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PURPOSE Metastatic pancreatic cancer (mPC) still harbors a dismal prognosis. Our previous trial (PRODIGE 4—ACCORD 11) demonstrated the superiority of 6-month chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) over gemcitabine for overall survival. The high limiting oxaliplatin-related neurotoxicity supports the evaluation of an oxaliplatin stop-and-go strategy and a sequential strategy in mPC. METHODS In this phase II study, patients were randomly assigned to receive either 6 months of FOLFIRINOX (arm A), 4 months of FOLFIRINOX followed by leucovorin plus fluorouracil maintenance treatment for controlled patients (arm B), or a sequential treatment alternating gemcitabine and fluorouracil, leucovorin, and irinotecan every 2 months (arm C). The primary end point was progression-free survival at 6 months. RESULTS Between January 2015 and November 2016, 276 patients (mean age: 63 years; range: 40-76 years) were enrolled (A: 91, B: 92, and C: 90). Grade 3 or 4 neurotoxicity occurred in 10.2% of patients in arm A and 19.8% in arm B. The median ratio of received dose/targeted dose of oxaliplatin was 83% in arm A and 92% in arm B. The 6-month progression-free survival was 47.1% in A, 42.9% in B, and 34.1% in C. The median overall survival was 10.1 months in arm A, 11.2 in arm B, and 7.3 in arm C. Median survival without deterioration in quality-of-life scores was higher in the maintenance arm (11.4 months) than in arms A and C (7.2 and 7.5 months, respectively). CONCLUSION Maintenance with leucovorin plus fluorouracil appears to be feasible and effective in patients with mPC controlled after 4 months of induction chemotherapy with FOLFIRINOX. Severe neurotoxicity was higher in the maintenance therapy arm, probably because of the higher cumulative dose of oxaliplatin.

Simple Summary With an increasing incidence, late diagnosis, and high mortality rate, pancreatic adenocarcinoma remains, in 2021, a real challenge for health institutions and professionals worldwide. Despite significant therapeutic progress, the five-year survival after diagnosis remains poor. Furthermore, disparities in the access to care (often participating in late diagnosis) have been described in demographic, clinical, and/or socioeconomic factors. We decided to assess in our region, over 1 year (2016), the real-life pancreatic cancer’s management by the analysis of French hospital discharge summaries database system. We pointed out, in a large patient population (n = 1872), the inverse correlation between the level of expertise of the health facility in which the patient had his first hospital stay and the likelihood of undergoing any specific treatment for PDAC. A deeper analysis of the medical pathway for pancreatic adenocarcinomas patients is ongoing in order to suggest adapted public health measures. Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a major public health challenge, and faces disparities and delays in the diagnosis and access to care. Our purposes were to describe the medical path of PDAC patients in the real-life setting and evaluate the overall survival at 1 year. We used the national hospital discharge summaries database system to analyze the management of patients with newly diagnosed PDAC over the year 2016 in Auvergne-Rhône-Alpes region (AuRA) (France). A total of 1872 patients met inclusion criteria corresponding to an incidence of 22.6 per 100,000 person-year. Within the follow-up period, 353 (18.9%) were operated with a curative intent, 743 (39.7%) underwent chemo- and/or radiotherapy, and 776 (41.4%) did not receive any of these treatments. Less than half of patients were operated in a high-volume center, defined by more than 20 PDAC resections performed annually, mainly university hospitals. The 1-year survival rate was 47% in the overall population. This study highlights that a significant number of patients with PDAC are still operated in low-volume centers or do not receive any specific oncological treatment. A detailed analysis of the medical pathways is necessary in order to identify the medical and territorial determinants and their impact on the patient’s outcome.

Background Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated. Patients and Methods In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and June 11, 2020. The primary endpoint was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary endpoints. Results From April 4 to June 11, 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), ECOG PS ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except cytotoxic chemotherapy in the subgroup of patients with detectable SARS-CoV-2 by RT-PCR, which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment interrupted or stopped following diagnosis of COVID-19. Conclusions Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis., Highlights • A total of 1289 patients with solid tumours and COVID-19 were analysed. • Mortality and COVID-19 severity were mainly driven by patient general characteristics. • Overall, we found no deleterious effects of recent anticancer treatments on mortality. . • Systemic anticancer treatment was interrupted or stopped in 39% of patients.

International audience; PURPOSE: This Phase IIb (NCT02195180) open-label study evaluated erythrocyte-encapsulated asparaginase (eryaspase) in combination with chemotherapy in second-line advanced pancreatic adenocarcinoma.METHODS: Eligible patients were randomized 2:1 to either eryaspase in combination with gemcitabine or mFOLFOX6 (eryaspase arm), or to gemcitabine or mFOLFOX6 alone (control arm). Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients with low asparagine synthetase (ASNS) expression. Secondary endpoints included OS and PFS in the entire population.RESULTS: 141 patients were randomized (eryaspase arm, n = 95; control arm, n = 46). Median OS and PFS in patients with low ASNS expression were 6.2 months (95% CI, 5.1-8.8) in the eryaspase arm versus 4.9 months (3.1-7.1) in the control arm (HR, 0.63; 95% CI, 0.39-1.01; P = 0.056) and 2.0 months (95% CI, 1.8-3.4) in the eryaspase arm versus 1.8 months (1.4-3.8) in the control arm (HR, 0.67; 95% CI, 0.40-1.12; P = 0.127), respectively. In the entire population, median OS and PFS for the eryaspase arm versus control were 6.0 months versus 4.4 months (HR, 0.60; P = 0.008) and 2.0 months versus 1.6 months (HR, 0.56; 95% CI, 0.37-0.84; P = 0.005), respectively. The combination of eryaspase and chemotherapy was well tolerated. The most frequent Grade 3/4 adverse events in the eryaspase arm (n = 93) were gamma-glutamyltransferase increase (16 [17.2%]), neutropenia (12 [12.9%]), and physical health deterioration (12 [12.9%]).CONCLUSION: Eryaspase in combination with chemotherapy is associated with improvements in OS and PFS, irrespective of ASNS expression in second-line advanced pancreatic adenocarcinoma. A Phase III trial is underway.

