[Show abstract][Hide abstract] ABSTRACT: Several bacterial species have been implicated in the development of colorectal carcinoma (CRC), but CRC-associated changes of fecal microbiota and their potential for cancer screening remain to be explored. Here, we used metagenomic sequencing of fecal samples to identify taxonomic markers that distinguished CRC patients from tumor-free controls in a study population of 156 participants. Accuracy of metagenomic CRC detection was similar to the standard fecal occult blood test (FOBT) and when both approaches were combined, sensitivity improved > 45% relative to the FOBT, while maintaining its specificity. Accuracy of metagenomic CRC detection did not differ significantly between early- and late-stage cancer and could be validated in independent patient and control populations (N = 335) from different countries. CRC-associated changes in the fecal microbiome at least partially reflected microbial community composition at the tumor itself, indicating that observed gene pool differences may reveal tumor-related host–microbe interactions. Indeed, we deduced a metabolic shift from fiber degradation in controls to utilization of host carbohydrates and amino acids in CRC patients, accompanied by an increase of lipopolysaccharide metabolism.
Molecular Systems Biology 11/2014; 10(11). · 14.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination.
Journal of Clinical Oncology 11/2014; · 17.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This two-arm, randomised, multicentre, open-label, phase IIIb study investigated the safety and efficacy of a 3-h catumaxomab infusion with/without prednisolone premedication to reduce catumaxomab-related adverse events. Patients with malignant ascites due to epithelial cancer received four 3-h intraperitoneal catumaxomab infusions with/without intravenous prednisolone (25 mg) premedication before each infusion. The primary safety endpoint was a composite safety score calculated from the incidence and intensity of the most frequent catumaxomab-related adverse events (pyrexia, nausea, vomiting and abdominal pain). Puncture-free survival (PuFS) was a co-primary endpoint. Time to next puncture (TTPu) and overall survival (OS) were secondary endpoints. Prednisolone premedication did not result in a significant reduction in the main catumaxomab-related adverse events. The mean composite safety score was comparable in both arms (catumaxomab plus prednisolone, 4.1; catumaxomab, 3.8; p = 0.383). Median PuFS (30 vs. 37 days) and TTPu (78 vs. 102 days) were shorter in the catumaxomab plus prednisolone arm than in the catumaxomab arm, but the differences were not statistically significant (p = 0.402 and 0.599, respectively). Median OS was longer in the catumaxomab plus prednisolone arm than in the catumaxomab arm (124 vs. 86 days), but the difference was not statistically significant (p = 0.186). The superiority of catumaxomab plus prednisolone versus catumaxomab alone could not be proven for the primary endpoint. Prednisolone did not result in a significant reduction in the main catumaxomab-related adverse events. The study confirms the safety and efficacy of catumaxomab administered as four 3-h intraperitoneal infusions for the treatment of malignant ascites.
Medical Oncology 08/2014; 31(8):76. · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The clinical benefit of guaiac fecal occult blood tests (FOBT) is now well established for colorectal cancer screening. Growing evidence has demonstrated that epigenetic modifications and fecal microbiota changes, also known as dysbiosis, are associated with CRC pathogenesis and might be used as surrogate markers of CRC.
PLoS ONE 07/2014; 9(7):e99233. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Health-related quality of life (QoL) has prognostic value in many cancers. A recent study found that the performance of prognostic systems for metastatic colorectal cancer (mCRC) were improvable. We evaluated the independent prognostic value of QoL for overall survival (OS) and its ability to improve two prognostic systems'performance (Kohne and GERCOR models) for patients with mCRC.
Health and Quality of Life Outcomes 05/2014; 12(1):69. · 2.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background & aims
We assessed the prevalence and risk factors of malnutrition in elderly cancer patients.
We studied a prospective cohort of solid cancer patients aged ≥70 years at referral to two geriatric oncology clinics between 2007 and 2010. Nutrition was evaluated using the Mini-Nutritional Assessment (MNA) using validated cut-offs (<17: malnutrition, 17–23.5: at-risk for malnutrition). Patients with non-digestive tumours (breast, prostate, urinary tract) and with digestive (colorectal, upper digestive tract and liver) were analysed separately using multinomial logistic regression.
