[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. · 2.27 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; · 3.78 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 01/2013; 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. · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: While surgery is the cornerstone treatment for early-stage colorectal cancer, chemotherapy is the first treatment option for metastatic disease when tumor lesions are frequently not fully resectable at presentation. Mortality from colon cancer has decreased over the past 30 years, but there is still a huge heterogeneity in survival rates that can be mainly explained by patient and tumor characteristics, host response factors, and treatment modalities. The management of unresectable metastatic colorectal cancer is a global treatment strategy, which applies several lines of therapy, salvage surgery, maintenance, and treatment-free intervals. The individualization of cancer treatment is based on the evaluation of prognostic factors for survival (serum lactate dehydrogenase level, performance status), and predictive factors for treatment efficacy [Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status]. The available treatment modalities for metastatic colorectal cancer are chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), anti-angiogenic agents (e.g. bevacizumab), and anti-epidermal growth factor agents (cetuximab, panitumumab). The increasing number of active compounds dictates the strategy of trials evaluating these treatments either in combination or sequentially. Alternative outcomes that can be measured earlier than overall survival are needed to shorten the duration and reduce the size and cost of clinical trials.
rapeutic Advances in Medical Oncology, The 03/2012; 4(2):75-89.
[Show abstract][Hide abstract] ABSTRACT: Adjuvant treatment of colon cancer, one of the most common malignancies, is an important issue in oncology. This article describes the development of adjuvant therapy and how the 2 major evolution steps, the successes of fluoropyrimidines, and then of oxaliplatin, have been achieved, Problems and failures, such as those of targeted therapies, also are addressed to help us to overcome their limitations. Special situations, such as stage II disease and an elderly population in which adjuvant chemotherapy is still controversial, are reviewed from the clinician perspective. The synthesis of these data allows us to conceive a future development focused on translational research.
Clinical Colorectal Cancer 12/2011; 10(4):218-26. · 1.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Carcinoma of the anal canal is a rare disease accounting for 1-5% of gastrointestinal tract malignancies. However, its incidence is increasing worldwide. Chemoradiation is the standard treatment for most patients with squamous-cell carcinoma of the anal canal and was first described by Nigro et al. Since then, no other effective treatment was developed. Patients with metastatic disease should be considered candidates for clinical trials. New treatment strategies, including molecular target therapies, are warranted in order to improve disease control. Despite the rarity of this disease, it is urgent to improve its treatment by introducing targeted therapy in the arena.
Gastroentérologie Clinique et Biologique 12/2011; 36(3):209-13. · 0.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Progression-free survival (PFS) is not an optimal end point to evaluate therapeutic strategies in advanced colorectal cancer (ACRC). Therefore, composite end points have been proposed to evaluate a chemotherapy strategy when sequential treatments are available: duration of disease control (DDC) and time to failure of strategy (TFS). The goal of this study was to evaluate these alternative end points and their potential surrogacy for overall survival (OS).
We pooled individual patient data from three randomized trials evaluating chemotherapy strategy, which accrued 1,042 patients with previously untreated ACRC. In these trials, first-line treatment was either oxaliplatin- or irinotecan-based chemotherapy. Compared with TFS, DDC included neither time interval between progression and next sequence of treatment nor time to progression if the best result of the next sequence of treatment was progression.
There was good correlation between DDC and OS (correlation of median: r, 0.62; correlation of hazard ratio [HR]: adjusted copula R(2), 0.72) and between TFS and OS (correlation of median: r, 0.59; correlation of HR: adjusted copula R(2), 0.67). There was no correlation between PFS and OS (correlation of median: r, 0.45; correlation of HR: adjusted copula R(2), 0.47).
DDC and TFS roughly achieved the same results. Both are acceptable new end points to evaluate a therapeutic strategy in ACRC. Although TFS achieved a pragmatic evaluation of a multiline strategy, DDC captured the effect of a specific sequence in a therapeutic strategy.
