate analysis, WHO PS 0–1 (P=0.0001) and mutated KRAS status (P=0.02) independently predicted longer OS.Conclusion:This large study suggests that molecular alterations in SBA are closer to those in colorectal cancer (CRC) than those in gastric cancer, with low levels of HER 2 overexpression and high frequencies of KRAS mutations. The seemingly higher frequency of dMMR than in CRC may be explained by the higher frequency of Lynch syndrome in SBA patients. A dMMR phenotype was significantly associated with a non-metastatic tumour (P=0.02). A trend for a good prognosis and a duodenum or jejunum primary site was associated with dMMR.

Tumour-infiltrating CD68+ and CD57+ cells predict patient outcome in stage II–III colorectal cancer

Background:The aim of our study was to evaluate the prognostic role of immunological microenvironnement in stage II–III CRC patients.Methods:We constructed a tissue microarray from 196 consecutive patients with stage II–III CRC and compared CD3, CD4, CD8, CD57, CD68, CXCL9/MIG, CXCL13, and PPARγ immunoreactivity in tumour samples and their matched non-tumour tissue. We assessed their association with relapse-free survival (RFS; primary endpoint) and overall survival (OS) in multivariate Cox models.Results:Low densities of CD57+ and CD68+ tumour-infiltrating cells (TIC) independently predicted worse outcomes. A prognostic score combining CD57 (+, > vs −, ⩽2 cells per spot) and CD68 (+, >0 vs −, =0 cells per spot) TIC density discriminated CRC patients at low (CD68+/CD57+), intermediate (CD68+/CD57−), or high (CD68−/CD57−) risk, with hazard ratios for the intermediate-risk and high-risk groups of 2.7 (95% confidence interval (CI): 1.3–5.8) and 9.0 (3.2–25.4) for RFS, and 2.5 (1.2–5.1) and 10.6 (3.8–29.2) for OS, respectively, as compared with the low-risk group. Corresponding 5-year survival rates (95% CI) in the low-, moderate- and high-risk groups were 84% (71–91), 65% (54–74), and 12% (2–47), respectively, for RFS, and 91% (80–96), 76% (66–84), and 25% (7–59), respectively, for OS.Conclusion:Tumour CD57+ and CD68+ TIC density assessment independently predicts survival in patients with stage II–III CRC. If validated, our score based on a quick, inexpensive, and well-established method such as point counting on diagnostic tissue sections could be used routinely as a prognostic tool in CRC patients.

A Phase II Study of Irinotecan with 5-Fluorouracil and Leucovorin in Patients with Pretreated Gastroenteropancreatic Well-Differentiated Endocrine Carcinomas

Only a few drugs are active in the treatment of well-differentiated endocrine carcinomas (WDEC). We evaluated the combination of the so-called ‘de Gramont schedule’ and irinotecan in these tumors in a phase II study. Methods: 20 patients were enrolled in the study. The combination regimen included irinotecan, 180 mg/m2 on day 1, followed by 200 mg/m2 folinic acid in a 2-hour infusion, an intravenous 10-min bolus of 400 mg/m2 5-fluorouracil (5FU) and finally 600 mg/m2 5FU in a 22-hour infusion. Folinic acid and 5FU were repeated on day 2. Clinical, biological and morphological parameters were assessed by CT every 8 weeks. The site of the primary tumor was the pancreas in 10 cases, the lung in 3 cases and other sites in 7 cases. Sixteen patients had previously received chemotherapy, and 6 of them had had two lines of treatment. Six patients had previously been treated with chemoembolization. Results: The median number of cycles administered was 8. Grade 3–4 neutropenia was observed in 8 patients, and 1 patient experienced febrile neutropenia. There was no toxicity-related death. No complete symptomatic response was observed in 7 evaluable patients; 4 patients had an objective biological response. One patient achieved a morphological objective response, stabilization was observed in 15, but progression occurred in 3 patients. Median survival was 15 months. Conclusion: The above-mentioned combination of LV5FU2 + irinotecan does not yield major activity in heavily pretreated unresectable metastatic gastroenteropancreatic WDEC, and significant toxicity was observed.

Systemic treatment of advanced hepatocellular carcinoma: From disillusions to new horizons

Hepatocellular carcinoma (HCC) is an aggressive malignancy, which accounts for a third of all cancer deaths globally each year. The management of patients with HCC is complex, as both the tumour stage and any underlying liver disease must be considered conjointly. Since the approval of sorafenib in advanced HCC, several phase III clinical trials have failed to demonstrate any superiority over sorafenib in the frontline setting, and no agent has been shown to impact outcomes after sorafenib failure. This review will focus on the range of experimental therapeutics for patients with advanced HCC and highlight the successes and failures of these treatments as well as areas for future development. Specifics such as dose limiting toxicity and safety profile in patients with liver dysfunction related to the underlying chronic liver disease should be considered when developing therapies in HCC. Finally, robust validated and reproducible surrogate end-points as well as predictive biomarkers should be defined in future randomised trials.

