[Show abstract][Hide abstract] ABSTRACT: DOSSIER Place de l'hystérectomie d'emblée dans la prise en charge des tumeurs trophoblastiques gestationnelles à bas risque Résumé Introduction : Le traitement recommandé des tumeurs trophoblastiques gestationnelles (TTG) à bas risque est une monochimiothérapie, habituellement par méthotre-xate. La place de l'hystérectomie en première intention est mal définie dans cette indication. Méthodes : Évaluation de la normalisation des hCG des TTG à bas risque après hystérectomie initiale, enregistrées par le Centre français des maladies trophoblastiques de Lyon, France, entre 1999 et 2013. Résultats : Sur les 54 patientes incluses, 43 (80 %) ont été guéries définitivement par une hystérectomie. Aucun critère d'échec n'a pu être mis en évidence de façon significative. Conclusion : Une hystérectomie est une option thérapeutique possible des TTG à bas risque en cas de demande de la patiente. Mots clés Hystérectomie · Tumeur trophoblastique gestationnelle · Môle hydatiforme Abstract Introduction: Single agent chemotherapy, most usually methotrexate, is the treatment for low-risk Gestatio-nal Trophoblastic Neoplasia (GTN). The role of hysterec-tomy is not clearly known in this situation. Methods: Complete hCG normalization after hysterectomy was evaluated in case of low-risk GTN, in the French Center for Trophoblastic Disease, Lyon, France, between 1999 and 2013. Results: Forty-three patients out of the fifty-four included (80%) were cured by hysterectomy alone. No criteria were predictive of failure. Conclusion: Hysterectomy could be an option in certain cases of low-risk GTN, especially on patient's request.
[Show abstract][Hide abstract] ABSTRACT: Early prediction of the expected benefit of treatment in recurrent ovarian cancer (ROC) patients may help in drug development decisions. The actual value of 50% CA-125 decrease is being reconsidered. The main objective of the present study was to quantify the links between longitudinal assessments of CA-125 kinetics and progression-free survival (PFS) in treated recurrent ovarian cancer (ROC) patients.
The CALYPSO randomized phase III trial database comparing two platinum-based regimens in ROC patients was randomly split into a "learning dataset" and a "validation dataset". A parametric survival model was developed to associate longitudinal modeled CA-125 changes (ΔCA125), predictive factors, and PFS. The predictive performance of the model was evaluated with simulations.
The PFS of 534 ROC patients were properly characterized by a parametric mathematical model. The modeled ΔCA125 from baseline to week 6 was a better predictor of PFS than the modeled fractional change in tumor size. Simulations confirmed the model's predictive performance.
We present the first parametric survival model quantifying the relationship between PFS and longitudinal CA-125 kinetics in treated ROC patients. The model enabled calculation of the increase in ΔCA125 required to observe a predetermined benefit in PFS to compare therapeutic strategies in populations. Therefore, ΔCA125 may be a predictive marker of the expected gain in PFS and an early predictive tool in drug development decisions.
[Show abstract][Hide abstract] ABSTRACT: The primary objective of this study was to determine the incidence rate of pathological complete responses (pCRs) following neoadjuvant systemic chemotherapy for the treatment of peritoneal carcinomatosis (PC) of colorectal origin. The secondary objective was to evaluate whether pathological response assessments predict survival of patients treated with curative intent by complete cytoreductive surgery (CRS).
A retrospective review was performed of 115 patients who underwent preoperative irinotecan- or oxaliplatin-based chemotherapy, followed by 124 procedures of complete CRS alone or combined with hyperthermic intraperitoneal chemotherapy (HIPEC). The pathological response was defined as the mean percentage of cancer cells remaining within all specimens. Univariate and multivariate analyses were performed to identify predictors of survival and pathological response outcome.