Of 643 consecutive patients, 519 had available data (median age, 80; men, 48.2%; metastases, 46.3%; digestive cancer 47.8%). In non-digestive group, 13.3% had malnutrition versus 28.6% in digestive group. The link between metastasis and malnutrition was significantly higher in non-digestive group (adjusted odds ratio [ORa ], 25.25; 95%CI: 5.97–106.8) than in digestive group (ORa, 2.59; 1.08–6.24; p for heterogeneity = 0.04). Other factors independently associated with malnutrition were cognitive impairment (ORa MMMSE ≤ 24 versus > 24 in non-digestive group: 16.68; 4.89–56.90 and in digestive group: 3.93; 1.34–11.50), and depressed mood (ORa MiniGDS ≥1 versus <1 in non-digestive group: 11.11; 3.32–37.17 and in digestive group: 3.25; 1.29–8.15) and fall risk (ORa fall risk versus no fall risk in non-digestive group: 4.68; 1.77–12.37; in digestive group: 100% of malnourished patients were faller's).
We highlighted, in elderly cancer patients, the high prevalence of malnutrition and that geriatrics syndromes (i.e. cognitive impairment, depressed mood and fall risk) were independent risk factors for malnutrition. Moreover, metastatic status was significantly much more strongly associated with malnutrition in non-digestive than digestive tumours.
[Show abstract][Hide abstract] ABSTRACT: Background/Objective
G-8 screening tool showed good screening properties for identifying vulnerable elderly patients with cancer who would benefit from a comprehensive geriatric assessment (CGA). We investigated whether tumour site and metastatic status affected its accuracy.
Materials and Methods
Design: Cross-sectional analysis of a prospective cohort study. Setting: Geriatric-oncology clinics of two teaching hospitals in the urban area of Paris. Participants: Patients aged 70 or over (n = 518) with breast (n = 113), colorectal (n = 108), urinary-tract (n = 89), upper gastrointestinal/liver (n = 85), prostate (n = 69), or other cancers (n = 54). Measurements: Reference standard for diagnosing vulnerability was the presence of at least one abnormal test among the Activities of Daily Living (ADLs), Instrumental ADL, Mini-Mental State Examination, Mini Nutritional Assessment, Cumulative Illness Rating Scale-Geriatrics, Timed Get-Up-and-Go, and Mini-Geriatric Depression Scale. Sensitivity, specificity and likelihood ratios of G-8 scores ≤ 14 were compared according to tumour site and patient characteristics.
Median age was 80; 48.2% had metastases. Prevalence of vulnerability and abnormal G-8 score was 84.2% (95% confidence interval [95% CI], 81–87.3) and 79.5% (95% CI, 76–83). The G-8 was 86.9% sensitive (95% CI, 83.4–89.9) and 59.8% specific (95% CI, 48.3–70.4). G-8 performance varied significantly (all p values < 0.001) across tumour sites (sensitivity, 65.2% in prostate cancer to 95.1% in upper gastrointestinal/liver cancer; and specificity, 23.1% in colorectal cancer to 95.7% in prostate cancer) and metastatic status (sensitivity and specificity, 93.8% and 53.3% in patients with metastases vs. 79.5% and 63.3% in those without, respectively). Differences remained significant after adjustment on age and performance status.
These G-8 accuracy variations across tumour sites should be considered when using G-8 to identify elderly patients with cancer who could benefit from CGA.
