Patient Identification and Tumor Identification Management: Quality Program in a Cancer Multicentric Clinical Data Warehouse.

Background: The Regional Basis of Solid Tumor (RBST), a clinical data warehouse, centralizes information related to cancer patient care in 5 health establishments in 2 French departments. Purpose: To develop algorithms matching heterogeneous data to "real" patients and "real" tumors with respect to patient identification (PI) and tumor identification (TI). Methods: A graph database programed in java Neo4j was used to build the RBST with data from ~20 000 patients. The PI algorithm using the Levenshtein distance was based on the regulatory criteria identifying a patient. A TI algorithm was built on 6 characteristics: tumor location and laterality, date of diagnosis, histology, primary and metastatic status. Given the heterogeneous nature and semantics of the collected data, the creation of repositories (organ, synonym, and histology repositories) was required. The TI algorithm used the Dice coefficient to match tumors. Results: Patients matched if there was complete agreement of the given name, surname, sex, and date/month/year of birth. These parameters were assigned weights of 28%, 28%, 21%, and 23% (with 18% for year, 2.5% for month, and 2.5% for day), respectively. The algorithm had a sensitivity of 99.69% (95% confidence interval [CI] [98.89%, 99.96%]) and a specificity of 100% (95% CI [99.72%, 100%]). The TI algorithm used repositories, weights were assigned to the diagnosis date and associated organ (37.5% and 37.5%, respectively), laterality (16%) histology (5%), and metastatic status (4%). This algorithm had a sensitivity of 71% (95% CI [62.68%, 78.25%]) and a specificity of 100% (95% CI [94.31%, 100%]). Conclusion: The RBST encompasses 2 quality controls: PI and TI. It facilitates the implementation of transversal structuring and assessments of the performance of the provided care.

Can the Six-Minute Walk Test Be Used to Individualize Physical Activity Intensity in Patients with Breast Cancer?

BACKGROUND: Adapted physical activity (APA) aids breast cancer patients. It is necessary to use an adapted target heart rate (HR) when prescribing exercise intensity. METHODS: In total, 138 patients previously included in two published randomized clinical trials underwent the CPET and 6MWT before and after adjuvant therapy. Of these patients, 85 had performed APA, and 53 had received only the usual therapy. HRs were recorded during the two tests. RESULTS: Before starting chemotherapy, good agreement (intraclass correlation (ICC) 0.69; confidence interval at 95% IC0.95 (0.591-0.769); p < 0.001) and a moderate correlation were evident between the 6MWT-HR and ventilatory threshold HR of the CPET (r = 0.70; p < 0.001). Good agreement and a high positive correlation were noted only in the group who engaged in APA (ICC 0.77; IC0.95 (0.659-0.848); p < 0.001; r = 0.8; p < 0.01); moderate agreement and a moderate positive correlation were apparent in the control group (ICC 0.57; IC0.95 (0.329-0.74); p < 0.001; r = 0.6; p < 0.01). The correlations were independent of age and body mass index. CONCLUSIONS: The 6MWT-HR can be used to prescribe exercise intensity for breast cancer patients both before and after specific treatment with concomitant APA.

Population pharmacokinetic model of irinotecan and its four main metabolites in patients treated with FOLFIRI or FOLFIRINOX regimen.

PURPOSE: The aim of the present study was to characterize the pharmacokinetics of irinotecan and its four main metabolites (SN-38, SN-38G, APC and NPC) in metastatic colorectal cancer patients treated with FOLFIRI and FOLFIRINOX regimens and to quantify and explain the inter-individual pharmacokinetic variability in this context. METHODS: A multicenter study including 109 metastatic colorectal cancer patients treated with FOLFIRI or FOLFIRINOX regimen, associated or not with a monoclonal antibody, was conducted. Concentrations of irinotecan and its four main metabolites were measured in 506 blood samples during the first cycle of treatment. Collected data were analyzed using the population approach. First, fixed and random effects models were selected using statistical and graphical methods; second, the impact of covariates on pharmacokinetic parameters was evaluated to explain the inter-individual variability in pharmacokinetic parameters. RESULTS: A seven-compartment model best described the pharmacokinetics of irinotecan and its four main metabolites. First-order rates were assigned to distribution, elimination, and metabolism processes, except for the transformation of irinotecan to NPC which was nonlinear. Addition of a direct conversion of NPC into SN-38 significantly improved the model. Co-administration of oxaliplatin significantly modified the distribution of SN-38. CONCLUSION: To our knowledge, the present model is the first to allow a simultaneous description of irinotecan pharmacokinetics and of its four main metabolites. Moreover, a direct conversion of NPC into SN-38 had never been described before in a population pharmacokinetic model of irinotecan. The model will be useful to develop pharmacokinetic-pharmacodynamic models relating SN-38 concentrations to efficacy and digestive toxicities. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT00559676.

