A. Zaanan

Chemotherapy of advanced small-bowel adenocarcinoma: a multicenter AGEO study

BACKGROUNDnSmall-bowel adenocarcinoma (SBA) is a rare tumor of poor prognosis. Data on the efficacy of chemotherapy for advanced SBA are scarce.nnnPATIENTS AND METHODSnAll patients with advanced SBA who received frontline chemotherapy from 1996 to 2008 were eligible for this retrospective multicenter study.nnnRESULTSnNinety-three consecutive patients were included. In the entire population, the median progression-free survival (PFS) and overall survival (OS) times were 6.6 and 15.1 months, respectively. Median PFS times among patients treated with LV5FU2 (n = 10), FOLFOX (n = 48), FOLFIRI (n = 19) and LV5FU2-cisplatin (n = 16) were 7.7, 6.9, 6.0 and 4.8 months, respectively, while median OS times were 13.5, 17.8, 10.6 and 9.3 months, respectively. In multivariate analysis, World Health Organization performance status (PS) (P < 0.0001) and elevated serum levels of carcinoembryonic antigen (CEA) (P = 0.02) and carbohydrate antigen 19-9 (CA 19-9) (P = 0.03) were the only variables significantly associated with poor OS. In the subgroup of patients treated with platinum-based chemotherapy, multivariate analysis showed that LV5FU2-cisplatin was associated with poorer PFS (P < 0.0001) and OS (P = 0.02) compared with FOLFOX.nnnCONCLUSIONSnThis is the largest study of chemotherapy in advanced SBA. Baseline PS and CEA and CA 19-9 levels were the main prognostic factors. FOLFOX seems to be the most effective platinum-based chemotherapy regimen.

FOLFOX as second-line chemotherapy in patients with pretreated metastatic pancreatic cancer from the FIRGEM study

BackgroundFOLFOX second-line treatment seems to be a validated option for patients with pancreatic cancer (PC) progressing after gemcitabine chemotherapy. However, other therapeutics strategy has developed in first-line therapy, as the FIRGEM phase II study that evaluated gemcitabine alone versus FOLFIRI.3 alternating with gemcitabine every two months. The present study assessed the efficacy and safety of FOLFOX after failure of the first-line therapy used in the FIRGEM study.MethodsIn this prospective observational cohort study, we analysed all consecutive patients who received second-line chemotherapy with FOLFOX among 98 patients with metastatic PC included in the FIRGEM study. Progression-free survival (PFS) and overall survival (OS) were estimated from the start of second-line chemotherapy using the Kaplan-Meier method.ResultsAmong 46 patients who received second-line chemotherapy, 27 patients (male, 55%; median age, 61xa0years; performance status (PS) 0–1, 44%) were treated with FOLFOX after progression to first-line gemcitabine alone (nu2009=u200920) or FOLFIRI.3 alternating with gemcitabine (nu2009=u20097). Grade 3 toxicity was observed in 33% of patients (no grade 4 toxicity). At the end of follow-up, all patients had progressed and 25 had died. No objective response was observed, and disease control rate was 36%. Median PFS and OS were 1.7 and 4.3xa0months, respectively. In multivariate analysis, PS was the only independent prognostic factor. For patients PS 0–1 versus 2–3, median PFS was 3.0 versus 1.2xa0months (log rank, pu2009=u20090.002), and median OS was 5.9 versus 2.6xa0months (log rank, pu2009=u20090.001).ConclusionsThis study suggests that FOLFOX second-line therapy offered interesting efficacy results with an acceptable toxicity profile in metastatic PC patients with a good PS.

Medical treatment of pancreatic cancer: New hopes after 10 years of gemcitabine

Exocrine pancreatic cancer has a very poor prognosis. R0 resection of the tumor is to date the only potentially curative approach, but less than 20% of patients are eligible for a curative surgery at diagnosis. Until recently, gemcitabine was the standard treatment for advanced and metastatic pancreatic cancer patients, since it was shown more than a decade ago to induce clinical benefit and to improve survival when compared to weekly bolus 5-fluorouracil. In order to improve patients outcome many trials have, during the last 10 years, explored the pharmacokinetic modulation of gemcitabine and combination therapies with gemcitabine and other anti-cancer agents with consistent negative results. It is finally a trial assessing the efficacy of a combination chemotherapy without gemcitabine: the FOLFIRINOX regimen, reported this year, that has shown for the first time a significant improvement in progression free and overall survivals. In parallel, many trials testing new targeted agents in these patients are currently ongoing. After 10 years without significant progress in the treatment of pancreatic cancer patients, the hope that a significant improvement in the outcome of these patients can be achieved has been raised.