Resume Introduction La dissemination metastatique hepatique greve le pronostic du cancer colo rectal. Apres chirurgie hepatique ou radiofrequence, aucun biomarqueur n’est actuellement valide pour predire la recidive precoce et intensifier le traitement adjuvant dans des groupes a risque. Par leurs fonctions biologiques d’homeostasie du microenvironnement tumoral, les metalloproteinases (MMPs) representent des biomarqueurs potentiellement interessants. Methodes Quarante-quatre patients porteurs de metastases hepatiques ayant beneficie d’une chirurgie hepatique carcinologique ou traites par radiofrequence ont ete inclus dans l’etude de janvier 2004 a decembre 2009. Le suivi serique de MMP-1, MMP-2, MMP-7, MMP-9 et TIMP-1 etait realise a differents temps precis post-operatoires par technique Elisa, en parallele du recueil des donnees cliniques et radiologiques de recidive. Resultats Le dosage post-interventionnel de MMP-9 augmente significativement entre J0, J1 et J45 quelle que soit la technique ablative utilisee (***p ≤ 0,001). Le taux de MMP-2 est significativement plus eleve au cours du suivi tardif a M3 et M6 (***p ≤ 0,001) sans que ce taux ne soit associe a un risque de recidive. Le taux de TIMP-1 a J0 est un facteur deletere (HR = 1,76, p = 0,042*). Conclusion Notre etude correle la variation serique post-operatoire de 4 MMPs et TIMP-1 au risque de recidive metastatique precoce apres une approche ablative carcinologique hepatique par chirurgie ou radiofrequence. Le taux de TIMP-1 a J0 semblerait associe au risque de recidive mais une etude sur une population plus importante est necessaire pour confirmer ces resultats.

The primary tumor side is emerging as a prognostic factor for patients with liver metastatic colorectal cancer (mCRC). In a combined analysis of data from 2 randomized studies, the addition of selective internal radiation therapy to first-line chemotherapy in patients with mCRC was associated with statistically and clinically significant overall survival gains for patients with a right-sided primary tumor. Background: The primary tumor side is emerging as a major prognostic factor for patients with metastatic colorectal cancer (mCRC). We examined the survival data from 2 randomized studies to determine whether the outcomes differ between patients with mCRC with right-sided primary (RSP) tumors and those with left-sided primary (LSP) tumors after selective internal radiation therapy (SIRT) plus mFOLFOX6 (folinic acid [leucovorin], 5-fluorouracil, oxaliplatin) chemotherapy, versus chemotherapy alone. Patients and Methods: Separate and combined analyses were performed on the data from the SIRFLOX and FOXFIRE global trials, which compared chemotherapy plus SIRT with chemotherapy alone for patients with mCRC liver metastases. The primary tumor side data were prospectively collected. The principal outcome measure was overall survival (OS) stratified by treatment and primary tumor side. Results: In the combined analysis of all 739 patients enrolled, SIRT had no effect on OS (median OS, 24.3 vs. 24.6 months; hazard ratio [HR], 1.021; P = .810). For the 179 patients (24.2%) with a RSP tumor, OS was improved with the addition of SIRT (median, 22.0 vs. 17.1 months HR, 0.641; P = .008). The addition of SIRT was not associated with a significant difference in OS among the 540 patients with a LSP tumor (median, 24.6 vs. 26.6 months; HR, 1.120; P = .264). A test of treatment interaction by primary tumor side was statistically significant for RSP and SIRT (P = .002). Conclusion: The addition of SIRT for patients with RSP tumors, but not for those with LSP tumors, was associated with a statistically and clinically significant OS gain. (C) 2018 Elsevier Inc. All rights reserved.

Purpose To compare epirubicin, cisplatin, and capecitabine (ECX) with fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatments in patients with advanced gastric or esophagogastric junction (EGJ) adenocarcinoma. Patients and Methods This open, randomized, phase III study was carried out in 71 centers. Patients with locally advanced or metastatic gastric or EGJ cancer were randomly assigned to receive either ECX as first-line treatment (ECX arm) or FOLFIRI (FOLFIRI arm). Second-line treatment was predefined (FOLFIRI for the ECX arm and ECX for the FOLFIRI arm). The primary criterion was time-to-treatment failure (TTF) of the first-line therapy. Secondary criteria were progression-free survival (PFS), overall survival (OS), toxicity, and quality of life. Results In all, 416 patients were included (median age, 61.4 years; 74% male). After a median follow-up of 31 months, median TTF was significantly longer with FOLFIRI than with ECX (5.1 v 4.2 months; P = .008). There was no significant difference between the two groups in median PFS (5.3 v 5.8 months; P = .96), median OS (9.5 v 9.7 months; P = .95), or response rate (39.2% v 37.8%). First-line FOLFIRI was better tolerated (overall rate of grade 3 to 4 toxicity, 69% v 84%; P < .001; hematologic adverse events [AEs], 38% v 64.5%; P < .001; nonhematologic AEs: 53% v 53.5%; P = .81). Conclusion FOLFIRI as first-line treatment for advanced gastric and EGJ cancer demonstrated significantly better TTF than did ECX. Other outcome results indicate that FOLFIRI is an acceptable first-line regimen in this setting and should be explored as a backbone regimen for targeted agents.