Comparison of 18FDG-PET/CT and conventional follow-up methods in colorectal cancer: A randomised prospective study.

BACKGROUND: A surveillance program was performed in colorectal cancer (CRC) patients after surgery, to diagnose asymptomatic recurrence. AIMS: To assess whether 18-FDG positron emission tomography/CT (PET/CT) improved the detection of recurrence during a 3-year follow-up. METHODS: A multicentre, two-arm randomised prospective trial comparing different 36-month follow-up strategies. Complete colonoscopy was performed at baseline and after 3 years and clinical exams with imaging every 3 months. The conventional arm (A) received carcinoembryonic antigen, liver echography, and alternated between lung radiography and computed tomography (CT) scans. The experimental arm (B) received PET/CT. RESULTS: A total of 365 patients with colon (79.4%) or rectal cancer (20.6%), stages II (48.2%) or III (50.8%), were enroled in this study. At 36 months, intention-to-treat analysis revealed recurrence in 31 (17.2%) patients in arm A and 47 (25.4%) in arm B (p = 0.063). At 3 years, 7 of 31 relapses (22.5%) in arm A were surgically treated with curative intent, compared to 17 of 47 (36.2%) in arm B (p = 0.25). The rates of recurrence and new cancers were higher in arm B than arm A (p = 0.038). CONCLUSIONS: PET/CT follow-up every 6 months did not increase the rate of recurrence at 3 years or the rate of surgically treated recurrence compared with conventional follow-up.

Home-Based Physical Activity in Patients With Breast Cancer: During and/or After Chemotherapy? Impact on Cardiorespiratory Fitness. A 3-Arm Randomized Controlled Trial (APAC).

OBJECTIVES: Physical activity (PA) programs are recommended for breast cancer care. However, their modalities remain to be discussed. This study determined the best time to begin a personalized or adapted program based on cardiopulmonary exercise test function. This randomized controlled trial evaluated the effect of home-based adapted PA (APA) performed during or after treatment on cardiorespiratory fitness (CRF) at 12 months. METHOD: The primary endpoint was the peak oxygen consumption (VO2peak) at 12 months (group A vs C and B vs C). Secondary endpoints included the 6-minute walking test, assessment of muscle strength, fatigue, quality of life, anxiety, and depression, and a questionnaire on PA levels. All tests were evaluated at baseline and at 6 and 12 months. A total of 94 patients with breast cancer were randomized to 3 different groups: group A, performing 6 months of APA during adjuvant care; group B, 6 months of APA after adjuvant care; and group C, 12 months of APA during and after specific care. The program combined 1 resistance session and 2 aerobic sessions per week. Analysis of variance was used for repeated measures, Student's t-test or the Mann-Whitney U-test for continuous variables, and χ2 test for binary or categorical variables. RESULTS: The study assessed 81 participants at 6 months and 73 at 12 months. The majority of patients completed more than 85% of the exercise sessions. The baseline for VO2peak and secondary outcomes did not differ among the groups. VO2peak increased during the exercise period and decreased during the chemotherapy period without APA, but at 12 months no significant difference was observed. The same variation was observed in the 6-minute walking test, with significance at 6 months between A+C versus B (P = .04), but no difference among the groups at 12 months. In the 3 groups, no decreases in other studied parameters were noted, except at 6 months in group B without APA. CONCLUSION: Home-based APA in breast cancer patients has a positive effect on CRF and physical functions, with no differences based on the timing of this program based on specific cancer treatment. TRIAL REGISTRATION: ClinicalTrials.gouv.fr (NCT01795612). Registered 20 February 2013.

Impact of Body Composition in Overweight and Obese Patients With Localised Renal Cell Carcinoma.