Twelve procedures (9.7 %) resulted in pCRs, defined as no residual cancer cells in all specimens, 25 (20.2 %) resulted in major responses (1 to 49 % residual cancer cells), and 87 (70.1 %) resulted in minor or no responses (>50 % residual cancer cells). The cumulative 5-year survival rates were 75 and 57 % for patients with pCR and major responses, respectively. Using multivariate analysis, pathological response was the only independent predictor of survival (P = 0.01; major response: hazard ratio [HR] = 4.91; minor response: HR = 13.46). No significant predictor of pathological response was identified.
Pathological complete response can be achieved with preoperative systemic chemotherapy for patients with PC of colorectal origin. The degree of pathological response can be assessed and represented as a new outcome for prognosis following treatment with curative intent.
Annals of Surgical Oncology 03/2014; · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:The main objective of the present study was to establish the relationships between CA-125 kinetics and tumour size changes during treatment.Methods:The data from the CALYPSO-randomised phase III trial, comparing two platinum-based regimens in recurrent ovarian cancer (ROC) patients, was randomly split into a 'learning data set' to estimate model parameters and a 'validation data set' to validate model performances. A kinetic-pharmacodynamic semi-mechanistic model was built to describe tumour size and CA-125 kinetics during chemotherapy. The ability of the model to predict tumour response induced by chemotherapy, based on CA-125 values, was assessed.Results:Data from 535 ROC patients were used to model CA-125 kinetics and tumour size changes during the first 513 days after treatment initiation. Using the validated model, we could predict with accuracy the tumour size changes induced by chemotherapy based on the baseline imaging assessment and longitudinal CA-125 values (mean prediction error: 0.3%, mean absolute prediction error: 10.6%).Conclusions:Using a semi-mechanistic model, the dynamic relationships between tumour size changes and CA-125 kinetics induced by chemotherapy were established in ROC patients. A modelling approach allowed CA-125 to be assessed as a biomarker for tumour size dynamics, to predict treatment efficacy for research and clinical purposes.British Journal of Cancer advance online publication, 20 February 2014; doi:10.1038/bjc.2014.75 www.bjcancer.com.
British Journal of Cancer 02/2014; · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oxaliplatin-based regimens induce a potential risk of hypersensitivity reaction (HSR), with incidence varying from 10% to 25% and lack of clearly identified risk factors. The present study aimed to assess incidence and risk factors in HSR.
All patients treated with oxaliplatin in the Medical Oncology Department of the Lyon Sud University Hospital (Hospices Civils de Lyon, France) from October 2004 to January 2011 were enrolled. Incidence and severity of HSR were analyzed retrospectively and the potential clinicopathological covariates were tested on univariate and multivariate analysis.
A total of 1,221 doses of oxaliplatin were administered for 191 patients, 8.9% of whom experienced an HSR. Seventeen HSRs were observed, with 1.6% grade 3 and no grade 4 events. The first reaction appeared after a median of 3 oxaliplatin infusions. Using univariate analysis, HSR was associated with younger age (mean age, 56.2 years; p = 0.04), female gender (p = 0.01) and prior exposure to platinum salts (p = 0.02). No increased risk was associated with mean dose or with presence of atopic background. Multivariate analysis confirmed that women were at higher risk of oxaliplatin HSR than men (p < 0.05). Reintroduction of oxaliplatin was effective in 64.7% of hypersensitive patients using an appropriate premedication strategy. Patients who experienced a grade 3 HSR were not rechallenged.
The risk of developing oxaliplatin HSR should not be underestimated (8.9% of patients). The medical team's vigilance should be increased with women, younger patients and patients with prior exposure to platinum salts.
[Show abstract][Hide abstract] ABSTRACT: Background
Even though anticancer drugs are prepared in dedicated pharmaceutical units, nurses remain exposed to cytotoxic agents during administration to patients.
The aim of this study was to assess this occupational exposure during the intravenous line–purging procedure at the patient’s bedside before administration in oncology departments.