Recurrence after liver surgery or radiofrequency is a clinical and biological challenge because it worsens the colorectal cancer prognosis. To date, no biomarker is yet validated to predict the recurrence in order to intensify adjuvant therapy for patients with higher risk. Matrix metalloproteinases play a major role in the metastasis dissemination and tumoral microenvironment and could be a potential biomarker of interest.Forty-four patients with liver metastasis treated by surgery or radiofrequency were enrolled in this study. Serum levels of MMP-1, MMP-2, MMP-7, MMP-9 and TIMP-1 were monitored in Elisa after therapy and correlated to the recurrence from January 2004 to December 2007. After the curative treatment, patients were assessed for the recurence for two years by CT-scan and examination.Post-operative serum level of MMP-9 was significantly higher between J0, J1 and J45 after liver surgery or radiofrequency (***P≤0.001). Level of MMP-2 was significantly increased at M3 and M6 (***P≤0.001) but does not appear to be a risk factor of liver recurrence. The level of TIMP-1 at J0 is a deleterious factor (HR=1.76, P=0.042*).This is the first study wich correlates the post-operative level of 4 MMPs and TIMP-1 with the risk of liver recurrence after surgery or radiofrequency. Serum TIMP-1 level at J0 could be helpful to identify patients with higher risk but these results need to be confirmed in a large-scale study.

Resume Cet article presente des recommandations de bonnes pratiques etablies par un groupe de travail pluridisciplinaire concernant l'indication et l'utilisation des differents moyens therapeutiques visant a lever l'occlusion ou en soulager les symptomes chez les patients presentant une occlusion intestinale sur carcinose peritoneale a un stade avance. Ces recommandations ont ete etablies a partir de revues de la litterature et d'accord d'experts. La strategie proposee passe par une evaluation radioclinique avec l'importance de la TDM abdominale qui permettra, associee a l'analyse de criteres pronostiques, de discuter de la place d'une chirurgie ou de la pose de stent qui sont le plus souvent non realisables. Ceci amene a preciser la place et les modalites d'utilisation des differents traitements medicamenteux symptomatiques : corticoides, anti-emetiques, antalgiques et antisecretoires (anti-cholinergiques, analogues de la somatostatine, inhibiteurs de la pompe a protons). La sonde nasogastrique n'est plus systematique et a discuter au cas par cas. Des recentes etudes confirment l'interet des analogues de la somatostatine sur les symptomes lies a l'occlusion, principalement les nausees, les vomissements et la douleur. Toutefois, l'absence d'AMM et leur cout eleve restent un obstacle pour les utiliser en premiere intention. En l'absence d'efficacite de ces traitements sur les symptomes de l'occlusion, la gastrostomie de decharge doit etre discutee rapidement. La rehydratation sera quasi systematique. La place de l'alimentation parenterale devra etre questionnee au regard de certains criteres pronostiques identifies. L'objectif de ces recommandations est bien d'etablir une strategie limitee dans le temps, faisant appel a des equipes pluridisciplinaires, avec pour objectif le confort optimal des patients.

4000Background: Metastatic pancreatic cancer (mPC) still harbors a dismal prognosis (5-year overall survival [OS]

TPS3622Background: According to the IDEA trial (Shi Q et al. ASCO 2017;LBA1), 6-month adjuvant chemotherapy should remain the standard in stage III T4 or N2 colon cancer. The relatively poor surviv...

Background: A phase-III trial showed the non-inferiority of oral capecitabine plus oxaliplatin (XELOX) vs 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) in terms of efficacy in first-line treatment of metastatic colorectal cancer. A secondary objective was to compare the quality of life (QoL) and health-care satisfaction of patients. Methods: Patients were randomised to receive XELOX (n=156) or FOLFOX-6 (n=150) for 6 months. Quality of life and satisfaction were assessed by the Quality of Life Questionnaire-C30 (QLQ-C30) and Functional Assessment of Chronic Illness Therapy Chemotherapy Convenience and Satisfaction Questionnaire (FACIT-CCSQ), respectively. Patients completed questionnaires at baseline, at Cycle3 (C3) and Cycle (C6) (XELOX) or at C4 and C8 visits (FOLFOX-6) and at their final visit. Results: A total of 245 and 225 patients were assessed using QLQ-C30 and FACIT-CCSQ, respectively. The completion rates were >80%. Global QoL scores did not differ significantly between groups during the study. According to FACIT-CCSQ, XELOX seemed more convenient (C3/C4, P

The c-erbB-2 protein is overexpressed in 7% of gastric cancer cases, suggesting that anti-c-erbB-2 antibody therapy (trastuzumab; Herceptin) could be used. We report here a 28-year-old woman with metastatic gastric cancer overexpressing c-erbB-2 (3 + strong membrane staining on immunohistochemistry) who was treated with trastuzumab in combination with chemotherapy. A complete response was obtained with a combination of trastuzumab and oxaliplatin and was maintained with trastuzumab alone for 18 months. The patient relapsed and chemotherapy (capecitabine, docetaxel) was combined with the anti-c-erbB-2 antibody. The patient survived for 4 years with metastatic disease controlled for 2 years by immunochemotherapy. We conclude that the combination of trastuzumab and chemotherapy is efficient in the treatment of metastatic gastric carcinoma with overexpression of the c-erbB-2 protein.