Journal of Geriatric Oncology 01/2014; 5(1):11–19. · 1.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aromatase inhibitors (AI) are the first-line treatment in women with breast cancer for total estrogen depletion. Half the treated women may develop pain and this condition may therefore be seen as a clinical model of pain related to estrogen deprivation. In this prospective multicenter study, we classified AI-related pain syndromes and identified their predictors. A one-year, prospective, multicenter cohort study, with six visits, was carried out on 135 women with early-stage breast cancer and no pain at the start of AI treatment. At initial assessment, we investigated clinical (demographic and psychosocial, cancer characteristics and treatment, sleep, quality of life), biological (sex hormones, vitamin D, bone biomarkers, oxidative stress, immunological and inflammatory markers), environmental and genetic (polymorphism for pain mechanisms) risk factors for pain. During one year of follow-up, 77 women (57%) developed pain, leading to AI discontinuation in 12 cases. Five pain syndromes were identified: joint pain (36%), diffuse pain (22%), tendinitis (22%), neuropathic pain (9%) and mixed pain (11%), mostly persistent (57%), with diffuse and joint pains the most intense. Risk factors for the development of pain included higher levels of anxiety and impaired quality of life at the initial assessment, whereas cancer characteristics, genetic background, inflammation, immunological and hormonal status at baseline were not significant predictors.
The journal of pain: official journal of the American Pain Society 12/2013; · 4.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with colorectal tumors with microsatellite instability MSI) have better prognoses than patients with tumors without MSI, but have a poor response to 5-fluorouracil-based chemotherapy. A dominant-negative form of HSP110 HSP110DE9) expressed by cancer cells with MSI, via exon skipping caused by somatic deletions in the T17 intron repeat, sensitizes the cells to 5-fluorouracil and oxaliplatin. We investigated whether HSP110 T17 could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin.
We characterized the interaction between HSP110 and HSP110DE9 using surface plasmon resonance. Using PCR and fragment analysis, we examined how the size of somatic allelic deletions in HSP110 T17 affected the HSP110 protein expressed by tumor cells. We screened a 329 consecutive patients with stage II-III colorectal tumors with MSI who underwent surgical resection, at tertiary medical centers, for HSP110 T17.
HSP110 and HSP110DE9 interacted in a 1:1 ratio. Tumor cells with large deletions in T17 had increased ratios of HSP110DE9:HSP110, due to the loss of expression of full-length HSP110. Deletions in HSP110 T17 were mostly bi-allelic in primary tumor samples with MSI. Patients with stage II-III cancer who received chemotherapy and had large HSP110 T17 deletions ≥5 bp; 18/77 patients, 23.4%) had longer times of relapse-free survival than patients with small or no deletions ≤4 bp; 59/77 patients, 76.6%) in multivariate analysis hazard ratio, 0.16; 95% confidence interval, 0.012-0.8; P=.03). We found a significant interaction between chemotherapy and T17 deletion P=.009).
About 25% of patients with stage II-III colorectal tumors with MSI have an excellent response to chemotherapy, due to large, bi-allelic deletions in the T17 intron repeat of HSP110 in tumor DNA.
[Show abstract][Hide abstract] ABSTRACT: HER2 is overexpressed in 10 to 20% of gastro-esophageal adenocarcinoma (GE-ADK), and is a target for trastuzumab in metastatic patients. We conducted a study to compare HER2 expression between diagnostic biopsies (DBs) and surgical specimens (SSs) of GE-ADK, and to determine the influence of non-trastuzumab containing neoadjuvant chemotherapy (NAC) on this expression.
Pathological specimens from biopsies of 228 patients operated on between 2004 and 2011 were collected. Two cohorts treated (n = 141) or not (n = 87) with a NAC were constituted. Two blind independent pathological HER2 analyses on DB and on SS were carried out using immunohistochemistry (IHC) and colorimetric in situ hybridization (CISH). HER-2 overexpression (HER2+) was defined by a score 3+ in IHC, or 2+ with a positive CISH test, according to the specific HER2 scoring guidelines for GE-ADK.
Paired HER2 status could be determined for 218 out of the 228 patients (95.6%). HER2+ rates were 13.3% on DB (29/218) and 14.7% on SS (32/218). HER2+ tumors were mainly cardial or esophageal adenocarcinomas, with a well-differentiated, intestinal histological type. HER2 status differed between DB and SS in 6% of cases. When DB analyses were added to SS analyses, the relative increase in HER2+ cases was 13.5% (17.1% for patients with NAC and 23.5% for patients with histological response to NAC, versus 7.1% for patients without NAC, P = 0.4, NS). Differences between DB and SS HER2 expression could be explained by intratumoral heterogeneity and by a HER2 expression decrease in SS after NAC in responding patients possibly due to a higher chemosensitivity of HER2-positive clones.