This prospective study was conducted over a 4-week period in the hematology and oncology departments at a university hospital. Amounts of doxorubicin and cyclophosphamide on the surface of nurses’ gloves were measured after the intravenous line purge of the infusion bag and the connection to the patient. For this purpose, gloves were washed with sterile water, following a validated procedure. Quantification of the 2 drugs into the water was performed using LC-MS/MS.
After 59 chemotherapy administrations, 30.5% of gloves were contaminated. Despite extremely low volumes of contamination (0.08–6.28 µL), amounts collected ranged from 190 to 2500 ng per pair of gloves that tested positive for doxorubicin (median, 1600 ng) and from 130 to 32,600 ng with cyclophosphamide (median, 2700 ng).
The intravenous line purge preceding antineoplastic infusion bag administration is a potential source of contamination in nurses. Contaminations appear to be invisible but frequent (in >30% of cases). Therefore, intravenous line purging performed under appropriately safe conditions should be mandated in pharmaceutical units dedicated to injectable-drug preparation. This measure should be included as a standard hospital practice as a matter of urgency.
[Show abstract][Hide abstract] ABSTRACT: Background
Patients with advanced metastatic disease are often treated aggressively with multiple lines of chemotherapy, even in the last month of life. The benefit of such an approach remains uncertain. The objective of the study was to investigate whether Ruta graveolens 9c homeopathic medicine can improve quality of life (QoL) and tumour progression in patients with advanced cancer.
Material and methods
This was a single-centre, open-label, uncontrolled, pilot study. Patients (>18-years, life-expectancy ≥3 months, performance status ≤2) with locally-advanced solid tumours or metastases, previously treated with all available standard anti-cancer treatments were recruited. Oral treatment consisted of two 1-mL ampoules of Ruta graveolens (9c dilution) given daily for a minimum of 8 weeks, or until tumour and/or clinical progression. Primary outcome was QoL measured using the EORTC QLQ-C30 questionnaire. Secondary outcome measures were anxiety/depression measured using the Hospital Anxiety and Depression Scale (HADS), WHO performance status (PS), tumour progression assessed using RECIST criteria and tumour markers, survival and tolerance.
Thirty-one patients were included (mean age: 64.3 years). Mean duration of treatment was 3.3 months (median: 2.1). QoL global health status improved significantly between baseline and week 8 (P < 0.001) and week 16 (P = 0.035), but was at the limit of significance (P = 0.057) at the end of the study. There was no significant change in anxiety/depression or PS during treatment. Ruta graveolens 9c had no obvious effect on tumour progression. Median survival was 6.7 months [95%CI: 4.8–14.9]. Ruta graveolens 9c was well-tolerated.
Some patients treated with Ruta graveolens 9c had a transitory improvement in QoL, but the effectiveness of this treatment remains to be confirmed in further studies.
[Show abstract][Hide abstract] ABSTRACT: Changes in serum tumor biomarkers may indicate treatment efficacy. Traditional tumor markers may soon be replaced by novel serum biomarkers, such as circulating tumor cells (CTCs) or circulating tumor nucleic acids. Given their promising predictive values, studies of their kinetics are warranted. Many methodologies meant to assess kinetics of traditional marker kinetics during anticancer treatment have been reported. Here, we review the methodologies, the advantages and the limitations of the analytical approaches reported in the literature. Strategies based on a single time point were first used (baseline value, normalization, nadir, threshold at a time t), followed by approaches based on two or more time points [half-life (HL), percentage decrease, time-to-events…]. Heterogeneities in methodologies and lack of consideration of inter- and intra-individual variability may account for the inconsistencies and the poor utility in routine. More recently, strategies based on a population kinetics approach and mathematical modeling have been reported. The identification of equations describing individual kinetic profiles of biomarkers may be an alternative strategy despite its complexity and higher number of necessary measurements. Validation studies are required. Efforts should be made to standardize biomarker kinetic analysis methodologies to ensure the optimized development of novel serum biomarkers and avoid the pitfalls of traditional markers.