The influence of p53 mutations on the response to ionizing radiation and survival was retrospectively evaluated in patients treated with preoperative radiotherapy for rectal carcinoma. From 1989 to 1991, 86 rectal cancer patients treated by preoperative radiotherapy were included in this series. For all patients, endorectal sonography (to define ultrasonography TNM [uTNM]) was performed before treatment; 19 patients were classified as stage 1, 27 as stage 2 and 40 as stage 3. Response to radiotherapy (39 Gy in 13 fractions delivered in 17 days) was assessed by comparing the uT and the T obtained by histologic examination of the resected specimen (TNM classification). A rectal cancer biopsy was performed before treatment and enabled the search for p53 mutations by denaturing gradient gel electrophoresis (DGGE) and sequencing. The status of the p53 gene was correlated with the response to radiotherapy and survival. Forty-nine percent of the tumors presented abnormal DGGE profiles. The prevalence of p53 mutations was significantly higher in patients who did not respond to radiotherapy (63%) than in those who did respond (34%) (p < 0.01). Presence of a p53 mutation was associated with significantly shorter 5-year survival compared to patients without mutations (p < 0.02). In a multivariate analysis, p53 mutation status remained a prognostic factor independent of tumor posttreatment staging (p < 0.05). p53 status is an independent prognostic factor of response to radiotherapy and survival in rectal carcinoma.

Objective: To evaluate the outcome of patients with non germ-cell neoplasms arising in germ-cell tumours [also designated teratoma with malignant transformation (TMT)]. Methods: The records of patients with TMT from three institutions were reviewed retrospectively. Results: 12 males were diagnosed as having TMT. All but 2 patients had a teratoma component in the primary tumour. Sarcoma was the most frequent histologic type of TMT, identified in 9 patients, with rhabdomyosarcoma ranking first among the subtypes (3/9). Other histological types included nephroblastoma and ependymoblastoma (1), adenocarcinoma (1) and bronchoalveolar carcinoma (1). All patients with advanced disease were treated with cisplatin-containing chemotherapy, followed by resection of residual masses in 5. Eight of the 10 patients who attained a complete remission subsequently relapsed. Histologically-adapted chemotherapy was administered to 7, of whom 3 obtained a partial response and 3 disease stabilisation. With a median follow-up of 5 years, 3 of 12 patients (25%) are alive and free of disease. Conclusions: TMT is a rare phenomenon occurring in a wide spectrum of histologic subtypes, the most common being sarcoma. Its poor prognosis compared with germ-cell tumours may be improved by histologically-adapted chemotherapy combined with optimal surgery.

BACKGROUND The objective of this study was to assess the natural history of the two disease courses, patient immune system tolerance, and results of therapy in human immunodeficiency virus (HIV)–infected patients with germ cell tumors (GCT). METHODS From 1985 to 1996, 34 HIV-infected men received a diagnosis of GCT. Their charts were analyzed retrospectively. RESULTS Sixteen patients had seminomas, and 18 had nonseminomatous GCTs (NSGCT); 71% had International Union Against Cancer (UICC), 1997 Stage I–II GCTs. At the time of chemotherapy, 69%, 6%, and 25% of patients with advanced NSGCT were in the International Germ Cell Consensus Classification (IGCCC) good, intermediate, and poor prognostic group, respectively. All except 1 of the 10 patients with advanced seminomas were in the IGCCC good prognostic group. At diagnosis of GCT, 85% of patients were classified as having asymptomatic HIV infection or only persistent generalized lymphadenectomy. The median CD4 cell count was 325/μL (range, 6–1125). Overall, 26 patients were given chemotherapy, but the planned dose intensity was respected in only 15 (57%) patients. Severe toxic effects included febrile neutropenia in 35% of patients. During chemotherapy, zidovudine, prophylactic granulocyte colony-stimulating factor (G-CSF), and a Pneumocystis carinii prophylaxis were given in 19%, 23%, and 35% of cases, respectively. CD4 cell count decreased in 7 (64%) of 11 patients during chemotherapy. Infradiaphragmatic radiotherapy was given in 10 cases and was clinically well tolerated. At a median follow-up of 27 months (range, 3–150), 50% of patients were alive, and only 18% of patients died of GCT. Two patients developed a non-GCT malignancy while in complete remission, namely, Hodgkin disease and an acute leukemia. CONCLUSIONS The prognosis of GCT in HIV-infected patients is mostly dictated by the HIV infection. Patients should be treated according to stage and histologic subtype, although dose reduction of chemotherapy might be necessary in approximately half of the patients. Close surveillance of neutrophil and CD4 cells counts, as well as the use of G-CSF and systematic anti-Pneumocystis carinii prophylaxis are recommended during chemotherapy. The use of highly active antiretroviral therapy during chemotherapy for GCT requires a prospective assessment. Cancer 2001;92:1460–7. © 2001 American Cancer Society.