Value of cardiophrenic angle lymph node for the diagnosis of colorectal peritoneal carcinomatosis.

BACKGROUND Cardiophrenic angle lymph nodes (CPALN) have been reported in patients with abdominopelvic malignancies. We aimed to assess whether the presence of CPALN is associated with peritoneal carcinomatosis (PC) in colorectal cancer. PATIENTS AND METHODS Between 2007 and 2011, 550 patients with colorectal cancer, including 165 (30%) with PC, had undergone surgery with complete peritoneal exploration. We retrospectively reviewed preoperative CT scans for the presence of CPALN and assessed its association with confirmed PC by univariate and multivariate analyses. RESULTS CPALN were present in 123 (75%) patients with PC, but absent in 263 (68%) patients without PC (Se: 0.72; Sp: 0.68; PPV: 0.49; NPV: 0.85; [OR], 3.3; p<0.001). PC was the only factor independently associated with CPALN in the multivariate analysis. CPALN was not correlated with the presence of liver metastases. 99 of the 165 patients with PC (62%) had visible signs of PC on CT scan. Among the remaining 66 patients, CPALN were the only potential sign of PC in 41 (62%), (Se 0.62, Sp 0.68, PPV 0.24, and NPV 0.92). CONCLUSION The detection of CPALN on CT may be of valuable help for the diagnosis of PC in patients with CRC.

Hommage à Franck Bonnetain

Après avoir dirigé l’Unité de Biostatistiques du Centre Georges-François Leclerc, Franck avait rejoint le CHRU de Besançon pour un poste hospitalo-universitaire. Il coordonnait également la Plateforme Nationale Qualité de Vie et Cancer et il était le secrétaire du groupe recherche UNICANCER-AFSOS. L’objectif qui lui tenait tant à cœur était de faire de la qualité de vie un critère de jugement reconnu en cancérologie. Rendre hommage à Franck ? Nous sommes ce matin du 22 mai 2017, en réunion du COPIL du groupe recherche UNICANCER-AFSOS à Paris ; une de ces réunions où aucun projet ne peut plus être envisagé et construit sans LE méthodologiste. Chacun parle et donne son avis de clinicien sur le projet d’étude à construire et systématiquement, à un moment donné, on va discuter de la qualité de vie qui est devenue un critère incontournable à inclure dans nos études, notamment dans le champ des soins de support ; et donc, à un moment ou à un autre, obligatoirement, on cherche « Franck LE méthodo »...

Chirurgie à visée curative des métastases péritonéales

RésuméL’exérèse complète des métastases péritonéales (MP), suivie de chimiohyperthermie intrapéritonéale (CHIP, dont l’impact thérapeutique précis n’est pas encore connu), permet d’obtenir de nombreuses guérisons chez les patients éligibles. C’est devenu le standard thérapeutique lorsqu’elle est possible. Ces résultats en termes de survie sont strictement identiques à ceux des hépatectomies pour métastases hépatiques (MH). La survie des patients présentant des MP débutantes est particulièrement bonne, bien supérieure à celle de tout patient hépatectomisé pour MH. La principale avancée sera de savoir opérer tôt les patients présentant des MP débutantes ou ceux qui ont un haut risque de développer des MP. Le concept de second-look + CHIP découle tout logiquement de ce constat. À l’opposé, une exérèse incomplète des MP contre-indique la CHIP, de même qu’une extension péritonéale importante (même si elle est complètement résécable).AbstractThe complete resection of the peritoneal metastases (PM), followed with HIPEC (hyperthermic intraperitoneal chemotherapy, whose precise therapeutic impact is not yet well-known), allows to obtain numerous cures in eligible patients. This is currently the gold-standard treatment when it is possible. Its survival results are strictly similar to those obtained with hepatectomy for liver metastases (LM). The survival rate of the patients with early PM is particularly high, far superior to those of any hepatectomized patient. The main progress will be to early-operate these patients, or to propose a prophylactic approach to those presenting a high-risk to develop PM. The concept of second-look surgery + HIPEC is the logical extension of this combined approach. In contrast, a non-complete cytoreductive surgery and a large peritoneal extension are contraindications to use this approach.