Annals of Oncology 01/2014; 25(1):41-56. · 7.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Consolidated Standards of Reporting Trials (CONSORT) guidance was extended in 2004 to provide a set of 10 specific and comprehensive guidelines regarding adverse event (AE) reporting in randomized clinical trials (RCTs). Limited data exist regarding adherence to these guidelines in publications of oncology RCTs.
All phase III RCTs published between 2007 and 2011 were reviewed using a 16-point AE reporting quality score (AERQS) based on the 2004 CONSORT extension. Multivariable linear regression was used to identify features associated with improved reporting quality.
A total of 325 RCTs were reviewed. The mean AERQS was 10.1 on a 16-point scale. The most common items that were poorly reported were the methodology of AE collection (adequately reported in only 10% of studies), the description of AE characteristics leading to withdrawals (15%), and whether AEs are attributed to trial interventions (38%). Even when reported, the methods of AE collection and analysis were highly heterogeneous. The multivariable regression model revealed that industry funding, intercontinental trials, and trials in the metastatic setting were predictors of higher AERQS. The quality of AE reporting did not improve significantly over time and was not better among articles published in journals with a high impact factor.
Our findings show that some methodologic aspects of AE collection and analysis were poorly reported. Given the importance of AEs in evaluating new treatments, authors should be encouraged to adhere to the 2004 CONSORT guidelines regarding AE reporting.
Journal of Clinical Oncology 09/2013; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare primary peritoneal malignancy. Its prognosis has been improved by an aggressive locoregional treatment combining extensive cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Prognostic factors are currently poorly defined for this disease but are essential if treatment is to be standardized.
Twenty-eight patients with DMPM, who were considered preoperatively to be candidates for CRS and HIPEC between June 1998 and August 2010 at our institution, were selected for this study. Medical records and histopathological features were retrospectively reviewed and 24 clinical, histological, and immunohistochemical parameters were assessed for their association with overall survival by univariate and multivariate analyses.
The following factors were significantly associated with overall survival by univariate analysis: predominant histological growth pattern in the epithelioid areas, nuclear grooves in the epithelioid areas, atypical mitoses, and calretinin and GLUT1 expression by immunohistochemistry in the epithelioid areas. Expression of the facilitative glucose transporter protein GLUT1 in the epithelioid areas was the only factor independently associated with overall survival by multivariate analysis.
GLUT1 expression appears to be an indicator of poor prognosis in DMPM. Standard histological classification of DMPM may not be adequate to select patients for aggressive locoregional treatments, such as CRS and HIPEC. Multicenter validation of the prognostic factors identified in this preliminary study is needed to refine patient selection for potential cure.
Annals of Surgical Oncology 06/2013; · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Unexpected results were recently reported about the poor surrogacy of Gynecologic Cancer Intergroup (GCIG) defined CA-125 response in recurrent ovarian cancer (ROC) patients. Mathematical modeling may help describe CA-125 decline dynamically and discriminate prognostic kinetic parameters. METHODS: Data from CALYPSO phase III trial comparing 2 carboplatin-based regimens in ROC patients were analyzed. Based on population kinetic approach, serum [CA-125] concentration-time profiles during first 50 treatment days were fit to a semi-mechanistic model with following parameters: "d[CA-125]/dt = (KPROD * exp (BETA*t)) * Effect -KELIM*[CA-125]" with time, t; tumor growth rate, BETA; CA-125 tumor production rate, KPROD; CA-125 elimination rate, KELIM and K-dependent treatment indirect Effect. The predictive values of kinetic parameters were tested regarding progression-free survival (PFS) against other reported prognostic factors. RESULTS: Individual CA-125 kinetic profiles from 895 patients were modeled. Three kinetic parameters categorized by medians had predictive values using univariate analyses: K; KPROD and KELIM (all P<0.001). Using Cox multivariate analysis, 5 independent predictors of PFS remained significant: GCIG CA-125 response (favoring carboplatin-paclitaxel arm), treatment arm, platinum free-interval, measurable lesions and KELIM (HR = 0.53; 95% CI 0.45-0.61; P<0.001). CONCLUSIONS: Mathematical modeling of CA-125 kinetics in ROC patients enables understanding of the time-change components during chemotherapy. The contradictory surrogacy of GCIG-defined CA-125 response was confirmed. The modeled CA-125 elimination rate KELIM, potentially assessable in routine, may have promising predictive value regarding PFS. Further validation of this predictive marker is warranted.