CO.32 Chimiothérapie des adénocarcinomes avancés de l’intestin grêle : résultats finaux de l’étude multicentrique AGEO

Introduction Les adenocarcinomes de l’intestin grele (AIG) sont des tumeurs rares et de mauvais pronostic. Les donnees concernant la chimiotherapie des AIG avances sont peu nombreuses. La plupart des etudes sont retrospectives et menees sur de faibles effectifs (inferieurs a 40 patients). Patients et Methodes Cette etude retrospective multicentrique a inclus tous les patients traites consecutivement par une premiere ligne de chimiotherapie entre 1996 et 2008 pour un AIG avance (tumeurs ampullaires et peri-ampullaires exclues). La survie sans progression (SSP) et la survie globale (SG) ont ete estimees par la methode de Kaplan Meier et comparees par le test du Log-Rank. Les modeles d’analyse univariee et multivariee de Cox ont ete utilises pour la recherche de facteurs cliniques et biologiques predictifs de survie. Resultats Au total, 99 patients ont ete inclus (âge moyen : 57 ans ; hommes : 54,5 %). La tumeur primitive etait duodenale (60 %), jejunale (28 %) ou ileale (12 %). Le stade tumoral etait localement avance (nxa0=xa013) ou metastatique (nxa0=xa086). Un total de 928 cures a ete analyse avec une mediane de 8 cures [2-37] par patient. Les schemas de chimiotherapie utilises en premiere ligne etaient les suivants : LV5FU2 (nxa0=xa010), FOLFOX (nxa0=xa048), FOLFIRI (nxa0=xa019), LV5FU2-cisplatine (nxa0=xa016) et autres (nxa0=xa06). Les medianes de SSP etaient de 7,9 ; 7,4 ; 6,0 ; 4,8 et 8,1 mois respectivement. Les medianes de SG etaient de 13,5 ; 17,8 ; 10,6 ; 9,3 et 10,6 mois respectivement. Pour l’ensemble de la population, les medianes de SSP et SG etaient de 7,2 et 15,1 mois respectivement. En analyse multivariee, le stade OMS (pxa0=xa00,0001) et un taux serique eleve de ACE (pxa0=xa00,01) ou de CA19-9 (pxa0=xa00,02) etaient les seules variables significatives predictives de SG moindre. Pour le sous-groupe de patients traites par sels de platine, le LV5FU2-cisplatine etait moins efficace en analyse multivariee que le FOLFOX en termes de SSP (risque relatif [RR]xa0=xa02,88 ; intervalle de confiance a 95 % [IC] : 1,13-7,30 ; pxa0=xa00,03) et SG (RRxa0=xa03,34 ; IC : 1,30-8,53 ; pxa0=xa00,01). Conclusion Cette etude multicentrique (qui correspond a la plus grande serie de patient rapportee a ce jour) suggere que le FOLFOX est la chimiotherapie de choix a utiliser en premiere ligne de traitement des AIG avances. Le stade OMS initial et le taux serique des marqueurs ACE et CA 19-9 sont les principaux facteurs pronostiques en analyse multivariee.

Abstract 508: Prognostic value of circulating tumor DNA in advanced colorectal cancer patients: quantification of hypermethylated or mutant sequences using picoliter-droplet digital PCR