This article reports on the clinical practice guidelines developed by a multidisciplinary group working on the indications and uses of the various available treatment options for relieving intestinal obstruction or its symptoms in patients with peritoneal carcinomatosis. These guidelines are based on a literature review and expert opinion. The recommended strategy involves a clinical and radiological evaluation, of which CT of the abdomen is a crucial component. The results, together with an analysis of the prognostic criteria, are used to determine whether surgery or stenting is the best option. In most patients, however, neither option is feasible, and the main emphasis, therefore, is on the role and administration of various symptomatic medications such as glucocorticoids, antiemetic agents, analgesics, and antisecretory agents (anticholinergic drugs, somatostatin analogues, and proton-pump inhibitors). Nasogastric tube feeding is no longer used routinely and should instead be discussed on a case-by-case basis. Recent studies have confirmed the efficacy of somatostatin analogues in relieving obstruction-related symptoms such as nausea, vomiting, and pain. However, the absence of a marketing license and the high cost of these drugs limit their use as the first-line treatment, except in highly selected patients (early recurrence). When these medications fail to alleviate the symptoms of obstruction, venting gastrostomy should be considered promptly. Rehydration is needed for virtually every patient. Parenteral nutrition and pain management should be adjusted according to the patient needs and guidelines.

This study was designed to evaluate neoadjuvant intensified chemotherapy in potentially resectable or unresectable liver metastases (LM) from colorectal cancer (CRC).Criteria for potentially resectable LM were complex hepatectomy and/or risky procedure, close contact with major vascular structures, and for unresectable LM, a future liver remnant predicted to be less than 25-30 % of total liver volume. Between October 2004 and August 2007, 125 patients were randomized to either standard (FOLFIRI/FOLFOX4) or intensified chemotherapy (FOLFIRI-HD/FOLFOX7/FOLFIRINOX). Primary endpoint was objective response rate (ORR) after 4 cycles of chemotherapy. Secondary endpoints included safety, R0 surgical resection, best ORR, progression-free survival (PFS), and overall survival (OS).A total of 122 patients were treated; 45 % of patients had less than 30 % of remaining liver tissue, 20 % had major vascular contact, and 35 % were potentially resectable. Grade 3/4 toxicities were neutropenia (24, 19, 10, 23 %) diarrhoea (0, 6, 3, 23 %), mucositis (0, 3, 0, 7 %), vomiting (7, 9, 0, 3 %), and neurotoxicity (0, 0, 10, 3 %) in arms (FOLFIRI + FOLFOX4)/FOLFIRI-HD/FOLFOX7/FOLFIRINOX, respectively. ORR was 33, 47, 43, and 57 % after the first 4 cycles in arms (FOLFIRI + FOLFOX4)/FOLFIRI-HD/FOLFOX7/FOLFIRINOX, respectively. FOLFIRINOX offered the best conversion rate to resectability (67 %). Disease-free status after chemotherapy and surgery (R0, R1, Rx) was achieved in 54 of 64 operated patients. Median PFS was 9.2 months in control arms versus 11.9 months in experimental arms (hazards ratio [HR] = 0.76, p = 0.115), and the median OS was 17.7 versus 33.4 months (HR = 0.73, p = 0.297), respectively.FOLFIRINOX showed promising activity in CRC patients with LM compared with standard or intensified bi-chemotherapy regimens.

Tolerability to irinotecan may be explained by pharmacogenomic polymorphisms. The purpose of this pharmacogenetic trial was to study the relevance of thymidylate synthase (TS) genotyping and of the isoform 1A1 of uridine diphosphate glucuronosyltransferase (UGT1A1) in order to tailor a combination chemotherapy regimen of 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) in metastatic colorectal cancer.Patients with favourable TS and UGT1A1 profiles received high-dose (HD) FOLFIRI. Patients with TS-3R/3R could not receive HD-FOLFIRI, and those with UGT1A1-7/7 received standard FOLFIRI. The endpoints were overall response rate and safety.Sixty-nine patients were enrolled in the study. Sixty-five patients received chemotherapy. Twenty patients (30.8%) achieved a partial response. The haematological toxicity was less in the HD-FOLFIRI subgroup. Patients having received HD-FOLFIRI did not experience increased levels of nausea-vomiting, asthenia or alopecia. Diarrhoea was more frequent with HD-FOLFIRI.The genotypic assessment allowed a safer use of HD-FOLFIRI. Further investigations may target patients who benefit from intensification.

A regimen consisting of 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) is widely used in France in the first-line treatment of metastatic colorectal cancer (MCRC). The aim of our study was to demonstrate the non-inferiority of capecitabine plus oxaliplatin (XELOX) versus FOLFOX-6 for this indication. Patients were randomly assigned to receive XELOX or FOLFOX-6 for 6 months. The primary endpoint was overall response rate (ORR) in the per-protocol (PP) population; however, progression-free and overall survival (OS), time to response and response duration were also assessed. A total of 306 patients were enrolled (XELOX n = 156; FOLFOX-6 n = 150). ORR was 42 and 46% with XELOX and FOLFOX-6, respectively, in the PP population. The difference between groups was 4.7%; the upper limit of the unilateral 95% confidence interval (14.4%) was below the non-inferiority margin of 15%. In the intent-to-treat population, median progression-free survival was 8.8 months with XELOX and 9.3 months with FOLFOX-6, and median OS was 19.9 and 20.5 months, respectively. XELOX patients had significantly more grade 3/4 thrombocytopenia (12% vs. 5%) and diarrhoea (14% vs. 7%), but significantly less grade 3/4 neutropenia (5% vs. 47%), febrile neutropenia (0% vs. 6%) and neuropathy (11% vs. 26%) than FOLFOX-6 patients. We conclude that XELOX is non-inferior in terms of efficacy to FOLFOX-6 in the first-line treatment of MCRC, but has a different toxicity profile.