[Show abstract][Hide abstract] ABSTRACT: Background:In low-risk gestational trophoblastic neoplasia (GTN) patients, a predictive marker for early identification of methotrexate (MTX) resistance would be useful. We previously demonstrated that kinetic modelling of human chorionic gonadotrophin (hCG) measurements could provide such a marker. Here we validate this approach in a large independent patient cohort.Methods:Serum hCG measurements of 800 low-risk GTN patients treated with MTX were analysed. The cohort was divided into Model and Test data sets. hCG kinetics were described from initial treatment day to day 50 using: '(hCG(time))=hCG0*exp(-k*time)+hCGres', where hCGres is the modelled residual production, hCG0 is the baseline hCG level, and k is the rate constant. HCGres-predictive value was investigated against previously reported predictors of MTX resistance.Results:Declining hCG measurements were well fitted by the model. The best discriminator of MTX resistance in the Model data set was hCGres, categorised by an optimal cut-off value of >20.44 IU l(-1): receiver-operating characteristic (ROC) area under the curve (AUC)=0.87; Se=0.91; Sp=0.83. The predictive value of hCGres was reproducible using the Test data set: ROC AUC=0.87; Se=0.88; Sp=0.86. Multivariate analyses revealed hCGres as a better predictor of MTX resistance (HR=1.01, P<0.0001) and MTX failure-free survival (HR=13.25, P<0.0001) than other reported predictive factors.Conclusion:hCGres, a modelled kinetic parameter calculated after fully dosed three MTX cycles, has a reproducible value for identifying patients with MTX resistance.British Journal of Cancer advance online publication, 16 April 2013; doi:10.1038/bjc.2013.123 www.bjcancer.com.
British Journal of Cancer 04/2013; · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antiangiogenic drugs were developed with the aim to inhibit the formation of intratumoural blood vessels and in consequence the growth of solid tumours. As these drugs are generally combined with classical cytotoxic drugs in the treatment of cancer patients, finding the optimal combinations remains a complex challenge due to possible interactions of the antiangiogenic compound with the hemodynamic property of the treated tumour. To analyze this problem, we developped a multiscale model of vascular tumour growth combining a molecular model of VEGF signalling pathways and a tissue model of the tumour expansion including the dynamics of cellular and tissue processes of tumour growth and response to treatments. We addressed the potential impact of antiangiogenic drug by defining a new index of vasculature quality which depends on the balance between stable and unstable vessels within the tumour mass. Our goal was to investigate the interactions between a chemotherapy and a antiangiogenic treatment, and, by simulating the model, to identify the optimal delay of chemotherapy delivery after the administration of the antiangiogenic compound. This theoretical analysis could be used in the future to optimize antiangiogenic drug delivery in preclinical settings and to facilitate the translation from preclinical to clinical studies.