BACKGROUND/AIM: To investigate the impact of body composition on morbidity and mortality at the initial diagnosis of localised renal cell carcinoma (RCC) in patients with overweight or obesity. PATIENTS AND METHODS: Sarcopenia was defined using sex-specific cut-off points and other body composition parameters by median values with computed tomography imaging. RESULTS: Among the 96 patients, 40 had sarcopenia (43.0%) at diagnosis. Body composition had no effect on morbidity and 5-year disease-free survival contrary to the classic factors (p<0.05). In the subgroup of obese patients, those with sarcopenia had a poor prognosis (p=0.04) but not in the population with overweight (p=0.9). CONCLUSION: Sarcopenia was frequently associated with localised RCC at the initial diagnosis. Body composition did not affect morbidity or outcomes. BMI was involved in morbidity and there was paradoxically longer survival in the obesity group.

Prospective evaluation of an anti-cancer drugs management programme in a dedicated oral therapy center (DICTO programme).

Oral therapies have highly modified cancer patient management and changed hospital practises. We introduce a specific Oral Therapy Centre and retrospectively review information prospectively recorded by co-ordination nurses (CNs) (the DICTO programme). We describe the roles played by CNs in the management of oral cancer therapies at Limoges Dupuytren Hospital between May 2015 and June 2018. All cancers, irrespective of stage or whether oral general chemotherapy or targeted therapy was prescribed, are included. We followed up 287 patients of median age 67 years (range 26-89 years). Of these, 76% had metastases and 44% were on first-line therapy. The vast majority (88%) of their first CN contacts occurred just after physician consultation and lasted an average of 60 min. As part of follow-up, the CNs made 2719 calls (average 10 min) to patients to educate them and to verify compliance and drug tolerance. They also received 833 calls from patients (70%) or their relatives or health professionals (30%) seeking advice on management of side effects. In addition to the initial appointments, 1069 non-scheduled follow-up visits were made to assess side effects (49.2%). The CNs devoted 5 h to each patient over 3 months of treatment (i.e. 25 min/day) and, also organised scheduled hospitalisations in the department of oncology for 51% of patients. We show the interest and real-life work in a specific oral therapy centre within oncology department with the role of CNs to facilitate the global health care of the patients.

[High fidelity simulation training for medical oncology announcement consultation]. / Simulation haute-fidélité à la consultation d'annonce en oncologie médicale.

INTRODUCTION: Medical oncology bad news consultation is a particularly stressful situation for both the patient and the physician. High-fidelity simulation is a learning option that has never been evaluated in France in this field. MATERIALS AND METHODS: This is a feedback from simulated announcement consultations carried out from January 2018 to May 2019. Residents from the medical oncology and radiotherapy departments performed high-fidelity simulations at the announcement consultation with an announcement nurse, a psychologist, a certified coach and an oncologist. A competency assessment was completed in pre-test, immediate post-test and after 5 months. RESULTS: Fourteen of the 16 eligible interns participated. The pre-test competency assessment showed that interns over 5 semesters reported being more comfortable at the consultation (P=0.04) and thought they were clearly explaining the disease (P=0.03). However, all residents, regardless of the semester, felt stressed before a consultation. The evolution of parameters skills after the simulation was positive for all criteria, particularly for adaptation to patient reactions, use of appropriate vocabulary and reduction of stress (P<0.05). This evolution was independent of the gender, curriculum, semester, or previous completion of a medical oncology internship. More than 80% of the students were ready to repeat this type of training. CONCLUSION: This training demonstrates the value of simulation training for medical oncology advertising consultation.

First validation of the G-8 geriatric screening tool in older patients with glioblastoma.

INTRODUCTION: Management of glioblastoma, with a very poor prognosis, remains a challenge in older patients because of coexisting comorbidities and the increased risk of toxic treatment effects. The use of screening tools to identify vulnerable patients is essential. This study was performed to establish whether the G8 scale can be used for screening older patients with glioblastoma. METHODS: We retrospectively reviewed the files of patients assessed by the G8 scale and diagnosed with glioblastoma at a single center from January 2010 to July 2017. Patients aged 65 years or older were classified into three groups (more efficiently than two groups) according to their G8 score to identify those with a poor prognosis: high score group, G8 score 14.5-17; intermediate score group, G8 score 10.5-14; and low score group, G8 score < 10.5. RESULTS: Of 89 patients, 19% were classified into the high score group, 43% into the intermediate score group, and 38% into the low score group. Median overall survival was four months in the low score group, 15 months in the intermediate score group, and 42 months in the high score group (p < .0001). On multivariate analysis, G8 score was a significant independent predictor of overall survival (hazard ratio: 55.46; 99.5% confidence interval: 13.42-229.13; p < .0001). CONCLUSIONS: Here, we highlighted the possibility of using the G8 score, with possibly three cut-offs, in the management of older patients with glioblastoma and determined the prognostic role of this quick and easy screening tool.