Elevated levels of α-fetoprotein (AFP), a fetal serum protein, usually signal the development of hepatoma or germ cell tumors, including endodermal sinus tumors. We report the case of a 52-year-old woman with an α-fetoprotein-producing malignant mixed Mullerian tumor (MMMT) of the ovary. Serum AFP was 5348 ng/ml at diagnosis. Immunohistochemistry confirmed that the carcinomatous component of this biphasic tumor was the seat of AFP production. After three cycles of combination chemotherapy, the patient achieved a complete remission. Serum AFP was strongly correlated with response to treatment. This is the first report of AFP production by a MMMT of the ovary without a yolk sac component.

Objective Germ-cell tumours (GCTs) with a non-GCT malignant component are a unique and rare phenomenon called teratoma with malignant transformation (TMT). The only published series of patients with TMT treated with chemotherapy comprised 10 patients. We report here our experience in treating 14 patients with TMT. Patients and methods Sarcoma was identified in 10 of 14 patients, with rhabdomyosarcoma ranking first ( n =4). Other histological types included adenocarcinoma ( n =3) and bronchoalveolar carcinoma ( n =1). Immunohistochemistry was performed to help in identifying the malignant non-GCT component. Results Primary treatment consisted of surgery alone in 4 patients. The remaining 10 patients received first-line cisplatin-based chemotherapy with resection of residual masses ( n =5): 4 patients had a complete response and 5 had a partial response. Overall, 9 patients developed a relapse with a median time of 84 mo (range: 6–168). At relapse, 8 patients received a chemotherapy regimen directed to the non-GCT component. Four of these patients achieved a partial response. With a median follow-up of 59 mo (range: 3–180), 4 of 14 patients are alive, including 3 who are disease-free. Conclusion To our knowledge, this is by far the largest reported European series of chemotherapy in TMT. Although TMT has a poor prognosis compared to GCT, its management may be improved by adapted chemotherapy associated with surgical resection of residual masses.

We evaluated the Epitax combination (epirubicin 60 mg/m2 and docetaxel 75 mg/m2, every 3 weeks) in advanced gastric cancer (AGC) as second-line treatment after fluorouracil and platinum in 50 patients, then as first-line treatment in 36 patients. We report here the results of these two phase II studies.In the second-line treatment, the response rate (RR) was 15.5%. Grade 3-4 neutropenia was observed in 68% (febrile neutropenia in 40%, one treatment-related death). Median time to progression (TTP) and overall survival (OS) were 2.4 and 5.0 months, respectively. In the first-line treatment, the RR was 19.4%. With prophylactic granulocyte colony-stimulating factor, grade 3-4 neutropenia was reported in 38.9%. Then 22 patients received a second-line and 11 patients a third-line treatment. Median TTP and OS were 4.5 and 12 months, respectively.Epitax showed moderate activity in AGC. RR in both trials suggests a non-cross resistance with fluorouracil/platinum combination. The 12-month OS in the first-line treatment could be partly explained by early evaluation and active non-cross resistant second-line therapy.

The influence of p53 mutations on the response to ionizing radiation and survival was retrospectively evaluated in patients treated with preoperative radiotherapy for rectal carcinoma. From 1989 to 1991, 86 rectal cancer patients treated by preoperative radiotherapy were included in this series. For all patients, endorectal sonography (to define ultrasonography TNM [uTNM]) was performed before treatment; 19 patients were classified as stage 1, 27 as stage 2 and 40 as stage 3. Response to radiotherapy (39 Gy in 13 fractions delivered in 17 days) was assessed by comparing the uT and the T obtained by histologic examination of the resected specimen (TNM classification). A rectal cancer biopsy was performed before treatment and enabled the search for p53 mutations by denaturing gradient gel electrophoresis (DGGE) and sequencing. The status of the p53 gene was correlated with the response to radiotherapy and survival. Forty-nine percent of the tumors presented abnormal DGGE profiles. The prevalence of p53 mutations was significantly higher in patients who did not respond to radiotherapy (63%) than in those who did respond (34%) (p0.01). Presence of a p53 mutation was associated with significantly shorter 5-year survival compared to patients without mutations (p0.02). In a multivariate analysis, p53 mutation status remained a prognostic factor independent of tumor posttreatment staging (p0.05). p53 status is an independent prognostic factor of response to radiotherapy and survival in rectal carcinoma.

Un homme de 66 ans, sans antecedent, consultait pour des epigastralgies evoluant depuis un mois, associees a une alteration de l'etat general et a un amaigrissement modere. Ces douleurs etaient permanentes sans position antalgique.