Journal of Clinical Oncology 11/2011; 29(31):4199-204. · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Heat shock proteins (HSPs) are necessary for cancer cell survival. We identified a mutant of HSP110 (HSP110ΔE9) in colorectal cancer showing microsatellite instability (MSI CRC), generated from an aberrantly spliced mRNA and lacking the HSP110 substrate-binding domain. This mutant was expressed at variable levels in almost all MSI CRC cell lines and primary tumors tested. HSP110ΔE9 impaired both the normal cellular localization of HSP110 and its interaction with other HSPs, thus abrogating the chaperone activity and antiapoptotic function of HSP110 in a dominant-negative manner. HSP110ΔE9 overexpression caused the sensitization of cells to anticancer agents such as oxaliplatin and 5-fluorouracil, which are routinely prescribed in the adjuvant treatment of people with CRC. The survival and response to chemotherapy of subjects with MSI CRCs was associated with the tumor expression level of HSP110ΔE9. HSP110 may thus constitute a major determinant for both prognosis and treatment response in CRC.
Nature medicine 09/2011; 17(10):1283-9. · 27.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epidermal growth factor receptor (EGFR) and VEGF(R) signaling show extensive cross-talk, providing a rationale for joint targeting of the two pathways. However, combinations of monoclonal antibodies (mAb) targeting EGFR and VEGF showed disappointing activity in patients with colorectal cancer (CRC). We speculated that inhibition of surface receptors and ligands might only partly prevent oncogenic signaling whereas small-molecule tyrosine kinase inhibitors (TKI) would also influence intracellular signaling.
Mice with CRC xenografts were treated with two TKIs, vargatef and afatinib, or with two mAbs, bevacizumab and cetuximab, and their influence on tumor growth, viability, in vivo DNA synthesis, and the presence of phosphorylated EGFR and VEGFR was determined. The activity of the TKIs was further characterized in CRC cells with different KRAS status.
Vargatef and afatinib together showed strong tumor growth inhibition toward HT-29 xenografts compared with either drug alone, which was associated with a 5-fold increase in apoptotic tumor cell death. In comparison, bevacizumab and cetuximab together were exclusively cytostatic with no more activity than either drug alone. Exposure to the two TKIs was accompanied by a marked decrease of tumor-associated intracellular phospho-VEGFR1 and phospho-EGFR, whereas similar exposure to the two mAbs had no detectable effect. A synergistic activity of vargatef plus afatinib was observed in all eight CRC cell lines examined, independent of KRAS status.
Our results indicate that attenuation of intracellular EGFR and/or VEGF signaling is required for cytotoxic activity. These findings provide a rationale for trials of the TKIs, even in patients with mutant KRAS.
Clinical Cancer Research 08/2011; 17(20):6522-30. · 7.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present study was done to establish a prognostic model for patients and trials using an oxaliplatin-based or irinotecan-based first-line chemotherapy in metastatic colorectal cancer.
Eight hundred three patients treated with FOLFOX or FOLFIRI in three prospective trials were randomly separated into learning (n = 535) and validation (n = 268) samples. Eleven baseline variables were evaluated in univariate and multivariate analysis as prognostic factors for overall survival, and a prognostic score was developed.
Independent prognostic factors identified in multivariate analysis for overall survival were performance status (PS) (p < .001), serum lactate dehydrogenase (LDH) (p < .001), and number of metastatic sites (p = .005). A prognostic score based on these three variables was found efficient (Harrell's C index 0.61). This new model was improved by selecting only PS and LDH (Harrell's C index 0.64). Three risk groups for death could be identified: a low-risk group (n = 184; median overall survival [OS] 29.8 months), an intermediate-risk group (n = 223; median OS 19.5 months), and a high-risk group (n = 128; median OS 13.9 months). Median survival for the low-, intermediate-, and high-risk groups were 26.8, 21.1, and 16.5 months, respectively, in the validation sample (Harrell's C index 0.63).
Serum LDH level was the main prognostic factor in predicting survival, followed by WHO PS. We identified three risk groups for death depending on these two baseline parameters. This simple prognostic model can be useful for clinician's use and patient stratification in future clinical trials.
The Oncologist 08/2011; 16(9):1228-38. · 4.10 Impact Factor