The determination of HER2 status on DB provides results that complete those obtained with SS. Combining the analysis of DB and of SS enables to optimize the selection of trastuzumab-eligible patients in case of metastatic relapse, and particularly in previously NAC-responding patients.
[Show abstract][Hide abstract] ABSTRACT: First-line oxaliplatin-based therapy is the standard treatment of metastatic colorectal cancer (mCRC), but its dose-limiting toxicity is sensory neuropathy. The OPTIMisation of OXaliplatin (OPTIMOX) stop-and-go approach with oxaliplatin-free interval (OFI) offers a reasonable strategy. Influence of the first-line oxaliplatin-based treatment efficacy and the duration of OFI on tumour sensitivity to oxaliplatin reintroduction were investigated.
This was a pooled analysis of OPTIMOX1 and OPTIMOX2 studies, on 285 patients with previously untreated mCRC and FOLFOX reintroduction. An optimal OFI was estimated. Efficacy endpoints measured from reintroduction of FOLFOX included response rate (RR), progression-free survival (PFS) and overall survival (OS).
Two groups of OFI <6 and ⩾6months, were defined. The RR following FOLFOX reintroduction were 14% and 22% in patients with an OFI <6 and ⩾6months, respectively (overall RR 19%). The median PFS after FOLFOX reintroduction following OFI< 6 and ⩾6months were 3.0 [95% confidence intervals (CI): 2.7-3.7] and 5.5months [95% CI: 4.8-6.5], respectively. The median OS following OFI <6months was 8.8months [95% CI: 7.5-10.5] and OFI ⩾6 was months 16.8months [95% CI: 15.3-19.6]. In the case of partial response (PR), median PFS and OS were 4.6 [95% CI: 4.1-5.0] and 14months [95% CI: 12.1-16.4], respectively, whereas in patients with initial stable disease (SD) 3.4 [95% CI: 2.7-4.7] and 10.3months [95% CI: 7.3-12.9], respectively.
A sensitive population of patients more likely to benefit from oxaliplatin reintroduction is defined by the efficacy of induction therapy followed by an OFI of at least 6months between two periods of FOLFOX therapy. OFI of <6months identifies a subgroup of partially-resistant patients who can still benefit from oxaliplatin reintroduction.
European journal of cancer (Oxford, England: 1990) 09/2013; · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives
Since 2002, identified palliative care beds (LISP) have contributed to the diversification and development of palliative care offer in France, but with a risk of structural imbalance with the palliative care units (USP). This clinical survey was born from questions of the team of oncology at Saint-Antoine Hospital (Paris) on transfer criteria in USP, and on subjectivity in the proposals made to the patient.
Materials and methods
Prospective, observational 1-year survey, including all patients hospitalized in 2010 for which a transfer request in an USP was performed. Parameters related to the patient, circumstances and ground of request, and the score of the GEMAU grid (admission criteria in USP), were collected.
In 2010, 131 patients died in the service, 34 transfer requests to USP were made (77 in 2004, 48 in 2006), no denial. Twenty-seven transfers were performed (79%), seven patients died before the transfer. The median time between request and transfer is five days (± 4.9). The prognosis at request time is between 15 days and 1 month in 49% of cases. The median time between transfer and death (all in USP) is 16 days (± 28.7).
The number of transfer requests in USP decreased after introduction of LISP. Absence of refusal by the USP shows a good congruence of criteria. Team management and physician training allow the application to be made at the right time for an optimal evaluation, however, the proposed grid do not define objective criteria for transfer proposal. Further studies are needed to better clarify the relationship between these two types of palliative care.