Comparative Study of Neoadjuvant Chemotherapy With and Without Zometa for Management of Locally Advanced Breast Cancer With Serum VEGF as Primary Endpoint: The NEOZOL Study.

INTRODUCTION: Neoadjuvant chemotherapy has become the treatment of choice for locally advanced breast cancer. Zoledronic acid (ZA) is a bisphosphonate initially used in the treatment of bone metastases because of its antibone resorption effect. Antitumor effects of ZA, including the inhibition of cell adhesion to mineralized bone or the antiangiogenic effect, have been demonstrated. However, the clinical significance of these effects remains to be determined. MATERIALS AND METHODS: We undertook a multicenter open-label randomized trial to analyze the value of adding ZA to neoadjuvant chemotherapy for TNM clinical stage T2/T3 breast cancer. The primary endpoint was the evolution of serum VEGF. RESULTS: The data from 24 patients were included in the ZA group and 26 in the control group. The evolution of serum VEGF was slightly in favor of ZA at 5.5 months (-0.7% vs. +7.5%), without reaching statistical significance (P = .52). The secondary endpoints were the breast conservation rate (higher with ZA; 83.3% vs. 65.4%; P = NS), pathologic complete response (no effect), and circulating tumor cells (odds ratio, 0.68 in favor of ZA; 95% confidence interval, 0.02-24.36). No cases of jaw necrosis or severe renal failure were observed in either group. CONCLUSION: ZA is an antitumor drug of interest because of its multiple effects on tumor biology. Larger trials with longer follow-up that include additional endpoints such as relapse and survival rates would be of interest.

Impact of body composition on outcome in patients with early breast cancer.

PURPOSE: We investigated the impact of body composition on outcomes of patients with early breast cancer. Skeletal muscle mass, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and muscle fat infiltration or inter-muscular adipose tissue areas (IMAT), obtained by computed tomography (CT), were assessed. METHODS: A total of 119 female patients who had breast cancer were included in this retrospective study. The total skeletal muscle and fat tissue areas were evaluated in two adjacent axial slices obtained at the third lumbar vertebra by CT used for disease staging. The women were assigned to either a sarcopenia or non-sarcopenia group based on their skeletal muscle index (cut-off 41.0 cm2/m2). They also were classified into high and low VAT/SAT ratio groups and assigned to either the high or low IMAT index group. The association of the body composition parameters and prognosis was statistically analyzed. RESULTS: Among the 119 evaluable patients, 58 were sarcopenic (48.8%), 55 (46.2%) had a high VAT/SAT ratio, and 62 (52.1%) had a high IMAT index. Median follow-up was 52.4 months. Multivariate analysis revealed sarcopenia and IMAT index as independent prognostic factors for disease-free survival (p = 0.02 and p = 0.04, respectively) and overall survival (p = 0.05 and p = 0.02, respectively). BMI was not significantly associated with disease-free survival, but a trend was observed (p = 0.09). CONCLUSIONS: Sarcopenia and IMAT index are independent prognostic factors in early breast cancer; therefore, assessing body composition could be a simple and useful approach to integrate into patient management.

Anticancer Activity and Tolerance of Treatments Received Beyond Progression in Men Treated Upfront with Androgen Deprivation Therapy With or Without Docetaxel for Metastatic Castration-naïve Prostate Cancer in the GETUG-AFU 15 Phase 3 Trial.