Introduction The importance of the tumoral response to induction chemotherapy for hepatic metastases which are not resectable straightaway but potentially resectable (class II ) in colorectal cancers is essential for a secondary resection. The aim of this study was to assess the efficiency and the tolerance to induction chemotherapy which associates LV5FU2 to increased doses of Irinotecan adapted to the UGT1A1 genotyping and Cetuximab. Six courses were planned and two more courses in case of borderline resectability. Methods Twenty-six patients, 0 or 1 PS, with hepatic metastases (with or without lung metastases) from a CRC which are potentially resectable without any mutation of the Kras oncogene (Kras WT) and having had no chemotherapy, received at least one course of chemotherapy associating Irinotecan Day 1 260 mg/sqm for UGT1A1 6/6 and 6/7 genotypes and 180 mg/sqm for UGT1A1 7/7 genotypes, with Leucovorin 200 mg/sqm Day 1, 5FU 400mg/sqm bolus and 2400mg/sqm continuous drip for 46 hours, and Cetuximab D1 400mg/sqm for the first injection then 250mg/sqm for the next injections ( Day 1=Day 14). A primary prevention by GCSF (Lenograstim D5 to D9) was achieved in UGT1A1 6/7 and 7/7 genotypes. The main point was the response rate (RECIST) and the secondary points were tolerance (NCI-CTC criteria), the R0 resection rate in hepatic metastases. Results The average age was 58 (41-77). The average number of courses per patient was 6 (+/- 1.9). Three patients (11.5 %) had potentially resectable lung metastases associated with hepatic metastases. The UGT1A1 genotype was 6/6 in 9 cases (34.6%), 6/7 in 14 cases (53.9%) and 7/7 in 3 cases (11.5%). In intent to treat, after 8 courses, 19 patients presented a partial response, 4 patients (15.3%) were stabilized, 2 patients (7.7%) passed away independently of chemotherapy and 1 patient (3.9%) was lost from sight. No progression was noted. Among patients who could be assessed (n=23), the kinetics of the response were fast (chart). The most frequent grade 3-4 toxicities were neutropenia (28.9%), diarrhea (17.7%), anorexia (13.9%) and nausea (3.9%). There was no death due to toxicity. Two years overall survival was 57% and 2 years progression free survival was 25.2%. Conclusion The high dose Folfiri associated with Cetuximab generates major response rates and enables complete resections of class II hepatic metastases in most patients. It seems to be well tolerated among healthy selected patients. Table 1 .

The aim of the study was to investigate the residual blood level of O before each cycle of various oxaliplatin (O) based protocols, and to explore its predictive value for potential occurrence of a severe neurotoxicity. Methods: Between 11/2005 and 06/2008, 220 Pts were included in a prospective cohort, in 7 French centers. Patients received a minimum of 7 cycles of O. Blood samples were taken before each cycle with a maximum of 12 cycles. In parallel neurotoxicity was assessed by the modified Levi score (grade 0 to 3) and by the Von Frey filament exam. Saliva was collected before the first cycle for genomics analysis. The O concentration was obtained by Atomic Absorption Spectrometry assay after nitric digestion of total blood. Polymorphism of different targets were investigated (carrier proteins: MRP2, OCT1, OCT2, GSTP1, adducts repair system: ERCC1, ERCC2). Time to first severe neurotoxicity occurrence (TTSN Events: Grade 2 or3) was estimated using Kaplan-Meier. Predictive value of severe neurotoxicity was explored using univariate and multivariate logistic or Cox regressions. Harrel C index was produced. Results: 206 pts with gastro-intestinal cancer had, at the time of analysis, completed follow-up and 201 pts (91.3%) were eligible for pharmacokinetics. (85%) received FOLFOX regimen (85mg/m2every 2 weeks), the others GEMOX or XELOX (100mg/m2 every 3 weeks). The mean total dose of O received for all pts was 1.18 ± 0.4 g. After cycle 1, 2 and 10, median residual level of O was respectively 0.31 mg/L, 0.43 mg/L and 0.60 mg/L. The maximal concentration was obtained between cycle 5 and cycle 9. Respectively 89 Pts (44%) and 15 pts (7%) had a Gr2 and a Gr3 neurotoxicity. Median time TTSN was 141 days (95% CI: 132 – 161). O concentration before 2nd cure (HR = 1.39, p < 0.0001) is associated with TTSN (cure N°2 for Gr0 and Gr1, cure N° 7 for Gr2 and Gr3) but not with the frequency. Multivariate logistic and Cox analyses confirmed these results. Conclusions: 1. The mean residual blood level of O before the second cure is correlated with the occurrence of Gr2 or Gr3 neurotoxicity (p Mann-Whitney = 0.0007) 2. The residual blood level of O before the second O cure is correlated with the delay of occurrence of a Gr2 or Gr3 neurotoxicity in patients receiving an O based-regimen (Harrel C=0.54, p=0.021). Further statistical analyses will be done to analyse the data from the Von Frey filaments and the gene polymorphism and will be presented at the meeting. An O posology adaptation or infusion duration modification based on Platinum residual level of cure 1 have to be considered in future clinical trial in order to avoid severe Gr2 or Gr3 neurotoxicity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C129.