Journal of Theoretical Biology 12/2012; · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ideally, statisticians should be involved in the design, analysis, and reporting of randomized clinical trials (RCTs). This study assessed the impact of a statistician involvement in published medical oncology RCTs between 2005 and 2009. The reporting quality of each publication was rated using the Overall Reporting Quality Score on the basis of either 2001 or 2010 Consolidated Standards of Reporting Trials criteria. A four-question email survey on the statistical design and analysis was sent to the corresponding authors of each trial. Nonresponders were approached a maximum of three times. Overall, 107 responses were received from 357 solicited authors (30%). Corresponding authors from industry-funded RCTs were less likely to respond (51 vs. 65%, P=0.013). The same person was responsible for statistical design and analyses in 47% of cases. Overall, the statistician involved held a PhD (or equivalent) in statistics in most cases. The statisticians responsible for the statistical design and analysis were listed as coauthors in 68 and 81% of RCT manuscripts. There was no statistically significant impact on manuscript reporting quality of the degree of statistician involvement in manuscript preparation. Fewer trials were reported as positive when the responsible statistician was listed as a coauthor. It is possible that RCTs included in this review are in general of higher quality or were more likely to have a greater level of statistician involvement than smaller, single-arm, or unpublished studies. This imbalance could explain the lack of significant difference observed in the Overall Reporting Quality Score between trials where statisticians were listed as coauthors or not.
[Show abstract][Hide abstract] ABSTRACT: To improve the quality of reporting of randomized clinical trials (RCTs), international registries for RCTs and guidelines for primary endpoint (PEP) analysis were established. The objectives of this systematic review were to evaluate concordance of PEP between publication and the corresponding registry and to assess the intrapublication consistency in PEP reporting. All adult oncology RCTs in solid tumors published in 10 journals between 2005 and 2009 were reviewed. Registration information was extracted from international trial registries. A total 366 RCTs were identified. Trial registration was found for 215 trials and the rate increased from 43% in 2005 to 82% in 2009 (P < 0.001). There were 134 RCTs with clearly defined PEPs in registry, with the rate increasing from 15 to 67% (P < 0.001). PEP differs between registration and final publication in 14% trials with clearly defined PEPs. Reporting issues in methodology were found in 15% RCTs, mainly due to inadequate reporting of PEP or of sample size calculation. Problems with the interpretation of trial results were found in 22% publications, mostly due to negative superiority studies being interpreted as showing equivalence. The rates of trial registration and of trials with clearly defined PEP have improved over time, however 14% of these trials reported a different PEP in the final publication. Intrapublication inconsistencies in PEP reporting are frequent. Our findings highlight the need for investigators, peer reviewers and readers for increased awareness and scrutiny of reporting outcomes of oncology RCTs.
Bulletin du cancer 10/2012; 99(10):943-952. · 0.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This phase I cohort study investigated aflibercept (vascular endothelial growth factor (VEGF) trap) plus docetaxel and cisplatin in patients with advanced solid tumours.
Patients received intravenous aflibercept 4, 5, or 6 mg kg(-1) with docetaxel and cisplatin (75 mg m(-2) each) on day 1 of a 3-week cycle until progressive disease or unacceptable toxicity. Primary objectives were determining cycle 1 dose-limiting toxicities (DLTs) and the aflibercept recommended phase II trial dose (RP2D) for this combination.
During the dose-escalation phase (n=16), there were two DLTs of febrile neutropenia (at 4 and 5 mg kg(-1)). Granulocyte colony-stimulating factor prophylaxis was subsequently recommended. The RP2D of aflibercept was established at 6 mg kg(-1) and administered to 14 additional patients. The most frequent grade 3/4 adverse events (AEs) were neutropenia (43.3%), stomatitis (20.0%), asthenia/fatigue (20.0%), and hypertension (16.7%). All-grade AEs associated with VEGF blockade included epistaxis (83.3%), dysphonia (70.0%), proteinuria (53.3%), and hypertension (50.0%). There were five partial responses (16.7%) and 18 cases of stable disease (60.0%) (lasting >3 months in 10 patients). There were no pharmacokinetic (PK) interactions between the three drugs.
Aflibercept 6 mg kg(-1) with docetaxel and cisplatin 75 mg m(-2) every 3 weeks is the RP2D based on tolerability, antitumour activity, and PKs.
British Journal of Cancer 07/2012; 107(4):598-603. · 5.08 Impact Factor