BACKGROUND: Androgen deprivation therapy (ADT) plus docetaxel is the standard of care in fit men with metastatic castration-naive prostate cancer (mCNPC) following results from GETUG-AFU 15, CHAARTED, and STAMPEDE. No data are available on the efficacy of treatments used for metastatic castration-resistant prostate cancer (mCRPC) in men treated upfront with ADT plus docetaxel for mCNPC. OBJECTIVE: To investigate the efficacy and tolerance of subsequent treatments in patients treated upfront with chemo-hormonal therapy for mCNPC. DESIGN, SETTING, AND PARTICIPANTS: Retrospective data from the GETUG-AFU 15 phase 3 trial were collected for treatments received for mCRPC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: For the first three lines of salvage treatment for mCRPC we investigated the biochemical progression-free survival, maximum prostate-specific antigen (PSA) decline, overall survival, and tolerance. RESULTS AND LIMITATIONS: Overall, 245 patients received at least one treatment for mCRPC. For docetaxel used in first-line, a PSA decline ≥50% was observed in 25/66 (38%) and in 4/20 patients (20%) who had received upfront ADT alone and ADT plus docetaxel (p=0.14). The median biochemical progression-free survival was 6.0 mo (95% confidence interval: 3.6-7.7) and 4.1 mo (95% confidence interval: 1.3-4.9), respectively. For docetaxel used in first- or second-line, a PSA decline ≥50% was observed in 36/80 (45%) and in 4/29 patients (14%) who had received upfront ADT alone and ADT plus docetaxel (p=0.07). PSA declines ≥50% were observed with bicalutamide in 12/28 (43%) and 4/23 patients (17%) who had received upfront ADT alone and ADT plus docetaxel. Among men treated upfront with ADT plus docetaxel who received abiraterone or enzalutamide for mCRPC, 10/19 patients (53%) achieved a PSA decline ≥50%. Few grade 3-4 events occurred. Study limitations include the observational design and retrospective characteristics of this analysis, without standardized therapeutic salvage protocols, and the limited number of patients in some of the treatment subgroups. CONCLUSIONS: Docetaxel rechallenge following progression to mCRPC after upfront ADT plus docetaxel for mCNPC was active only in a limited number of patients. Available data on abiraterone and enzalutamide support maintained efficacy in this setting. The lack of standardized therapeutic protocols for men developing mCRPC limits the comparability between patients. PATIENT SUMMARY: Rechallenging docetaxel at castration-resistance was active only in a limited number of patients treated upfront with chemo-hormonal therapy for metastatic castration-naive prostate cancer. Anticancer activity was suggested with abiraterone or enzalutamide in this setting.

Single-Agent Oral Vinorelbine as First-Line Chemotherapy for Endocrine-Pretreated Breast Cancer With Bone Metastases and No Visceral Involvement: NORBREAST-228 Phase II Study.

PURPOSE: Single-agent oral chemotherapy is widely used in patients with bone metastases without visceral involvement, especially in hormone receptor-positive metastatic breast cancer (mBC). However, this option has been poorly evaluated in clinical trials. METHODS: Eligible patients had mBC with predominantly bone but not visceral metastases, were receiving bisphosphonate therapy, and had previously received endocrine therapy (any setting) but not chemotherapy for mBC. Patients received oral vinorelbine 60 mg/m2 on days 1, 8, 15, and 22 every 4 weeks (escalating to 80 mg/m2 from cycle 2 in the absence of grade 3/4 toxicity) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included clinical benefit rate (complete/partial response or ≥24 weeks' stable disease), overall survival, and safety. RESULTS: Seventy patients were treated for a median of 6 cycles (range 1-18). Most (73%) continued treatment until disease progression. After 43 months' median follow-up, median PFS was 8.2 months (95% confidence interval [CI], 5.5-9.8). The clinical benefit rate was 56% (95% CI, 43%-68%). Median overall survival was 35.2 months (95% CI, 26.8-47.1). The most common grade 3/4 adverse event was neutropenia (38% of patients); febrile neutropenia was absent. The most common grade 1/2 adverse events were bone pain, fatigue, and gastrointestinal toxicities. Alopecia was infrequent. CONCLUSIONS: In patients with hormone receptor-positive mBC, bone disease, and prior endocrine therapy, first-line oral vinorelbine chemotherapy demonstrated long PFS and good tolerability. In this setting, it could be considered as an active oral alternative to intravenous chemotherapy.

Common variants in glucuronidation enzymes and membrane transporters as potential risk factors for colorectal cancer: a case control study.