Chimiothérapie des métastases d’origine colorectale jamais résécables : stratégie multiligne, thérapies ciblées

RésuméLe développement d’anticancéreux plus actifs (oxaliplatine, irinotécan) associés aux thérapies ciblées ainsi que les avancées de la chirurgie ont allongé la survie des patients atteints de cancer colorectal métastatique (CCRm). Concernant les patients avec métastases considérées comme définitivement non résécables, le choix du traitement de première ligne est guidé par le bien-fondé et la faisabilité d’un traitement agressif, la notion d’une chimiothérapie antérieure par oxaliplatine, d’autant plus qu’elle est récente, et le statut tumoral RAS devenu désormais incontournable. Un facteur pronostique majeur est l’accès du patient à tous les anticancéreux, corrélé de façon linéaire à la survie. Il en est probablement de même avec les agents ciblés. Les combinaisons bithérapie-cytotoxique associée à un agent ciblé (bevacizumab ou anticorps anti-EGFR si RAS sauvage) constituent actuellement le traitement standard de première ligne chez les patients avec métastases sans espoir de résécabilité. En cas de maladie contrôlée après quatre à six mois de bithérapie cytotoxique, un traitement d’entretien par fluoropyrimidine (seule ou associée au bevacizumab) jusqu’à progression est devenu une option thérapeutique. Des données supplémentaires sont nécessaires pour identifier les sous-groupes de malades pouvant bénéficier d’une pause thérapeutique complète susceptible d’améliorer la qualité de vie des patients. En cas de maladie peu évolutive et/ou chez un patient « fragile », une fluoropyrimidine (seule ou associée au bevacizumab) peut constituer un traitement de première intention (ajout de l’oxaliplatine ou de l’irinotécan uniquement à la progression tumorale), sans détriment sur la survie comparé à une bithérapie cytotoxique d’emblée poursuivie jusqu’à progression ou toxicité limitante. Inversement, des survies jamais égalées ont été obtenues chez des malades sélectionnés recevant une trichimiothérapie cytotoxique d’induction (seule ou associée à une thérapie ciblée) suivie d’une désescalade thérapeutique. Ces stratégies méritent d’être comparées par des essais randomisés.AbstractThe advent of more active cytotoxic drugs (oxaliplatin, irinotecan), combined with targeted therapies and advances in surgery, has increased the survival of patients with metastatic colorectal cancer. The choice of first-line chemotherapy in case of patients with definitely non-resectable metastasis is guided by the merits and feasibility of aggressive treatment, history of prior adjuvant oxaliplatin, and tumor RAS status that has become essential. A major prognostic factor is patient’s access to all anticancer drugs, which is linearly correlated to survival. The same is probably true regarding targeted agents. The combination of doublet chemotherapy (fluoropyrimidine combined with oxaliplatin or irinotecan) and a targeted agent (bevacizumab or anti-EGFR antibodies if wild-type RAS) is the first-line standard of care for patients with non-resectable metastasis. In case of disease control after a 4–6 month induction bitherapy, treatment maintenance with a fluoropyrimidine (alone or combined with bevacizumab) until disease progression is a therapeutic option. Supplementary data are warranted to select subgroups of patients that may benefit from intermittent treatment to improve quality of life. In case of slowly growing metastatic disease and/or in frail patients, fluoropyrimidine (alone or combined with bevacizumab) may also be a first-line treatment option (oxaliplatin or irinotecan being added at the time of disease progression), without damage to survival compared with a strategy based on immediate doublet chemotherapy continued until progression or dose-limiting toxicity. On the other hand, survival rates ever achieved were obtained in selected patients after tricytotoxic-induction therapy (alone or combined with targeted agent) followed by maintenance treatment. These strategies deserve to be compared through further randomized trials.

Caractérisation des tumeurs neuroendocrines digestives ou thoraciques

Once the diagnosis of a neuroendocrine tumour has been made, characterisation is an essential step before therapy. It comes before the decision regarding treatment is made. This requires a multidisciplinary team of experts located in specialist centres that currently make up the RENATEN and TENPATH networks. It is directed by knowledge of the location of the primary tumour and anatomical pathological differentiation. The aim of this characterisation step is to highlight factors that may have an impact on the diagnosis and the prognosis or predict the response to treatment.RésuméUne fois le diagnostic de tumeur neuroendocrine (TNE) posé, la caractérisation est une étape essentielle de la prise en charge d’une TNE. Elle précède la décision thérapeutique. Celle-ci fait appel à une expertise multidisciplinaire au sein des centres experts actuellement regroupés au sein des réseaux RENATEN et TENpath. Elle est orientée par la connaissance de la localisation du primitif et la différenciation anatomopathologique. Cette étape de caractérisation a comme objectif: la mise en évidence de facteurs à impact diagnostique, pronostique ou prédictif de la réponse thérapeutique.