Background: Circulating tumor DNA (ctDNA) has been suggested as a new marker in different cancer types including colorectal cancer (CRC). Its prognostic role needs to be validated in prospective clinical studies using precise and robust procedures. In this context, picoliter-droplet digital PCR has arisen as a highly sensitive and quantitative approach offering a broad dynamic range of detection. Patients and methods: All consecutive advanced CRC patients receiving first-line chemotherapy were included in this monocentric prospective study. Plasma samples were collected before the 1st cycle of chemotherapy, then at 14 and 28 days after the beginning of the chemotherapy. Both, carcinoembryonic antigen (CEA) dosages and computed tomography (CT) were performed at baseline and every 8 weeks. For each patient, tumor DNA from biopsies was tested for the presence of KRAS, BRAF and TP53 mutations either by conventional qPCR or Next-Generation Sequencing. When no mutation was identified in the tumor, ctDNA was screened for hypermethylated sequences of WIF1 and NPY genes. CtDNA sequences (mutated or hypermethylated) were quantified (concentration, ng/mL) using picoliter-droplet digital PCR coupled to Taqman probes. Associations of ctDNA concentration with progression-free survival (PFS) and overall survival (OS) were analysed using a Cox proportional hazards model. Multivariate models were adjusted on age, gender, Kohne9s score, CEA and type of genetic alteration. Results: Up to now 43 patients were included (mean age: 66±1.8years [62.6-69.6], gender ratio: M/F 1.15). At baseline ctDNA was detectable in 38/43 (88%) patients based on KRAS, BRAF or TP53 mutation (n = 27), or hypermethylation of the WIF1 or NPY genes (n = 16). Values ranged from 0 to 208 ng/mL, mean and median ctDNA concentration were 12.7 ng/mL and 2.05 ng/mL, respectively. After adjustment on prognostic covariates, the concentration of baseline ctDNA was significantly positively associated with a worse PFS (HR: 1.01 CI95% [1-1.02]; padj = 0.03) and OS (HR: 1.02 CI95% [1.01-1.035] padj = 0.004). The median PFS were 8.6 and 2.3 months in patients with less or more than 5 ng/mL of baseline ctDNA, respectively (HR: 6.7, CI95% 2-22; padj = 0.001). When ctDNA concentration was considered at 14 or 28 days, patients with a ctDNA ≥ 0.2 ng /mL have a significantly worse PFS (HR: 4.12 CI95% [1.41-12.0]; padj = 0.009) than the others independently of the baseline concentration of ctDNA. Conclusion: This study suggests that ctDNA is a strong prognostic factor highlighting the clinical relevance of quantifying circulating tumor DNA by picoliter-droplet digital PCR in first-line advanced colorectal cancer treatment. Citation Format: Fanny Garlan, Pierre Laurent-Puig, Nathalie Siauve, Audrey Didelot, Geraldine Perkins, Helene Blons, Julien Taieb, Valerie Taly, Aziz Zaanan. Prognostic value of circulating tumor DNA in advanced colorectal cancer patients: quantification of hypermethylated or mutant sequences using picoliter-droplet digital PCR. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 508.

Sequential FOLFIRI.3 + Gemcitabine Improves Health-Related Quality of Life Deterioration-Free Survival of Patients with Metastatic Pancreatic Adenocarcinoma: A Randomized Phase II Trial

Background A randomized multicenter phase II trial was conducted to assess the sequential treatment strategy using FOLFIRI.3 and gemcitabine alternately (Arm 2) compared to gemcitabine alone (Arm 1) in patients with metastatic non pre-treated pancreatic adenocarcinoma. The primary endpoint was the progression-free survival (PFS) rate at 6 months. It concludes that the sequential treatment strategy appears to be feasible and effective with a PFS rate of 43.5% in Arm 2 at 6 months (26.1% in Arm 1). This paper reports the results of the longitudinal analysis of the health-related quality of life (HRQoL) as a secondary endpoint of this study. Methods HRQoL was evaluated using the EORTC QLQ-C30 at baseline and every two months until the end of the study or death. HRQoL deterioration-free survival (QFS) was defined as the time from randomization to a first significant deterioration as compared to the baseline score with no further significant improvement, or death. A propensity score was estimated comparing characteristics of partial and complete responders. Analyses were repeated with inverse probability weighting method using the propensity score. Multivariate Cox regression analyses were performed to identify independent factors influencing QFS. Results 98 patients were included between 2007 and 2011. Adjusting on the propensity score, patients of Arm 2 presented a longer QFS of Global Health Status (Hazard Ratio: 0.52 [0.31-0.85]), emotional functioning (0.35 [0.21–0.59]) and pain (0.50 [0.31 – 0.81]) than those of Arm 1. Conclusion Patients of Arm 2 presented a better HRQoL with a longer QFS than those of Arm 1. Moreover, the propensity score method allows to take into account the missing data depending on patients’ characteristics. Trial registration information Eudract N° 2006-005703-34. (Name of the Trial: FIRGEM).

Chemosensitivity in ovarian metastases from gastric cancer: A case series

The development of ovarian metastases from gastric cancer indicates a turning point of the disease progression and is usually associated with poor prognosis. Efficacy of modern chemotherapy protocols in ovarian metastases from gastric cancer is unknown. In this case series, we have evaluated the chemosensitivity of ovarian metastases from gastric cancer in eight consecutive patients treated in our institution between January 2000 and April 2012. Median age at gastric cancer diagnosis was 48.3 years and ovarian metastases were mainly metachronous (88%). Patients were treated with FOLFOX or FOLFIRI protocols in first-line and with EOX protocol in second-line chemotherapy. These protocols of chemotherapy used in first- and second-line treatment were able to control the disease in 33.3% for ovarian metastases compared to 66.7% for extraovarian metastases. Mean overall survival (OS) from ovarian metastases diagnosis was 14.2 months. The four patients treated by bilateral oophorectomy had a longer mean OS (16 months) than the four patients who did not experienced surgery (12.3 months). In conclusion, this case series suggests that ovarian metastases from gastric cancer are less sensitive than extraovarian metastases to modern protocol of chemotherapy. To confirm these observations, a large retrospective study is ongoing.