BACKGROUND: Associations between polymorphisms of UDP-glucuronosyltransferases (UGTs) or efflux transporters (e.g., P-glycoprotein and MRP2) and different types of cancer have been described, whereas the role of influx transporters (e.g. OATP1B1 and OATP2B1) has been seldom explored. The GenColon study investigated potential associations between variant alleles of UGTs, efflux and influx transporters and CRC. METHODS: Three hundred CRC cases were matched with 300 controls for age, sex and enrolment site. Fifteen SNPs in UGT1A6-9, UGT2B7, ABCB1, ABCC2, SLCO1B1 and SLCO2B1 genes were characterized using Taqman® PCR. Using multivariate conditional logistic regression, we investigated the relationships between CRC and "environmental" risk factors (physical activity, housing and working areas, consumption of red meat, tobacco, alcohol); genetic polymorphisms, in the study population and in the subgroups with "environmental" risk factors. RESULTS: No significant association was observed for the analyzed SNPs (or haplotypes). However, an increased CRC risk was found in carriers of the UGT1A8 rs1042597-G variant allele (additive risk OR = 3.39[1.29-8.89], p = 0.02951) in the subgroup of meat-consumers (n = 84), and in carriers of the ABCB1 rs1045642-T (exon26) variant allele (additive risk; OR = 1.89[1.10-3.39], p = 0.0257) in the "never alcohol consumption subgroup" (n = 125). In addition, as previously reported, the following CRC risk factors were identified: absence of physical activity (OR = 6.35[3.70-10.9], p < 0.0001), living or working in rural or mix area (OR = 2.50[1.48-4.23], p = 0.0006 and OR = 2.99[1.63-5.48], p = 0.004, respectively) and tobacco exposure >30 years (3.37[1.63-6.96], p = 0.0010). CONCLUSIONS: Variant genotypes of influx transporters (OATP1B1 and 2B1) were not associated with CRC. This study confirmed the influence of lifestyle factors, but not the previously reported detrimental effect of SNPs in intestinal UGTs or efflux transporters, except for a UGT1A8 variant in subjects consuming meat and the exon 26 SNP of ABCB1 in the never alcohol consumption subgroup. TRIAL REGISTRATION: Registered in Direction Générale de la Santé the 1st July 2008 under the number DGS2008-0144.

Assessment of Ki67 and uPA/PAI-1 expression in intermediate-risk early stage breast cancers.

BACKGROUND: The objective of this study was to compare the efficacy of biomarkers in assessing the risk of breast cancer recurrence in patients with node-negative or micrometastatic grade II breast cancer. Specifically, we compared risk assessments based on the St. Gallen clinicopathological criteria, Ki67 expression and urokinase plasminogen activator (uPA)/plasminogen activator inhibitor-1 (PAI-1) expression. METHODS: This retrospective study included 347 patients with breast cancer followed at Limoges University Hospital. The optimal cut-off for high Ki67 expression (Ki67hi) was established as 20%. The threshold for uPA and PAI-1 positivity was 3 ng/mg and 14 ng/mg, respectively. RESULTS: Ki67 expression was lower in uPA/PAI-1-negative than in uPA/PAI-1-positive tumours (227 tumours; P = 0.04). The addition of Ki67 status to the St. Gallen criteria resulted in a 28% increase in the rate of identification of high-risk tumours with a potential indication for chemotherapy (P < 0.001). When considering uPA/PAI-1 levels together with the St Gallen criteria (including Ki67 expression), the number of cases identified as having a high recurrence risk with a potential indication for adjuvant chemotherapy increased by 20% (P < 0.001). Adjuvant chemotherapy was 9% less likely to be recommended by a multidisciplinary board when using the current criteria compared with using a combination of the St. Gallen criteria and Ki67 and uPA/PAI-1 status (P = 0.03). CONCLUSIONS: Taken together, our data show discordance among markers in identifying the risk of recurrence, even though each marker may prove to be independently valid.

Towards therapeutic drug monitoring of everolimus in cancer? Results of an exploratory study of exposure-effect relationship.