e15024 The aim of the study was to investigate the residual blood level of O before each cycle of various oxaliplatin (O)-based protocols, and to explore its predictive value for potential occurrence of a severe neurotoxicity. Methods: Between 11/2005 and 06/2008, 220 Pts were included in a prospective cohort, in 7 French centers. Patients received a minimum of 7 cycles of O. Blood samples were taken before each cycle with a maximum of 12 cycles. In parallel neurotoxicity was assessed by the modified Levi score (grade 0 to 3) and by the Von Frey filament exam. Saliva was collected before the first cycle for genomics analysis. The O concentration was obtained by Atomic Absorption Spectrometry assay. Polymorphism of different targets were investigated (carrier proteins: MRP2, OCT1, OCT2, GSTP1, adducts repair system: ERCC1, ERCC2). Time to first severe neurotoxicity occurrence (TTSN Events: Grade 2 or3) was estimated using Kaplan-Meier. Predictive value of severe neurotoxicity was explored using univariate and multivariate logistic or Cox regressions. Harrel C index was produced. Results: 206 pts with gastro-intestinal cancer had, at the time of analysis, completed follow-up and 171 pts were eligible. 84% received FOLFOX regimen (85mg/m2every 2 weeks), the others GEMOX or XELOX (100mg/m2 every 3 weeks). After cycle 1, 2 and 10, median residual level of O was respectively 0.23 mg/L, 0.40 mg/L and 0.58 mg/L. The maximal concentration was obtained between cycle 5 and cycle 9. Respectively 83 Pts (40%) and 15 pts (7%) had a Gr2 and a Gr3 neurotoxicity. Median time TTSN was 141 days (95% CI: 132 - 161). O concentration before 2nd (HR = 1.39, p = 0.34, C =0.53) or 3rd cycle (HR = 1.00, p = 0.99, C =0.54) were not associated with TTSN. Multivariate logistic and Cox analyses confirmed these results. Conclusions: Despite a trend, which needs to be confirmed, the residual blood level of O is not predictive of a Gr 2 or Gr 3 neurotoxicity in patients with an O based-regimen. With updated data, further statistical analyses will be done to be presented at the next ASCO meeting. They will take into account more precise data as the cycle delay or the dose-intensity of O received by the patients. [Table: see text]

Background Linking independent sources of data describing the same individuals enable innovative epidemiological and health studies but require a robust record linkage approach. We describe a hybrid record linkage process to link databases from two independent ongoing French national studies, GEMO (Genetic Modifiers of BRCA1 and BRCA2), which focuses on the identification of genetic factors modifying cancer risk of BRCA1 and BRCA2 mutation carriers, and GENEPSO (prospective cohort of BRCAx mutation carriers), which focuses on environmental and lifestyle risk factors. Methods To identify as many as possible of the individuals participating in the two studies but not registered by a shared identifier, we combined probabilistic record linkage (PRL) and supervised machine learning (ML). This approach (named “PRL + ML”) combined together the candidate matches identified by both approaches. We built the ML model using the gold standard on a first version of the two databases as a training dataset. This gold standard was obtained from PRL-derived matches verified by an exhaustive manual review. Results The Random Forest (RF) algorithm showed a highest recall (0.985) among six widely used ML algorithms: RF, Bagged trees, AdaBoost, Support Vector Machine, Neural Network. Therefore, RF was selected to build the ML model since our goal was to identify the maximum number of true matches. Our combined linkage PRL + ML showed a higher recall (range 0.988–0.992) than either PRL (range 0.916–0.991) or ML (0.981) alone. It identified 1995 individuals participating in both GEMO (6375 participants) and GENEPSO (4925 participants). Conclusions Our hybrid linkage process represents an efficient tool for linking GEMO and GENEPSO. It may be generalizable to other epidemiological studies involving other databases and registries.

Introduction : Colorectal cancer is the third cancer in Europa in terms of incidence. Liver metastases, synchronous in 20 to 30% of patients or metachronous in the follow up in 50% of the patients, impact the prognosis. Methods : One hundred and seventy eight patients treated by surgery and/or radiofrequency for liver metastases exclusively have been included. Clinical, radiological data and features of the primary tumor and metastasis have been analysed. Results : The median survival was 52,5 months in the synchronous population and 70,2 months in the metachronous population. The initial lymph node staging and preoperative radiofrequency (p=0,03 and 0,04 respectively) are associated with a decrease of the overall survival in the synchronous population. Multivariate analysis indicates that a number of metastasis > 5 and delivery of post operative chemotherapy are significantly associated with decreased overall survival in case of metachronous metastasis. Conclusion : Synchronous presentation is a pejorative feature correlated with a OS decreasing. Synchronous and metachronous liver metastasis don’t share the same prognosis features. The onco surgical management should be differenciated. Metachronous metastasis can be cured by an exclusive surgery but our study demonstrates the benefits of an adjuvant treatment.; Introduction : Le cancer colorectal représente le 3è cancer en terme d’incidence en Europe. Les métastases hépatiques, synchrones chez 20 à 30% des patients ou d’apparition métachrone dans le suivi de 50% des patients, grèvent son pronostic. L’exérèse carcinologique à visée curative reste primordiale puisqu’elle améliore significativement la survie. L’objectif principal de ce travail était donc l’évaluation de leurs facteurs pronostiques respectifs en population réelle sur une série rétrospective monocentrique. Matériel et méthodes : 178 patients opérés et/ou traités par radiofréquence pour des métastases hépatiques exclusives ont été inclus dans l’étude. Les données clinico radiologiques et les caractéristiques de l’atteinte primitive et métastatique ont été analysées. Résultats : La survie médiane était de 52,5 mois pour les métastases synchrones versus 70,2 mois dans la population de métastases métachrones. L’envahissement ganglionnaire initial (p=0,03) et la radiofréquence peropératoire (p=0,04) sont associés à une diminution de la survie globale dans la population synchrone. En analyse multivariée, seul le nombre de métastases supérieur à 5 et la chimiothérapie post opératoire sont statistiquement associés à la survie des métastases métachrones. Conclusion : Le caractère synchrone est un facteur péjoratif corrélé à une diminution de la survie globale. Les métastases hépatiques synchrones et métachrones ne partagent donc pas les mêmes facteurs pronostiques et leur prise en charge onco-chirurgicale doit être différenciée. Les patients avec atteinte hépatique métachrone peuvent parfois relever d’une exérèse chirurgicale exclusive mais notre étude conforte les bénéfices d’un traitement adjuvant.