Médecine Palliative Soins de Support - Accompagnement - Éthique 08/2013; 12(4):185–191.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Supportive care in cancer (SCC) was further enhanced in the Second National Cancer Act decreed in December 2009. The aim of our study was to assess current SCC efficacy. PATIENTS AND METHODS: The French speaking association for supportive care in cancer (AFSOS) conducted an observational study to evaluate practices, organisations and information given to patients. A specific 32 point questionnaire was sent to 1621 French physicians (MDs) caring for cancer patients. RESULTS: Three different organisations were evaluated: the individual MDs, the transversal team and its particular structure specialised in global patient care specifically developed at comprehensive cancer centres - CCC. During their disease, 68% of patients received SCC, which was more available during the palliative period (90%) than at the diagnosis (44%). Our results found that 71% of cancer departments had a specific interdisciplinary cross-team to provide SCC, particularly in CCC (62%; p=0.01) while 37% had specific inpatient units. A specific organisation dedicated to home care was greater in CCC than in public or private centres (69%, 45%, 20% respectively; p=0.01). Adverse event information was performed more by an oncologist than other specialists (p=0.01). CONCLUSION: Our results suggest that the specific SCC organisation could be a useful management tool to improve supportive care for cancer patients.
European journal of cancer (Oxford, England: 1990) 12/2012; · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The purpose of this study was to evaluate the combination of panitumumab and irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines-irinotecan and bevacizumab).Patients and methodsKRAS status was first determined locally but subsequent validation of KRAS status and additional screenings (rare KRAS, NRAS, BRAF mutations and EGFR copy number) were centrally assessed. Patients received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks.ResultsSixty-five eligible patients were analyzed. The objective response rate (ORR) was 29.2% [95% confidence interval (95% CI) 18.2-40.3]. Median progression-free and overall survivals were 5.5 and 9.7 months, respectively. Most frequent grade 3/4 toxic effects were skin 32.3%, diarrhea 15.4% and neutropenia 12.3%. Tissue samples were available for 60 patients. For the confirmed KRAS wild-type population codon 12 or 13 mutation (n = 54), ORR was 35.2% (95% CI 22.4.1-47.9). Thirteen patients had a NRAS, a BRAF or a rare KRAS mutation, and no tumor response was observed in this subgroup when compared with 46.3% (95% CI 31.1-61.6) ORR in the subgroup of 41 patients with no identified mutation.Conclusion
Panitumumab and irinotecan is an active third-line regimen in a well-defined population based on biomarkers.ClinicalTrials.gov IdentifierNCT00655499.
[Show abstract][Hide abstract] ABSTRACT: PURPOSE Oxaliplatin combined with fluoropyrimidine improves survival in patients with stage III colon cancer. However, adjuvant chemotherapy with oxaliplatin is controversial in stage II and elderly patients. PATIENTS AND METHODS We performed subgroup analyses of stage II and elderly patients randomly assigned fluorouracil with leucovorin (FL) ± oxaliplatin (FOLFOX4) in the Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer study. Comorbidities, severe adverse events, second cancers, management of relapse and death as a result of causes than other colon cancer were studied. Results Two thousand two hundred forty-six patients were enrolled. Overall, 899 patients had stage II disease, including 330 low-risk and 569 high-risk patients. A total of 315 patients were ages 70 to 75 years. For stage II patients, the hazard ratio (HR) for comparing FOLFOX4 with FL was 0.84 (95% CI, 0.62 to 01.14) for disease-free survival (DFS), 0.70 (95% CI, 0.49 to 0.99) for time to recurrence (TTR), and 1.00 (95% CI, 0.70 to 1.41) for overall survival (OS). There was no interaction between treatment and stage or age. Low-risk stage II patients did not benefit from oxaliplatin. In high-risk stage II patients, the HR comparing FOLFOX4 with FL was 0.72 (95% CI, 0.51 to 1.01) for DFS, 0.62 (95% CI, 0.41 to 0.92) for TTR, and 0.91 (95% CI, 0.61 to 1.36) for OS. In elderly patients, the HR comparing FOLFOX4 with FL was 0.93 (95% CI, 0.64 to 1.35) for DFS, 0.72 (95% CI, 0.47 to 1.11) for TTR, and 1.10 (95% CI, 0.73 to 1.65) for OS. CONCLUSION The results of these subset analyses show no statistically significant benefit (OS and DFS) for the addition of oxaliplatin to FL as adjuvant treatment for either stage II and elderly patients.
Journal of Clinical Oncology 08/2012; 30(27):3353-60. · 17.88 Impact Factor