INTRODUCTION: Therapeutic drug monitoring (TDM) of everolimus is not performed in oncology and no trough level (C0) target has been yet defined. The aim of this study was to determine everolimus C0 target for toxicity and efficacy. MATERIALS AND METHODS: Clinical, biological and radiologic data from 54 patients were collected. Toxicity event was defined by termination, temporary interruption and/or dose reduction of everolimus while efficacy was defined as progression-free survival. C0 values were dichotomized by ROC curve analysis and the association between exposure and outcome was determined using Cox models for repeated events (toxicity) or Cox model censured at the first event (progression free survival). RESULTS: Among the 42 patients (77.8%) with breast cancer, 10 (18.5%) kidney cancer and 2 (3.7%) neuroendocrine cancer, adverse events were reported in 75.9% of the patients (everolimus termination in 25.9% patients). C0 everolimus higher than 26.3ng/mL (Sen=0.38,Spe=0.88) were associated with a 4-fold increased risk of toxicity (HR=4.12, IC95%=[1.48-11.5], p=0.0067) whereas C0 lower than 11.9ng/mL were associated with a 3-fold increased risk of progression (HR=3.2, IC95%=[1.33-7.81],p=0.001). DISCUSSION: Further studies are required to evaluate the everolimus C0 threshold proposed for toxicity (26.3ng/mL) and for progression (11.9ng/mL) especially with a large number of patients and more homogeneous types of cancer. However, these results are in favour of TDM for everolimus in oncology.

Final Results of the Randomized Phase II NorCap-CA223 Trial Comparing First-Line All-Oral Versus Taxane-Based Chemotherapy for HER2-Negative Metastatic Breast Cancer.

BACKGROUND: The purpose of this study was to evaluate the efficacy of 3 first-line chemotherapy combination regimens for HER2-negative metastatic breast cancer (mBC). PATIENTS AND METHODS: In this open-label, 3-arm, randomized phase II trial, patients were randomized to all-oral NORCAP (vinorelbine/capecitabine), GEMPAC (gemcitabine/paclitaxel), or GEMDOC (gemcitabine/docetaxel) as first-line chemotherapy for HER2-negative mBC. Stratification factors were center, previous (neo)adjuvant anthracycline, and age. The primary end point was disease control rate (DCR; complete or partial response, or stable disease for ≥3 months). RESULTS: The DCR was 73% (95% confidence interval [CI], 59-85) with NORCAP (36 of 49 patients), 78% (95% CI, 64-88) with GEMPAC (39 of 50 patients), and 80% (95% CI, 66-90) with GEMDOC (40 of 50 patients). Objective response rates were 33% (16 of 49 patients), 24% (12 of 50 patients), and 50% (25 of 50 patients), respectively; median progression-free survival was 7.6, 9.0, and 11.4 months, respectively. Median overall survival was 30 to 31 months with all regimens. The most common Grade ≥3 adverse event with each regimen was neutropenia (24 patients [50%], 23 patients [46%], and 43 patients [86%], respectively). The most common nonhematological Grade ≥3 adverse event was fatigue. Grade 2 alopecia occurred in 36 patients (72%) who received GEMPAC and 38 patients (76%) who received GEMDOC, but only 4 patients (8%) who received NORCAP. There was no evidence of a detrimental effect of NORCAP on quality of life. CONCLUSION: All-oral NORCAP is an active first-line chemotherapy regimen and might be offered as an alternative to first-line taxane-based therapy for HER2-negative mBC, particularly if patients wish to avoid alopecia or frequent intravenous administrations.

Effectiveness and safety of first-line bevacizumab plus FOLFIRI in elderly patients with metastatic colorectal cancer: Results of the ETNA observational cohort.

OBJECTIVES: Effectiveness of bevacizumab for metastatic colorectal cancer in elderly patients has been investigated in observational studies, mainly associated with oxaliplatin-based regimens. Here, using the ETNA cohort in which the majority of patients received bevacizumab+FOLFIRI, the effectiveness of this combination in elderly patients is explored. MATERIALS AND METHODS: Patients initiating first-line therapy with bevacizumab between January 2006 and December 2007 were identified in 28 French centres and followed for 24months. Vital status was collected over 36months. In the present analysis those who received FOLFIRI were retained (85% of those included), and patients were stratified by age (<70/≥70years). The Kaplan-Meier method estimated progression-free survival (PFS) and overall survival (OS), and Cox models were used to assess the independent effect of age on survival outcomes. RESULTS: Among the 351 patients who received bevacizumab+FOLFIRI, 33.9% were aged ≥70years, 66.1% <70years. Respectively 15.1% and 9.5% of patients had ECOG-PS ≥2; 49.6% and 40.1% used 'stop-and-go' treatment scheduling; and 56.3% and 44.4% experienced grade 3/4 adverse events. Overall response rate was 58.8% and 62.5%. Median [95% confidence interval, CI] OS was respectively 24.1 [20.4; 26.2] and 28.5 [25.0; 31.0] months; age≥70years and ECOG-PS≥2 were significantly associated with death. Median PFS [95% CI] was respectively 10.9 [9.4; 12.6] and 9.8 [9.2; 11.2] months; hepatic metastases was associated with progression, and age ≥70years was associated with progression after 14months of follow-up but not before. CONCLUSIONS: The present study adds to the literature on the safe and beneficial effect of bevacizumab in the elderly receiving FOLFIRI regimen.

Chemotherapy outcome predictive effectiveness by the Oncogramme: pilot trial on stage-IV colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) remains a major public concern. While conventional chemotherapeutic regimens have proved useful against advanced/metastatic diseases, progresses are to be made to effectively cure the large portion of patients not benefiting from these treatments. One direction to improve response rates is to develop chemosensitivity and resistance assays (CSRAs) efficiently assisting clinicians in treatment selection process, an already long preoccupation of oncologists and researchers. Several methods have been described to this day, none achieving yet sufficient reliability for recommended use in the clinical routine. METHODS: We led a pilot study on 19 metastatic CRC patients evaluating capacity of the Oncogramme, a standardized process using tumor ex vivo models, to provide chemosensitivity profiles and predict clinical outcome of patients receiving standard CRC chemotherapeutics. Oncogramme responses were categorized according to the method of percentiles to assess sensitivity, specificity and concordance. RESULTS: We report from a primary analysis a success rate of 97.4 %, a very good sensitivity (84.6 %), a below-average specificity (33.3 %), along with a global agreement of 63.6 % and a concordance between Oncogramme results and patients' responses (Kappa coefficient) of 0.193. A supplementary analysis, focusing on CRC patients with no treatment switch over a longer time course, demonstrated improvement in specificity and concordance. CONCLUSIONS: Results establish feasibility and usefulness of the Oncogramme, prelude to a larger-scale trial. Advantages and drawbacks of the procedure are discussed, as well as the place of CSRAs within the future arsenal of methods available to clinicians to individualize treatments and improve patient prognosis. TRIAL REGISTRATION: ClinicalTrials.gov database, registration number: NCT02305368.

Secondary Metastases Resection After Bevacizumab Plus Irinotecan-Based Chemotherapy in First-Line Therapy of Metastatic Colorectal Cancer in a Real-Life Setting: Results of the ETNA Cohort.

PURPOSE: Resection of metastases after chemotherapy improves survival outcomes of patients with initially inoperable metastatic colorectal cancer (mCRC), yet little data is available for those treated in the first-line setting with bevacizumab plus irinotecan. To provide data on this, the present study described the subgroup of the ETNA cohort who underwent metastases surgery. METHODS: The population of operated patients was described according to metastatic site (exclusively hepatic, non-exclusively hepatic, and non-hepatic). Factors associated with overall survival (OS) and progression-free survival (PFS) were evaluated using multivariable Cox analysis. RESULTS: A total of 76 patients (21.1 % of the ETNA cohort) underwent metastases resection: 50 % male, median age 61.9 years, 85.5 % ECOG ≤ 1, and median duration of bevacizumab use 7.2 months. No surgery-related deaths were observed and 30.6 % of patients had at least one post-operative complication, mainly infections (11.8 % of resections), bleeding complications (3.5 %), or delayed wound healing (2.4 %). Complete remission was higher for those with exclusively hepatic metastases (22/32, 68.8 %) than those with non-exclusively hepatic metastases (12/24, 50.0 %), or non-hepatic metastases (12/20, 60.0 %). Among operated patients, 52.6 % had died after 5 years of follow-up. In multivariable analysis at 2 years of follow-up, death (HR 0.09 [95 % CI 0.02-0.35]) and progression (HR 0.35 [95 % CI 0.23-0.56]) were less likely for patients with complete remission (CR) after surgery R0-R1 or radiofrequency ablation (RFA) [CR RFA] compared with those who were not resected or with R2 resection. CONCLUSION: In real-life practice, bevacizumab with irinotecan in first-line therapy for mCRC allows secondary resection of metastases and survival is more favourable in those with complete remission (R0-R1/CR RFA).